Endothelin-1 promotes epithelial-mesenchymal transition in human chondrosarcoma cells by repressing miR-300.

PubMed

Wu, Min-Huan; Huang, Pei-Han; Hsieh, Mingli; Tsai, Chun-Hao; Chen, Hsien-Te; Tang, Chih-Hsin

2016-10-25

Chondrosarcoma is a malignant tumor of mesenchymal origin predominantly composed of cartilage-producing cells. This type of bone cancer is extremely resistant to radiotherapy and chemotherapy. Surgical resection is the primary treatment, but is often difficult and not always practical for metastatic disease, so more effective treatments are needed. In particular, it would be helpful to identify molecular markers as targets for therapeutic intervention. Endothelin-1 (ET-1), a potent vasoconstrictor, has been shown to enhance chondrosarcoma angiogenesis and metastasis. We report that ET-1 promotes epithelial-mesenchymal transition (EMT) in human chondrosarcoma cells. EMT is a key pathological event in cancer progression, during which epithelial cells lose their junctions and apical-basal polarity and adopt an invasive phenotype. Our study verifies that ET-1 induces the EMT phenotype in chondrosarcoma cells via the AMP-activated protein kinase (AMPK) pathway. In addition, we show that ET-1 increases EMT by repressing miR-300, which plays an important role in EMT-enhanced tumor metastasis. We also show that miR-300 directly targets Twist, which in turn results in a negative regulation of EMT. We found a highly positive correlation between ET-1 and Twist expression levels as well as tumor stage in chondrosarcoma patient specimens. Therefore, ET-1 may represent a potential novel molecular therapeutic target in chondrosarcoma metastasis.

Endothelin-1 promotes epithelial–mesenchymal transition in human chondrosarcoma cells by repressing miR-300

PubMed Central

Wu, Min-Huan; Huang, Pei-Han; Hsieh, Mingli; Tsai, Chun-Hao; Chen, Hsien-Te; Tang, Chih-Hsin

2016-01-01

Chondrosarcoma is a malignant tumor of mesenchymal origin predominantly composed of cartilage-producing cells. This type of bone cancer is extremely resistant to radiotherapy and chemotherapy. Surgical resection is the primary treatment, but is often difficult and not always practical for metastatic disease, so more effective treatments are needed. In particular, it would be helpful to identify molecular markers as targets for therapeutic intervention. Endothelin-1 (ET-1), a potent vasoconstrictor, has been shown to enhance chondrosarcoma angiogenesis and metastasis. We report that ET-1 promotes epithelial–mesenchymal transition (EMT) in human chondrosarcoma cells. EMT is a key pathological event in cancer progression, during which epithelial cells lose their junctions and apical-basal polarity and adopt an invasive phenotype. Our study verifies that ET-1 induces the EMT phenotype in chondrosarcoma cells via the AMP-activated protein kinase (AMPK) pathway. In addition, we show that ET-1 increases EMT by repressing miR-300, which plays an important role in EMT-enhanced tumor metastasis. We also show that miR-300 directly targets Twist, which in turn results in a negative regulation of EMT. We found a highly positive correlation between ET-1 and Twist expression levels as well as tumor stage in chondrosarcoma patient specimens. Therefore, ET-1 may represent a potential novel molecular therapeutic target in chondrosarcoma metastasis. PMID:27602960

Retroperitoneal Extraskeletal Osteosarcoma: Imaging Findings and Transarterial Chemoembolization

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang Huojun, E-mail: chyyzhj@hotmail.com; Yang Jijin, E-mail: yangjijin@live.com; Lu Jianping

2010-04-15

Extraskeletal osteosarcoma (EOS) is an uncommon and usually highly aggressive mesenchymal tumor. Retroperitoneal extraskeletal osteosarma (REOS) is exceedingly rare. Due to the rare nature of the disease, both the diagnosis and the management of REOS can be challenging. We present the clinical history, CT findings, angiographic manifestations, and use of transarterial chemoembolization for treatment in a case of REOS. To our knowledge, the angiographic features of and attempt at transarterial treatment of REOS have not been reported in the literature.

Cixutumumab and Doxorubicin Hydrochloride in Treating Patients With Unresectable, Locally Advanced, or Metastatic Soft Tissue Sarcoma

ClinicalTrials.gov

2016-05-16

Adult Angiosarcoma; Adult Desmoplastic Small Round Cell Tumor; Adult Epithelioid Sarcoma; Adult Extraskeletal Myxoid Chondrosarcoma; Adult Extraskeletal Osteosarcoma; Adult Fibrosarcoma; Adult Leiomyosarcoma; Adult Liposarcoma; Adult Malignant Mesenchymoma; Adult Malignant Peripheral Nerve Sheath Tumor; Adult Rhabdomyosarcoma; Adult Synovial Sarcoma; Adult Undifferentiated High Grade Pleomorphic Sarcoma of Bone; Childhood Angiosarcoma; Childhood Desmoplastic Small Round Cell Tumor; Childhood Epithelioid Sarcoma; Childhood Fibrosarcoma; Childhood Leiomyosarcoma; Childhood Liposarcoma; Childhood Malignant Mesenchymoma; Childhood Malignant Peripheral Nerve Sheath Tumor; Childhood Pleomorphic Rhabdomyosarcoma; Childhood Rhabdomyosarcoma With Mixed Embryonal and Alveolar Features; Childhood Synovial Sarcoma; Dermatofibrosarcoma Protuberans; Malignant Adult Hemangiopericytoma; Malignant Childhood Hemangiopericytoma; Metastatic Childhood Soft Tissue Sarcoma; Previously Treated Childhood Rhabdomyosarcoma; Recurrent Adult Soft Tissue Sarcoma; Recurrent Childhood Rhabdomyosarcoma; Recurrent Childhood Soft Tissue Sarcoma; Stage III Adult Soft Tissue Sarcoma; Stage IV Adult Soft Tissue Sarcoma; Untreated Childhood Rhabdomyosarcoma

A rare case of laryngotracheal chondrosarcoma in a patient with past history of radioiodine therapy for thyroid cancer.

PubMed

Mohajeri, Gholamreza; Hekmatnia, Ali; Ahrar, Hossein; Hekmatnia, Farzane; Nia, Reza Basirat; Afsharmoghadam, Nushin; Eftekhari, Mehdi; Jafarpishe, Saleh

2013-01-01

Tracheal chondrosarcoma is a rare malignant mesenchymal tumor and there are less than 15 reports in the literature. We report a rare case of laryngotracheal chondrosarcoma in a 74-year-old man. He gave a history of radioiodine therapy for thyroid papillary carcinoma about 24 years ago. Diagnostic steps, histological presentation, and therapy are described in detail.

A case of dedifferentiated chondrosarcoma arising in the cricoid cartilage that mimicked an aneurysmal bone cyst.

PubMed

Chen, Lixiao; Yu, Ziwei; Jiang, Rui; Dong, Pin; Shen, Bin; Li, Yu

2018-03-01

Dedifferentiated chondrosarcoma of the larynx is a rare and highly malignant tumor. We present the report of a 59-year-old man with dedifferentiated laryngeal chondrosarcoma, which was difficult to diagnose even under microscopic examination. The original diagnosis was an aneurysmal bone cyst, and the final diagnosis was established only after careful consideration of the imaging, surgical, and microscopic findings. In clinical practice, there are many similarities between dedifferentiated chondrosarcoma and aneurysmal bone cysts. Furthermore, it is difficult to identify dedifferentiated laryngeal chondrosarcoma with a giant-cell malignant mesenchymal component. This report describes our experience and discusses this phenomenon.

Primary extraskeletal Ewing sarcoma involving the carotid artery: a case report and review of the current literature

PubMed Central

Nikkhah, D; Nix, P; Woodhead, C

2012-01-01

Extraskeletal Ewing sarcoma (EES) is a rare soft tissue neoplasm of primitive mesenchymal cells. There is a scarcity of data on EES involving the head and neck, with studies being over years or even decades. We are the first to report a case of EES involving the carotid artery and its subsequent surgical excision and reconstruction. PMID:22613280

Next generation sequencing of extraskeletal myxoid chondrosarcoma.

PubMed

Davis, Elizabeth J; Wu, Yi-Mi; Robinson, Dan; Schuetze, Scott M; Baker, Laurence H; Athanikar, Jyoti; Cao, Xuhong; Kunju, Lakshmi P; Chinnaiyan, Arul M; Chugh, Rashmi

2017-03-28

Extraskeletal myxoid chondrosarcoma (EMC) is an indolent translocation-associated soft tissue sarcoma with a high propensity for metastases. Using a clinical sequencing approach, we genomically profiled patients with metastatic EMC to elucidate the molecular biology and identify potentially actionable mutations. We also evaluated potential predictive factors of benefit to sunitinib, a multi-targeted tyrosine kinase inhibitor with reported activity in a subset of EMC patients. Between January 31, 2012 and April 15, 2016, six patients with EMC participated in the clinical sequencing research study. High quality DNA and RNA was isolated and matched normal samples underwent comprehensive next generation sequencing (whole or OncoSeq capture exome of tumor and normal, tumor PolyA+ and capture transcriptome). The expression levels of sunitinib targeted-kinases were measured by transcriptome sequencing for KDR, PDGFRA/B, KIT, RET, FLT1, and FLT4. The previously reported EWSR1-NR4A3 translocation was identified in all patient tumors; however, other recurring genomic abnormalities were not detected. RET expression was significantly greater in patients with EMC relative to other types of sarcomas except for liposarcoma (p<0.0002). The folate receptor was overexpressed in two patients. Our study demonstrated that similar to other translocation-associated sarcomas, the mutational profile of metastatic EMC is limited beyond the pathognomonic translocation. The clinical significance of RET expression in EMC should be explored. Additional pre-clinical investigations of EMC may help elucidate molecular mechanisms contributing to EMC tumorigenesis that could be translated to the clinical setting.

Mesenteric extraskeletal osteosarcoma with telangiectatic features: a case report.

PubMed

Lee, Kyung Hwa; Joo, Jae Kyoon; Kim, Dong Yi; Lee, Ji Shin; Choi, Chan; Lee, Jae Hyuk

2007-05-15

Extraskeletal osteosarcoma is a rare malignant mesenchymal tumor, with a predominant occurrence in the extremities. Only two cases of mesenteric extraskeletal osteosarcoma have been documented. We describe an unusual case of extraskeletal osteosarcoma with telangiectatic features occurring in the mesentery. A 67-year-old male presented with blood-tinged stool of 1-month's duration. On colonoscopy, a solid mass was detected protruding from the colon wall. Computed tomography showed a 15 x 9.7 cm heterogeneously enhancing mass, with mottled calcification and a cystic portion, occupying the left upper quadrant of the abdominal cavity. Curative resection of the tumor was performed, and the excised tumor was composed of large multilocular cysts containing old hematomas and necrotic debris. The histology revealed an osteosarcoma showing osteoid formation and blood-filled spaces lined with atypical cells. Despite postoperative chemotherapy, he developed a recurrent peritoneal mass and multiple lung metastases 3 months postoperatively. Given the rarity of cases of mesenteric extraskeletal osteosarcoma, its biologic behavior at this location remains to be determined. However, extraskeletal osteosarcoma with telangiectatic features is an uncommon entity to be recognized because of the possible fatal outcome related to the tumors.

Mesenteric extraskeletal osteosarcoma with telangiectatic features: a case report

PubMed Central

Lee, Kyung Hwa; Joo, Jae Kyoon; Kim, Dong Yi; Lee, Ji Shin; Choi, Chan; Lee, Jae Hyuk

2007-01-01

Background Extraskeletal osteosarcoma is a rare malignant mesenchymal tumor, with a predominant occurrence in the extremities. Only two cases of mesenteric extraskeletal osteosarcoma have been documented. We describe an unusual case of extraskeletal osteosarcoma with telangiectatic features occurring in the mesentery. Case presentation A 67-year-old male presented with blood-tinged stool of 1-month's duration. On colonoscopy, a solid mass was detected protruding from the colon wall. Computed tomography showed a 15 × 9.7 cm heterogeneously enhancing mass, with mottled calcification and a cystic portion, occupying the left upper quadrant of the abdominal cavity. Curative resection of the tumor was performed, and the excised tumor was composed of large multilocular cysts containing old hematomas and necrotic debris. The histology revealed an osteosarcoma showing osteoid formation and blood-filled spaces lined with atypical cells. Despite postoperative chemotherapy, he developed a recurrent peritoneal mass and multiple lung metastases 3 months postoperatively. Conclusion Given the rarity of cases of mesenteric extraskeletal osteosarcoma, its biologic behavior at this location remains to be determined. However, extraskeletal osteosarcoma with telangiectatic features is an uncommon entity to be recognized because of the possible fatal outcome related to the tumors. PMID:17504524

Bortezomib induces apoptosis and suppresses cell growth and metastasis by inactivation of Stat3 signaling in chondrosarcoma.

PubMed

Bao, Xing; Ren, Tingting; Huang, Yi; Ren, Chongmin; Yang, Kang; Zhang, Hongliang; Guo, Wei

2017-02-01

Bortezomib, formerly known as PS341, is a novel proteasome inhibitor with in vitro and in vivo antineoplastic effects in many malignancies. However, diverse antitumor mechanisms of bortezomib have been identified in many investigations and preclinical studies. Understanding the molecular and cellular mechanisms through which bortezomib acts will improve the therapeutic utility of this drug in different cancer types. In the present study, we investigated the in vitro and in vivo effects of bortezomib on chondrosarcoma. Bortezomib selectively inhibited cell growth in chondrosarcoma cells but not in normal articular cartilage cells. In addition to growth inhibition, apoptosis and cell cycle arrest, bortezomib triggered alleviation of migratory and invasive properties of chondrosarcoma cells. Mechanistically, signal transducer and activator of transcription 3 (Stat3) and its downstream targets Bcl-2, cyclin D1 and c-Myc was inactivated by bortezomib treatment. Accordingly, small interfering RNA (siRNA)-mediated Stat3 knockdown enhanced bortezomib-induced apoptosis, and concomitantly enhanced the inhibitory effect of bortezomib on cell viability, migration and invasion. Moreover, while Slug, MMP9, MMP2, CD44, N-cadherin and vimentin, the mesenchymal cell markers, were repressed by bortezomib concomitant increased expression of E-cadherin was observed. In vivo, bortezomib downregulated Stat3 activity and mesenchymal cell marker expression, induced apoptosis and inhibition of metastasis and tumor growth. Together, inactivation of Stat3 signaling contributes to bortezomib-induced inhibition of tumor growth, migration and invation on chondrosarcoma. Bortezomib demonstrates an antineoplastic role on chondrosarcoma both in vitro and in vivo. These beneficial effects can be explained by bortezomib-mediated Stat3 supression. The present study suggests a promising therapeutics target in chondrosarcoma and probably in other kinds of metastatic malignant tumors.

Temporo-mandibular joint chondrosarcoma: Case report and review of the literature.

PubMed

Giorgione, C; Passali, F M; Varakliotis, T; Sibilia, M; Ottaviani, F

2015-06-01

Chondrosarcoma is a malignant mesenchymal tumour of cartilaginous origin. It represents 11% of all malignant primary bone tumours, and the pelvis, ribs, femur and humerus are most frequently involved. Chondrosarcoma of the head and neck region is a rare disease, and represents approximately 0.1% of all head and neck neoplasms. This report describes a rare localisation of chondrosarcoma in a 56-year-old man who presented with swelling in the right preauricular area and mild limitation and pain in the mouth opening. Since 1959, just a few cases of temporomandibular joint (TMJ) chondrosarcoma have been described. Computed tomography revealed a large mass (39 x 46 x 40 mm) in the right preauricular and parotid region with morpho-structural alterations of the condyle and an intense periostotic reaction. The tumour was treated by total parotidectomy and condylotomy. The VII cranial nerve was preserved. Histopathologic examination revealed a low grade chondrosarcoma with a 50% proliferation index. At present, the patient is still receiving routine follow-up after radiotherapy and physiotherapy.

Analysis of microRNAs expressions in chondrosarcoma.

PubMed

Yoshitaka, Teruhito; Kawai, Akira; Miyaki, Shigeru; Numoto, Kunihiko; Kikuta, Kazutaka; Ozaki, Toshifumi; Lotz, Martin; Asahara, Hiroshi

2013-12-01

MicroRNAs (miRNAs) are small non-coding RNAs capable of inhibiting gene expression post-transcriptionally and expression profiling can provide therapeutic targets and tools for cancer diagnosis. Chondrosarcoma is a mesenchymal tumor with unknown cause and differentiation status. Here, we profiled miRNA expression of chondrosarcoma, namely clinical samples from human conventional chondrosarcoma tissue, established chondrosarcoma cell lines, and primary non-tumorous adult articular chondrocytes, by miRNA array and quantitative real-time PCR. A wide variety of miRNAs were differently downregulated in chondrosarcoma compared to non-tumorous articular chondrocytes; 27 miRNAs: miR-10b, 23b, 24-1*, 27b, 100, 134, 136, 136*, 138, 181d, 186, 193b, 221*, 222, 335, 337-5p, 376a, 376a*, 376b, 376c, 377, 454, 495, 497, 505, 574-3p, and 660, were significantly downregulated in chondrosarcoma and only 2: miR-96 and 183, were upregulated. We further validated the expression levels of miRNAs by quantitative real-time PCR for miR-181a, let-7a, 100, 222, 136, 376a, and 335 in extended number of chondrosarcoma clinical samples. Among them, all except miR-181a were found to be significantly downregulated in chondrosarcoma derived samples. The findings provide potential diagnostic value and new molecular understanding of chondrosarcoma. © 2013 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Harwood, A.R.; Krajbich, J.I.; Fornasier, V.L.

A retrospective analysis of 31 cases of chondrosarcoma of bone treated by radiotherapy is presented. In comparison with other large series, our group of patients were found to have been unfavourably selected with respect to the known prognostic factors: histology site, adequacy of operative treatment, and presenting symptoms. Twelve patients with primary chondrosarcoma were radically irradiated; 6 of these 12 have been alive and well without tumor for periods ranging from three and a half to 16 years and 3 of these are alive and well for 15 years or more following radiotherapy. The other 6 patients responded or deseasemore » stabilized following radiotherapy for periods ranging from 16 months to eight years. One poorly differentiated tumor was radically irradiated and did not respond. Eleven patients were irradiated palliatively, generally with low doses of irradiation, and only 4 responded transiently for periods ranging from three to 12 months. Seven patients with mesenchymal and dedifferentiated tumors were radically irradiated. Four responded or disease stabilized, and 1 of these patients was alive and well at 3 years; 3 did not respond. Six died with distant metastasis. It is concluded that chondrosarcoma of bone is a radioresponsive tumor and the place of radiotherapy in the treatment of this disease and the reason for its being labelled a radioresistant tumor are discussed. The problems of assessing response of chondrosarcoma to therapy are also discussed. It is suggested that chemotherapy may have a role in the management of mesenchymal and dedifferentiated chondrosarcoma.« less

Clinicopathologic and radiologic features of extraskeletal myxoid chondrosarcoma: a retrospective study of 40 Chinese cases with literature review.

PubMed

Shao, Rui; Lao, I Weng; Wang, Lei; Yu, Lin; Wang, Jian; Fan, Qinhe

2016-08-01

The aim of this study is to describe the clinicopathologic and radiologic features of 40 cases of extraskeletal myxoid chondrosarcoma (EMC) from China. There were 25 males and 15 females (sex ratio, 1.7:1). Apart from an adolescent, all patients were adults with a median age of 49years. Twenty-four tumors (60%) occurred in the lower limb and limb girdles, especially the thigh, followed by the upper limb and limb girdles (20%) and trunk (10%). Other less commonly involved locations included the head and neck, sacrococcygeal region, and perineum. Tumors ranged in size from 1.5 to 19cm (mean, 7cm). By radiology, they appeared as hypoattenuated or isoattenuated masses on computed tomography with hyperintense signal on T2-weighted magnetic resonance imaging. Intralesional hypointense septa were present in most cases. Of the 40 tumors, 30 belonged to the classic subtype, whereas 9 cases were cellular, and 1 case had a rhabdoid phenotype. Tumor cells showed variable expression of synaptophysin (36%), S-100 protein (29%), epithelial membrane antigen (11%), and neuron-specific enolase (7%). Ki-67 index was remarkably higher in the cellular variant (mean, 30%). EWSR1-related rearrangement was detected in 12 of 14 cases tested by fluorescence in situ hybridization using break-apart probes. The overall 5- and 7-year survival was 71% and 60%, respectively. Awareness of the imaging features may help pathologists in the diagnosis of EMC. Fluorescence in situ hybridization also serves as a useful diagnostic tool for EMC, especially in the distinction from its mimics. Copyright © 2016 Elsevier Inc. All rights reserved.

Chondrosarcoma: A Rare Misfortune in Aging Human Cartilage? The Role of Stem and Progenitor Cells in Proliferation, Malignant Degeneration and Therapeutic Resistance

PubMed Central

Boehme, Karen A.; Schleicher, Sabine B.; Rolauffs, Bernd

2018-01-01

Unlike other malignant bone tumors including osteosarcomas and Ewing sarcomas with a peak incidence in adolescents and young adults, conventional and dedifferentiated chondrosarcomas mainly affect people in the 4th to 7th decade of life. To date, the cell type of chondrosarcoma origin is not clearly defined. However, it seems that mesenchymal stem and progenitor cells (MSPC) in the bone marrow facing a pro-proliferative as well as predominantly chondrogenic differentiation milieu, as is implicated in early stage osteoarthritis (OA) at that age, are the source of chondrosarcoma genesis. But how can MSPC become malignant? Indeed, only one person in 1,000,000 will develop a chondrosarcoma, whereas the incidence of OA is a thousandfold higher. This means a rare coincidence of factors allowing escape from senescence and apoptosis together with induction of angiogenesis and migration is needed to generate a chondrosarcoma. At early stages, chondrosarcomas are still assumed to be an intermediate type of tumor which rarely metastasizes. Unfortunately, advanced stages show a pronounced resistance both against chemo- and radiation-therapy and frequently metastasize. In this review, we elucidate signaling pathways involved in the genesis and therapeutic resistance of chondrosarcomas with a focus on MSPC compared to signaling in articular cartilage (AC). PMID:29361725

Induction of the mesenchymal to epithelial transition by demethylation-activated microRNA-125b is involved in the anti-migration/invasion effects of arsenic trioxide on human chondrosarcoma.

PubMed

Bao, Xing; Ren, Tingting; Huang, Yi; Wang, Shidong; Zhang, Fan; Liu, Kuisheng; Zheng, Bingxin; Guo, Wei

2016-08-30

In addition to treating acute promyelocytic leukemia, arsenic trioxide (ATO) suppresses other solid tumors, including chondrosarcoma. However, the effects of ATO on metastasis in chondrosarcoma cells, and the underlying molecular mechanisms remain unclear. The effects of ATO on the migratory and invasive capacities of chondrosarcoma cells were investigated by Wound healing, Transwell and EMT assays. The expression of miR-125b in human chondrosarcoma tissues and cell lines was detected by real-time PCR analysis. Bisulfite sequencing analysis (BSP) was used to detect the effects of ATO on the expression of miR-125b. The gain-of-function and loss-of-function experiments were performed on chondrosarcoma cell lines to investigate the effects of miR-125b on chondrosarcoma invasion, and to determine whether signal transducer and activator of transcription 3(Stat3) mediates these effects. Dual-luciferase reporter assay was used to identify whether Stat3 is a direct target of miR-125b. MiR-125b was significantly downregulated in human metastatic chondrosarcoma tissues and cell lines but not in non-metastatic chondrosarcoma tissues. ATO up-regulates the expression of miR-125b by the demethylation of DNA. ATO induces MET and attenuates the invasive capacities of chondrosarcoma cells through miR-125b. Stat3 was verified as a direct target of miR-125b, which is involved in ATO regulating EMT-associated traits. These findings, for the first time, provides evidence that the miR-125b-mediated inhibition of Stat3 is involved in the ATO-induced attenuation of metastasis in chondrosarcoma cells.

Pancreatic Extraskeletal Osteosarcoma Metastasizing to the Scalp.

PubMed

Kim, Young Jae; Kim, Hak Tae; Won, Chong Hyun; Chang, Sung Eun; Lee, Mi Woo; Choi, Jee Ho; Lee, Woo Jin

2018-06-01

Extraskeletal osteosarcoma (ESOS) is a rare mesenchymal soft-tissue neoplasm that accounts for approximately 1% of all soft-tissue sarcomas. Over 70% of these malignant tumor progress to local recurrence and metastasis. It commonly metastasizes to the lungs, lymph nodes, bone, and skin and has a poor survival outcome. Cutaneous metastasis is exceedingly rare and known to be a sign of widespread metastases. We present a 57-year-old woman who presented with a rapidly growing protuberant mass on the scalp that was finally diagnosed as metastatic ESOS from a primary pancreatic ESOS. To our knowledge, there has been no reported case of pancreatic ESOS metastasizing to the scalp.

Massive dedifferentiated chondrosarcoma affecting whole mandible with high recurrence potential

PubMed Central

Mishra, Niranjan; Singh, Akhilesh Kumar; Agrawal, Rahul; Singh, Shreya

2015-01-01

Chondrosarcomas (CS) are slow-growing, malignant mesenchymal tumors characterized by the formation of cartilage by the tumor cells. Benign cartilage-producing tumors within the jaws are extremely uncommon, but most ultimately prove to represent low-grade CS. In the maxillofacial region, the maxilla is more commonly affected than the mandible, it comprises less than 2% of all jaw tumors. Clinically, the tumor presents as a swelling that may be painful and cause loosening of the involved teeth, with widening of the periodontal ligament space. The treatment of such lesions is wide surgical excision with regular follow up. The present report discusses the case of a 55-year-old female patient with massive multiple recurring dedifferentiated CS of mandible. PMID:27390502

Outcome following treatment of soft tissue and visceral extraskeletal osteosarcoma in 33 dogs: 2008-2013.

PubMed

Duffy, D; Selmic, L E; Kendall, A R; Powers, B E

2017-03-01

Extraskeletal osteosarcoma (EOS) is a rare, highly malignant mesenchymal neoplasm arising from viscera or soft tissues characterised by the formation of osteoid in the absence of bone involvement. Owing to the rarity of these neoplasms very little information exists on treatment outcomes. The purpose of this study was to describe the outcome following surgical treatment of non-mammary and non-thyroidal soft tissue and visceral EOS in dogs. Thirty-three dogs were identified; the most common primary tumour site was the spleen. Dogs that had wide or radical tumour excision had longer survival times compared with dogs that had only marginal tumour excision performed [median survival time of 90 days (range: 0-458 days) versus median survival time of 13 days (range: 0-20 days)]. The use of surgery should be considered in the management of dogs with non-mammary and non-thyroidal soft tissue and visceral EOS. © 2015 John Wiley & Sons Ltd.

MUC4 is a highly sensitive and specific marker for low-grade fibromyxoid sarcoma.

PubMed

Doyle, Leona A; Möller, Emely; Dal Cin, Paola; Fletcher, Christopher D M; Mertens, Fredrik; Hornick, Jason L

2011-05-01

Low-grade fibromyxoid sarcoma (LGFMS) is a distinctive fibroblastic neoplasm that is characterized by alternating collagenous and myxoid areas, deceptively bland spindle cell morphology, a whorling architecture, and a t(7;16) translocation involving FUS and CREB3L2. Owing to variable morphology and a lack of discriminatory markers, LGFMS can be difficult to distinguish from benign mesenchymal tumors and other low-grade sarcomas. Gene expression profiling has identified differential upregulation of the mucin 4 (MUC4) gene in LGFMS compared with histologically similar tumors. MUC4 is a transmembrane glycoprotein that functions in cell growth signaling pathways; aberrant MUC4 expression has been reported in various carcinomas. We investigated MUC4 protein expression by immunohistochemistry in LGFMS and in other soft tissue tumors to determine the potential diagnostic use of this novel marker. Whole-tissue sections of 309 tumors were evaluated: 49 LGFMSs (all with FUS gene rearrangement confirmed by fluorescence in situ hybridization), 40 soft tissue perineuriomas, 40 myxofibrosarcomas, 20 cellular myxomas, 20 solitary fibrous tumors, 20 low-grade malignant peripheral nerve sheath tumors, 20 cases of desmoid fibromatosis, 20 neurofibromas, 20 schwannomas, 20 monophasic synovial sarcomas, 20 cases of dermatofibrosarcoma protuberans, 10 myxoid liposarcomas, and 10 extraskeletal myxoid chondrosarcomas. The LGFMS cases included 7 with marked hypercellularity, 4 with prominent hemangiopericytoma-like vessels, 3 with giant collagen rosettes, 3 with epithelioid morphology, 2 with focal nuclear pleomorphism, and 2 with areas of sclerosing epithelioid fibrosarcoma. All 49 LGFMS cases (100%) showed cytoplasmic staining for MUC4, which was usually diffuse and intense. All the other tumor types were negative for MUC4, apart from 6 (30%) monophasic synovial sarcomas. In conclusion, MUC4 is a highly sensitive and quite specific immunohistochemical marker for LGFMS, and can be helpful to distinguish this tumor type from histologic mimics.

HDAC inhibitor-loaded bone cement for advanced local treatment of osteosarcoma and chondrosarcoma.

PubMed

Tonak, Marcus; Becker, Marc; Graf, Claudine; Eckhard, Lukas; Theobald, Matthias; Rommens, Pol-Maria; Wehler, Thomas C; Proschek, Dirk

2014-11-01

The treatment of osteosarcoma, especially wide resection, is challenging. An additional local drug therapy after resection using anti-neoplastic bone cement (Polymethylmethacrylate (PMMA)) could help improve the outcome of therapy. In this study, we evaluated the effects of PMMA loaded with valproic acid (VPA) and suberoylanilide hydroxamic acid (SAHA) on the cell activity of a SaOs-2 cell culture, as well as the elution rate of the drugs out of the bone cement. In our experiments, we used the SaOs-2 osteosarcoma and the SW1353 chondrosarcoma cell line. Bone cement clots (5 g) were prepared and loaded with different drug concentrations of VPA (25 mg and 50 mg) and SAHA (1 mg, 2.5 mg and 5 mg). Two control groups were established, one with a native cement clot, the other with human mesenchymal stem cells, in order to evaluate toxicity on non tumor-cells. Cell activity was measured using an Alamar Blue assay on days 1, 2, 3, 4 and 7. The cement clots were additionally examined in a material testing unit for biomechanical and structural changes. Tumor cells showed a significant and complete reduction of activity under therapy with VPA and SAHA. Drug release of VPA was extensive between days 0 and 3 and decreased progressively to day 7. Cumulative drug concentration in the medium continuously increased. Biomechanical testing of the cement clots showed no differences in stability and architecture compared to the control group. SaOs-2 and SW1353 cells with medium from native cement clots without drug therapy presented a cell activity of 100% in all groups and during all measurements. Human mesenchymal stem cells were not significantly affected during therapy with VPA and low concentrations of SAHA. In contrast, cell activity of human mesenchymal stem cells was significantly reduced under therapy with higher concentrations of SAHA, with an approximately linear decrease between days 0-3 and a rapidly decreasing activity between days 4-7. A local cytotoxic therapy in the treatment of osteosarcoma and chondrosarcoma might improve the rate of metastasis and survival of patients. Our results present an encouraging approach to loading PMMA with anti-neoplastic drugs. Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Bladder chondrosarcoma plus urothelial carcinoma in recurred transitional cell carcinoma of the upper urinary tract: a case report and literature review.

PubMed

Cho, Min Hyun; Kim, Sung Han; Park, Weon Seo; Joung, Jae Young; Seo, Ho Kyung; Chung, Jinsoo; Lee, Kang Hyun

2016-10-20

Sarcomatoid urothelial carcinoma (SUC) is a rare malignant neoplasm of the urinary bladder comprising 0.2-0.6 % of all histological bladder tumor subtypes. It presents as a high-stage malignancy and exhibits aggressive biological behavior, regardless of the treatment employed. It is defined as histologically indistinguishable from sarcoma and as a high-grade biphasic neoplasm with malignant epithelial and mesenchymal components. The mean age of patients presenting with SUC is 66 years, and the male-to-female ratio is 3:1. In addition, gross hematuria is usually present. The prognosis of SUC is poorer than that of typical urothelial carcinoma because of uncertainty concerning the optimal treatment regimen. We report the case of a 77-year-old woman with SUC containing a chondrosarcoma component who, 12 years previously, had undergone a nephroureterectomy for pT3N0M0 ureter cancer of the contralateral upper urinary tract. From the 4th year of follow-up after nephroureterectomy, multiple recurrent bladder tumors staged as Ta transitional cell carcinoma developed, and six transurethral resections of the bladder (TURB) with multiple intravesical instillations were performed without any evidence of metastases and upper tract recurrences. In 2015, a right partial distal ureterectomy and an additional TURB were performed due to a papillary mass at the right contralateral ureterovesical junction of the bladder, which was confirmed as a high-grade pT1 transitional cell carcinoma. After a further 2 years of follow-up, total pelvic exenteration with an ileal conduit diversion was performed to remove the mass, which was a pT4N0M0 tumor composed of carcinomatous and sarcomatous elements compatible with a sarcomatoid carcinoma including grade 3 transitional cell carcinoma and chondrosarcoma. Immunohistochemical examination showed that tumor cells were positive for vimentin and p63 and negative for NSE and Cd56 markers. In the first postoperative month, a metastatic lung nodule was detected on chest CT. The patient was scheduled for adjuvant gemcitabine-cisplatin chemotherapy. The present case was interesting because we cannot be sure if the SUC chondrosarcoma originated from the 12-year-ago proximal ureter tumor, the 2-year-ago contralateral distal ureter tumor, or a new primary bladder tumor. Genetic profiling might have been useful to determine the origin of the SUC chondrosarcoma.

Congenital extraskeletal Ewing's sarcoma of chest wall--a rare case report.

PubMed

Atla, Bhagyalakshmi; Prasad, B Satya Vara; Sri, K Satya; Vandana, Geeta

2011-01-01

Congenital extraskeletal Ewing's sarcoma or peripheral primitive neuroectodermal tumor is an extremely uncommon and invariably fatal tumor. We report a case of extraskeletal congenital Ewing's sarcoma in a female fetus delivered at 34 weeks of gestation who died immediately after birth. In English literature, majority of cases of Ewing's sarcoma in neonates reported were skeletal. To the best of our knowledge, very few cases of extra-skeletal Ewing's sarcoma in neonates are reported in the literature.

Dedifferentiated chondrosarcoma: an aggressive variant of chondrosarcoma.

PubMed

Bharath, Gangadhara; Burrah, Rajaram; Shivakumar, Kuppuswamy; Manjunath, Suraj; Bhanumathi, Rao

2015-02-01

Dedifferentiated chondrosarcomas are a rare and aggressive subtype of chondrosarcoma with a bimorphic pattern on histopathology. Rib is a rare site of dedifferentiated chondrosarcoma. Diagnosis of this subtype preoperatively can be challenging. Treatment options for dedifferentiated chondrosarcoma are limited because they are chemoresistant, and therefore adequate surgery forms the main stay of treatment. We present our experience with a dedifferentiated chondrosarcoma of the rib, and discuss the management of this rare entity. © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

Long non-coding RNA BCAR4 promotes chondrosarcoma cell proliferation and migration through activation of mTOR signaling pathway

PubMed Central

Shui, Xiaolong; Zhou, Chengwei; Lin, Wei; Yu, Yang; Feng, Yongzeng

2017-01-01

Background: Chondrosarcoma is one of the common malignant histologic tumors, very difficult to treat, but the concrete cause and mechanism have not yet been elucidated. The present study aimed to investigate the functional involvement of BCAR4 in chondrosarcoma and its potentially underlying mechanism. QRT-PCR and western blot were used to determine the expression of BCAR4 and mTOR signaling pathway proteins both in chondrosarcoma tissues and cells. Chondrosarcoma cell proliferation and migration were assessed by MTT assay and transwell migration assay, respectively. The expression vectors were constructed and used to modulate the expression of BCAR4 and mTOR. Chondrosarcoma xenograft mouse model was established by subcutaneous injection with chondrosarcoma cell lines. The tumor volume was monitored to evaluate the effect of BCAR4 on chondrosarcoma cell tumorigenicity. The expressions of BCAR4, p-mTOR and p-P70S6K were up-regulated in chondrosarcoma tissues and cell lines. Moreover, BCAR4 overexpression had significant promoting effect on cell proliferation and migration in chondrosarcoma cells. Furthermore, mTOR signaling pathway was epigenetically activated by BCAR4-induced hyperacetylation of histone H3. We also found that mTOR overexpression abolished the decrease of chondrosarcoma cell proliferation and migration induced by BCAR4 knockdown. In vivo experiments confirmed that BCAR4 overexpression significantly accelerated tumor growth, while the knockdown of BCAR4 significantly inhibited tumor growth. BCAR4 promoted chondrosarcoma cell proliferation and migration through activation of mTOR signaling pathway, and thus contributed to chondrosarcoma progression. Impact statement LncRNA BCAR4 promoted chondrosarcoma cell proliferation and migration through activation of mTOR signaling pathway, and thus contributed to chondrosarcoma progression. PMID:28399646

Long non-coding RNA BCAR4 promotes chondrosarcoma cell proliferation and migration through activation of mTOR signaling pathway.

PubMed

Shui, Xiaolong; Zhou, Chengwei; Lin, Wei; Yu, Yang; Feng, Yongzeng; Kong, Jianzhong

2017-05-01

Chondrosarcoma is one of the common malignant histologic tumors, very difficult to treat, but the concrete cause and mechanism have not yet been elucidated. The present study aimed to investigate the functional involvement of BCAR4 in chondrosarcoma and its potentially underlying mechanism. QRT-PCR and western blot were used to determine the expression of BCAR4 and mTOR signaling pathway proteins both in chondrosarcoma tissues and cells. Chondrosarcoma cell proliferation and migration were assessed by MTT assay and transwell migration assay, respectively. The expression vectors were constructed and used to modulate the expression of BCAR4 and mTOR. Chondrosarcoma xenograft mouse model was established by subcutaneous injection with chondrosarcoma cell lines. The tumor volume was monitored to evaluate the effect of BCAR4 on chondrosarcoma cell tumorigenicity. The expressions of BCAR4, p-mTOR and p-P70S6K were up-regulated in chondrosarcoma tissues and cell lines. Moreover, BCAR4 overexpression had significant promoting effect on cell proliferation and migration in chondrosarcoma cells. Furthermore, mTOR signaling pathway was epigenetically activated by BCAR4-induced hyperacetylation of histone H3. We also found that mTOR overexpression abolished the decrease of chondrosarcoma cell proliferation and migration induced by BCAR4 knockdown. In vivo experiments confirmed that BCAR4 overexpression significantly accelerated tumor growth, while the knockdown of BCAR4 significantly inhibited tumor growth. BCAR4 promoted chondrosarcoma cell proliferation and migration through activation of mTOR signaling pathway, and thus contributed to chondrosarcoma progression. Impact statement LncRNA BCAR4 promoted chondrosarcoma cell proliferation and migration through activation of mTOR signaling pathway, and thus contributed to chondrosarcoma progression.

MicroRNA-494 inhibits cell proliferation and invasion of chondrosarcoma cells in vivo and in vitro by directly targeting SOX9.

PubMed

Li, Jingyuan; Wang, Lijuan; Liu, Zongzhi; Zu, Chao; Xing, Fanfan; Yang, Pei; Yang, Yongkang; Dang, Xiaoqian; Wang, Kunzheng

2015-09-22

Accumulating evidence indicates that dysregulation of miRNAs could contribute to tumor growth and metastasis of chondrosarcoma by infuencing cell proliferation and invasion. In the current study, we are interested to examine the role of miRNAs in the carcinogenesis and progression of chondrosarcoma. Here, using comparative miRNA profiling of tissues and cells of chondrosarcoma and cartilage, we identified miR-494 as a commonly downregulated miRNA in the tissues of patients with chondrosarcoma and chondrosarcoma cancer cell line, and upregulation of miR-494 could inhibit proliferation and invasion of chondrosarcoma cancer cells in vivo and in vitro. Moreover, our data demonstrated that SOX9, the essential regulator of the process of cartilage differentiation, was the direct target and functional mediator of miR-494 in chondrosarcoma cells. And downregulation of SOX9 could also inhibit migration and invasion of chondrosarcoma cells. In the last, we identified low expression of miR-494 was significantly correlated with poor overall survival and prognosis of chondrosarcoma patients. Thus, miR-494 may be a new common therapeutic target and prognosis biomarker for chondrosarcoma.

Molecular oncogenesis of chondrosarcoma: impact for targeted treatment.

PubMed

Speetjens, Frank M; de Jong, Yvonne; Gelderblom, Hans; Bovée, Judith V M G

2016-07-01

The prognosis of patients with unresectable or metastatic chondrosarcoma of the bone is poor. Chondrosarcomas are in general resistant to chemotherapy and radiotherapy. This review discusses recent developments in the characterization of molecular pathways involved in the oncogenesis of chondrosarcoma that should be explored to improve prognosis of patients with advanced chondrosarcoma. The different oncogenic pathways for chondrosarcoma have become better defined. These include alterations in pathways such as isocitrate dehydrogenase mutation, hedgehog signalling, the retinoblastoma protein and p53 pathways, apoptosis and survival mechanisms, and several tyrosine kinases. These specific alterations can be employed for use in clinical interventions in advanced chondrosarcoma. As many different genetic alterations in chondrosarcoma have been identified, it is of the utmost importance to classify druggable targets that may improve the prognosis of chondrosarcoma patients. In recent years an increased number of trials evaluating targeted therapies are being conducted. As chondrosarcoma is an orphan disease consequently all studies are performed with small numbers of patients. The results of clinical studies so far have been largely disappointing. Therapeutic intervention studies of these new targets emerging from preclinical studies are of highest importance to improve prognosis of chondrosarcoma patients with advanced disease.

MicroRNA-494 inhibits cell proliferation and invasion of chondrosarcoma cells in vivo and in vitro by directly targeting SOX9

PubMed Central

Liu, Zongzhi; Zu, Chao; Xing, Fanfan; Yang, Pei; Yang, Yongkang; Dang, Xiaoqian; Wang, Kunzheng

2015-01-01

Accumulating evidence indicates that dysregulation of miRNAs could contribute to tumor growth and metastasis of chondrosarcoma by infuencing cell proliferation and invasion. In the current study, we are interested to examine the role of miRNAs in the carcinogenesis and progression of chondrosarcoma. Here, using comparative miRNA profiling of tissues and cells of chondrosarcoma and cartilage, we identified miR-494 as a commonly downregulated miRNA in the tissues of patients with chondrosarcoma and chondrosarcoma cancer cell line, and upregulation of miR-494 could inhibit proliferation and invasion of chondrosarcoma cancer cells in vivo and in vitro. Moreover, our data demonstrated that SOX9, the essential regulator of the process of cartilage differentiation, was the direct target and functional mediator of miR-494 in chondrosarcoma cells. And downregulation of SOX9 could also inhibit migration and invasion of chondrosarcoma cells. In the last, we identified low expression of miR-494 was significantly correlated with poor overall survival and prognosis of chondrosarcoma patients. Thus, miR-494 may be a new common therapeutic target and prognosis biomarker for chondrosarcoma. PMID:26317788

BMPR2 inhibition induced apoptosis and autophagy via destabilization of XIAP in human chondrosarcoma cells

PubMed Central

Jiao, G; Guo, W; Ren, T; Lu, Q; Sun, Y; Liang, W; Ren, C; Yang, K; Sun, K

2014-01-01

Bone morphogenetic proteins (BMPs) are multifunctional proteins, and their receptors (BMPRs) have crucial roles in the process of signaling. However, their function in cancer is somewhat inconsistent. It has been demonstrated that more prevalent expression of bone morphogenetic protein receptor 2 (BMPR2) has been detected in dedifferentiated chondrosarcomas than conventional chondrosarcomas. Here, we find that BMPR2 inhibition induces apoptosis and autophagy of chondrosarcoma. We found that BMPR2 expression was correlated with the clinicopathological features of chondrosarcomas, and could predict the treatment outcome. Knockdown of BMPR2 by small interfering RNA results in growth inhibition in chondrosarcoma cells. Silencing BMPR2 promoted G2/M cell cycle arrest, induced chondrosarcoma cell apoptosis through caspase-3-dependent pathway via repression of X-linked inhibitor of apoptosis protein (XIAP) and induced autophagy of chondrosarcoma cells via XIAP-Mdm2-p53 pathway. Inhibition of autophagy induced by BMPR2 small interfering RNA (siBMPR2) sensitized chondrosarcoma cells to siBMPR2-induced apoptotic cell death, suggesting that autophagy has a protective role for chondrosarcoma cells in context of siBMPR2-induced apoptotic cell death. In vivo tumorigenicity assay in mice indicated that inhibition of BMPR2 reduced tumor growth. Taken together, our results suggest that BMPR2 has a significant role in the tumorigenesis of chondrosarcoma, and could be an important prognostic marker for chondrosarcoma. BMPR2 inhibition could eventually provide a promising therapy for chondrosarcoma treatment. PMID:25501832

Functional profiling of receptor tyrosine kinases and downstream signaling in human chondrosarcomas identifies pathways for rational targeted therapy.

PubMed

Zhang, Yi-Xiang; van Oosterwijk, Jolieke G; Sicinska, Ewa; Moss, Samuel; Remillard, Stephen P; van Wezel, Tom; Bühnemann, Claudia; Hassan, Andrew B; Demetri, George D; Bovée, Judith V M G; Wagner, Andrew J

2013-07-15

Chondrosarcomas are notoriously resistant to cytotoxic chemotherapeutic agents. We sought to identify critical signaling pathways that contribute to their survival and proliferation, and which may provide potential targets for rational therapeutic interventions. Activation of receptor tyrosine kinases (RTK) was surveyed using phospho-RTK arrays. S6 phosphorylation and NRAS mutational status were examined in chondrosarcoma primary tumor tissues. siRNA or small-molecule inhibitors against RTKs or downstream signaling proteins were applied to chondrosarcoma cells and changes in biochemical signaling, cell cycle, and cell viability were determined. In vivo antitumor activity of BEZ235, a phosphoinositide 3-kinase (PI3K)/mTOR inhibitor, was evaluated in a chondrosarcoma xenograft model. Several RTKs were identified as critical mediators of cell growth, but the RTK dependencies varied among cell lines. In exploration of downstream signaling pathways, strong S6 phosphorylation was found in 69% of conventional chondrosarcomas and 44% of dedifferentiated chondrosarcomas. Treatment with BEZ235 resulted in dramatic reduction in the growth of all chondrosarcoma cell lines. Tumor growth was similarly inhibited in a xenograft model of chondrosarcoma. In addition, chondrosarcoma cells with an NRAS mutation were sensitive to treatment with a mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK) inhibitor. Functional NRAS mutations were found in 12% of conventional central chondrosarcomas. RTKs are commonly activated in chondrosarcoma, but because of their considerable heterogeneity, targeted inhibition of the PI3K/mTOR pathway represents a rational therapeutic strategy. Chondrosarcomas with NRAS mutations may benefit from treatment with MEK inhibitors.

Chondrosarcoma in Childhood: The Radiologic and Clinical Conundrum

DTIC Science & Technology

2012-12-01

Radiology Case. 2012 Dec; 6(12):32-42 Pediatric Radiology: Chondrosarcoma in Childhood: The Radiologic and Clinical Conundrum Mosier et...w w w .R ad io lo g y C ases.co m 32 Chondrosarcoma in Childhood: The Radiologic and Clinical... chondrosarcomas occur in children. In addition, as little as 0.5% of low-grade chondrosarcomas arise secondarily from benign chondroid lesions

MicroRNA Gene Regulatory Networks in Peripheral Nerve Sheath Tumors

DTIC Science & Technology

2012-09-01

chondrosarcoma are identified based on the unique histology, cell of origin, clinical features and site distribution. The following are the major... Chondrosarcoma Chondrosarcoma is a cancer composed of cells derived from transformed cells that produce cartilage. Peripheral chondrosarcoma is a malignant...biosynthesis. This is in line with gene expression analyses previously performed in osteochondroma and chondrosarcoma samples showing modulation of

The antiapoptotic gene survivin is highly expressed in human chondrosarcoma and promotes drug resistance in chondrosarcoma cells in vitro

PubMed Central

2011-01-01

Background Chondrosarcoma is virtually resistant to chemotherapy and radiation therapy. Survivin, the smallest member of the inhibitor of apoptosis protein family, is a critical factor for tumor progression and resistance to conventional therapeutic approaches in a wide range of malignancies. However, the role of survivin in chondrosarcoma has not been well studied. We examined the importance of survivin gene expression in chondrosarcoma and analysed its influences on proliferation, apoptosis and resistance to chemotherapy in vitro. Methods Resected chondrosarcoma specimens from which paraffin-embedded tissues could be extracted were available from 12 patients. In vitro experiments were performed in human chondrosarcoma cell lines SW1353 and Hs819.T. Immunohistochemistry, immunoblot, quantitative PCR, RNA interference, gene-overexpression and analyses of cell proliferation and apoptosis were performed. Results Expression of survivin protein was detected in all chondrosarcoma specimens analyzed, while undetectable in adult human cartilage. RNA interference targeting survivin resulted in a G2/M-arrest of the cell cycle and led to increased rates of apoptosis in chondrosarcoma cells in vitro. Overexpression of survivin resulted in pronounced resistance to doxorubicin treatment. Conclusions These findings indicate that survivin plays a role in the pathogenesis and pronounced chemoresistance of high grade chondrosarcoma. Survivin antagonizing therapeutic strategies may lead to new treatment options in unresectable and metastasized chondrosarcoma. PMID:21457573

Targeting survivin as a potential new treatment for chondrosarcoma of bone

PubMed Central

de Jong, Y; van Oosterwijk, J G; Kruisselbrink, A B; Briaire-de Bruijn, I H; Agrogiannis, G; Baranski, Z; Cleven, A H G; Cleton-Jansen, A-M; van de Water, B; Danen, E H J; Bovée, J V M G

2016-01-01

Chondrosarcomas are malignant cartilage-forming bone tumors, which are intrinsically resistant to chemo- and radiotherapy, leaving surgical removal as the only curative treatment option. Therefore, our aim was to identify genes involved in chondrosarcoma cell survival that could serve as a target for therapy. siRNA screening for 51 apoptosis-related genes in JJ012 chondrosarcoma cells identified BIRC5, encoding survivin, as essential for chondrosarcoma survival. Using immunohistochemistry, nuclear as well as cytoplasmic survivin expression was analyzed in 207 chondrosarcomas of different subtypes. Nuclear survivin has been implicated in cell-cycle regulation while cytoplasmic localization is important for its anti-apoptotic function. RT–PCR was performed to determine expression of the most common survivin isoforms. Sensitivity to YM155, a survivin inhibitor currently in phase I/II clinical trial for other tumors, was examined in 10 chondrosarcoma cell lines using viability assay, apoptosis assay and cell-cycle analysis. Survivin expression was found in all chondrosarcoma patient samples. Higher expression of nuclear and cytoplasmic survivin was observed with increasing histological grade in central chondrosarcomas. Inhibition of survivin using YM155 showed that especially TP53 mutant cell lines were sensitive, but no caspase 3/7 or PARP cleavage was observed. Rather, YM155 treatment resulted in a block in S phase in two out of three chondrosarcoma cell lines, indicating that survivin is more involved in cell-cycle regulation than in apoptosis. Thus, survivin is important for chondrosarcoma survival and chondrosarcoma patients might benefit from survivin inhibition using YM155, for which TP53 mutational status can serve as a predictive biomarker. PMID:27159675

Expression of MMPs is dependent on the activity of mitogen-activated protein kinase in chondrosarcoma.

PubMed

Yao, Min; Wang, Xiaomei; Zhao, Yufeng; Wang, Xiaomeng; Gao, Feng

2017-02-01

Matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs) serve an important role in chondrosarcoma. The present study investigated whether the expression of MMPs was dependent on the activity of mitogen-activated protein kinase (MAPK) in chondrosarcoma. Surgical pathological specimens were collected to detect MMP-1, MMP-13, TIMP-1, type II collagen and phosphorylated MAPK levels in normal cartilage, enchondroma and chondrosarcoma tissues. The expression of MMP‑1, MMP‑13, TIMP‑1 and type II collagen was investigated utilizing MAPK inhibitors in chondrosarcoma cells. It was noted that the expression levels of MMP‑1, MMP‑13 and TIMP‑1 were increased in chondrosarcoma with the activity of MAPK. After chondrosarcoma cells were pretreated with MAPK inhibitors, the levels of MMP‑1, MMP‑13 and TIMP‑1 were inhibited. Furthermore, MMP‑1 and MMP‑13 are essential in regulating the degradation of type II collagen and decomposing cartilage matrix major. The high expression levels of MMP‑1 and MMP‑13 in chondrosarcoma expedite the invasion by chondrosarcoma cells and their expression can be depressed by MAPK inhibitors.

Review of Extraskeletal Activity on Tc-99m Methylene Diphosphonate Bone Scintigraphy and Value of Cross-Sectional and SPECT-CT Imaging Correlation.

PubMed

Bermo, Mohammed; Behnia, Sanaz; Fair, Joanna; Miyaoka, Robert S; Elojeimy, Saeed

2017-07-31

Recognizing the different mechanisms and imaging appearance of extraskeletal Tc-99m methylene diphosphonate uptake enhances the diagnostic value of bone scan interpretation. In this article, we present a pictorial review of the different mechanisms of extraskeletal Tc-99m methylene diphosphonate uptake on bone scintigraphy including neoplastic, inflammatory, ischemic, traumatic, excretory, and iatrogenic. We also illustrate through case examples the added value of correlation with cross-sectional and single photon emission computed tomography and computed tomography imaging in localizing and characterizing challenging cases of extraskeletal uptake. Copyright © 2017 Elsevier Inc. All rights reserved.

Extraskeletal Ewing sarcoma of the abdominal wall

PubMed Central

Farhat, L. Ben; Ghariani, B.; Rabeh, A.; Dali, N.; Said, W.; Hendaoui, L.

2008-01-01

Abstract Ewing sarcoma is most commonly a bone tumour which has usually extended into the soft tissues at the time of diagnosis. Exceptionally, this tumour can have an extraskeletal origin. Clinical or imaging findings are non-specific and diagnosis is based on histology. We report a case of an extraskeletal Ewing sarcoma developed in the soft tissues of the abdominal wall in a 35-year-old woman who presented a painful abdominal wall tumefaction. Ultrasongraphy and computed tomography showed a large, well-defined soft tissue mass developed in the left anterolateral muscle group of the abdominal wall. Surgical biopsy was performed and an extraskeletal Ewing sarcoma was identified histologically. PMID:18818133

Inhibition of Src by microRNA-23b increases the cisplatin sensitivity of chondrosarcoma cells.

PubMed

Huang, Kai; Chen, Jun; Yang, Mo-Song; Tang, Yu-Jun; Pan, Feng

2017-01-01

Chondrosarcomas are malignant cartilage-forming tumors from low-grade to high-grade aggressive tumors characterized by metastasis. Cisplatin is an effective DNA-damaging anti-tumor agent for the treatment against a wide variety of solid tumors. However, chondrosarcomas are notorious for their resistance to conventional chemo- and radio- therapies. In this study, we report miR-23b acts as a tumor suppressor in chondrosarcoma. The expressions of miR-23b are down-regulated in chondrosarcoma patient samples and cell lines compared with adjacent normal tissues and human primary chondrocytes. In addition, overexpression of miR-23b suppresses chondrosarcoma cell proliferation. By comparison of the cisplatin resistant chondrosarcoma cells and parental cells, we observed miR-23b was significantly down regulated in cisplatin resistant cells. Moreover, we demonstrate here Src kinase is a direct target of miR-23b in chondrosarcoma cells. Overexpression of miR-23b suppresses Src-Akt pathway, leading to the sensitization of cisplatin resistant chondrosarcoma cells to cisplatin. This chemo-sensitivity effect by the miR-23b-mediated inhibition of Src-Akt pathway is verified with the restoration of Src kinase in miR-23b-overespressing chondrosarcoma cells, resulting in the acquirement of resistance to cisplatin. In summary, our study reveals a novel role of miR-23b in cisplatin resistance in chondrosarcoma and will contribute to the development of the microRNA-targeted anti-cancer therapeutics.

MRI differentiation of low-grade from high-grade appendicular chondrosarcoma.

PubMed

Douis, Hassan; Singh, Leanne; Saifuddin, Asif

2014-01-01

To identify magnetic resonance imaging (MRI) features which differentiate low-grade chondral lesions (atypical cartilaginous tumours/grade 1 chondrosarcoma) from high-grade chondrosarcomas (grade 2, grade 3 and dedifferentiated chondrosarcoma) of the major long bones. We identified all patients treated for central atypical cartilaginous tumours and central chondrosarcoma of major long bones (humerus, femur, tibia) over a 13-year period. The MRI studies were assessed for the following features: bone marrow oedema, soft tissue oedema, bone expansion, cortical thickening, cortical destruction, active periostitis, soft tissue mass and tumour length. The MRI-features were compared with the histopathological tumour grading using univariate, multivariate logistic regression and receiver operating characteristic curve (ROC) analyses. One hundred and seventy-nine tumours were included in this retrospective study. There were 28 atypical cartilaginous tumours, 79 grade 1 chondrosarcomas, 36 grade 2 chondrosarcomas, 13 grade 3 chondrosarcomas and 23 dedifferentiated chondrosarcomas. Multivariate analysis demonstrated that bone expansion (P = 0.001), active periostitis (P = 0.001), soft tissue mass (P < 0.001) and tumour length (P < 0.001) were statistically significant differentiating factors between low-grade and high-grade chondral lesions with an area under the ROC curve of 0.956. On MRI, bone expansion, active periostitis, soft tissue mass and tumour length can reliably differentiate high-grade chondrosarcomas from low-grade chondral lesions of the major long bones. • Accurate differentiation of low-grade from high-grade chondrosarcomas is essential before surgery • MRI can reliably differentiate high-grade from low-grade chondrosarcomas of long bone • Differentiating features are bone expansion, periostitis, soft tissue mass and tumour length • Presence of these four MRI features demonstrated a diagnostic accuracy (AUC) of 95.6 % • The findings may result in more accurate diagnosis before definitive surgery.

BAG3 promotes chondrosarcoma progression by upregulating the expression of β-catenin

PubMed Central

Shi, Huijuan; Chen, Wenfang; Dong, Yu; Lu, Xiaofang; Zhang, Wenhui; Wang, Liantang

2018-01-01

To investigate the roles of B-cell lymphoma-2 associated athanogene 3 (BAG3) in human chondrosarcoma and the potential mechanisms, the expression levels of BAG3 were detected in the present study, and the associations between BAG3 and clinical pathological parameters, clinical stage as well as the survival of patients were analyzed. The present study detected BAG3 mRNA and protein expression in the normal cartilage cell line HC-a and in SW1353 chondrosarcoma cells by reverse transcription-quantitative polymerase chain reaction and western blot analysis. The BAG3 protein expression in 59 cases of chondrosarcoma, 30 patients with endogenous chondroma and 8 cases of normal cartilage was semi-quantitatively analyzed using the immunohistochemical method. In addition, the BAG3 protein expression level, the clinical pathological parameters, clinical stage and the survival time of patients with chondrosarcoma were analyzed. The plasmid transfection method was employed to upregulate the expression BAG3 and small RNA interference to downregulate the expression of BAG3 in SW1353 cells. The expression levels of BAG3 protein and mRNA were significantly increased in the chondrosarcoma cell line when compared with the normal cartilage cell line. The immunohistochemistry results indicated that BAG3 protein was overexpressed in the tissue of human chondrosarcoma. Statistical analysis showed that the expression level of BAG3 was significantly increased in the different Enneking staging of patients with chondrosarcoma and Tumor staging, and there were no statistical differences in age, gender, histological classification and tumor size. In the in vitro experiments, the data revealed that BAG3 significantly promoted chondrosarcoma cell proliferation, colony-formation, migration and invasion; however, it inhibited chondrosarcoma cell apoptosis. It was observed that BAG3 upregulated β-catenin expression at the mRNA and protein levels. In addition, BAG3 induced the expression of runt-related transcription factor 2 (RUNX2) in chondrosarcoma cells by upregulating β-catenin. These clinical analyses revealed a positive association between β-catenin and BAG3 in chondrosarcoma tumors. BAG3 was significantly increased in chondrosarcoma cells and tissues compared with the normal cartilage cells, tissue and cartilage benign tumors. Thus, BAG3 may serve as an oncogene in the development of chondrosarcoma via the induction of RUNX2 expression. The results of the present study contribute to further research on the biological development of chondrosarcoma. PMID:29484408

Primary extraskeletal Ewing's sarcoma/primitive neuroectodermal tumour of breast.

PubMed

Ikhwan, S M; Kenneth, V K T; Seoparjoo, A; Zin, A A M

2013-06-21

Primary primitive neuroectodermal tumour (PNET) and extraskeletal Ewing's sarcoma belongs to the Ewing's family of tumours. Primary tumours arising from breast are very rare. There are only a few case reports published on primary extraskeletal Ewing's sarcoma and PNET arising from breast. We present an extremely rare case of an inoperable primary Ewing's sarcoma arising from left breast with contralateral breast, lymphatic and lung metastasis.

Diagnostic utility of IDH1/2 mutations to distinguish dedifferentiated chondrosarcoma from undifferentiated pleomorphic sarcoma of bone.

PubMed

Chen, Shaoxiong; Fritchie, Karen; Wei, Shi; Ali, Naser; Curless, Kendra; Shen, Tiansheng; Brini, Anna T; Latif, Farida; Sumathi, Vaiyapuri; Siegal, Gene P; Cheng, Liang

2017-07-01

Histologically, it is nearly impossible to distinguish the dedifferentiated component of dedifferentiated chondrosarcoma from undifferentiated pleomorphic sarcoma (UPS) of bone when the low-grade cartilaginous component is absent. Previous studies have revealed that isocitrate dehydrogenase 1 (IDH1) and IDH2 mutations are present in a significant number of cartilaginous tumors including most conventional chondrosarcomas and dedifferentiated chondrosarcomas. These mutations have not been studied in UPSs of bone. We sought to investigate whether an IDH1 or IDH2 mutation signature could be used as a clinically diagnostic marker for the distinction of dedifferentiated component of chondrosarcoma from UPS of bone. Sixty-eight bone tumor cases, including 31 conventional chondrosarcomas, 23 dedifferentiated chondrosarcomas, and 14 UPSs of bone, were collected for IDH1/2 mutation analysis either using the Qiagen IDH1/2 RGQ PCR Kit or using whole-exome sequencing. IDH1/2 mutations were detected in 87% (20/23) of dedifferentiated chondrosarcomas and 30% (6/20) of conventional chondrosarcomas. No mutations were detected in the IDH1/2 codon 132 or codon 172 among 14 UPSs of bone. Identification of IDH1 or IDH2 mutations supports the diagnosis of dedifferentiated chondrosarcoma rather than UPS of bone while also providing some insight into the pathogenesis of these 2 lesions. Copyright © 2017 Elsevier Inc. All rights reserved.

Array-based DNA-methylation profiling in sarcomas with small blue round cell histology provides valuable diagnostic information.

PubMed

Koelsche, Christian; Hartmann, Wolfgang; Schrimpf, Daniel; Stichel, Damian; Jabar, Susanne; Ranft, Andreas; Reuss, David E; Sahm, Felix; Jones, David T W; Bewerunge-Hudler, Melanie; Trautmann, Marcel; Klingebiel, Thomas; Vokuhl, Christian; Gessler, Manfred; Wardelmann, Eva; Petersen, Iver; Baumhoer, Daniel; Flucke, Uta; Antonescu, Cristina; Esteller, Manel; Fröhling, Stefan; Kool, Marcel; Pfister, Stefan M; Mechtersheimer, Gunhild; Dirksen, Uta; von Deimling, Andreas

2018-03-23

Undifferentiated solid tumors with small blue round cell histology and expression of CD99 mostly resemble Ewing sarcoma. However, they also may include other tumors such as mesenchymal chondrosarcoma, synovial sarcoma, or small cell osteosarcoma. Definitive classification usually requires detection of entity-specific mutations. While this approach identifies the majority of Ewing sarcomas, a subset of lesions remains unclassified and, therefore, has been termed "Ewing-like sarcomas" or small blue round cell tumors not otherwise specified. We developed an approach for further characterization of small blue round cell tumors not otherwise specified using an array-based DNA-methylation profiling approach. Data were analyzed by unsupervised clustering and t-distributed stochastic neighbor embedding analysis and compared with a reference methylation data set of 460 well-characterized prototypical sarcomas encompassing 18 subtypes. Verification was performed by additional FISH analyses, RNA sequencing from formalin-fixed paraffin-embedded material or immunohistochemical marker analyses. In a cohort of more than 1,000 tumors assumed to represent Ewing sarcomas, 30 failed to exhibit the typical EWS translocation. These tumors were subjected to methylation profiling and could be assigned to Ewing sarcoma in 14 (47%), to small blue round cell tumors with CIC alteration in 6 (20%), to small blue round cell tumors with BCOR alteration in 4 (13%), to synovial sarcoma and to malignant rhabdoid tumor in 2 cases each. One single case each was allotted to mesenchymal chondrosarcoma and adamantinoma. 12/14 tumors classified as Ewing sarcoma could be verified by demonstrating either a canonical EWS translocation evading initial testing, by identifying rare breakpoints or fusion partners. The methylation-based assignment of the remaining small blue round cell tumors not otherwise specified also could be verified by entity-specific molecular alterations in 13/16 cases. In conclusion, array-based DNA-methylation analysis of undifferentiated tumors with small blue round cell histology is a powerful tool for precisely classifying this diagnostically challenging tumor group.

Novel therapeutic approaches in chondrosarcoma.

PubMed

Polychronidou, Genovefa; Karavasilis, Vasilios; Pollack, Seth M; Huang, Paul H; Lee, Alex; Jones, Robin L

2017-03-01

Chondrosarcoma is a malignant tumor of bones, characterized by the production of cartilage matrix. Due to lack of effective treatment for advanced disease, the clinical management of chondrosarcomas is exceptionally challenging. Current research focuses on elucidating the molecular events underlying the pathogenesis of this rare bone malignancy, with the goal of developing new molecularly targeted therapies. Signaling pathways suggested to have a role in chondrosarcoma include Hedgehog, Src, PI3k-Akt-mTOR and angiogenesis. Mutations in IDH1/2, present in more than 50% of primary conventional chondrosarcomas, make the development of IDH inhibitors a promising treatment option. The present review discusses the preclinical and early clinical data on novel targeted therapeutic approaches in chondrosarcoma.

By activating matrix metalloproteinase-7, shear stress promotes chondrosarcoma cell motility, invasion and lung colonization.

PubMed

Guan, Pei-Pei; Yu, Xin; Guo, Jian-Jun; Wang, Yue; Wang, Tao; Li, Jia-Yi; Konstantopoulos, Konstantinos; Wang, Zhan-You; Wang, Pu

2015-04-20

Interstitial fluid flow and associated shear stress are relevant mechanical signals in cartilage and bone (patho)physiology. However, their effects on chondrosarcoma cell motility, invasion and metastasis have yet to be delineated. Using human SW1353, HS.819.T and CH2879 chondrosarcoma cell lines as model systems, we found that fluid shear stress induces the accumulation of cyclic AMP (cAMP) and interleukin-1β (IL-1β), which in turn markedly enhance chondrosarcoma cell motility and invasion via the induction of matrix metalloproteinase-7 (MMP-7). Specifically, shear-induced cAMP and IL-1β activate PI3-K, ERK1/2 and p38 signaling pathways, which lead to the synthesis of MMP-7 via transactivating NF-κB and c-Jun in human chondrosarcoma cells. Importantly, MMP-7 upregulation in response to shear stress exposure has the ability to promote lung colonization of chondrosarcomas in vivo. These findings offer a better understanding of the mechanisms underlying MMP-7 activation in shear-stimulated chondrosarcoma cells, and provide insights on designing new therapeutic strategies to interfere with chondrosarcoma invasion and metastasis.

Resistin facilitates VEGF-C-associated lymphangiogenesis by inhibiting miR-186 in human chondrosarcoma cells.

PubMed

Su, Chen-Ming; Tang, Chih-Hsin; Chi, Meng-Ju; Lin, Chih-Yang; Fong, Yi-Chin; Liu, Yueh-Ching; Chen, Wei-Cheng; Wang, Shih-Wei

2018-05-03

Chondrosarcoma is a common primary malignant tumor of the bone that can metastasize through the vascular system to other organs. A key step in the metastatic process, lymphangiogenesis, involves vascular endothelial growth factor-C (VEGF-C). However, the effects of lymphangiogenesis in chondrosarcoma metastasis remain to be clarified. Accumulating evidence shows that resistin, a cytokine secreted from adipocytes and monocytes, also promotes tumor pathogenesis. Notably, chondrosarcoma can easily metastasize. In this study, we demonstrate that resistin enhances VEGF-C expression and lymphatic endothelial cells (LECs)-associated lymphangiogenesis in human chondrosarcoma cells. We also show that resistin triggers VEGF-C-dependent lymphangiogenesis via the c-Src signaling pathway and down-regulating micro RNA (miR)-186. Overexpression of resistin in chondrosarcoma cells significantly enhanced VEGF-C production and LECs-associated lymphangiogenesis in vitro and tumor-related lymphangiogenesis in vivo. Resistin levels were positively correlated with VEGF-C-dependent lymphangiogenesis via the down-regulation of miR-186 expression in clinical samples from chondrosarcoma tissue. This study is the first to evaluate the mechanism underlying resistin-induced promotion of LECs-associated lymphangiogenesis via the upregulation of VEGF-C expression in human chondrosarcomas. We suggest that resistin may represent a molecular target in VEGF-C-associated tumor lymphangiogenesis in chondrosarcoma metastasis. Copyright © 2018 Elsevier Inc. All rights reserved.

miRNA-497 Negatively Regulates the Growth and Motility of Chondrosarcoma Cells by Targeting Cdc25A.

PubMed

Lu, Yandong; Li, Fangguo; Xu, Tao; Sun, Jie

2016-01-01

Chondrosarcoma (CHS) is the second most common malignant bone sarcoma with increased risk of invasion and metastasis. However, the regulatory mechanisms of CHS tumorigenesis remain unknown. Here we investigated the novel role of miR-497 in regulating chondrosarcoma cell growth and cell cycle arrest. RT-PCR analysis showed that the expression of miR-497 is aberrantly downregulated in human chondrosarcoma samples and cells. After transfection with miR-497 mimic or antagomir, the proliferation and apoptosis of JJ012 and OUMS-27 chondrosarcoma cells were determined by CCK-8 assay and flow cytometric analysis, respectively. Results showed that the proliferation capacity of JJ012 and OUMS-27 cells was significantly decreased by miR-497 overexpression but increased by miR-497 repression. Apoptosis in both cell types was remarkably enhanced by miR-497 mimic but inhibited by miR-497 antagomir. By bioinformatics and luciferase reporter analysis, Cdc25A was proven to be a direct target of miR-497 in chondrosarcoma cells. Further studies indicated that miR-497 modulates the growth of chondrosarcoma cells by targeting Cdc25A, in which the cell cycle inhibitor p21 is involved through a p53-independent pathway. In conclusion, we demonstrated that miR-497 represents a potential tumor suppressor in human chondrosarcoma that regulates the growth of chondrosarcoma cells by targeting Cdc25A. This may provide a novel therapeutic target for chondrosarcoma.

The epigenetic regulation of SOX9 by miR-145 in human chondrosarcoma.

PubMed

Mak, Isabella W Y; Singh, Shalini; Turcotte, Robert; Ghert, Michelle

2015-01-01

Chondrosarcoma is the most common primary bone malignancy in the adult population with a high rate of pulmonary metastasis. Chondrosarcoma is managed with surgical excision as the tumors do not respond well to conventional chemotherapy or radiation therapy. Thus, there exists a dire need to develop systemic treatment options to target chondrosarcoma cells for metastatic spread. We hypothesized that the expression of miR-145 is low in chondrosarcoma, leading to decreased transcriptional control of SOX9 (the master regulator of chondrogenesis), and downstream activation of the transcription factor ETV5. We have previously shown that ETV5 activates MMP-2 expression in chondrosarcoma, which in turn increases local bone matrix resorption. In this study, we confirm high expression of SOX9 in human chondrosarcoma using real-time PCR, Western blotting, and immunofluorescence. An ETV5 promoter-reporter plasmid was transfected into chondrosarcoma cells to determine if SOX9 directly regulates the expression of ETV5. Co-transfection of the ETV5 promoter-plasmid with SOX9 lentivirus significantly increased the luciferase activity derived from the ETV5 promoter, from which the regulatory relationship between SOX9 and ETV5 is established. MiR-145 was found to be down-regulated in chondrosarcoma cell lines, patient samples, and further confirmed with a public sarcoma database. After stable miR-145 lentiviral transfection, the subsequent mRNA expression levels of SOX9, ETV5, and MMP-2 were significantly decreased in chondrosarcoma cells. The results generated by this study may have important clinical significance in the treatment of patients with chondrosarcoma in that targeted miRNA may have the potential to downregulate the upstream activators of proteases such as MMP-2. © 2014 Wiley Periodicals, Inc.

No preclinical rationale for IGF1R directed therapy in chondrosarcoma of bone.

PubMed

Peterse, Elisabeth F P; Cleven, Arjen H G; De Jong, Yvonne; Briaire-de Bruijn, Inge; Fletcher, Jonathan A; Danen, Erik H J; Cleton-Jansen, Anne-Marie; Bovée, Judith V M G

2016-07-14

Chondrosarcoma is a malignant cartilage forming bone tumour for which no effective systemic treatment is available. Previous studies illustrate the need for a better understanding of the role of the IGF pathway in chondrosarcoma to determine if it can be a target for therapy, which was therefore explored in this study. Expression of mediators of IGF1R signalling and phosphorylation status of IRS1 was determined in chondrosarcoma cell lines by qRT-PCR and western blot. The effect of activation and inhibition of IGF1R signalling on downstream targets was assessed by western blot. Ten chondrosarcoma cell lines were treated with OSI-906 (IGF1R and IR dual inhibitor) after which cell proliferation and migration were determined by a viability assay and the xCELLigence system, respectively. In addition, four chondrosarcoma cell lines were treated with a combination of doxorubicin and OSI-906. By immunohistochemistry, IGF1R expression levels were determined in tissue microarrays of 187 cartilage tumours and ten paraffin embedded cell lines. Mediators of IGF1R signalling are heterogeneously expressed and phosphorylated IRS1 was detected in 67 % of the tested chondrosarcoma cell lines, suggesting that IGF1R signalling is active in a subset of chondrosarcoma cell lines. In the cell lines with phosphorylated IRS1, inhibition of IGF1R signalling decreased phosphorylated Akt levels and increased IGF1R expression, but it did not influence MAPK or S6 activity. In line with these findings, treatment with IGF1R/IR inhibitors did not impact proliferation or migration in any of the chondrosarcoma cell lines, even upon stimulation with IGF1. Although synergistic effects of IGF1R/IR inhibition with doxorubicin are described for other cancers, our results demonstrate that this was not the case for chondrosarcoma. In addition, we found minimal IGF1R expression in primary tumours in contrast to the high expression detected in chondrosarcoma cell lines, even if both were derived from the same tumour, suggesting that in vitro culturing upregulates IGF1R expression. The results from this study indicate that the IGF pathway is not essential for chondrosarcoma growth, migration or chemoresistance. Furthermore, IGF1R is only minimally expressed in chondrosarcoma primary tumours. Therefore, the IGF pathway is not expected to be an effective therapeutic target for chondrosarcoma of bone.

BAG3 promotes chondrosarcoma progression by upregulating the expression of β-catenin.

PubMed

Shi, Huijuan; Chen, Wenfang; Dong, Yu; Lu, Xiaofang; Zhang, Wenhui; Wang, Liantang

2018-04-01

To investigate the roles of B‑cell lymphoma‑2 associated athanogene 3 (BAG3) in human chondrosarcoma and the potential mechanisms, the expression levels of BAG3 were detected in the present study, and the associations between BAG3 and clinical pathological parameters, clinical stage as well as the survival of patients were analyzed. The present study detected BAG3 mRNA and protein expression in the normal cartilage cell line HC‑a and in SW1353 chondrosarcoma cells by reverse transcription‑quantitative polymerase chain reaction and western blot analysis. The BAG3 protein expression in 59 cases of chondrosarcoma, 30 patients with endogenous chondroma and 8 cases of normal cartilage was semi-quantitatively analyzed using the immunohistochemical method. In addition, the BAG3 protein expression level, the clinical pathological parameters, clinical stage and the survival time of patients with chondrosarcoma were analyzed. The plasmid transfection method was employed to upregulate the expression BAG3 and small RNA interference to downregulate the expression of BAG3 in SW1353 cells. The expression levels of BAG3 protein and mRNA were significantly increased in the chondrosarcoma cell line when compared with the normal cartilage cell line. The immunohistochemistry results indicated that BAG3 protein was overexpressed in the tissue of human chondrosarcoma. Statistical analysis showed that the expression level of BAG3 was significantly increased in the different Enneking staging of patients with chondrosarcoma and Tumor staging, and there were no statistical differences in age, gender, histological classification and tumor size. In the in vitro experiments, the data revealed that BAG3 significantly promoted chondrosarcoma cell proliferation, colony‑formation, migration and invasion; however, it inhibited chondrosarcoma cell apoptosis. It was observed that BAG3 upregulated β‑catenin expression at the mRNA and protein levels. In addition, BAG3 induced the expression of runt‑related transcription factor 2 (RUNX2) in chondrosarcoma cells by upregulating β‑catenin. These clinical analyses revealed a positive association between β‑catenin and BAG3 in chondrosarcoma tumors. BAG3 was significantly increased in chondrosarcoma cells and tissues compared with the normal cartilage cells, tissue and cartilage benign tumors. Thus, BAG3 may serve as an oncogene in the development of chondrosarcoma via the induction of RUNX2 expression. The results of the present study contribute to further research on the biological development of chondrosarcoma.

Leptin promotes VEGF-C production and induces lymphangiogenesis by suppressing miR-27b in human chondrosarcoma cells.

PubMed

Yang, Wei-Hung; Chang, An-Chen; Wang, Shih-Wei; Wang, Shoou-Jyi; Chang, Yung-Sen; Chang, Tzu-Ming; Hsu, Shao-Keh; Fong, Yi-Chin; Tang, Chih-Hsin

2016-06-27

Chondrosarcoma is the second most frequently occurring type of bone malignancy that is characterized by the distant metastasis propensity. Vascular endothelial growth factor-C (VEGF-C) is the chief lymphangiogenic mediator, and makes crucial contributions to tumor lymphangiogenesis. Leptin is an adipocytokine and has been indicated to facilitate tumorigenesis, angiogenesis and metastasis. However, the effect of leptin on VEGF-C regulation and lymphangiogenesis in human chondrosarcoma has hugely remained a mystery. Our results showed a clinical correlation between leptin and VEGF-C as well as tumor stage in human chondrosarcoma tissues. We further demonstrated that leptin promoted VEGF-C production and secretion in human chondrosarcoma cells. The conditioned medium from leptin-treated chondrosarcoma cells induced lymphangiogenesis of human lymphatic endothelial cells. We also found that leptin-induced VEGF-C is mediated by the FAK, PI3K and Akt signaling pathway. Furthermore, the expression of microRNA-27b was negatively regulated by leptin via the FAK, PI3K and Akt cascade. Our study is the first to describe the mechanism of leptin-promoted lymphangiogenesis by upregulating VEGF-C expression in chondrosarcomas. Thus, leptin could serve as a therapeutic target in chondrosarcoma metastasis and lymphangiogenesis.

By activating matrix metalloproteinase-7, shear stress promotes chondrosarcoma cell motility, invasion and lung colonization

PubMed Central

Guan, Pei-Pei; Yu, Xin; Guo, Jian-Jun; Wang, Yue; Wang, Tao; Li, Jia-Yi; Konstantopoulos, Konstantinos; Wang, Zhan-You; Wang, Pu

2015-01-01

Interstitial fluid flow and associated shear stress are relevant mechanical signals in cartilage and bone (patho)physiology. However, their effects on chondrosarcoma cell motility, invasion and metastasis have yet to be delineated. Using human SW1353, HS.819.T and CH2879 chondrosarcoma cell lines as model systems, we found that fluid shear stress induces the accumulation of cyclic AMP (cAMP) and interleukin-1β (IL-1β), which in turn markedly enhance chondrosarcoma cell motility and invasion via the induction of matrix metalloproteinase-7 (MMP-7). Specifically, shear-induced cAMP and IL-1β activate PI3-K, ERK1/2 and p38 signaling pathways, which lead to the synthesis of MMP-7 via transactivating NF-κB and c-Jun in human chondrosarcoma cells. Importantly, MMP-7 upregulation in response to shear stress exposure has the ability to promote lung colonization of chondrosarcomas in vivo. These findings offer a better understanding of the mechanisms underlying MMP-7 activation in shear-stimulated chondrosarcoma cells, and provide insights on designing new therapeutic strategies to interfere with chondrosarcoma invasion and metastasis. PMID:25823818

Naringin suppress chondrosarcoma migration through inhibition vascular adhesion molecule-1 expression by modulating miR-126.

PubMed

Tan, Tzu-Wei; Chou, Ying-Erh; Yang, Wei-Hung; Hsu, Chin-Jung; Fong, Yi-Chin; Tang, Chih-Hsin

2014-09-01

Chondrosarcoma, a primary malignant bone cancer, has a potent capacity to invade locally and cause distant metastasis, especially to the lungs. Patients diagnosed with it have poor prognosis. Naringin, polymethoxylated flavonoid commonly found in citrus fruits, has anti-oxidant, anti-inflammatory and anti-tumor activity; whether naringin regulates migration of chondrosarcoma is largely unknown. Here we report that naringin does not expedite apoptosis in human chondrosarcoma. By contrast, at noncytotoxic concentrations, naringin suppressed migration and invasion of chondrosarcoma cells. Vascular cell adhesion molecule-1 (VCAM-1) of the immunoglobulin superfamily is linked with metastasis; we found incubation of chondrosarcoma cells with naringin reducing mRNA transcription for, and cell surface expression of, VCAM-1. We also observed that naringin enhancing miR-126 expression, and miR-126 inhibitor reversed the naringin-inhibited cell motility and VCAM-1 expression. Therefore, naringin inhibits migration and invasion of human chondrosarcoma via down-regulation of VCAM-1 by increasing miR-126. Thus, naringin may be a novel anti-migration agent for the treatment of migration in chondrosarcoma. Copyright © 2014 Elsevier B.V. All rights reserved.

Clonal evolution through loss of chromosomes and subsequent polyploidization in chondrosarcoma.

PubMed

Olsson, Linda; Paulsson, Kajsa; Bovée, Judith V M G; Nord, Karolin H

2011-01-01

Near-haploid chromosome numbers have been found in less than 1% of cytogenetically reported tumors, but seem to be more common in certain neoplasms including the malignant cartilage-producing tumor chondrosarcoma. By a literature survey of published karyotypes from chondrosarcomas we could confirm that loss of chromosomes resulting in hyperhaploid-hypodiploid cells is common and that these cells may polyploidize. Sixteen chondrosarcomas were investigated by single nucleotide polymorphism (SNP) array and the majority displayed SNP patterns indicative of a hyperhaploid-hypodiploid origin, with or without subsequent polyploidization. Except for chromosomes 5, 7, 19, 20 and 21, autosomal loss of heterozygosity was commonly found, resulting from chromosome loss and subsequent duplication of monosomic chromosomes giving rise to uniparental disomy. Additional gains, losses and rearrangements of genetic material, and even repeated rounds of polyploidization, may affect chondrosarcoma cells resulting in highly complex karyotypes. Loss of chromosomes and subsequent polyploidization was not restricted to a particular chondrosarcoma subtype and, although commonly found in chondrosarcoma, binucleated cells did not seem to be involved in these events.

Is Needle Biopsy Clinically Useful in Preoperative Grading of Central Chondrosarcoma of the Pelvis and Long Bones?

PubMed

Roitman, Pablo D; Farfalli, Germán L; Ayerza, Miguel A; Múscolo, D Luis; Milano, Federico E; Aponte-Tinao, Luis A

2017-03-01

Central chondrosarcoma of bone is graded on a scale of 1 to 3 according to histological criteria. Clinically, these tumors can be divided into low-grade (Grade 1) and high-grade (Grade 2, Grade 3, and dedifferentiated) chondrosarcomas. Although en bloc resection has been the most widely used treatment, it has become generally accepted that in selected patients with low-grade chondrosarcomas of long bones, curettage is safe and effective. This approach requires an accurate preoperative estimation of grade to avoid under- or overtreatment, but prior reports have indicated that both imaging and biopsy do not always give an accurate prediction of grade. (1) What is the concordance of image-guided needle preoperative biopsy and postoperative grading in central (intramedullary) chondrosarcomas of long bones, and how does this compare with the concordance of image-guided needle preoperative biopsy and postoperative grading in central pelvic chondrosarcomas? (2) What is the concordance of preoperative image-guided needle biopsy and postoperative findings in differentiating low-grade from high-grade central chondrosarcomas of long bones, and how does this compare with the concordance in central pelvic chondrosarcomas? Between 1997 and 2014, in our institution, we treated 126 patients for central chondrosarcomas located in long bones and the pelvis. Of these 126 cases, 41 were located in the pelvis and the remaining 85 cases were located in long bones. This study considers 39 (95%) and 40 (47%) of them, respectively. We included all cases in which histological information was complete regarding preoperative and postoperative tumor grading. We excluded all cases with incomplete data sets or nondiagnostic preoperative biopsies. To evaluate the needle biopsy accuracy, we compared the histological tumor grade, obtained from the preoperative biopsy, with the final histological grade obtained from the postoperative surgical specimen. The weighted and nonweighted kappa statistics were used to evaluate the agreement. Concordance between the preoperative biopsy and the final pathological analysis in terms of histological grade was much higher in long-bone chondrosarcoma than in pelvic chondrosarcoma (83% [33 of 40] versus 36% [14 of 39]; odds ratio, 8, 48). Likewise, the weighted kappa coefficients were higher in long-bone chondrosarcoma than in pelvic chondrosarcoma for the determination of histological grade (0.63; 95% confidence interval [CI], 0.34-0.91 versus 0.12; -0.32 to 0.57; p < 0.001). When categorizing the lesions as low grade or high grade, concordance between the preoperative biopsy and the final pathological analysis was much higher in long-bone chondrosarcoma than in pelvic chondrosarcoma (90% [36 of 40] versus 67% [26 of 39]; odds ratio, 4, 5). Likewise, the weighted kappa coefficients were higher in long-bone chondrosarcoma than in pelvic chondrosarcoma (0.73; 95% CI, 0.51-0.94 versus 0.26; 0.04-0.48; p < 0.001). Image-guided needle biopsy, when performed by a specialist radiologist and evaluated by an experienced bone pathologist, is a useful tool in determining the histological grade of long-bone chondrosarcomas allowing identification of true low-grade tumors. The histological grade should be correlated with imaging and the clinical presentation, but under these circumstances, experienced tumor surgeons may use this information in planning surgical treatment. The same appears not to be true for pelvic lesions, in which histological grade established by needle biopsy should be interpreted with caution. Level III, diagnostic study.

Costal chondrosarcoma requiring differential diagnosis from metastatic tumor.

PubMed

Matsuoka, Katsunari; Ueda, Mitsuhiro; Miyamoto, Yoshihiro

2017-02-01

Although chondrosarcoma is a common malignant bone tumor, cases arising in the rib are relatively rare. We experienced a case of chondrosarcoma arising in the right 10th rib during follow-up after lung cancer surgery. Although the finding of an osteolytic mass suggested a metastatic bone tumor, 18F-fluorodeoxyglucose positron-emission tomography demonstrated low fluorodeoxyglucose uptake, and a primary bone tumor was suspected. The bone tumor was resected and diagnosed as chondrosarcoma. Four years after resection, there has been no recurrence or metastasis. Positron-emission tomography was useful for differential diagnosis between a chondrosarcoma and a metastatic bone tumor.

Extraskeletal Ewing's Sarcoma: insight into a ten years follow-up.

PubMed

Zitelli, A; Manfredelli, S; Brunotti, G; Marcantonio, M; Pontone, S; Angelici, A

2013-01-01

Extraskeletal Ewing's sarcoma is a rare malignant soft tissue tumor, classified within the Ewing's Sarcoma Family Tumors. While the classical Ewing's Sarcoma affects mainly the bone during youth, the Extraskeletal histotype differs for age incidence, primary location and prognosis. Peak incidence and typical location are during adolescence and in the extremities respectively. We report a 30 year old woman case with a positive outcome after ten years from first diagnosis of Extraskeletal Ewing's sarcoma. Treatment was achieved through surgical resection plus adjuvant chemoradiotherapy derived from EW93 and IRS III trials. Conclusion. Our report represents an unusual case due to age of presentation, neoplasm location and long survival reached. In last decades several trials results demonstrated that long survival could be achieved by combined surgery and adjuvant multi-drug treatment.

Ewing Sarcoma of the External Ear Canal

PubMed Central

Kecelioglu Binnetoglu, Kiymet; Gerin, Fatma; Sari, Murat

2016-01-01

Background. Ewing sarcoma (ES) is a high-grade malignant tumor that has skeletal and extraskeletal forms and consists of small round cells. In the head and neck region, reported localization of extraskeletal ES includes the larynx, thyroid gland, submandibular gland, nasal fossa, pharynx, skin, and parotid gland, but not the external ear canal. Methods. We present the unique case of a 2-year-old boy with extraskeletal ES arising from the external ear canal, mimicking auricular hematoma. Results. Surgery was performed and a VAC/IE (vincristine, adriamycin, cyclophosphamide alternating with ifosfamide, and etoposide) regimen was used for adjuvant chemotherapy for 12 months. Conclusion. The clinician should consider extraskeletal ES when diagnosing tumors localized in the head and neck region because it may be manifested by a nonspecific clinical picture mimicking common otorhinolaryngologic disorders. PMID:27313930

Chondromyxoid Fibroma of the Ethmoid Sinus

DTIC Science & Technology

2011-06-01

and its perceptible recurrence rate. It is for these reasons that CMF should be distinguished from a myxoid variant of chondrosarcoma (which usually...cartilage of the type seen in chondroma or chondrosarcoma and is a focal finding in less than 20% of CMF cases [5]. Mitotic figures are sparse, accounting...CMF from chondrosarcoma [5]. The histologic differential diagnosis of CMF includes, most importantly, myxoid chondrosarcoma and chondro- blastoma [7

[Dedifferentiated chondrosarcoma: radiologic-pathologic correlation].

PubMed

Bierry, G; Feydy, A; Larousserie, F; Pluot, E; Guerini, H; Campagna, R; Dufau-Andreu, C; Anract, P; Babinet, A; Dietemann, J L; Chevrot, A; Drapé, J L

2010-03-01

Dedifferentiated chondrosarcomas are highly malignant tumors characterized by conventional low-grade chondrosarcoma with abrupt transition to foci that have dedifferentiated into a higher-grade noncartilaginous more aggressive sarcoma. The dedifferentiated component, an osteosarcoma or fibrosarcoma, determines the prognosis. Its identification is key for management. A diagnosis of dedifferentiated chondrosarcoma should be suggested by the presence of "tumoral dimorphism" with cartilaginous component and aggressive lytic component invading adjacent soft tissues.

Challenges of local recurrence and cure in low grade malignant tumors of the spine.

PubMed

Boriani, Stefano; Saravanja, Davor; Yamada, Yoshiya; Varga, Peter Pal; Biagini, Roberto; Fisher, Charles G

2009-10-15

Systematic review and ambispective multicenter cohort study. 1. To compare the effects of wide/marginal (en bloc) resection with intralesional resection on local recurrence and survival for chordomas and chondrosarcomas of the spine. 2. To determine the influence of radiation therapy in the management of chordomas and chondrosarcomas. Chordomas and chondrosarcomas of the spine are prone to local recurrence and death despite being low-grade malignant tumors. No study to date has enough numbers or adequate scientific rigor to determine the influence of resection or radiation therapy on outcome. A systematic review was performed to evaluate the 2 objectives. In addition an ambispective multicenter cohort analysis of chordomas and chondrosarcomas was performed. The GRADE system of analysis integrating the results of the systematic review, the multicenter cohort study and the expert opinion of the Spine Oncology Study Group (SOSG) was used to arrive at treatment recommendations. A total of 63 articles were included in the systematic reviews. Evidence was low quality. En bloc resection appeared to improve both local recurrence and disease free survival in Chordoma and Chondrosarcoma. Radiation therapy had a positive impact on the management of Chordoma and Chondrosarcoma with predictably low side effects. The cohort analysis showed significantly decreased local recurrence for Chordoma (P < 0.0001) and Chondrosarcoma (P < 0.0001) with en bloc resection, and significantly decreased death for both Chordoma (P = 0.0001) and Chondrosarcoma (P = 0.0015) with en bloc resection. When wide or marginal margins (en bloc) are achieved in surgical resection of chordomas and chondrosarcomas of the spine there is a decrease in local recurrence and mortality. Therefore, en bloc resection should be undertaken for the treatment of chordomas and chondrosarcomas of the spine. Strong Recommendation, Moderate Quality Evidence.Radiation therapy of at least 60 to 65 Gy equivalents is indicated as an adjuvant treatment for chordoma and chondrosarcoma of the spine when there has been incomplete resection or an intralesional margin. Weak Recommendation, Low Quality Evidence.

BMP and TGFbeta pathways in human central chondrosarcoma: enhanced endoglin and Smad 1 signaling in high grade tumors

PubMed Central

2012-01-01

Background As major regulators of normal chondrogenesis, the bone morphogenic protein (BMP) and transforming growth factor β (TGFB) signaling pathways may be involved in the development and progression of central chondrosarcoma. In order to uncover their possible implication, the aim of this study was to perform a systematic quantitative study of the expression of BMPs, TGFBs and their receptors and to assess activity of the corresponding pathways in central chondrosarcoma. Methods Gene expression analysis was performed by quantitative RT-PCR in 26 central chondrosarcoma and 6 healthy articular cartilage samples. Expression of endoglin and nuclear localization of phosphorylated Smad1/5/8 and Smad2 was assessed by immunohistochemical analysis. Results The expression of TGFB3 and of the activin receptor-like kinase ALK2 was found to be significantly higher in grade III compared to grade I chondrosarcoma. Nuclear phosphorylated Smad1/5/8 and Smad2 were found in all tumors analyzed and the activity of both signaling pathways was confirmed by functional reporter assays in 2 chondrosarcoma cell lines. Immunohistochemical analysis furthermore revealed that phosphorylated Smad1/5/8 and endoglin expression were significantly higher in high-grade compared to low-grade chondrosarcoma and correlated to each other. Conclusions The BMP and TGFβ signaling pathways were found to be active in central chondrosarcoma cells. The correlation of Smad1/5/8 activity to endoglin expression suggests that, as described in other cell types, endoglin could enhance Smad1/5/8 signaling in high-grade chondrosarcoma cells. Endoglin expression coupled to Smad1/5/8 activation could thus represent a functionally important signaling axis for the progression of chondrosarcoma and a regulator of the undifferentiated phenotype of high-grade tumor cells. PMID:23088614

Prognosis of Primary and Recurrent Chondrosarcoma of the Rib.

PubMed

Roos, Eva; van Coevorden, Frits; Verhoef, Cornelis; Wouters, Michel W; Kroon, Herman M; Hogendoorn, Pancras C W; van Houdt, Winan J

2016-03-01

Chondrosarcoma of the rib is a rare disease. Although surgery is the only curative treatment option, rib resection with an adequate margin can be challenging and local recurrence is a frequent problem. In this study, the prognosis of primary and recurrent chondrosarcoma of the rib is reported. Retrospective analysis was performed of patients treated for chondrosarcoma of the rib between 1984 and 2014 in three major tertiary referral centers in The Netherlands. Clinical and histopathological features were analyzed for their prognostic value using Kaplan-Meier and Cox proportional hazard analysis. Endpoints were set at local recurrent disease, metastasis rate, or death. Overall, 76 patients underwent a resection for a primary chondrosarcoma, and 26 patients underwent a resection for a recurrent chondrosarcoma. Five-year overall survival in the primary group was 90%, local recurrence rate was 17%, and metastasis rate was 12%. The 5-year outcome after recurrent chondrosarcoma was lower, with an overall survival of 65%, local recurrence rate of 27%, and metastasis rate of 27%. For primary chondrosarcoma, tumor size >5 cm and a positive resection margin were correlated with worse overall survival [hazard ratio (HR) 3.28, 95% confidence interval (CI) 1.03-10.44; HR 2.92, 95% CI 1.03-8.25). A higher histological grade was correlated with a higher local recurrence and metastasis rate (HR 5.92, 95% CI 1.11-31.65; HR 6.96, 95% CI 1.15-42.60). Surgical resection of both primary and recurrent chondrosarcoma of the rib is an effective treatment strategy. The oncological outcome after surgery is worse in tumors >5 cm, in tumors with positive resection margins and grade 3 chondrosarcoma.

Image-guided, intensity-modulated radiation therapy (IG-IMRT) for skull base chordoma and chondrosarcoma: preliminary outcomes.

PubMed

Sahgal, Arjun; Chan, Michael W; Atenafu, Eshetu G; Masson-Cote, Laurence; Bahl, Gaurav; Yu, Eugene; Millar, Barbara-Ann; Chung, Caroline; Catton, Charles; O'Sullivan, Brian; Irish, Jonathan C; Gilbert, Ralph; Zadeh, Gelareh; Cusimano, Michael; Gentili, Fred; Laperriere, Normand J

2015-06-01

We report our preliminary outcomes following high-dose image-guided intensity modulated radiotherapy (IG-IMRT) for skull base chordoma and chondrosarcoma. Forty-two consecutive IG-IMRT patients, with either skull base chordoma (n = 24) or chondrosarcoma (n = 18) treated between August 2001 and December 2012 were reviewed. The median follow-up was 36 months (range, 3-90 mo) in the chordoma cohort, and 67 months (range, 15-125) in the chondrosarcoma cohort. Initial surgery included biopsy (7% of patients), subtotal resection (57% of patients), and gross total resection (36% of patients). The median IG-IMRT total doses in the chondrosarcoma and chordoma cohorts were 70 Gy and 76 Gy, respectively, delivered with 2 Gy/fraction. For the chordoma and chondrosarcoma cohorts, the 5-year overall survival and local control rates were 85.6% and 65.3%, and 87.8% and 88.1%, respectively. In total, 10 patients progressed locally: 8 were chordoma patients and 2 chondrosarcoma patients. Both chondrosarcoma failures were in higher-grade tumors (grades 2 and 3). None of the 8 patients with grade 1 chondrosarcoma failed, with a median follow-up of 77 months (range, 34-125). There were 8 radiation-induced late effects-the most significant was a radiation-induced secondary malignancy occurring 6.7 years following IG-IMRT. Gross total resection and age were predictors of local control in the chordoma and chondrosarcoma patients, respectively. We report favorable survival, local control and adverse event rates following high dose IG-IMRT. Further follow-up is needed to confirm long-term efficacy. © The Author(s) 2014. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

[Extraskeletal Ewing's sarcoma].

PubMed

Baram, J; Tichler, T; Nass, D; Brenner, H J

1992-01-01

5 patients diagnosed as having extraskeletal Ewing's sarcoma have been referred to our adult oncology unit since 1980. All were men, ranging in age from 18-57 (mean 32 years). The primary tumor was located on the trunk in 4 and in an extremity in 1. Wide tumor excision was feasible in only 2. 3 died within 27 months and 2 are alive, 13 and 67 months, respectively, following diagnosis. This study demonstrates the highly aggressive nature of extraskeletal Ewing's sarcoma and the need for early diagnosis and efficient chemotherapy.

Chondrosarcoma third metacarpal: Diagnosis and management options.

PubMed

Sharma, Vipin; Verma, Lucky; Chander, Bal; Sharma, Seema

2018-01-01

Chondrosarcoma is a rare malignant tumor of cartilage commonly arising in the pelvis, proximal femur, and humerus, but quite uncommon in the small bones of the hand. Although limited surgical procedures such as curettage are mentioned as a management option in low-grade chondrosarcomas, they tend to have a high rate of recurrences. Hence, wide excision is recommended as a treatment option even in low-grade chondrosarcomas of the hand.

miR-125b acts as a tumor suppressor in chondrosarcoma cells by the sensitization to doxorubicin through direct targeting the ErbB2-regulated glucose metabolism

PubMed Central

Tang, Xian-ye; Zheng, Wei; Ding, Min; Guo, Kai-jin; Yuan, Feng; Feng, Hu; Deng, Bin; Sun, Wei; Hou, Yang; Gao, Lu

2016-01-01

Chondrosarcoma is the second most common type of primary bone malignancy in the United States after osteosarcoma. Surgical resections of these tumors are the only effective treatment to chondrosarcoma patients due to their resistance to conventional chemo- and radiotherapy. In this study, miR-125b was found to perform its tumor-suppressor function to inhibit glucose metabolism via the direct targeting of oncogene, ErbB2. We report miR-125b was downregulated in both chondrosarcoma patient samples and cell lines. The total 20 Asian chondrosarcoma patients showed significantly downregulated miR-125b expression compared with normal tissues. Meanwhile, miR-125 was downregulated in chondrosarcoma cells and doxorubicin resistant cells. Overexpression of miR-125 enhanced the sensitivity of both parental and doxorubicin resistant cells to doxorubicin through direct targeting on the ErbB2-mediated upregulation of glycolysis in chondrosarcoma cells. Moreover, restoration of the expression of ErbB2 and glucose metabolic enzymes in miR-125 pretransfected cells recovered the susceptibility to doxorubicin. Our study will provide a novel aspect on the overcoming chemoresistance in human chondrosarcoma cells and may help in the development of therapeutic strategies for the treatments of patients. PMID:26966351

Rapamycin causes growth arrest and inhibition of invasion in human chondrosarcoma cells.

PubMed

Song, Jian; Wang, Xiaobo; Zhu, Jiaxue; Liu, Jun

2016-01-01

Chondrosarcoma is a highly malignant tumor that is characterized by a potent capacity to invade locally and cause distant metastasis and notable for its lack of response to conventional chemotherapy or radiotherapy. Rapamycin, the inhibitor of mammalian target of rapamycin (mTOR), is a valuable drug with diverse clinical applications and regulates many cellular processes. However, the effects of rapamycin on cell growth and invasion of human chondrosarcoma cells are not well known. We determined the effect of rapamycin on cell proliferation, cell cycle arrest and invasion by using MTS, flow cytometry and invasion assays in two human chondrosarcoma cell lines, SW1353 and JJ012. Cell cycle regulatory and invasion-related genes' expression analysis was performed by quantitative RT-PCR (qRT-PCR). We also evaluated the effect of rapamycin on tumor growth by using mice xenograph models. Rapamycin significantly inhibited the cell proliferation, induced cell cycle arrest and decreased the invasion ability of human chondrosarcoma cells. Meanwhile, rapamycin modulated the cell cycle regulatory and invasion-related genes' expression. Furthermore, the tumor growth of mice xenograph models with human chondrosarcoma cells was significantly inhibited by rapamycin. These results provided further insight into the role of rapamycin in chondrosarcoma. Therefore, rapamycin targeted therapy may be a potential treatment strategy for chondrosarcoma.

miR-125b acts as a tumor suppressor in chondrosarcoma cells by the sensitization to doxorubicin through direct targeting the ErbB2-regulated glucose metabolism.

PubMed

Tang, Xian-ye; Zheng, Wei; Ding, Min; Guo, Kai-jin; Yuan, Feng; Feng, Hu; Deng, Bin; Sun, Wei; Hou, Yang; Gao, Lu

2016-01-01

Chondrosarcoma is the second most common type of primary bone malignancy in the United States after osteosarcoma. Surgical resections of these tumors are the only effective treatment to chondrosarcoma patients due to their resistance to conventional chemo- and radiotherapy. In this study, miR-125b was found to perform its tumor-suppressor function to inhibit glucose metabolism via the direct targeting of oncogene, ErbB2. We report miR-125b was downregulated in both chondrosarcoma patient samples and cell lines. The total 20 Asian chondrosarcoma patients showed significantly downregulated miR-125b expression compared with normal tissues. Meanwhile, miR-125 was downregulated in chondrosarcoma cells and doxorubicin resistant cells. Overexpression of miR-125 enhanced the sensitivity of both parental and doxorubicin resistant cells to doxorubicin through direct targeting on the ErbB2-mediated upregulation of glycolysis in chondrosarcoma cells. Moreover, restoration of the expression of ErbB2 and glucose metabolic enzymes in miR-125 pretransfected cells recovered the susceptibility to doxorubicin. Our study will provide a novel aspect on the overcoming chemoresistance in human chondrosarcoma cells and may help in the development of therapeutic strategies for the treatments of patients.

Clonal Evolution through Loss of Chromosomes and Subsequent Polyploidization in Chondrosarcoma

PubMed Central

Olsson, Linda; Paulsson, Kajsa; Bovée, Judith V. M. G.; Nord, Karolin H.

2011-01-01

Near-haploid chromosome numbers have been found in less than 1% of cytogenetically reported tumors, but seem to be more common in certain neoplasms including the malignant cartilage-producing tumor chondrosarcoma. By a literature survey of published karyotypes from chondrosarcomas we could confirm that loss of chromosomes resulting in hyperhaploid-hypodiploid cells is common and that these cells may polyploidize. Sixteen chondrosarcomas were investigated by single nucleotide polymorphism (SNP) array and the majority displayed SNP patterns indicative of a hyperhaploid-hypodiploid origin, with or without subsequent polyploidization. Except for chromosomes 5, 7, 19, 20 and 21, autosomal loss of heterozygosity was commonly found, resulting from chromosome loss and subsequent duplication of monosomic chromosomes giving rise to uniparental disomy. Additional gains, losses and rearrangements of genetic material, and even repeated rounds of polyploidization, may affect chondrosarcoma cells resulting in highly complex karyotypes. Loss of chromosomes and subsequent polyploidization was not restricted to a particular chondrosarcoma subtype and, although commonly found in chondrosarcoma, binucleated cells did not seem to be involved in these events. PMID:21949816

Chondrosarcoma of the temporomandibular joint: a case report and review of the literature.

PubMed

Oh, Kyu-Young; Yoon, Hye-Jung; Lee, Jae-Il; Hong, Sam-Pyo; Hong, Seong-Doo

2016-07-01

Chondrosarcoma is the second most common sarcoma arising in the bone, but it rarely involves the temporomandibular joint (TMJ). To date, 30 cases of TMJ chondrosarcoma have been reported in the English literature, and the authors report an additional case arising from a cystic lesion in a 60-year-old female patient. The clinical and radiological diagnosis of the lesion was initially synovial cyst, and periodic check-ups were done after aspiration of the lesion. After three years, the patient perceived swelling of the lesion, and surgical excision was performed. The final diagnosis was grade I chondrosarcoma. When clinicians detect a cystic lesion in the radiographic imaging of the TMJ, chondrosarcoma should be included in the differential diagnosis. In addition, computed tomography (CT) as well as magnetic resonance imaging (MRI) is recommended for the accurate diagnosis and proper preoperative planning in TMJ chondrosarcoma.

Paeonol Suppresses Chondrosarcoma Metastasis through Up-Regulation of miR-141 by Modulating PKCδ and c-Src Signaling Pathway

PubMed Central

Horng, Chi-Ting; Shieh, Po-Chuen; Tan, Tzu-Wei; Yang, Wei-Hung; Tang, Chih-Hsin

2014-01-01

Chondrosarcoma, a primary malignant bone cancer, has potential for local invasion and distant metastasis, especially to the lungs. Patients diagnosed with it show poor prognosis. Paeonol (2'-hydroxy-4'-methoxyacetophenone), the main active compound of traditional Chinese remedy Paeonia lactiflora Pallas, exhibits anti-inflammatory and anti-tumor activity; whether paeonol regulates metastatic chondrosarcoma is largely unknown. Here, we find paeonol do not increase apoptosis. By contrast, at non-cytotoxic concentrations, paeonol suppresses migration and invasion of chondrosarcoma cells. We also demonstrate paeonol enhancing miR-141 expression and miR-141 inhibitor reversing paeonol-inhibited cell motility; paeonol also reduces protein kinase C (PKC)δ and c-Src kinase activity. Since paeonol inhibits migration and invasion of human chondrosarcoma via up-regulation of miR-141 via PKCδ and c-Src pathways, it thus might be a novel anti-metastasis agent for treatment of metastatic chondrosarcoma. PMID:24992595

Gamma Knife surgery for intracranial chordoma and chondrosarcoma: radiosurgical perspectives and treatment outcomes.

PubMed

Kim, Ji Hee; Jung, Hyun Ho; Chang, Jong Hee; Chang, Jin Woo; Park, Yong Gou; Chang, Won Seok

2014-12-01

Intracranial chordomas and chondrosarcomas are histologically low-grade, locally invasive tumors that are reported to be similar in terms of anatomical location, clinical presentation, and radiological findings but different in terms of behavior and outcomes. The purpose of this study was to investigate and compare clinical outcomes after Gamma Knife surgery (GKS) for the treatment of intracranial chordoma and chondrosarcoma. The authors conducted a retrospective review of the results of radiosurgical treatment of intracranial chordomas and chondrosarcomas. They enrolled patients who had undergone GKS for intracranial chordoma or chondrosarcoma at the Yonsei Gamma Knife Center, Yonsei University College of Medicine, from October 2000 through June 2007. Analyses included only patients for whom the disease was pathologically diagnosed before GKS and for whom more than 5 years of follow-up data after GKS were available. Rates of progression-free survival and overall survival were analyzed and compared according to tumor pathology. Moreover, the association between tumor control and the margin radiation dose to the tumor was analyzed, and the rate of tumor volume change after GKS was quantified. A total of 10 patients were enrolled in this study. Of these, 5 patients underwent a total of 8 sessions of GKS for chordoma, and the other 5 patients underwent a total of 7 sessions of GKS for chondrosarcoma. The 2- and 5-year progression-free survival rates for patients in the chordoma group were 70% and 35%, respectively, and rates for patients in the chondrosarcoma group were 100% and 80%, respectively (log-rank test, p = 0.04). The 2- and 5-year overall survival rates after GKS for patients in the chordoma group were 87.5% and 72.9%, respectively, and rates for patients in the chondrosarcoma group were 100% and 100%, respectively (log-rank test, p = 0.03). The mean rates of tumor volume change 2 years after radiosurgery were 79.64% and 39.91% for chordoma and chondrosarcoma, respectively (p = 0.05). No tumor progression was observed when margin doses greater than 16 Gy for chordoma and 14 Gy for chondrosarcoma were prescribed. Outcomes after GKS were more favorable for patients with chondrosarcoma than for those with chordoma. The data also indicated that at 2 years after GKS, the rate of volume change is significantly higher for chordomas than for chondrosarcomas. The authors conclude that radiosurgery with a margin dose of more than 16 Gy for chordomas and more than 14 Gy for chondrosarcomas seems to enhance local tumor control with relatively few complications. Further studies are needed to determine the optimal dose of GKS for patients with intracranial chordoma or chondrosarcoma.

Three new chondrosarcoma cell lines: one grade III conventional central chondrosarcoma and two dedifferentiated chondrosarcomas of bone

PubMed Central

2012-01-01

Background Chondrosarcoma is the second most common primary sarcoma of bone. High-grade conventional chondrosarcoma and dedifferentiated chondrosarcoma have a poor outcome. In pre-clinical research aiming at the identification of novel treatment targets, the need for representative cell lines and model systems is high, but availability is scarce. Methods We developed and characterized three cell lines, derived from conventional grade III chondrosarcoma (L835), and dedifferentiated chondrosarcoma (L2975 and L3252) of bone. Proliferation and migration were studied and we used COBRA-FISH and array-CGH for karyotyping and genotyping. Immunohistochemistry for p16 and p53 was performed as well as TP53 and IDH mutation analysis. Cells were injected into nude mice to establish their tumorigenic potential. Results We show that the three cell lines have distinct migrative properties, L2975 had the highest migration rate and showed tumorigenic potential in mice. All cell lines showed chromosomal rearrangements with complex karyotypes and genotypic aberrations were conserved throughout late passaging of the cell lines. All cell lines showed loss of CDKN2A, while TP53 was wild type for exons 5–8. L835 has an IDH1 R132C mutation, L2975 an IDH2 R172W mutation and L3252 is IDH wild type. Conclusions Based on the stable culturing properties of these cell lines and their genotypic profile resembling the original tumors, these cell lines should provide useful functional models to further characterize chondrosarcoma and to evaluate new treatment strategies. PMID:22928481

Elevated Levels of Dickkopf-1 Are Associated with β-Catenin Accumulation and Poor Prognosis in Patients with Chondrosarcoma

PubMed Central

Chen, Changbao; Zhou, Hua; Zhang, Xiaolin; Ma, Xinlong; Liu, Zhongjun; Liu, Xiaoguang

2014-01-01

Background Dickkopf-1 (DKK1) is an antagonist of Wnt/β-catenin signaling implicated in tumorigenesis. However, the biological role of DKK1 and β-catenin involved in chondrosarcoma has not been sufficiently investigated. This study was designed to investigate the expression profiles of DKK1 and β-catenin, and to clarify their clinical values in chondrosarcoma. Methods The mRNA and protein levels of DKK1 and β-catenin in fresh chondrosarcoma and the corresponding non-tumor tissues were analyzed by Real-time PCR and Western blot, respectively. The protein expression patterns of DKK1 and β-catenin were investigated by immunohistochemistry. The associations among DKK1 level, β-catenin accumulation, clinicopathological factors and the overall survival were separately evaluated. Results Both DKK1 and β-catenin levels were remarkably elevated in chondrosarcoma compared with the corresponding non-tumor tissues. High DKK1 level and positive β-catenin accumulation in chondrosarcoma specimens were 58.7% and 53.9%, respectively. Elevated DKK1 level significantly correlated with positive β-catenin accumulation, and they were remarkably associated with histological grade and Musculoskeletal Tumor Society stage. Furthermore, DKK1 level and β-catenin accumulation had significant impacts on the prognosis of chondrosarcoma patients. Multivariate analysis revealed that DKK1 level was an independent prognostic factor for overall survival. Conclusions Elevated DKK1 levels associated with β-catenin accumulation play a crucial role in chondrosarcoma. DKK1 can serve as a novel predictor of poor prognosis in patients with chondrosarcoma. PMID:25144498

Oncological outcomes of patients with Ewing's sarcoma: is there a difference between skeletal and extra-skeletal Ewing's sarcoma?

PubMed

Pradhan, A; Grimer, R J; Spooner, D; Peake, D; Carter, S R; Tillman, R M; Abudu, A; Jeys, L

2011-04-01

The aim of this study was to identify whether there was any difference in patient, tumour, treatment or outcome characteristics between patients with skeletal or extra-skeletal Ewing's sarcoma. We identified 300 patients with new primary Ewing's sarcoma diagnosed between 1980 and 2005 from the centres' local database. There were 253 (84%) with skeletal and 47 (16%) with extra-skeletal Ewing's sarcomas. Although patients with skeletal Ewing's were younger (mean age 16.8 years) than those with extra-skeletal Ewing's sarcoma (mean age 27.5 years), there was little difference between the groups in terms of tumour stage or treatment. Nearly all the patients were treated with chemotherapy and most had surgery. There was no difference in the overall survival of patients with skeletal (64%) and extra-skeletal Ewing's sarcoma (61%) (p = 0.85), and this was also the case when both groups were split by whether they had metastases or not. This large series has shown that the oncological outcomes of Ewing's sarcoma are related to tumour characteristics and patient age, and not determined by whether they arise in bone or soft tissue.

Extra-skeletal Ewing's sarcoma of the nasal fossa.

PubMed

Lane, S; Ironside, J W

1990-07-01

Extraskeletal Ewing's sarcoma is rarely found arising in the head and neck region. An unusual case arising in the nasal fossa in a young child is reported and the differential diagnosis, pathology and treatment discussed.

The expression of miR-181a-5p and miR-371b-5p in chondrosarcoma.

PubMed

Mutlu, S; Mutlu, H; Kirkbes, S; Eroglu, S; Kabukcuoglu, Y S; Kabukcuoglu, F; Duymus, T M; ISık, M; Ulasli, M

2015-07-01

Chondrosarcomas are malignant tumors of chondrocytes that affect bones and joints, and it represents the third most common type of primary bone tumors. Chondrosarcoma is difficult to treat because it is relatively resistant to both chemotherapy and radiation. Thus, surgery remains the best available treatment. It is important to find new diagnostic markers and improve treatment options. miRNAs are small non-coding transcripts (19-25 nucleotides) that regulate gene expression via targeting complementary sequences within messenger RNAs (mRNAs). miRNAs have been shown to be involved in regulation of many biochemical pathways. Dysregulated expression of many miRNAs has also been associated with multiple human diseases, such as cancer. 18 surgical chondrosarcoma specimens were obtained from patients. RNA extractions were performed from decalcified paraffin embedded tissues. The aim of this study was to investigate the expression levels of miR-181a and miR-371b in patients with chondrosarcoma by using RT-PCR and to evaluate the relationship between these miRNAs and chondrosarcoma. miR-181a was found to be upregulated in chondrosarcoma specimens whereas no significant alteration was found for miR-371b expression. It has been proposed that miRNA expression studies might be used as diagnostic, prognostic marker in cancer. miRNA expression data produced in our study may contribute future chondrosarcoma diagnosis and therapy.

BL-038, a Benzofuran Derivative, Induces Cell Apoptosis in Human Chondrosarcoma Cells through Reactive Oxygen Species/Mitochondrial Dysfunction and the Caspases Dependent Pathway.

PubMed

Liu, Ju-Fang; Chen, Chien-Yu; Chen, Hsien-Te; Chang, Chih-Shiang; Tang, Chih-Hsin

2016-09-07

Chondrosarcoma is a highly malignant cartilage-forming bone tumor that has the capacity to invade locally and cause distant metastasis. Moreover, chondrosarcoma is intrinsically resistant to conventional chemotherapy or radiotherapy. The novel benzofuran derivative, BL-038 (2-amino-3-(2,6-dichlorophenyl)-6-(4-methoxyphenyl)benzofuran-4-yl acetate), has been evaluated for its anticancer effects in human chondrosarcoma cells. BL-038 caused cell apoptosis in two human chondrosarcoma cell lines, JJ012 and SW1353, but not in primary chondrocytes. Treatment of chondrosarcoma with BL-038 also induced reactive oxygen species (ROS) production. Furthermore, BL-038 decreased mitochondrial membrane potential (MMP) and changed mitochondrial-related apoptosis, by downregulating the anti-apoptotic activity members (Bcl-2, Bcl-xL) and upregulating pro-apoptotic members (Bax, Bak) of the B-cell lymphoma 2 (Bcl-2) family of proteins, key regulators of the apoptotic machinery in cells. These results demonstrate that in human chondrosarcoma cells, the apoptotic and cytotoxic effects of BL-038 are mediated by the intrinsic mitochondria-mediated apoptotic pathway, which in turn causes the release of cytochrome c, the activation of caspase-9 and caspase-3, and the cleavage of poly (ADP-ribose) polymerase (PARP), to elicit apoptosis response. Our results show that the benzofuran derivative BL-038 induces apoptosis in chondrosarcoma cells.

BL-038, a Benzofuran Derivative, Induces Cell Apoptosis in Human Chondrosarcoma Cells through Reactive Oxygen Species/Mitochondrial Dysfunction and the Caspases Dependent Pathway

PubMed Central

Liu, Ju-Fang; Chen, Chien-Yu; Chen, Hsien-Te; Chang, Chih-Shiang; Tang, Chih-Hsin

2016-01-01

Chondrosarcoma is a highly malignant cartilage-forming bone tumor that has the capacity to invade locally and cause distant metastasis. Moreover, chondrosarcoma is intrinsically resistant to conventional chemotherapy or radiotherapy. The novel benzofuran derivative, BL-038 (2-amino-3-(2,6-dichlorophenyl)-6-(4-methoxyphenyl)benzofuran-4-yl acetate), has been evaluated for its anticancer effects in human chondrosarcoma cells. BL-038 caused cell apoptosis in two human chondrosarcoma cell lines, JJ012 and SW1353, but not in primary chondrocytes. Treatment of chondrosarcoma with BL-038 also induced reactive oxygen species (ROS) production. Furthermore, BL-038 decreased mitochondrial membrane potential (MMP) and changed mitochondrial-related apoptosis, by downregulating the anti-apoptotic activity members (Bcl-2, Bcl-xL) and upregulating pro-apoptotic members (Bax, Bak) of the B-cell lymphoma 2 (Bcl-2) family of proteins, key regulators of the apoptotic machinery in cells. These results demonstrate that in human chondrosarcoma cells, the apoptotic and cytotoxic effects of BL-038 are mediated by the intrinsic mitochondria-mediated apoptotic pathway, which in turn causes the release of cytochrome c, the activation of caspase-9 and caspase-3, and the cleavage of poly (ADP-ribose) polymerase (PARP), to elicit apoptosis response. Our results show that the benzofuran derivative BL-038 induces apoptosis in chondrosarcoma cells. PMID:27618007

Apoptosis Signal-Regulating Kinase 1 Is Involved in Brain-Derived Neurotrophic Factor (BDNF)-Enhanced Cell Motility and Matrix Metalloproteinase 1 Expression in Human Chondrosarcoma Cells

PubMed Central

Lin, Chih-Yang; Chang, Sunny Li-Yun; Fong, Yi-Chin; Hsu, Chin-Jung; Tang, Chih-Hsin

2013-01-01

Chondrosarcoma is the primary malignancy of bone that is characterized by a potent capacity to invade locally and cause distant metastasis, and is therefore associated with poor prognoses. Chondrosarcoma further shows a predilection for metastasis to the lungs. The brain-derived neurotrophic factor (BDNF) is a small molecule in the neurotrophin family of growth factors that is associated with the disease status and outcome of cancers. However, the effect of BDNF on cell motility in human chondrosarcoma cells is mostly unknown. Here, we found that human chondrosarcoma cell lines had significantly higher cell motility and BDNF expression compared to normal chondrocytes. We also found that BDNF increased cell motility and expression of matrix metalloproteinase-1 (MMP-1) in human chondrosarcoma cells. BDNF-mediated cell motility and MMP-1 up-regulation were attenuated by Trk inhibitor (K252a), ASK1 inhibitor (thioredoxin), JNK inhibitor (SP600125), and p38 inhibitor (SB203580). Furthermore, BDNF also promoted Sp1 activation. Our results indicate that BDNF enhances the migration and invasion activity of chondrosarcoma cells by increasing MMP-1 expression through a signal transduction pathway that involves the TrkB receptor, ASK1, JNK/p38, and Sp1. BDNF thus represents a promising new target for treating chondrosarcoma metastasis. PMID:23892595

THE EXTRASKELETAL ACTIONS OF VITAMIN D--MYTHS AND FACTS.

PubMed

Sebaaly, Amer; Bachour, Falah; Bayoud, Wael; Adib, Gemma; Bedran, Farid; Daher, Clea; Maalouf, Ghassan

2015-01-01

Vitamin D is well known for its effects on bone metabolism, calcium and phosphorus homeostasis. Recently, a worldwide focus has been made on the extraskeletal effects of this liposoluble vitamin. The New York Times even called it the "wonder drug". Vitamin D is a liposoluble vitamin and acts via an intracellular receptor. This article reviews the extra-skeletal effects of vitamin D focusing on cardiovascular effects, regulation of glucose, antitumoral properties, and effect on the immune system and the skeletal muscle and attempts to offer possible molecular explanations to these effects.

Resistin promotes tumor metastasis by down-regulation of miR-519d through the AMPK/p38 signaling pathway in human chondrosarcoma cells

PubMed Central

Huang, Ho-Ning; Hung, Chih-Hung; Hsu, Chin-Jung; Fong, Yi-Chin; Hsu, Horng-Chaung; Huang, Yuan-Li; Tang, Chih-Hsin

2015-01-01

Resistin is a recently discovered adipocyte-secreting adipokine, which may play a critical role in modulating cancer pathogenesis. Chondrosarcoma is a highly malignant tumor known to frequently metastasize; however, the role of resistin in the metastasis of human chondrosarcoma is largely unknown. Here, we found that the expression of resistin was higher in chondrosarcoma biopsy tissues than in normal cartilage. Moreover, treatment with resistin increased matrix metalloproteinase (MMP)-2 expression and promoted cell migration in human chondrosarcoma cells. Co-transfection with microRNA (miR)-519d mimic resulted in reversed resistin-mediated cell migration and MMP-2 expression. Additionally, AMP-activated protein kinase (AMPK) and p38 inhibitors or siRNAs reduced the resistin-increased cell migration and miR-519d suppression, and inhibition of resistin expression resulted in suppression of MMP-2 expression and lung metastasis in vivo. Taken together, our results indicate that resistin promotes chondrosarcoma metastasis and MMP-2 expression through activation of the AMPK/p38 signaling pathway and down-regulation of miR-519d expression. Therefore, resistin may represent a potential novel molecular therapeutic target in chondrosarcoma metastasis. PMID:25404641

HGF and c-Met Interaction Promotes Migration in Human Chondrosarcoma Cells

PubMed Central

Tsou, Hsi-Kai; Chen, Hsien-Te; Hung, Ya-Huey; Chang, Chia-Hao; Li, Te-Mao; Fong, Yi-Chin; Tang, Chih-Hsin

2013-01-01

Chondrosarcoma is a type of highly malignant tumor with a potent capacity for local invasion and causing distant metastasis. Chondrosarcoma shows a predilection for metastasis to the lungs. Hepatocyte growth factor (HGF) has been demonstrated to stimulate cancer proliferation, migration, and metastasis. However, the effect of HGF on migration activity of human chondrosarcoma cells is not well known. Here, we found that human chondrosarcoma tissues demonstrated significant expression of HGF, which was higher than that in normal cartilage. We also found that HGF increased the migration and expression of matrix metalloproteinase (MMP)-2 in human chondrosarcoma cells. c-Met inhibitor and siRNA reduced HGF-increased cell migration and MMP-2 expression. HGF treatment resulted in activation of the phosphatidylinositol 3′-kinase (PI3K)/Akt/PKCδ/NF-κB pathway, and HGF-induced expression of MMP-2 and cell migration was inhibited by specific inhibitors or siRNA-knockdown of PI3K, Akt, PKCδ, and NF-κB cascades. Taken together, our results indicated that HGF enhances migration of chondrosarcoma cells by increasing MMP-2 expression through the c-Met receptor/PI3K/Akt/PKCδ/NF-κB signal transduction pathway. PMID:23320110

Outcomes of curettage and anhydrous alcohol adjuvant for low-grade chondrosarcoma of long bone.

PubMed

Kim, Wanlim; Han, Ilkyu; Kim, Eo Jin; Kang, Seungcheol; Kim, Han-Soo

2015-06-01

Low-grade chondrosarcoma of long bones can be treated successfully with extended intralesional curettage using adjuvants. However, there is no study reporting the use of anhydrous alcohol as an adjuvant in the treatment of low-grade chondrosarcoma. We asked (1) whether intralesional curettage and anhydrous alcohol adjuvant for low-grade chondrosarcoma is associated with good oncologic outcomes; and we report (2) the complications of the procedure. Thirty-six patients (13 men, 23 women) with a mean age of 46 years (range, 18-67 years) were treated for low-grade chondrosarcoma and followed up for a median of 62 months (range, 24-169 months). After intralesional curettage, and additional burring, anhydrous alcohol was used as an adjuvant therapy. At the time of last follow-up, there were no local recurrences or distant metastases. Six patients developed complications: 4 postoperative fractures (11%), 1 intra-articular loose body (3%) and 1 postoperative joint stiffness (3%). Anhydrous alcohol is a reasonable adjuvant for the curettage of low-grade chondrosarcoma of long bones. A long-term follow-up study is necessary, considering the slow biological progression of low-grade chondrosarcoma. Copyright © 2015 Elsevier Ltd. All rights reserved.

MicroRNA-100 resensitizes resistant chondrosarcoma cells to cisplatin through direct targeting of mTOR.

PubMed

Zhu, Zhe; Wang, Cun-Ping; Zhang, Yin-Feng; Nie, Lin

2014-01-01

Chondrosarcomas are malignant cartilage-forming tumors of bone which exhibit resistance to both chemotherapy and radiation treatment. miRNAs have been well demonstrated to regulate gene expression and play essential roles in a variety of biological processes, including proliferation, differentiation, migration, cell cycling and apoptosis. In this study, we obtained evidence that miR-100 acts as a tumor suppressor in human chondrosarcomas. Interestingly, cisplatin resistant chondrosarcoma cells exhibit decreased expression of miR-100 compared with parental cells. In addition, we identified mTOR as a direct target of miR-100. Overexpression of miR-100 complementary pairs to the 3' untranslated region (UTR) of mTOR, resulted in sensitization of cisplatin resistant cells to cisplatin. Moreover, recovery of the mTOR pathway by overexpression of S6K desensitized the chondrosarcoma cells to cisplatin, suggesting the miR-100-mediated sensitization to cisplatin dependent on inhibition of mTOR. In summary, the present studies highlight miR-100 as a tumor suppressor in chondrosarcoma contributing to anti-chemoresistance. Overexpression of miR-100 might be exploited as a therapeutic strategy along with cisplatin-based combined chemotherapy for the treatment of clinical chondrosarcoma patients.

HDAC6 inhibition suppresses chondrosarcoma by restoring the expression of primary cilia.

PubMed

Xiang, Wei; Guo, Fengjing; Cheng, Weiting; Zhang, Jiaming; Huang, Junming; Wang, Rui; Ma, Zhongxi; Xu, Kai

2017-07-01

Chondrosarcoma is a bone tumor characterized by the secretion of a cartilage-like extracellular matrix. It has been proved to lack extracellular sensor primary cilia. This study aimed to illustrate a feasible therapeutic method for chondrosarcoma by regulating primary cilia assembly through inhibiting histone deacetylases 6 (HDAC6) activation. In order to detect the interaction between primary cilia and HDAC6 in human chondrosarcoma, Tubastatin A and small interfering RNA (siRNA) were used to inhibit the endogenous expression of HDAC6. Cell viability test and Transwell assay were applied to evaluate the effects of malignant biological properties. Primary cilia staining and related proteins were detected. The abnormal expression of HDAC6 and cilia intraflagellar transport protein 88 (IFT88) was found in chondrosarcoma tissues. The inhibition of HDAC6 could downregulate the proliferation of chondrosarcoma cells in a concentration- and time-dependent manner and suppress the invasion capacity of tumor cells. Besides, the downregulation of HDAC6 exhibited a negative effect on the proliferation of relevant proteins but a positive effect on the primary cilia-related expression of IFT88 and acetylated α-tubulin. Primary cilia restoration could be observed after HDAC6 siRNA transfection. The Aurora A-HDAC6 cascade was involved in regulating primary cilia resorption by affecting α-tubulin deacetylation and Tubastatin A could inhibit chondrosarcoma cell growth in vivo. These results indicate that restricting HDAC6 can restore primary cilia assembly accompanied with suppressed chondrosarcoma cell proliferation and invasion capacities. Thus, promoting primary cilia restoration by targeting HDAC6 may be a feasible potential therapeutic method for chondro-sarcoma treatment.

Andrographolide Induces Cell Cycle Arrest and Apoptosis of Chondrosarcoma by Targeting TCF-1/SOX9 Axis.

PubMed

Zhang, Huan-Tian; Yang, Jie; Liang, Gui-Hong; Gao, Xue-Juan; Sang, Yuan; Gui, Tao; Liang, Zu-Jian; Tam, Man-Seng; Zha, Zhen-Gang

2017-12-01

Chondrosarcoma is the second most malignant bone tumor with poor prognosis and limited treatment options. Thus, development of more effective treatments has become urgent. Recently, natural compounds derived from medicinal plants have emerged as promising therapeutic options via targeting multiple key cellular molecules. Andrographolide (Andro) is such a compound, which has previously been shown to induce cell cycle arrest and apoptosis in several human cancers. However, the molecular mechanism through which Andro exerts its anti-cancer effect on chondrosarcoma remains to be elucidated. In the present study, we showed that Andro-induced G2/M cell cycle arrest of chondrosarcoma by fine-tuning the expressions of several cell cycle regulators such as p21, p27, and Cyclins, and that prolonged treatment of cells with Andro caused pronounced cell apoptosis. Remarkably, we found that SOX9 was highly expressed in poor-differentiated chondrosarcoma, and that knockdown of SOX9 suppressed chondrosarcoma cell growth. Further, our results showed that Andro dose-dependently down-regulated SOX9 expression in chondrosarcoma cells. Concomitantly, an inhibition of T cell factor 1 (TCF-1) mRNA expression and an enhancement of TCF-1 protein degradation by Andro were observed. In contrast, the expression and subcellular localization of β-catenin were not altered upon the treatment of Andro, suggesting that β-catenin might not function as the primary target of Andro. Additionally, we provided evidence that there was a mutual regulation between TCF-1 and SOX9 in chondrosarcoma cells. In conclusion, these results highlight the potential therapeutic effects of Andro in treatment of chondrosarcoma via targeting the TCF-1/SOX9 axis. J. Cell. Biochem. 118: 4575-4586, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Treatment with a Small Molecule Mutant IDH1 Inhibitor Suppresses Tumorigenic Activity and Decreases Production of the Oncometabolite 2-Hydroxyglutarate in Human Chondrosarcoma Cells

PubMed Central

Li, Luyuan; Paz, Ana C.; Wilky, Breelyn A.; Johnson, Britt; Galoian, Karina; Rosenberg, Andrew; Hu, Guozhi; Tinoco, Gabriel; Bodamer, Olaf; Trent, Jonathan C.

2015-01-01

Chondrosarcomas are malignant bone tumors that produce cartilaginous matrix. Mutations in isocitrate dehydrogenase enzymes (IDH1/2) were recently described in several cancers including chondrosarcomas. The IDH1 inhibitor AGI-5198 abrogates the ability of mutant IDH1 to produce the oncometabolite D-2 hydroxyglutarate (D-2HG) in gliomas. We sought to determine if treatment with AGI-5198 would similarly inhibit tumorigenic activity and D-2HG production in IDH1-mutant human chondrosarcoma cells. Two human chondrosarcoma cell lines, JJ012 and HT1080 with endogenous IDH1 mutations and a human chondrocyte cell line C28 with wild type IDH1 were employed in our study. Mutation analysis of IDH was performed by PCR-based DNA sequencing, and D-2HG was detected using tandem mass spectrometry. We confirmed that JJ012 and HT1080 harbor IDH1 R132G and R132C mutation, respectively, while C28 has no mutation. D-2HG was detectable in cell pellets and media of JJ012 and HT1080 cells, as well as plasma and urine from an IDH-mutant chondrosarcoma patient, which decreased after tumor resection. AGI-5198 treatment decreased D-2HG levels in JJ012 and HT1080 cells in a dose-dependent manner, and dramatically inhibited colony formation and migration, interrupted cell cycling, and induced apoptosis. In conclusion, our study demonstrates anti-tumor activity of a mutant IDH1 inhibitor in human chondrosarcoma cell lines, and suggests that D-2HG is a potential biomarker for IDH mutations in chondrosarcoma cells. Thus, clinical trials of mutant IDH inhibitors are warranted for patients with IDH-mutant chondrosarcomas. PMID:26368816

Chondrosarcoma of the nasal septum.

PubMed

Magnano, Mauro; Boffano, Paolo; Machetta, Giacomo; Garibaldi, Elisabetta; Delmastro, Elena; Gabriele, Pietro

2015-03-01

Chondrosarcomas are non-epithelial malignant, slow growing tumors that usually involve pelvis, ribs, and long bones of extremities, scapula and sternum. Median age at diagnosis for head and neck chondrosarcomas is in the fourth decade. The etiopathogenesis of chondrosarcomas remains unknown. Treatment of choice is surgical, with adjuvant therapy having a limited role. In fact, radiation therapy and chemotherapy are reserved for residual or recurrent disease and palliation. As for surgery, several surgical procedures have been described. Recently, endoscopic surgery has allowed for the successful and less invasive treatment of inverting papillomas and even nasopharyngeal angiofibromas, lesions previously requiring extended external approaches. The aim of this paper was to present a case of nasal septal chondrosarcoma that was successfully treated with endoscopic surgery and radiation adjuvant therapy.

Long-term Outcome of Chondrosarcoma: A Single Institutional Experience.

PubMed

Bindiganavile, Srimanth; Han, Ilkyu; Yun, Ji Yeon; Kim, Han-Soo

2015-10-01

The prognostic factors of chondrosarcoma remain uncertain as only a few large studies with long-term follow-up have been reported. The aim of this study was to analyze oncological outcomes and prognostic factors. A retrospective review of oncological outcomes and prognostic factors was performed on 125 consecutive chondrosarcoma patients who underwent surgery at our institution. Overall survival was 91.6%±2.5%, 84.1%±3.8%, and 84.1%±3.8% at 5, 10, and 15 years respectively. Among the histological types, dedifferentiated type showed the worst survival (p < 0.001). As for conventional type chondrosarcoma, histologic grade and anatomical location predicted outcome, with high-grade with axial location having the worst outcome (p < 0.001). In contrast, low-grade chondrosarcoma of appendicular skeleton could be treated safely by intralesional curettage. Histological type was significantly associated with the outcome of chondrosarcoma. For the conventional type, histologic grade and anatomical location predicted outcome, with high-grade with axial location having the worst outcome.

Functional roles of CSPG4/NG2 in chondrosarcoma.

PubMed

Jamil, Nuor S M; Azfer, Asim; Worrell, Harrison; Salter, Donald M

2016-04-01

CSPG4/NG2 is a multifunctional transmembrane protein with limited distribution in adult tissues including articular cartilage. The purpose of this study was to investigate the possible roles of CSPG4/NG2 in chondrosarcomas and to establish whether this molecule may have potential for targeted therapy. Stable knock-down of CSPG4/NG2 in the JJ012 chondrosarcoma cell line by shRNA resulted in decreased cell proliferation and migration as well as a decrease in gene expression of the MMP (matrix metalloproteinase) 3 protease and ADAMTS4 (aggrecanase). Chondrosarcoma cells in which CSPG4/NG2 was knocked down were more sensitive to doxorubicin than wild-type cells. The results indicate that CSPG4/NG2 has roles in regulating chondrosarcoma cell function in relation to growth, spread and resistance to chemotherapy and that anti-CSPG4/NG2 therapies may have potential in the treatment of surgically unresectable chondrosarcoma. © 2016 The Authors. International Journal of Experimental Pathology © 2016 International Journal of Experimental Pathology.

Trichodermin induces cell apoptosis through mitochondrial dysfunction and endoplasmic reticulum stress in human chondrosarcoma cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Su, Chen-Ming; Wang, Shih-Wei; Lee, Tzong-Huei

2013-10-15

Chondrosarcoma is the second most common primary bone tumor, and it responds poorly to both chemotherapy and radiation treatment. Nalanthamala psidii was described originally as Myxosporium in 1926. This is the first study to investigate the anti-tumor activity of trichodermin (trichothec-9-en-4-ol, 12,13-epoxy-, acetate), an endophytic fungal metabolite from N. psidii against human chondrosarcoma cells. We demonstrated that trichodermin induced cell apoptosis in human chondrosarcoma cell lines (JJ012 and SW1353 cells) instead of primary chondrocytes. In addition, trichodermin triggered endoplasmic reticulum (ER) stress protein levels of IRE1, p-PERK, GRP78, and GRP94, which were characterized by changes in cytosolic calcium levels. Furthermore,more » trichodermin induced the upregulation of Bax and Bid, the downregulation of Bcl-2, and the dysfunction of mitochondria, which released cytochrome c and activated caspase-3 in human chondrosarcoma. In addition, animal experiments illustrated reduced tumor volume, which led to an increased number of terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL)-positive cells and an increased level of cleaved PARP protein following trichodermin treatment. Together, this study demonstrates that trichodermin is a novel anti-tumor agent against human chondrosarcoma cells both in vitro and in vivo via mitochondrial dysfunction and ER stress. - Highlights: • Trichodermin induces chondrosarcoma apoptosis. • ER stress is involved in trichodermin-induced cell death. • Trichodermin induces chondrosarcoma death in vivo.« less

CCL5 promotes VEGF-C production and induces lymphangiogenesis by suppressing miR-507 in human chondrosarcoma cells

PubMed Central

Lin, Chih-Yang; Liu, Shih-Chia; Chen, Yen-Ling; Chen, Jih-Jung; Chan, Chia-Han; Lin, Ting-Yi; Chen, Chi-Kuan; Xu, Guo-Hong; Chen, Shiou-Sheng; Tang, Chih-Hsin; Wang, Shih-Wei

2016-01-01

Chondrosarcoma is the second most frequently occurring type of bone malignancy that is characterized by the distant metastasis propensity. Vascular endothelial growth factor-C (VEGF-C) is the major lymphangiogenic factor, and makes crucial contributions to tumor lymphangiogenesis and lymphatic metastasis. Chemokine CCL5 has been reported to facilitate angiogenesis and metastasis in chondrosarcoma. However, the effect of chemokine CCL5 on VEGF-C regulation and lymphangiogenesis in chondrosarcoma has largely remained a mystery. In this study, we showed a clinical correlation between CCL5 and VEGF-C as well as tumor stage in human chondrosarcoma tissues. We further demonstrated that CCL5 promoted VEGF-C expression and secretion in human chondrosarcoma cells. The conditioned medium (CM) from CCL5-overexpressed cells significantly induced tube formation of human lymphatic endothelial cells (LECs). Mechanistic investigations showed that CCL5 activated VEGF-C-dependent lymphangiogenesis by down-regulating miR-507. Moreover, inhibiting CCL5 dramatically reduced VEGF-C and lymphangiogenesis in the chondrosarcoma xenograft animal model. Collectively, we document for the first time that CCL5 induces tumor lymphangiogenesis by the induction of VEGF-C in human cancer cells. Our present study reveals miR-507/VEGF-C signaling as a novel mechanism in CCL5-mediated tumor lymphangiogenesis. Targeting both CCL5 and VEGF-C pathways might serve as the potential therapeutic strategy to block cancer progression and metastasis in chondrosarcoma. PMID:27166194

CCL5 promotes VEGF-C production and induces lymphangiogenesis by suppressing miR-507 in human chondrosarcoma cells.

PubMed

Wang, Li-Hong; Lin, Chih-Yang; Liu, Shih-Chia; Liu, Guan-Ting; Chen, Yen-Ling; Chen, Jih-Jung; Chan, Chia-Han; Lin, Ting-Yi; Chen, Chi-Kuan; Xu, Guo-Hong; Chen, Shiou-Sheng; Tang, Chih-Hsin; Wang, Shih-Wei

2016-06-14

Chondrosarcoma is the second most frequently occurring type of bone malignancy that is characterized by the distant metastasis propensity. Vascular endothelial growth factor-C (VEGF-C) is the major lymphangiogenic factor, and makes crucial contributions to tumor lymphangiogenesis and lymphatic metastasis. Chemokine CCL5 has been reported to facilitate angiogenesis and metastasis in chondrosarcoma. However, the effect of chemokine CCL5 on VEGF-C regulation and lymphangiogenesis in chondrosarcoma has largely remained a mystery. In this study, we showed a clinical correlation between CCL5 and VEGF-C as well as tumor stage in human chondrosarcoma tissues. We further demonstrated that CCL5 promoted VEGF-C expression and secretion in human chondrosarcoma cells. The conditioned medium (CM) from CCL5-overexpressed cells significantly induced tube formation of human lymphatic endothelial cells (LECs). Mechanistic investigations showed that CCL5 activated VEGF-C-dependent lymphangiogenesis by down-regulating miR-507. Moreover, inhibiting CCL5 dramatically reduced VEGF-C and lymphangiogenesis in the chondrosarcoma xenograft animal model. Collectively, we document for the first time that CCL5 induces tumor lymphangiogenesis by the induction of VEGF-C in human cancer cells. Our present study reveals miR-507/VEGF-C signaling as a novel mechanism in CCL5-mediated tumor lymphangiogenesis. Targeting both CCL5 and VEGF-C pathways might serve as the potential therapeutic strategy to block cancer progression and metastasis in chondrosarcoma.

β5 Integrin Up-Regulation in Brain-Derived Neurotrophic Factor Promotes Cell Motility in Human Chondrosarcoma

PubMed Central

Li, Te-Mao; Fong, Yi-Chin; Liu, Shan-Chi; Chen, Po-Chun; Tang, Chih-Hsin

2013-01-01

Chondrosarcoma is a primary malignant bone cancer, with a potent capacity to invade locally and cause distant metastasis; it has a poor prognosis and shows a predilection for metastasis to the lungs. Brain derived neurotrophic factor (BDNF) is a small-molecule protein from the neurotrophin family of growth factors that is associated with the disease status and outcomes of cancers. However, the effect of BDNF on migration activity in human chondrosarcoma cells is mostly unknown. Here, we found that human chondrosarcoma tissues showed significant expression of BDNF, which was higher than that in normal cartilage and primary chondrocytes. We also found that BDNF increased the migration and expression of β5 integrin in human chondrosarcoma cells. In addition, knockdown of BDNF expression markedly inhibited migratory activity. BDNF-mediated migration and β5 integrin up-regulation were attenuated by antibody, inhibitor, or siRNA against the TrkB receptor. Pretreatment of chondrosarcoma cells with PI3K, Akt, and NF-κB inhibitors or mutants also abolished BDNF-promoted migration and integrin expression. The PI3K, Akt, and NF-κB signaling pathway was activated after BDNF treatment. Taken together, our results indicate that BDNF enhances the migration of chondrosarcoma by increasing β5 integrin expression through a signal transduction pathway that involves the TrkB receptor, PI3K, Akt, and NF-κB. BDNF thus represents a promising new target for treating chondrosarcoma metastasis. PMID:23874483

Dedifferentiated chondrosarcoma of the larynx: Radiological, gross, microscopic and clinical features.

PubMed

Magliocca, Kelly R; Edgar, Mark A; Corey, Amanda; Villari, Craig R

2017-10-01

Laryngeal chondrosarcoma is an uncommon malignancy with a predilection for the cricoid cartilage of adult male patients. Although rare, identification of aggressive chondrosarcoma variants, such as dedifferentiated chondrosarcoma (DDCS) may influence preoperative patient counseling, definitive surgical management, potential implementation of post-operative adjuvant therapy and prognosis. Herein we describe clinical and imaging features of laryngeal DDCS, the unique perspective of fresh and formalin fixed macroscopic examination, a spectrum of histopathologic findings, and detail the full course of the patient's disease. Copyright © 2017 Elsevier Inc. All rights reserved.

BH3 mimetics inhibit growth of chondrosarcoma--a novel targeted-therapy for candidate models.

PubMed

Morii, Takeshi; Ohtsuka, Kouki; Ohnishi, Hiroaki; Mochizuki, Kazuo; Yoshiyama, Akira; Aoyagi, Takayuki; Hornicek, Francis J; Ichimura, Shoichi

2014-11-01

Chondrosarcoma is refractory to conventional chemotherapy. BH-3 mimetics ABT-737 and ABT-263 are synthetic small-molecule inhibitors of anti-apoptotic proteins B-cell lymphoma-2 (Bcl2) and Bcl-xL, which play a critical role in survival of chondrosarcoma cells. Chondrosarcoma cell lines SW-1353 and CS-1 were used as the disease model. We used immunoblotting to assess the expression of target molecules Bcl2 and Bcl-xL, and the apoptotic inducers Bcl2-associated X (Bax) and Bcl2-antagonist/killer (Bak). In vitro growth inhibition by BH-3 mimetics was confirmed by photomicroscopic cell counting and 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt (MTS) assay. Apoptotic induction was confirmed by Enzyme-Linked ImmunoSorbent Assay (ELISA). In vivo growth inhibition was assessed in a non-obese diabetic/severe combined immunodeficient (NOD/SCID) mouse model. Expression of the target and effector molecules was confirmed in chondrosarcoma cell lines. BH3 mimetics significantly inhibited cell growth and induced apoptosis in vitro. Administration of ABT-263 inhibited chondrosarcoma growth and improved survival in a mouse model. BH3 mimetics represent a novel treatment modality for chondrosarcoma. Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

A novel benzofuran derivative, ACDB, induces apoptosis of human chondrosarcoma cells through mitochondrial dysfunction and endoplasmic reticulum stress.

PubMed

Su, Chen-Ming; Chen, Chien-Yu; Lu, Tingting; Sun, Yi; Li, Weimin; Huang, Yuan-Li; Tsai, Chun-Hao; Chang, Chih-Shiang; Tang, Chih-Hsin

2016-12-13

Chondrosarcoma is one of the bone tumor with high mortality in respond to poor radiation and chemotherapy treatment. Here, we analyze the antitumor activity of a novel benzofuran derivative, 2-amino-3-(2-chlorophenyl)-6-(4-dimethylaminophenyl)benzofuran-4-yl acetate (ACDB), in human chondrosarcoma cells. ACDB increased the cell apoptosis of human chondrosarcomas without harm in chondrocytes. ACDB also enhanced endoplasmic reticulum (ER) stress, which was characterized by varieties in the cytosolic calcium levels and induced the expression of glucose-regulated protein (GRP) and calpain. Furthermore, the ACDB-induced chondrosarcoma apoptosis was associated with the upregulation of the B cell lymphoma-2 (Bcl-2) family members including pro- and anti-apoptotic proteins, downregulation of dysfunctional mitochondria that released cytochrome C, and subsequent activation of caspases-3. In addition, the ACDB-mediated cellular apoptosis was suppressed by transfecting cells with glucose-regulated protein (GRP) and calpain siRNA or treating cells with ER stress chelators and caspase inhibitors. Interestingly, animal experiments illustrated a reduction in the tumor volume following ACDB treatment. Together, these results suggest that ACDB may be a novel tumor suppressor of chondrosarcoma, and this study demonstrates that the novel antitumor agent, ACDB, induced apoptosis by mitochondrial dysfunction and ER stress in human chondrosarcoma cells in vitro and in vivo.

Adiponectin promotes VEGF-A-dependent angiogenesis in human chondrosarcoma through PI3K, Akt, mTOR, and HIF-α pathway.

PubMed

Lee, Hsiang-Ping; Lin, Chih-Yang; Shih, Jhao-Sheng; Fong, Yi-Chin; Wang, Shih-Wei; Li, Te-Mao; Tang, Chih-Hsin

2015-11-03

Chondrosarcoma is a type of highly malignant tumor with a potent capacity to invade locally and cause distant metastasis. Adiponectin is a protein hormone secreted predominantly by differentiated adipocytes. On the other hand, angiogenesis is a critical step in tumor growth and metastasis. However, the relationship of adiponectin with vascular endothelial growth factor-A (VEGF-A) expression and angiogenesis in human chondrosarcoma is mostly unknown. In this study we first demonstrated that the expression of adiponectin was correlated with tumor stage of human chondrosarcoma tissues. In addition, we also found that adiponectin increased VEGF-A expression in human chondrosarcoma cells and subsequently induced migration and tube formation in human endothelial progenitor cells (EPCs). Adiponectin promoted VEGF-A expression through adiponectin receptor (AdipoR), phosphoinositide 3 kinase (PI3K), Akt, mammalian target of rapamycin (mTOR), and hypoxia-inducible factor-1α (HIF)-1α signaling cascades. Knockdown of adiponectin decreased VEGF-A expression and also abolished chondrosarcoma conditional medium-mediated tube formation in EPCs in vitro as well as angiogenesis effects in the chick chorioallantoic membrane and Matrigel plug nude mice model in vivo. Therefore, adiponectin is crucial for tumor angiogenesis and growth, which may represent a novel target for anti-angiogenic therapy in human chondrosarcoma.

Immunohistochemical localization of steroid receptor coactivators in chondrosarcoma: an in vivo tissue microarray study.

PubMed

Li, Wei; Fu, Jingshu; Bian, Chen; Zhang, Jiqiang; Xie, Zhao

2014-12-01

Chondrosarcoma is the second most common type of primary bone malignancy following up osteosarcoma, characterized by resistance to conventional chemotherapeutic agents and radiation regimens. The p160 family members steroid receptor coactivator-1 and -3 (SRC-1 and SRC-3) have been implied in the regulation of cancer growth, migration, invasion, metastasis and chemotherapeutic resistance; but we still lack detailed information about the levels of SRCs in chondrosarcoma. In this study, expression of SRC-1 and SRC-3 in chondrosarcoma was examined by immunohistochemistry with tissue microarrays; the four score system (0, 1, 2 and 3) was used to evaluate the staining. The results showed that there were no gender-, site- or age-differences regarding the expression of SRC-1 or SRC-3 (p>0.05); organ (bone or cartilage) -differences were only detected for SRC-1 but not SRC-3 (p<0.05). Significant higher levels of SRC-1 and SRC-3 were detected in MDC and PDC when compared to WDC. Our study clearly demonstrated differentiation-dependant expression of SRC-1 and SRC-3 in chondrosarcoma, may be novel targets for the prognosis and/or treatment of chondrosarcoma, would have opened a new avenue and established foundation for studying chondrosarcoma. Copyright © 2014 Elsevier GmbH. All rights reserved.

Adiponectin promotes VEGF-A-dependent angiogenesis in human chondrosarcoma through PI3K, Akt, mTOR, and HIF-α pathway

PubMed Central

Shih, Jhao-Sheng; Fong, Yi-Chin; Wang, Shih-Wei; Li, Te-Mao; Tang, Chih-Hsin

2015-01-01

Chondrosarcoma is a type of highly malignant tumor with a potent capacity to invade locally and cause distant metastasis. Adiponectin is a protein hormone secreted predominantly by differentiated adipocytes. On the other hand, angiogenesis is a critical step in tumor growth and metastasis. However, the relationship of adiponectin with vascular endothelial growth factor-A (VEGF-A) expression and angiogenesis in human chondrosarcoma is mostly unknown. In this study we first demonstrated that the expression of adiponectin was correlated with tumor stage of human chondrosarcoma tissues. In addition, we also found that adiponectin increased VEGF-A expression in human chondrosarcoma cells and subsequently induced migration and tube formation in human endothelial progenitor cells (EPCs). Adiponectin promoted VEGF-A expression through adiponectin receptor (AdipoR), phosphoinositide 3 kinase (PI3K), Akt, mammalian target of rapamycin (mTOR), and hypoxia-inducible factor-1α (HIF)-1α signaling cascades. Knockdown of adiponectin decreased VEGF-A expression and also abolished chondrosarcoma conditional medium-mediated tube formation in EPCs in vitro as well as angiogenesis effects in the chick chorioallantoic membrane and Matrigel plug nude mice model in vivo. Therefore, adiponectin is crucial for tumor angiogenesis and growth, which may represent a novel target for anti-angiogenic therapy in human chondrosarcoma. PMID:26468982

Comparison of Clinical Features and Outcomes in Patients with Extraskeletal Versus Skeletal Localized Ewing Sarcoma: A Report from the Children’s Oncology Group

PubMed Central

Cash, Thomas; McIlvaine, Elizabeth; Krailo, Mark D.; Lessnick, Stephen L.; Lawlor, Elizabeth R.; Laack, Nadia; Sorger, Joel; Marina, Neyssa; Grier, Holcombe E.; Granowetter, Linda; Womer, Richard B.; DuBois, Steven G.

2016-01-01

BACKGROUND The prognostic significance of having extraskeletal vs. skeletal Ewing sarcoma in the setting of modern chemotherapy protocols is unknown. The purpose of this study was to compare the clinical characteristics, biologic features, and outcomes for patients with extraskeletal and skeletal Ewing sarcoma. METHODS Patients had localized Ewing sarcoma (ES) and were treated on two consecutive protocols using 5-drug chemotherapy (INT-0154 and AEWS0031). Patients were analyzed based on having an extraskeletal (n=213) or skeletal (n=826) site of tumor origin. Event-free survival (EFS) was estimated using the Kaplan-Meier method, compared using the log-rank test, and modeled using Cox multivariate regression. RESULTS Patients with extraskeletal Ewing Sarcoma (EES) were more likely to have axial tumors (72% vs. 55%; P < 0.001), less likely to have tumors > 8 cm (9% vs. 17%; P < 0.01), and less likely to be white (81% vs. 87%; P < 0.001) compared to patients with skeletal ES. There was no difference in key genomic features (type of EWSR1 translocation, TP53 mutation, CDKN2A mutation/loss) between groups. After controlling for age, race, and primary site, EES was associated with superior EFS [hazard ratio = 0.69; 95% CI: 0.50–0.95; P = 0.02]. Among patients with EES, age ≥ 18 years, non-white race, and elevated baseline erythrocyte sedimentation rate (ESR) were independently associated with inferior EFS. CONCLUSION Clinical characteristics, but not key tumor genomic features, differ between EES and skeletal ES. Extraskeletal origin is a favorable prognostic factor, independent of age, race, and primary site. PMID:27297500

Suppressed invasive and migratory behaviors of SW1353 chondrosarcoma cells through the regulation of Src, Rac1 GTPase, and MMP13.

PubMed

Xu, Wenxiao; Wan, Qiaoqiao; Na, Sungsoo; Yokota, Hiroki; Yan, Jing-Long; Hamamura, Kazunori

2015-12-01

Chondrosarcoma is the second frequent type of primary bone cancer. In response to stress to the endoplasmic reticulum, activation of eIF2α-mediated signaling is reported to induce apoptosis. However, its effects on invasive and migratory behaviors of chondrosarcoma have not been understood. Focusing on potential roles of Src kinase, Rac1 GTPase, and MMP13, we investigated eIF2α-driven regulation of SW1353 chondrosarcoma cells. In particular, we employed two chemical agents (salubrinal, Sal; and guanabenz, Gu) that elevate the level of eIF2α phosphorylation. The result revealed that both Sal and Gu reduced invasion and motility of SW1353 chondrosarcoma cells in a dose dependent manner. Live imaging using a fluorescent resonance energy transfer (FRET) technique showed that Sal and Gu downregulated activities of Src kinase as well as Rac1 GTPase in an eIF2α dependent manner. RNA interference experiments supported an eIF2α-mediated regulatory network in the inhibitory role of Sal and Gu. Partial silencing of MMP13 also suppressed malignant phenotypes of SW1353 chondrosarcoma cells. However, MMP13 was not regulated via eIF2α since administration of Sal but not Gu reduced expression of MMP13. In summary, we demonstrate that eIF2α dependent and independent pathways regulate invasion and motility of SW1353 chondrosarcoma cells, and inactivation of Src, Rac1, and MMP13 by Sal could provide a potential adjuvant therapy for combating metastatic chondrosarcoma cells. Copyright © 2015 Elsevier Inc. All rights reserved.

Comprehensive high-resolution genomic profiling and cytogenetics of human chondrocyte cultures by GTG-banding, locus-specific FISH, SKY and SNP array.

PubMed

Wallenborn, M; Petters, O; Rudolf, D; Hantmann, H; Richter, M; Ahnert, P; Rohani, L; Smink, J J; Bulwin, G C; Krupp, W; Schulz, R M; Holland, H

2018-04-23

In the development of cell-based medicinal products, it is crucial to guarantee that the application of such an advanced therapy medicinal product (ATMP) is safe for the patients. The consensus of the European regulatory authorities is: "In conclusion, on the basis of the state of art, conventional karyotyping can be considered a valuable and useful technique to analyse chromosomal stability during preclinical studies". 408 chondrocyte samples (84 monolayers and 324 spheroids) from six patients were analysed using trypsin-Giemsa staining, spectral karyotyping and fluorescence in situ hybridisation, to evaluate the genetic stability of chondrocyte samples from non-clinical studies. Single nucleotide polymorphism (SNP) array analysis was performed on chondrocyte spheroids from five of the six donors. Applying this combination of techniques, the genetic analyses performed revealed no significant genetic instability until passage 3 in monolayer cells and interphase cells from spheroid cultures at different time points. Clonal occurrence of polyploid metaphases and endoreduplications were identified associated with prolonged cultivation time. Also, gonosomal losses were observed in chondrocyte spheroids, with increasing passage and duration of the differentiation phase. Interestingly, in one of the donors, chromosomal aberrations that are also described in extraskeletal myxoid chondrosarcoma were identified. The SNP array analysis exhibited chromosomal aberrations in two donors and copy neutral losses of heterozygosity regions in four donors. This study showed the necessity of combined genetic analyses at defined cultivation time points in quality studies within the field of cell therapy.

C11orf95-MKL2 is the Resulting Fusion Oncogene of t(11;16)(q13;p13) in Chondroid Lipoma

PubMed Central

Huang, Dali; Sumegi, Janos; Cin, Paola Dal; Reith, John D.; Yasuda, Taketoshi; Nelson, Marilu; Muirhead, David; Bridge, Julia A.

2010-01-01

Chondroid lipoma, a rare benign adipose tissue tumor, may histologically resemble myxoid liposarcoma or extraskeletal myxoid chondrosarcoma, but is genetically distinct. In the current study, an identical reciprocal translocation, t(11;16)(q13;p13) was identified in three chondroid lipomas, a finding consistent with previous isolated reports. A fluorescence in situ hybridization (FISH)-based positional cloning strategy using a series of bacterial artificial chromosome (BAC) probe combinations designed to narrow the 16p13 breakpoint revealed MKL2 as the candidate gene. Subsequent 5′ RACE studies demonstrated C11orf95 as the MKL2 fusion gene partner. MKL/myocardin-like 2 (MKL2) encodes myocardin-related transcription factor B (MRTF-B) in a megakaryoblastic leukemia gene family, and C11orf95 (chromosome 11 open reading frame 95) is a hypothetical protein. Sequencing analysis of RT-PCR generated transcripts from all three chondroid lipomas defined the fusion as occurring between exons 5 and 9 of C11orf95 and MKL2, respectively. Dual-color breakpoint spanning probe sets custom-designed for recognition of the translocation event in interphase cells confirmed the anticipated rearrangements of the C11orf95 and MKL2 loci in all cases. The FISH and RT-PCR assays developed in this study can serve as diagnostic adjuncts for identification of this novel C11orf95-MKL2 fusion oncogene in chondroid lipoma. PMID:20607705

Radiation-induced chondrosarcoma of the clavicle complicating Hodgkin's disease. A case report

DOE Office of Scientific and Technical Information (OSTI.GOV)

Aprin, H.; Calandra, J.; Mir, R.

1986-08-01

Review of the literature reveals that postradiation chondrosarcoma is a rare secondary malignant bone tumor. This case report demonstrates a Grade 1 chondrosarcoma of the proximal right clavicle in a 17-year-old boy, eight years after extensive chemotherapy and radiation therapy for a Stage IIB Hodgkin's disease.

Chondrosarcoma of the hyoid bone - Report of a case and a literature review of the suitable treatment strategy.

PubMed

Maki, Daisuke; Mori, Taisuke; Teshima, Masanori; Kobayashi, Kenya; Matsumoto, Fumihiko; Sakai, Akihiro; Okami, Kenji; Yoshimoto, Seiichi

2017-10-01

Chondrosarcoma is a rare malignant tumor occurring in the trunk and long bones. We present an extremely rare case of chondrosarcoma of the hyoid bone with clinical and pathological correlation and a literature review. We searched all cases of the hyoid chondrosarcoma in PubMed (MEDLINE) between 1990 and 2015. Eighteen cases were analyzed, including the present case. Most of them were low grade type. In 12 cases where intraoperative findings were recorded, no adhesion to the surrounding tissue was observed. Chondrosarcoma of the hyoid bone is usually low grade type, and there may be no invasion to the adjacent structures even if invasion is suspected by imaging findings. In order to preserve swallowing and laryngeal function, total hyoidectomy without laryngectomy should be indicated according to the intraoperative findings. Needle biopsy is an effective diagnostic technique, but open biopsy should be avoided to prevent the dissemination. To the best of our knowledge, this is the first presentation of hyoid bone chondrosarcoma with the investigation of intraoperative findings and pre-operative diagnostic modality. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Interleukin-1β and cyclic AMP mediate the invasion of sheared chondrosarcoma cells via a matrix metalloproteinase-1-dependent mechanism.

PubMed

Wang, Pu; Guan, Pei-Pei; Wang, Tao; Yu, Xin; Guo, Jian-Jun; Konstantopoulos, Konstantinos; Wang, Zhan-You

2014-05-01

Matrix metalloproteinase-1 (MMP-1) is a potential biomarker for chondrosarcoma that is overexpressed at the invading edges of articular cartilage, and its expression correlates with poor survival rates. However, the molecular mechanisms of MMP-1 regulation and its potential contribution to chondrosarcoma cell invasion have yet to be elucidated, especially in shear-activated cells. Using molecular biology tools and an in vitro fluid shear model, we report that shear stress upregulates cyclic AMP (cAMP) and interleukin-1β (IL-1β) release, which in turn promotes the invasion of chondrosarcoma cells via the induction of MMP-1 in a phosphoinositide 3-kinase (PI3-K)- and ERK1/2-dependent manner. Activated PI3-K and ERK1/2 signaling pathways phosphorylate c-Jun, which in turn transactivates MMP-1 in human chondrosarcoma cells. Collectively, fluid shear stress upregulates matrix MMP-1 expression, which is responsible for the enhanced invasion of human chondrosarcoma cells. Copyright © 2014 Elsevier B.V. All rights reserved.

Spontaneous extraskeletal osteosarcoma with various histological growth patterns in the abdominal wall of an ICR mouse

PubMed Central

Ito, Tsuyoshi; Katoh, Yoshitaka; Shimada, Yuko; Ohnuma-Koyama, Aya; Takahashi, Naofumi; Kuwahara, Maki; Harada, Takanori

2015-01-01

Extraskeletal osteosarcoma is extremely rare in mice. This case report demonstrates a spontaneous murine extraskeletal osteosarcoma that exhibited various histological growth patterns in an ICR mouse. At necropsy, the tumor mass was located in the abdominal wall and was 45 × 30 × 25 mm in size. Histopathologically, the tumor showed the following four growth patterns: a solid pattern of polygonal cells embedded in an osteoid eosinophilic matrix with calcification, an irregular sheet pattern of short spindle cells accompanying some eosinophilic multinucleated cells, a fascicular pattern of spindle cells and a cystic pattern lined by short spindle cells. Immunohistochemically, most of the tumor cells were positive for vimentin, proliferating cell nuclear antigen and osterix. The multinucleated cells mentioned above were desmin positive and were regarded as regenerative striated muscles but not tumor cells. Since no clear continuity with normal bone tissues was observed, the tumor was diagnosed as an “extraskeletal osteosarcoma.” PMID:26989300

Dedifferentiated Chondrosarcoma of the Larynx.

PubMed

Fidai, Shiraz S; Ginat, Daniel T; Langerman, Alexander J; Cipriani, Nicole A

2016-09-01

Primary dedifferentiated chondrosarcoma occurring in the larynx is a rare head and neck malignancy. The cases reported in the literature suggest male gender predilection and variable clinical outcomes ranging from disease-free survival to disease-related death. Although a calcified matrix is suggestive of chondrosarcoma, the dedifferentiated component is not readily appreciated on conventional imaging modalities and thorough tissue sampling is necessary for confirming the diagnosis. Histologically, there is an abrupt transition from a well-differentiated chondrosarcoma to a high-grade spindle cell component, which can show focal heterologous differentiation. These features are exemplified in this sine qua non radiology-pathology correlation article.

Molecular Pathogenesis and Diagnostic, Prognostic and Predictive Molecular Markers in Sarcoma.

PubMed

Mariño-Enríquez, Adrián; Bovée, Judith V M G

2016-09-01

Sarcomas are infrequent mesenchymal neoplasms characterized by notable morphological and molecular heterogeneity. Molecular studies in sarcoma provide refinements to morphologic classification, and contribute diagnostic information (frequently), prognostic stratification (rarely) and predict therapeutic response (occasionally). Herein, we summarize the major molecular mechanisms underlying sarcoma pathogenesis and present clinically useful diagnostic, prognostic and predictive molecular markers for sarcoma. Five major molecular alterations are discussed, illustrated with representative sarcoma types, including 1. the presence of chimeric transcription factors, in vascular tumors; 2. abnormal kinase signaling, in gastrointestinal stromal tumor; 3. epigenetic deregulation, in chondrosarcoma, chondroblastoma, and other tumors; 4. deregulated cell survival and proliferation, due to focal copy number alterations, in dedifferentiated liposarcoma; 5. extreme genomic instability, in conventional osteosarcoma as a representative example of sarcomas with highly complex karyotype. Copyright © 2016 Elsevier Inc. All rights reserved.

A novel benzofuran derivative, ACDB, induces apoptosis of human chondrosarcoma cells through mitochondrial dysfunction and endoplasmic reticulum stress

PubMed Central

Su, Chen-Ming; Chen, Chien-Yu; Lu, Tingting; Sun, Yi; Li, Weimin; Huang, Yuan-Li; Tsai, Chun-Hao; Chang, Chih-Shiang; Tang, Chih-Hsin

2016-01-01

Chondrosarcoma is one of the bone tumor with high mortality in respond to poor radiation and chemotherapy treatment. Here, we analyze the antitumor activity of a novel benzofuran derivative, 2-amino-3-(2-chlorophenyl)-6-(4-dimethylaminophenyl)benzofuran-4-yl acetate (ACDB), in human chondrosarcoma cells. ACDB increased the cell apoptosis of human chondrosarcomas without harm in chondrocytes. ACDB also enhanced endoplasmic reticulum (ER) stress, which was characterized by varieties in the cytosolic calcium levels and induced the expression of glucose-regulated protein (GRP) and calpain. Furthermore, the ACDB-induced chondrosarcoma apoptosis was associated with the upregulation of the B cell lymphoma-2 (Bcl-2) family members including pro- and anti-apoptotic proteins, downregulation of dysfunctional mitochondria that released cytochrome C, and subsequent activation of caspases-3. In addition, the ACDB-mediated cellular apoptosis was suppressed by transfecting cells with glucose-regulated protein (GRP) and calpain siRNA or treating cells with ER stress chelators and caspase inhibitors. Interestingly, animal experiments illustrated a reduction in the tumor volume following ACDB treatment. Together, these results suggest that ACDB may be a novel tumor suppressor of chondrosarcoma, and this study demonstrates that the novel antitumor agent, ACDB, induced apoptosis by mitochondrial dysfunction and ER stress in human chondrosarcoma cells in vitro and in vivo. PMID:27835579

CCL5 promotes VEGF-dependent angiogenesis by down-regulating miR-200b through PI3K/Akt signaling pathway in human chondrosarcoma cells

PubMed Central

Liu, Guan-Ting; Chen, Hsien-Te; Tsou, Hsi-Kai; Tan, Tzu-Wei; Fong, Yi-Chin; Chen, Po-Chen; Yang, Wei-Hung; Wang, Shih-Wei; Chen, Jui-Chieh; Tang, Chih-Hsin

2014-01-01

Chondrosarcoma is the second most common primary malignant bone cancer, with potential for local invasion and distant metastasis. Chemokine CCL5 (formerly RANTES) of the CC-chemokine family plays a crucial role in metastasis. Angiogenesis is essential for the cancer metastasis. However, correlation of CCL5 with vascular endothelial growth factor (VEGF) expression and angiogenesis in human chondrosarcoma is still unknown. CCL5-mediated VEGF expression was assessed by qPCR, ELISA, and Western blotting. CCL5-induced angiogenesis was examined by migration and tube formation in endothelial progenitor cells in vitro. CCL5 increased VEGF expression and also promoted chondrosarcoma conditional medium-mediated angiogenesis in vitro and in vivo. Stimulation of chondrosarcoma with CCL5 augmented PI3K and Akt phosphorylation, while PI3K and Akt inhibitor or siRNA abolished CCL5-induced VEGF expression and angiogenesis. We also demonstrated CCL5 inhibiting miR-200b expression and miR-200b mimic reversing the CCL5-enhanced VEGF expression and angiogenesis. Moreover, in chondrosarcoma patients showed the positive correlation between CCL5 and VEGF; negative correlation between CCL5 and miR-200b. Taken together, results demonstrate CCL5 promoting VEGF-dependent angiogenesis in human chondrosarcoma cells by down-regulating miR-200b through PI3K/Akt signaling pathway. PMID:25301739

Src kinases in chondrosarcoma chemoresistance and migration: dasatinib sensitises to doxorubicin in TP53 mutant cells

PubMed Central

van Oosterwijk, J G; van Ruler, M A J H; Briaire-de Bruijn, I H; Herpers, B; Gelderblom, H; van de Water, B; Bovée, J V M G

2013-01-01

Background: Chondrosarcomas are malignant cartilage-forming tumours of bone. Because of their resistance to conventional chemotherapy and radiotherapy, currently no treatment strategies exist for unresectable and metastatic chondrosarcoma. Previously, PI3K/AKT/GSK3β and Src kinase pathways were shown to be activated in chondrosarcoma cell lines. Our aim was to investigate the role of these kinases in chemoresistance and migration in chondrosarcoma in relation to TP53 mutation status. Methods: We used five conventional and three dedifferentiated chondrosarcoma cell lines and investigated the effect of PI3K/AKT/GSK3β pathway inhibition (enzastaurin) and Src pathway inhibition (dasatinib) in chemoresistance using WST assay and live cell imaging with AnnexinV staining. Immunohistochemistry on tissue microarrays (TMAs) containing 157 cartilaginous tumours was performed for Src family members. Migration assays were performed with the RTCA xCelligence System. Results: Src inhibition was found to overcome chemoresistance, to induce apoptosis and to inhibit migration. Cell lines with TP53 mutations responded better to combination therapy than wild-type cell lines (P=0.002). Tissue microarray immunohistochemistry confirmed active Src (pSrc) signalling, with Fyn being most abundantly expressed (76.1%). Conclusion: These results strongly indicate Src family kinases, in particular Fyn, as a potential target for the treatment of inoperable and metastatic chondrosarcomas, and to sensitise for doxorubicin especially in the presence of TP53 mutations. PMID:23922104

Osteoclast inhibition impairs chondrosarcoma growth and bone destruction.

PubMed

Otero, Jesse E; Stevens, Jeff W; Malandra, Allison E; Fredericks, Douglas C; Odgren, Paul R; Buckwalter, Joseph A; Morcuende, Jose

2014-12-01

Because Chondrosarcoma is resistant to available chemotherapy and radiation regimens, wide resection is the mainstay in treatment, which frequently results in high morbidity and which may not prevent local recurrence. There is a clear need for improved adjuvant treatment of this malignancy. We have observed the presence of osteoclasts in the microenvironment of chondrosarcoma in human pathological specimens. We utilized the Swarm rat chondrosarcoma (SRC) model to test the hypothesis that osteoclasts affect chondrosarcoma pathogenesis. We implanted SRC tumors in tibia of Sprague-Dawley rats and analyzed bone histologically and radiographically for bone destruction and tumor growth. At three weeks, tumors invaded local bone causing cortical disruption and trabecular resorption. Bone destruction was accompanied by increased osteoclast number and resorbed bone surface. Treatment of rats with the zoledronic acid prevented cortical destruction, inhibited trabecular resorption, and resulted in decreased tumor volume in bone. To confirm that inhibition of osteoclasts per se, and not off-target effects of drug, was responsible for the prevention of tumor growth and bone destruction, we implanted SRC into osteopetrotic rat tibia. SRC-induced bone destruction and tumor growth were impaired in osteopetrotic bone compared with control bone. The results from our animal model demonstrate that osteoclasts contribute to chondrosarcoma-mediated bone destruction and tumor growth and may represent a therapeutic target in particular chondrosarcoma patients. © 2014 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

Knockdown of long non-coding RNA HOTAIR increases miR-454-3p by targeting Stat3 and Atg12 to inhibit chondrosarcoma growth.

PubMed

Bao, Xing; Ren, Tingting; Huang, Yi; Sun, Kunkun; Wang, Shidong; Liu, Kuisheng; Zheng, Bingxin; Guo, Wei

2017-02-09

Current practices for the therapy of chondrosarcoma, including wide-margin surgical resection and chemotherapy, are less than satisfactory. Recently, emerging evidence has demonstrated that long non-coding RNAs (lncRNAs) have an essential role in the initiation and progression of tumors. As a typical lncRNA, HOTAIR is significantly overexpressed in various tumors. However, the function and potential biological mechanisms of HOTAIR in human chondrosarcoma remain unknown. Quantitative RT-PCR demonstrated that HOTAIR expression was upregulated in chondrosarcoma tissues and cell lines. High HOTAIR expression is correlated with tumor stage and poor prognosis. Functional experiments reveal that HOTAIR knockdown leads to growth inhibition of human chondrosarcoma cells in vitro and in vivo. In addition to cycle arrest and apoptosis, knockdown of HOTAIR inhibits autophagy, which favors cell death. Mechanistically, we demonstrated that HOTAIR induced DNA methylation of miR-454-3p by recruiting EZH2 and DNMT1 to the miR-454-3p promoter regions, which markedly silences miR-454-3p expression. Further analysis revealed that STAT3 and ATG12 are targets of miR-454-3p, initiate HOTAIR deficiency-induced apoptosis and reduce autophagy. Collectively, our data reveal the roles and functional mechanisms of HOTAIR in human chondrosarcoma and suggest that HOTAIR may act as a prognostic biomarker and potential therapeutic target for chondrosarcoma.

A large extraskeletal osteochondroma of the foot.

PubMed

Estil, Jose Carlos C; Yeo, Eui-Dong; Kim, Hak Jun; Cho, Won Tae; Lee, Jeong-Ju

2013-01-01

Osteochondromas are very common benign tumors composed of cartilage and bone. They are usually found at the end of the growth plate of long bones, most often at the area of the joints, and are contiguous with the medullary cavity. Extraskeletal osteochondromas, the same as their namesake, are composed of cartilage and bone. However, unlike typical osteochondromas, extraskeletal osteochondromas are not contiguous with bone, as their name implies. They usually arise from the synovial tissue and tendon sheaths. Although rare, extraskeletal osteochondromas have been reported to occur within the knee and around the hip; however, they are more commonly reported to occur in the hands and feet. When found in the hands or feet, these new growths are often very small and only occasionally symptomatic. We present the case of a 49-year-old female who had a slow-growing mass of 4 years' duration, located on the plantar aspect of her left foot. The mass was slowly becoming more palpable as it increased in size and was progressively causing pain and discomfort during ambulation. Imaging studies revealed an ossified mass bearing no connection to any other structure on the plantar aspect of her foot. An excision biopsy was performed, and the easily dissectible mass, although much larger than its usual presentation, proved to be an extraskeletal osteochondroma. Copyright © 2013 American College of Foot and Ankle Surgeons. Published by Elsevier Inc. All rights reserved.

Chondroblastoma with Secondary Aneurysmal Bone Cyst

DTIC Science & Technology

2008-02-01

dysplasia, chondroblastoma, chondromyxoid fibroma, osteochondroma, giant cell tumors, or enchondroma. Chondrosarcoma , osteoblastoma–aggressive variant and...Histology reveals cartilage with a layer of smooth, thin bone surrounding. 2 Chondrosarcomas tend to occur in an older population than most primary bone...mentioned was considered. All of those suspected neoplasms, with the exception of chondrosarcoma , fit this patient’s age group, as all frequently

Development of a Novel Synthetic Drug for Osteoporosis and Fracture Healing

DTIC Science & Technology

2012-09-01

application to chondrosarcoma , and preparation for bone fracture study. Body Aim 1: Development of salubrinal formulations and determination of...development of bone marrow derived cells, osteoclasts, osteoblasts, and chondrocytes. Application to chondrosarcoma : Besides osteoporosis and...osteoarthritis, we considered a potential application of salubrinal to skeletal malignancies. Approximately one-third of skeletal cancers form chondrosarcoma

Is there a role for conventional MRI and MR diffusion-weighted imaging for distinction of skull base chordoma and chondrosarcoma?

PubMed

Müller, Uta; Kubik-Huch, Rahel A; Ares, Carmen; Hug, Eugen B; Löw, Roland; Valavanis, Antonios; Ahlhelm, Frank J

2016-02-01

Chordoma and chondrosarcoma are locally invasive skull base tumors with similar clinical symptoms and anatomic imaging features as reported in the literature. To determine differentiation of chordoma and chondrosarcoma of the skull base with conventional magnetic resonance imaging (cMRI) and diffusion-weighted MR imaging (DWI) in comparison to histopathological diagnosis. This retrospective study comprised 96 (chordoma, n = 64; chondrosarcoma, n = 32) patients with skull base tumors referred to the Paul Scherrer Institute (PSI) for proton therapy. cMRI signal intensities of all tumors were investigated. In addition, median apparent diffusion coefficient (ADC) values were measured in a subgroup of 19 patients (chordoma, n = 11; chondrosarcoma, n = 8). The majority 81.2% (26/32) of chondrosarcomas displayed an off-midline growth pattern, 18.8% (6/32) showed clival invasion, 18.8% (6/32) were located more centrally. Only 4.7% (3/64) of chordomas revealed a lateral clival origin. Using cMRI no significant differences in MR signal intensities were observed in contrast to significantly different ADC values (subgroup of 19/96 patients examined by DWI), with the highest mean value of 2017.2 × 10(-6 )mm(2)/s (SD, 139.9( )mm(2)/s) for chondrosarcoma and significantly lower value of 1263.5 × 10(-6 )mm(2)/s (SD, 100.2 × 10(-6 )mm(2)/s) for chordoma (P = 0.001/median test). An off-midline growth pattern can differentiate chondrosarcoma from chordoma on cMRI in a majority of patients. Additional DWI is a promising tool for the differentiation of these skull base tumors. © The Foundation Acta Radiologica 2015.

miR-181a Targets RGS16 to Promote Chondrosarcoma Growth, Angiogenesis, and Metastasis.

PubMed

Sun, Xiaojuan; Charbonneau, Cherie; Wei, Lei; Chen, Qian; Terek, Richard M

2015-09-01

Chondrosarcoma is the most common primary malignant bone tumor in adults, has no effective systemic treatment, and patients with this disease have poor survival. Altered expression of microRNA (miR) is involved in tumorigenesis; however, its role in chondrosarcoma is undetermined. miR-181a is overexpressed in high-grade chondrosarcoma, is upregulated by hypoxia, and increases VEGF expression. Here, the purpose was to determine the mechanism of miR-181a regulation of VEGF, determine whether miR-181a overexpression promotes tumor progression, and to evaluate an antagomir-based approach for chondrosarcoma treatment. Therapeutic inhibition of miR-181a decreased expression of VEGF and MMP1 in vitro, and angiogenesis, MMP1 activity, tumor growth, and lung metastasis, all by more than 50%, in a xenograft mouse model. A target of miR-181a is a regulator of G-protein signaling 16 (RGS16), a negative regulator of CXC chemokine receptor 4 (CXCR4) signaling. CXCR4 signaling is increased in chondrosarcoma, its expression is also increased by hypoxia, and is associated with angiogenesis and metastasis; however, receptor blockade is only partially effective. RGS16 expression is restored after miR-181a inhibition and partially accounts for the antiangiogenic and antimetastatic effects of miR-181a inhibition. These data establish miR-181a as an oncomiR that promotes chondrosarcoma progression through a new mechanism involving enhancement of CXCR4 signaling by inhibition of RGS16. Targeting miR-181a can inhibit tumor angiogenesis, growth, and metastasis, thus suggesting the possibility of antagomir-based therapy in chondrosarcoma. ©2015 American Association for Cancer Research.

Sphingosine-1-phosphate suppresses chondrosarcoma metastasis by upregulation of tissue inhibitor of metalloproteinase 3 through suppressing miR-101 expression.

PubMed

Tsai, Chun-Hao; Yang, Dong-Ying; Lin, Chih-Yang; Chen, Tsung-Ming; Tang, Chih-Hsin; Huang, Yuan-Li

2017-10-01

Chondrosarcoma is the second most common primary malignancy form of bone cancer, exhibiting resistance to chemotherapy and radiation therapy as well as developing high metastasis ability in late-stage tumors. Thus, understanding the metastatic processes of chondrosarcoma is considered a strategy for the treatment of this disease. Sphingosine 1-phosphate (S1P), a bioactive sphingolipid, is produced intracellularly by sphingosine kinase (SphK) and is regarded as a second signaling molecule that regulates inflammation, proliferation, angiogenesis, and metastasis. However, the effect of S1P on chondrosarcoma remains uncertain. As demonstrated by the transwell, immunoblotting, and real-time PCR analyses, we found that S1P inhibited cell migration and MMP-2 expression through the upregulation of the tissue inhibitor of metalloproteinase-3 (TIMP-3) expression in human chondrosarcoma cells. Additionally, we also showed that microRNA (miRNA)-101, which targets the 3' untranslated region (3'UTR) of TIMP-3, decreased significantly following S1P treatment. After transfection with miR-101 mimics, the S1P-regulated cell migration and TIMP-3 expression were both reversed. Furthermore, we also showed that the S1P-inhibited cell migration is mediated through the c-Src/MEK/ERK signaling axis. Meanwhile, the in vivo study indicated that overexpression of SphK1 decreases chondrosarcoma metastasis to the lungs. Our results illustrate the clinical significance between SphK1, TIMP-3, and miR-101 in human chondrosarcoma patients. Taken together, our results suggest that S1P and miR-101 may prove to be potential therapeutic targets for future chondrosarcoma treatment. © 2017 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.

Chondrosarcoma of the patella: A case report.

PubMed

Ye, Conglin; Luo, Zhiping; Zeng, Jin; Dai, Min

2017-09-01

Chondrosarcoma, characterized by the production of cartilage matrix, is a common bone tumor, accounting for 20% to 27% of all malignant bone tumors. It often occurs in the cartilage of the pelvis, femur, tibia, and humerus. However, chondrosarcoma of the patella is extremely rare. The present study describes a case of chondrosarcoma affecting the right patella in a 68-year-old woman. The chief complaints were painful swelling and limitation of motion of the right knee for about half a year. The pain was a kind of dull ache. The skin around the right knee was red and hot. Moreover, she had a claudication gait due to the symptoms. Irregular lytic lesions with ill-defined margins in the patella were determined through computed tomography and magnetic resonance imaging. The diagnosis of primary grade II chondrosarcoma was finally confirmed on the basis of postoperative pathological examination. The patient underwent an open surgery named extensive resection of patellar tumor to remove the tumor tissue completely. The patient was discharged without any complications 1 week after the surgery. At the 3-month follow-up, the patient was completely free from pain during daily activities, and normal range of motion of the right knee was achieved. Her gait was normal. There was no evidence of recurrence. We believe that an extensive resection is suitable for treating chondrosarcoma to avoid as far as possible local recurrence. An awareness of the potential for chondrosarcoma to present in the patella is crucial for both orthopedic surgeons and radiologists when confronted with similar cases. Besides, as reports of chondrosarcoma of the patella are rare, this study adds a better understanding of this rare condition to the medical literature.

Effectiveness and Safety of Spot Scanning Proton Radiation Therapy for Chordomas and Chondrosarcomas of the Skull Base: First Long-Term Report

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ares, Carmen, E-mail: carmen.ares@psi.c; Hug, Eugen B.; Lomax, Antony J.

2009-11-15

Purpose: To evaluate effectiveness and safety of spot-scanning-based proton radiotherapy (PT) in skull-base chordomas and chondrosarcomas. Methods and Materials: Between October 1998 and November 2005, 64 patients with skull-base chordomas (n = 42) and chondrosarcomas (n = 22) were treated at Paul Scherrer Institute with PT using spot-scanning technique. Median total dose for chordomas was 73.5 Gy(RBE) and 68.4 Gy(RBE) for chondrosarcomas at 1.8-2.0 Gy(RBE) dose per fraction. Local control (LC), disease specific survival (DSS), and overall survival (OS) rates were calculated. Toxicity was assessed according to CTCAE, v. 3.0. Results: Mean follow-up period was 38 months (range, 14-92 months).more » Five patients with chordoma and one patient with chondrosarcoma experienced local recurrence. Actuarial 5-year LC rates were 81% for chordomas and 94% for chondrosarcomas. Brainstem compression at the time of PT (p = 0.007) and gross tumor volume >25 mL (p = 0.03) were associated with lower LC rates. Five years rates of DSS and OS were 81% and 62% for chordomas and 100% and 91% for chondrosarcomas, respectively. High-grade late toxicity consisted of one patient with Grade 3 and one patient with Grade 4 unilateral optic neuropathy, and two patients with Grade 3 central nervous system necrosis. No patient experienced brainstem toxicity. Actuarial 5-year freedom from high-grade toxicity was 94%. Conclusions: Our data indicate safety and efficacy of spot-scanning based PT for skull-base chordomas and chondrosarcomas. With target definition, dose prescription and normal organ tolerance levels similar to passive-scattering based PT series, complication-free, tumor control and survival rates are at present comparable.« less

Intracardiac metastasis originated from chondrosarcoma.

PubMed

Maurea, Nicola; Ragone, Gianluca; Coppola, Carmela; Caronna, Antonietta; Tocchetti, Carlo G; Agozzino, Lucio; Apice, Gaetano; Iaffaioli, Rosario V

2017-05-01

Primary cardiac tumors are extremely rare. By comparison, metastatic involvement of the heart is over 20 times more common and has been reported in autopsy series in up to one in five patients dying of cancer. Cardiac metastasis of chondrosarcoma is absolutely not frequent. In the recent literature, a cardiac metastasis from chondrosarcoma has never been described. We report the case of an 18-year-old man with a diagnosis of cardiac metastasis that originated from a left scapular chondrosarcoma. Chondrosarcoma is a skeletal tumor with various grades of malignancy, rapidly evolving, and with a strong tendency to metastasize, with low responsiveness to chemotherapy. The onset of characteristic systemic symptoms in the late stage of the disease led to the diagnosis of a mass localized in the right atrium. Management and differential diagnosis of infective heart lesions were also very complex in a rapidly evolving life-threatening condition.

Chondrosarcoma of the nasal septum: A case report.

PubMed

Kainuma, Kazuyuki; Netsu, Kiminori; Asamura, Kenji; Hayashi, Keiko; Takumi, Yutaka; Ota, Hiroyoshi; Usami, Shin-ichi

2009-10-01

Chondrosarcoma make up only 10-20% of malignant primary bone tumors, with 5-10% located in the head and neck (Downey TJ, Clark SK, Moore DW. Chondrosarcoma of the nasal septum. Otolaryngol Head Neck Surg 2001;125:98-100), and nasal septal chondrosarcoma is extremely rare. Surgical excision is the only curative treatment and radiation and chemotherapy have a limited role for palliation. We used a navigation system in endoscopic surgery without complications for a case of chondrosarcoma of the nasal septum by means of a midfacial degloving approach at primary operation and an external incision approach at salvage operation for local recurrence. To our knowledge, this is the first report of the use of such a system for this surgical approach along with a salvage operation. We discuss the clinical presentation, diagnosis, and treatment of this case as well as present a review of the literature.

Quantitative in Situ Assessment of the Somatostatin Receptor in Breast Cancer to Assess Response to Targeted Therapy with 111-In-Pentetreotide

DTIC Science & Technology

2005-05-01

chondrosarcoma . Clin Nuc Med 1996 ;21 :1008-9 . 25. Redding TW, Schally AV . Inhibition of growth of the transplantable rat chondrosarcoma by analogs of...hypothalami c hormones . P Nat Acad Sci USA 1983 ;80 :1078-82 . 26. Reubi JC . A somatostatin analogue inhibits chondrosarcoma an d insulinoma tumor

Interaction of Electromagnetic Fields with Biosynthetic Processes in Connective Tissue Cells

DTIC Science & Technology

1989-12-01

Normal Chondrocytes.............................................10 Swarm Rat Chondrosarcoma Cells..................................15 Conclusions...articular cartilage, and in rat chondrosarcoma cells (a continuous cell line). Another long-term goal is to study the possible role of fields in...Investigators have recently found that bovine [12, 13, 14], rabbit [15], and human [161 chondrocytes as well as Swarm rat chondrosarcoma cells [171 isolated a

[Costal chondrosarcoma. 4 cases].

PubMed

Ben M'rad, S; el Hammami, S; Merai, S; Kamoun, N; Horchani, H; Ben Miled, K; Kilani, T; Djenayah, F

1999-09-04

Tumors of the rib cage are uncommon and malignant in 29% of the cases. Chondrosarcoma predominates, accounting for 40% of all cases of malignant costal tumors. Four patients (3 women, 1 man, mean age 28.2 years) were hospitalized for costal chondrosarcoma. Pain and tumefaction dominated the clinical presentation. Calcifications suggested the diagnosis in 3 cases. Curative surgery was performed in all cases. Postoperative radiotherapy was unable to improve prognosis in 2 patients. Chondrosarcoma of the ribs is characterized by a strong potential for invasive extension. Diagnosis is suspected on the basis of imaging findings and confirmed at pathology. Surgery is required. Chemotherapy and radiotherapy do not improve prognosis significantly.

Retrobulbar chondrosarcoma in a dog.

PubMed

Ralić, M; Vasić, J; Jovanović, M; Cameron, B

2014-01-01

This paper presents a review of a dog, with a retrobulbar chondrosarcoma, which was admitted for surgery for visible changes in his eye during inspection. Orbital neoplasia in dogs may be primary and secondary. Sixty percent of orbital neoplasia in dogs are primary, ninety percent of which are malignant. Retrobulbar neoplasms are rare and in their early stage represent a diagnostic challenge. Chondrosarcoma of the skull is a slow-progressing malignant disease which occurs locally, aggressive with invasion into the surrounding tissues. Dogs with chondrosarcoma of the skull have life expectancy between 210 and 580 days - in our case it was 180 days - after the first alterations on the eye of the dog occurred.

Amphiregulin enhances VEGF-A production in human chondrosarcoma cells and promotes angiogenesis by inhibiting miR-206 via FAK/c-Src/PKCδ pathway.

PubMed

Wang, Chao-Qun; Huang, Yu-Wen; Wang, Shih-Wei; Huang, Yuan-Li; Tsai, Chun-Hao; Zhao, Yong-Ming; Huang, Bi-Fei; Xu, Guo-Hong; Fong, Yi-Chin; Tang, Chih-Hsin

2017-01-28

Chondrosarcoma is the second most common primary malignancy of bone after myeloma and osteosarcoma. Chondrosarcoma development may be linked to angiogenesis, which is principally elicited by vascular endothelial growth factor-A (VEGF-A). The expression of VEGF-A has been recognized as a prognostic marker in angiogenesis. Amphiregulin (AR), an epidermal growth factor receptor ligand, promotes tumor proliferation, metastasis and angiogenesis. However, the role of AR in VEGF-A expression and angiogenesis in human chondrosarcoma remains largely unknown. This current study shows that AR promoted VEGF-A production and induced angiogenesis of human endothelial progenitor cells. Moreover, AR-enhanced VEGF-A expression and angiogenesis involved the FAK, c-Src and PKCδ signaling pathways, while miR-206 expression was negatively mediated by AR via the FAK, c-Src and PKCδ pathways. Our results illustrate the clinical significance between AR, VEGF-A and miR-206, as well as tumor stage, in human chondrosarcoma. AR may represent a novel therapeutic target in the metastasis and angiogenesis of chondrosarcoma. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

WISP-3 inhibition of miR-452 promotes VEGF-A expression in chondrosarcoma cells and induces endothelial progenitor cells angiogenesis.

PubMed

Lin, Chih-Yang; Tzeng, Huey-En; Li, Te-Mao; Chen, Hsien-Te; Lee, Yi; Yang, Yi-Chen; Wang, Shih-Wei; Yang, Wei-Hung; Tang, Chih-Hsin

2017-06-13

Chondrosarcoma is the second most prevalent general primary tumor of bone following osteosarcoma. Chondrosarcoma development may be linked to angiogenesis, which is principally elicited by vascular endothelial growth factor-A (VEGF-A). VEGF-A level has been recognized as a prognostic marker in angiogenesis. WNT1-inducible signaling pathway protein-3 (WISP)-3/CCN6 belongs to the CCN family and is involved in regulating several cellular functions, including cell proliferation, differentiation, and migration. Nevertheless, the effect of WISP-3 on VEGF-A production and angiogenesis in human chondrosarcoma remains largely unknown. This current study shows that WISP-3 promoted VEGF-A production and induced angiogenesis of human endothelial progenitor cells. Moreover, WISP-3-enhanced VEGF-A expression and angiogenesis involved the c-Src and p38 signaling pathways, while miR-452 expression was negatively affected by WISP-3 via the c-Src and p38 pathways. Our results illustrate the clinical significance of WISP-3, VEGF-A and miR-452 in human chondrosarcoma patients. WISP-3 may illustrate a novel therapeutic target in the metastasis and angiogenesis of chondrosarcoma.

Swarm chondrosarcoma: a continued resource for chondroblastic-like extracellular matrix and chondrosarcoma biology research.

PubMed

Stevens, Jeff W

2013-01-01

Since its first description over four decades ago, the Swarm chondrosarcoma (Swarm rat chondrosarcoma, SRC) remains a valuable tool for studies of chondroblastic-like extracellular matrix (ECM) biology and as an animal model of human chondrosarcoma of histological grades I-III. Moreover, articular joints and skeletal anomalies such as arthritis as well as cartilage regeneration, skeletal development, tissue engineering, hard tissue tumorigenesis and space flight physiology are advanced through studies in hyaline cartilage-like models. With more than 500 articles published since the first report on the characteristics of mucopolysaccharides (glycosaminoglycans) of the tumor in 1971, several transplantable tumor and cell lines have been developed by multiple laboratories worldwide. This review describes the characterization of SRC tumors and cell lines, including the use of SRC lines as a resource for isolation and characterization of several ECM elements that have become vital for the advancement of our understanding of cartilage biology. Also presented is the importance of pertubation of ECM components and the influence of the tumor microenvironment on disease progression. Therapeutic failure and currently pursued avenues of intervention utilizing the SRC lines in treatment of chondrosarcoma are also discussed.

Extraskeletal Ewing's sarcoma.

PubMed

El-Essawy, Manar T

2009-06-01

We report 2 rare cases of extraskeletal Ewing's sarcoma, one is arising primarily from the posterior mediastinum in a middle-aged man (patient 1), and the other one is arising from the left kidney in a young male patient (patient 2). The CT in the first case showed a large mass of heterogeneous texture, with areas of cystic changes in the right side of the posterior mediastinum, no underlying bony changes or intra-spinal extension, and this mass was diagnosed as lymphoma. The second case showed almost complete replacement of the left kidney by a mass with extension through the renal vein and inferior vena cava, and it was diagnosed as renal cell carcinoma. The histological analysis of these lesions revealed extraskeletal Ewing's sarcoma.

miR-181a Targets RGS16 to Promote Chondrosarcoma Growth, Angiogenesis, and Metastasis

PubMed Central

Sun, Xiaojuan; Charbonneau, Cherie; Wei, Lei; Chen, Qian; Terek, Richard M.

2015-01-01

Chondrosarcoma is the most common primary malignant bone tumor in adults, has no effective systemic treatment, and patients with this disease have poor survival. Altered expression of microRNA (miR) is involved in tumorigenesis, however its role in chondrosarcoma is undetermined. MicroRNA-181a is overexpressed in high grade chondrosarcoma, is upregulated by hypoxia, and increases VEGF expression. Here, the purpose was to determine the mechanism of miR-181a regulation of VEGF, determine if miR-181a overexpression promotes tumor progression, and to evaluate an antagomir-based approach for chondrosarcoma treatment. Therapeutic inhibition of miR-181a decreased expression of VEGF and MMP1 in vitro, and angiogenesis, MMP1 activity, tumor growth, and lung metastasis, all by more than 50%, in a xenograft mouse model. A target of miR-181a is regulator of G-protein signaling 16 (RGS16), a negative regulator of CXC chemokine receptor 4 (CXCR4) signaling. CXCR4 signaling is increased in chondrosarcoma, its expression is also increased by hypoxia, and is associated with angiogenesis and metastasis, however, receptor blockade is only partially effective. RGS16 expression is restored after miR-181a inhibition and partially accounts for the anti-angiogenic and anti-metastatic effects of miR-181a inhibition. These data establish miR-181a as an oncomiR that promotes chondrosarcoma progression through a new mechanism involving enhancement of CXCR4 signaling by inhibition of RGS16. PMID:26013170

Knockdown of long non-coding RNA HOTAIR increases miR-454-3p by targeting Stat3 and Atg12 to inhibit chondrosarcoma growth

PubMed Central

Bao, Xing; Ren, Tingting; Huang, Yi; Sun, Kunkun; Wang, Shidong; Liu, Kuisheng; Zheng, Bingxin; Guo, Wei

2017-01-01

Current practices for the therapy of chondrosarcoma, including wide-margin surgical resection and chemotherapy, are less than satisfactory. Recently, emerging evidence has demonstrated that long non-coding RNAs (lncRNAs) have an essential role in the initiation and progression of tumors. As a typical lncRNA, HOTAIR is significantly overexpressed in various tumors. However, the function and potential biological mechanisms of HOTAIR in human chondrosarcoma remain unknown. Quantitative RT-PCR demonstrated that HOTAIR expression was upregulated in chondrosarcoma tissues and cell lines. High HOTAIR expression is correlated with tumor stage and poor prognosis. Functional experiments reveal that HOTAIR knockdown leads to growth inhibition of human chondrosarcoma cells in vitro and in vivo. In addition to cycle arrest and apoptosis, knockdown of HOTAIR inhibits autophagy, which favors cell death. Mechanistically, we demonstrated that HOTAIR induced DNA methylation of miR-454-3p by recruiting EZH2 and DNMT1 to the miR-454-3p promoter regions, which markedly silences miR-454-3p expression. Further analysis revealed that STAT3 and ATG12 are targets of miR-454-3p, initiate HOTAIR deficiency-induced apoptosis and reduce autophagy. Collectively, our data reveal the roles and functional mechanisms of HOTAIR in human chondrosarcoma and suggest that HOTAIR may act as a prognostic biomarker and potential therapeutic target for chondrosarcoma. PMID:28182000

CCL5 promotes vascular endothelial growth factor expression and induces angiogenesis by down-regulating miR-199a in human chondrosarcoma cells.

PubMed

Liu, Guan-Ting; Huang, Yuan-Li; Tzeng, Huey-En; Tsai, Chun-Hao; Wang, Shih-Wei; Tang, Chih-Hsin

2015-02-28

Chondrosarcoma is a primary malignant bone cancer, with a potent capacity to invade locally and cause distant metastasis. Angiogenesis is a critical step in tumor growth and metastasis. Chemokine CCL5 (previously called RANTES) has been shown to facilitate tumor progression and metastasis. However, the relationship of CCL5 with vascular endothelial growth factor (VEGF) expression and angiogenesis in human chondrosarcoma is mostly unknown. In this study, CCL5 increased VEGF expression and also promoted chondrosarcoma medium-mediated angiogenesis in vitro as well as angiogenesis effects in the chick chorioallantoic membrane and Matrigel plug nude mice model in vivo. MicroRNA analysis was performed in CCL5-treated chondrosarcoma cells versus control cells to investigate the mechanism of CCL5-mediated promotion of chondrosarcoma angiogenesis. Among the miRNAs regulated by CCL5, miR-199a was the most downregulated miRNA after CCL5 treatment. In addition, co-transfection with miR-199a mimic reversed the CCL5-mediated VEGF expression and angiogenesis in vitro and in vivo. Moreover, overexpression of CCL5 increased tumor-associated angiogenesis and tumor growth by downregulating miR-199a in the xenograft tumor angiogenesis model. Taken together, these results demonstrated that CCL5 promotes VEGF-dependent angiogenesis in human chondrosarcoma cells by downregulating miR-199a. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Expression of MMP-9 decreases metastatic potential of Chondrosarcoma: an immunohistochemical study.

PubMed

Malcherczyk, Dominik; Heyse, Thomas J; El-Zayat, Bilal F; Kunzke, Vanessa; Moll, Roland; Fuchs-Winkelmann, Susanne; Paletta, Jürgen R J

2018-01-09

Chondrosarcoma is the second most common primary malignant bone tumor. Because of their heterogeneity, with differences in invasive and metastatic behavior, it is important to identify biological markers that will allow for a more accurate estimation of prognosis in patients with these tumors. Matrix metalloproteinases (MMP) play a crucial role in tumor progression, invasion and metastasis. The mechanism of tumor progression dependent of MMPs is complex and influences malignant transformation, angiogenesis and tumor growth at the primary and metastatic sites. The purpose of this study was to investigate immunohistochemicaly the influence of MMP-1, MMP-3, MMP-9 and MMP-13 expression on prognostic parameter in chondrosarcoma. We investigated tissue samples of 28 patients with chondrosarcoma. Immunohistochemical staining to evaluate the expression of MMP-1, MMP-3, MMP-9 and MMP-13 was performed. Subsequently, the expression level was correlated with metastatic potential, histological grading and overall survival in patients with this neoplasm. In consideration of semi quantitative scoring 64% of chondrosarcoma were scored as positive for MMP-1, 46% for MMP-3, 61% for MMP-9. The specimens had shown no expression of MMP-13. High expression of MMP-9 was associated with better histological differentiation, decreased metastatic potential and favourable overall survival. No correlation was found for expression of MMP-1, MMP-3 or MMP-13. MMP-1, MMP-3 and MMP-9 are expressed in chondrosarcoma. Our findings suggest that the expression of MMP-9 is associated with clinical outcome parameters in chondrosarcoma.

A single institution experience of combined modality management of extra skeletal Ewings sarcoma.

PubMed

Venkitaraman, Ramachandran; George, Mathew K; Ramanan, S Ganapathy; Sagar, T G

2007-01-11

Extraskeletal Ewings sarcoma are rare tumors for which there is no consensus on optimal management. A retrospective review of the clinical features, treatment and outcome of patients with extraskeletal Ewings sarcoma who reported to a single institution between January 1992-December 2003 is reported. A total of 19 patients with extraskeletal Ewings sarcoma were identified. Of these, 4 patients had metastatic disease at presentation and 15 patients with non-metastatic disease received combined modality treatment with primary combination chemotherapy followed by local treatment with radiotherapy or surgery. Disease free survival and overall survival for patients with non metastatic disease after combined modality treatment were 60% and 30% respectively. The significant predictors for prolonged disease free survival and overall survival were high haemoglobin (p = 0.002), low lactate dehydrogenase (p = 0.028), chemotherapy with Vincristine, Adriamycin, Cyclophosphamide, Ifosfamide and Etoposide regime (p = 0.008) and complete response to chemotherapy (p = 0.001). Aggressive combination chemotherapy followed by complete surgery or radiotherapy to a dose of more than 50 Gy is essential to confer optimal outcome for patients with extraskeletal Ewings sarcoma.

Radiation-induced chondrosarcoma of the maxilla 7-year after combined chemoradiation for tonsillar lymphoma.

PubMed

Mohammadianpanah, M; Gramizadeh, B; Omidvari, Sh; Mosalaei, A

2004-01-01

Radiation-induced sarcoma is a rare complication of radiation therapy. We report a case of radiation-induced chondrosarcoma of the maxilla. An 80-year-old Persian woman developed radiation-induced chondrosarcoma of the left maxilla 7 years after combined chemotherapy and external beam radiation therapy for the Ann Arbor stage IE malignant lymphoma of the right tonsil. She underwent suboptimal tumour resection and died due to extensive locoregional disease 8 months later. An English language literature search of Medline using the terms chondrosarcoma, radiation-induced sarcoma and maxilla revealed only one earlier reported case. We describe the clinical and pathological features of this case and review the literature on radiation-induced sarcomas.

Retrobulbar chondrosarcoma in a dog

PubMed Central

Ralić, M.; Vasić, J.; Jovanović, M.; Cameron, B.

2014-01-01

This paper presents a review of a dog, with a retrobulbar chondrosarcoma, which was admitted for surgery for visible changes in his eye during inspection. Orbital neoplasia in dogs may be primary and secondary. Sixty percent of orbital neoplasia in dogs are primary, ninety percent of which are malignant. Retrobulbar neoplasms are rare and in their early stage represent a diagnostic challenge. Chondrosarcoma of the skull is a slow-progressing malignant disease which occurs locally, aggressive with invasion into the surrounding tissues. Dogs with chondrosarcoma of the skull have life expectancy between 210 and 580 days - in our case it was 180 days - after the first alterations on the eye of the dog occurred. PMID:26623338

Advances in the Classification and Treatment of Osteogenesis Imperfecta.

PubMed

Thomas, Inas H; DiMeglio, Linda A

2016-02-01

Osteogenesis imperfecta (OI) is a rare disorder of type 1 collagen with 13 currently identified types attributable to inherited abnormalities in type 1 collagen amount, structure, or processing. The disease is characterized by an increased susceptibility to bony fracture. In addition to the skeletal phenotype, common additional extraskeletal manifestations include blue sclerae, dentinogenesis imperfecta, vascular fragility, and hearing loss. Medical management is focused on minimizing the morbidity of fractures, pain, and bone deformities by maximizing bone health. Along with optimizing Vitamin D status and calcium intake and physical/occupational therapy, individualized surgical treatment may be indicated. Pharmacological therapy with bisphosphonate medications is now routinely utilized for moderate to severe forms and appears to have a good safety profile and bone health benefits. New therapies with other anti-resorptives as well as anabolic agents and transforming growth factor (TGF)β antibodies are in development. Other potential treatment modalities could include gene therapy or mesenchymal cell transplant. In the future, treatment choices will be further individualized in order to reduce disease morbidity and mortality.

Presumed post-traumatic ocular chondrosarcoma with intrathoracic metastases in a cat.

PubMed

Moreira, Matheus V L; de Andrade, Maria C; Fulgêncio, Gustavo O; Langohr, Ingeborg M; Ecco, Roselene

2017-10-03

An indoor-only, 5-year-old, spayed female domestic shorthair cat presented for an ophthalmic examination of the left eye. An intraocular tumor with secondary glaucoma and blindness was diagnosed; the globe was enucleated and sent for histopathological examination. Gross examination revealed a solid white mass filling the entire vitreous space and replacing the iris and ciliary body. The lens and retina appeared to be similarly replaced by the neoplasm. Histological examination revealed a complete loss of the internal ocular structures, with a ruptured capsule as the only remnant of the lens within an extensive malignant mesenchymal neoplastic cell proliferation. The cells were polygonal, with well-defined cytoplasmic borders and abundant weakly basophilic cytoplasm, embedded within the islands of chondroid matrix. No neoplastic invasion of the sclera was apparent. The animal died 6 months after the enucleation due to respiratory distress. Gross examination revealed numerous firm, white to tan nodular masses with smooth to mildly irregular surfaces dispersed throughout the parietal pleura, thoracic surface of the diaphragm, tracheobronchial and mediastinal lymph nodes, pericardium, and lungs. On cross-section, the neoplastic nodules were solid and variably translucent, resembling hyaline cartilage. Histologically, these nodules were similar to the neoplasm identified earlier in the left globe. Metastasis of post-traumatic ocular chondrosarcoma has not yet been described in cats. This is therefore believed to be the first report of metastases of this type of neoplasm in cats. This case adds to the limited set of data on the outcome of this type of tumor. © 2017 American College of Veterinary Ophthalmologists.

Interaction of Electromagnetic Fields with Chondrocytes in Gel Culture

DTIC Science & Technology

1990-02-01

biosynthesis due to applied electromagnetic fields. The results suggest that both normal chondrocytes and swarm rat chondrosarcoma cells in agarose Culture...and Swarm rat chondrosarcoma cells in agarose iii culture can, under proper culture conditions, continue to synthesize ma- trix macromolecules at a...cartilagc, and in rat chondrosarcoma cells (a continuous cell line). The overt gene expression of chondrocytes results in the synthesis and deposition of a

3-D Ultrasound Vascularity Assessment for Breast Cancer Diagnosis

DTIC Science & Technology

2000-09-01

circumscribed mass with no microcalcifications. Final pathologic studies revealed carcinosarcoma (half ductal, half chondrosarcoma ). (a) Lateral-axial...Prostate 2 0 0 2 Angiosarcoma 0 0 2 2 Chondrosarcoma 0 1 0 1 Nasopharyngeal tumor 0 0 1 1 Hemangioendothelioma 0 0 1 1 Renal tumor 1 0 2 3 Baseline...patient with metastatic rendered copper deficient. Table 2 summarizes the clinical chondrosarcoma secondary to radiation treatment for breast course of

Chondrosarcoma of the nasal septum.

PubMed

Indudharan, R; Das, P K; Azman, A A; Suhaiza, S

1998-08-01

A case of chondrosarcoma of the nasal septum is presented with the result of treatment. The patient was admitted for a growth in the nose of four years' duration. Fine needle aspiration for cytological examination was suggestive of squamous cell carcinoma. She was treated with lateral rhinotomy and wide excision followed by septorhinoplasty. Histological examination showed that the lesion was chondrosarcoma. The patient remained free of disease 26 months after surgery.

The urokinase receptor-derived cyclic peptide [SRSRY] suppresses neovascularization and intravasation of osteosarcoma and chondrosarcoma cells.

PubMed

Ingangi, Vincenzo; Bifulco, Katia; Yousif, Ali Munaim; Ragone, Concetta; Motti, Maria Letizia; Rea, Domenica; Minopoli, Michele; Botti, Giovanni; Scognamiglio, Giuseppe; Fazioli, Flavio; Gallo, Michele; De Chiara, Annarosaria; Arra, Claudio; Grieco, Paolo; Carriero, Maria Vincenza

2016-08-23

The receptor for the urokinase-type plasminogen activator (uPAR) is a widely recognized master regulator of cell migration and uPAR88-92 is the minimal sequence required to induce cell motility and angiogenesis by interacting with the formyl peptide receptor type 1 (FPR1). In this study, we present evidence that the cyclization of the uPAR88-92 sequence generates a new potent inhibitor of migration, and extracellular matrix invasion of human osteosarcoma and chondrosarcoma cells expressing comparable levels of FPR1 on cell surface. In vitro, the cyclized peptide [SRSRY] prevents formation of capillary-like tubes by endothelial cells co-cultured with chondrosarcoma cells and trans-endothelial migration of osteosarcoma and chondrosarcoma cells. When chondrosarcoma cells were subcutaneously injected in nude mice, tumor size, intra-tumoral microvessel density and circulating tumor cells in blood samples collected before the sacrifice, were significantly reduced in animals treated daily with i.p-administration of 6 mg/Kg [SRSRY] as compared to animals treated with vehicle only. Our findings indicate that [SRSRY] prevents three key events occurring during the metastatic process of osteosarcoma and chondrosarcoma cells: the extracellular matrix invasion, the formation of a capillary network and the entry into bloodstream.

The urokinase receptor-derived cyclic peptide [SRSRY] suppresses neovascularization and intravasation of osteosarcoma and chondrosarcoma cells

PubMed Central

Ingangi, Vincenzo; Bifulco, Katia; Yousif, Ali Munaim; Ragone, Concetta; Motti, Maria Letizia; Rea, Domenica; Minopoli, Michele; Botti, Giovanni; Scognamiglio, Giuseppe; Fazioli, Flavio; Gallo, Michele; De Chiara, Annarosaria; Arra, Claudio; Grieco, Paolo; Carriero, Maria Vincenza

2016-01-01

The receptor for the urokinase-type plasminogen activator (uPAR) is a widely recognized master regulator of cell migration and uPAR88–92 is the minimal sequence required to induce cell motility and angiogenesis by interacting with the formyl peptide receptor type 1 (FPR1). In this study, we present evidence that the cyclization of the uPAR88–92 sequence generates a new potent inhibitor of migration, and extracellular matrix invasion of human osteosarcoma and chondrosarcoma cells expressing comparable levels of FPR1 on cell surface. In vitro, the cyclized peptide [SRSRY] prevents formation of capillary-like tubes by endothelial cells co-cultured with chondrosarcoma cells and trans-endothelial migration of osteosarcoma and chondrosarcoma cells. When chondrosarcoma cells were subcutaneously injected in nude mice, tumor size, intra-tumoral microvessel density and circulating tumor cells in blood samples collected before the sacrifice, were significantly reduced in animals treated daily with i.p-administration of 6 mg/Kg [SRSRY] as compared to animals treated with vehicle only. Our findings indicate that [SRSRY] prevents three key events occurring during the metastatic process of osteosarcoma and chondrosarcoma cells: the extracellular matrix invasion, the formation of a capillary network and the entry into bloodstream. PMID:27323409

Adiponectin promotes VEGF-C-dependent lymphangiogenesis by inhibiting miR-27b through a CaMKII/AMPK/p38 signaling pathway in human chondrosarcoma cells.

PubMed

Huang, Chun-Yin; Chang, An-Chen; Chen, Hsien-Te; Wang, Shih-Wei; Lo, Yuan-Shun; Tang, Chih-Hsin

2016-09-01

Chondrosarcoma is the second most frequently occurring type of bone malignancy characterized by distant metastatic propensity. Vascular endothelial growth factor-C (VEGF-C) is the major lymphangiogenic factor, and makes crucial contributions to tumour lymphangiogenesis and lymphatic metastasis. Adiponectin is a protein hormone secreted predominantly by differentiated adipocytes. In recent years, adiponectin has also been indicated as facilitating tumorigenesis, angiogenesis and metastasis. However, the effect of adiponectin on VEGF-C regulation and lymphangiogenesis in chondrosarcoma has remained largely a mystery. In the present study, we have shown a clinical correlation between adiponectin and VEGF-C, as well as tumour stage, in human chondrosarcoma tissues. We further demonstrated that adiponectin promoted VEGF-C expression and secretion in human chondrosarcoma cells. The conditioned medium from adiponectin-treated cells significantly induced tube formation and migration of human lymphatic endothelial cells. In addition, adiponectin knock down inhibited lymphangiogenesis in vitro and in vivo We also found that adiponectin-induced VEGF-C is mediated by the calmodulin-dependent protein kinase II (CaMKII), AMP-activated protein kinase (AMPK) and p38 signaling pathway. Furthermore, the expression of miR-27b was negatively regulated by adiponectin via the CaMKII, AMPK and p38 cascade. The present study is the first to describe the mechanism of adiponectin-promoted lymphangiogenesis by up-regulating VEGF-C expression in chondrosarcomas. Thus, adiponectin could serve as a therapeutic target in chondrosarcoma metastasis and lymphangiogenesis. © 2016 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society.

MicroRNA‑10b suppresses the migration and invasion of chondrosarcoma cells by targeting brain‑derived neurotrophic factor.

PubMed

Aili, Abudunaibi; Chen, Yong; Zhang, Hongqi

2016-01-01

MicroRNAs (miRs) can lead to mRNA degradation or inhibit protein translation through directly binding to the 3'‑untranslational region (UTR) of their target mRNAs. Deregulation of miR‑10b has been reported to be associated with chondrosarcoma. However, the role of miR‑10b in chondrosarcoma cell migration and invasion, as well as the underlying mechanisms, has not been investigated. In the present study, it was demonstrated that miR‑10b was notably downregulated in the JJ012 and SW1353 chondrosarcoma cell lines compared with the TC28a2 normal chondrocyte line. Treatment with DNA demethylating agent 5‑aza‑2'‑deoxycytidine and histone deacetylase inhibitor 4‑phenylbutyric acid, or transfection with miR‑10b mimics promoted the expression of miR‑10b, which further suppressed the migratory and invasive capacities of JJ012 chondrosarcoma cells. Moreover, brain‑derived neurotrophic factor (BDNF) was identified as a novel target of miR‑10b, and its protein expression level was negatively regulated by miR‑10b in JJ012 cells. Furthermore, overexpression of BDNF reversed the inhibitory effect of miR‑10b upregulation on the migration and invasion of JJ012 cells. In addition, the data suggest that matrix metalloproteinase 1 (MMP1) may be involved in the miR‑10b/BDNF‑mediated chondrosarcoma cell migration and invasion in JJ012 cells. In conclusion, these findings suggest that miR‑10b/BDNF may serve as a potential therapeutic target for chondrosarcoma.

The Investigation of ADAMTS16 in Insulin-Induced Human Chondrosarcoma Cells.

PubMed

Cakmak, Ozlem; Comertoglu, Ismail; Firat, Ridvan; Erdemli, Haci Kemal; Kursunlu, S Fatih; Akyol, Sumeyya; Ugurcu, Veli; Altuntas, Aynur; Adam, Bahattin; Demircan, Kadir

2015-08-01

A disintegrin-like metalloproteinase with thrombospondin motifs (ADAMTS) is a group of proteins that have enzymatic activity secreted by cells to the outside extracellular matrix. Insulin induces proteoglycan biosynthesis in chondrosarcoma chondrocytes. The purpose of the present in vitro study is to assess the time course effects of insulin on ADAMTS16 expression in OUMS-27 (human chondrosarcoma) cell line to examine whether insulin regulates ADAMTS16 expression as well as proteoglycan biosynthesis with multifaceted properties or not. Chondrosarcoma cells were cultured in Dulbecco's modified Eagle's medium having either 10 μg/mL insulin or not. While the experiment was going on, the medium containing insulin had been changed every other day. Cells were harvested at 1st, 3rd, 7th, and 11th days; subsequently, RNA and proteins were isolated in every experimental group according to their time interval. RNA expression of ADAMTS was estimated by quantitative real-time polymerase chain reaction (qRT-PCR) by using primers. Immunoreactive protein levels were encountered by the western blot protein detection technique by using proper anti-ADAMTS16 antibodies. ADAMTS16 mRNA expression level of chondrosarcoma cells was found to be insignificantly decreased in chondrosarcoma cells induced by insulin detected by the qRT-PCR instrument. On the other hand, there was a gradual decrease in immune-reactant ADAMTS16 protein amount by the time course in insulin-treated cell groups when compared with control cells. It has been suggested that insulin might possibly regulate ADAMTS16 levels/activities in OUMS-27 chondrosarcoma cells taking a role in extracellular matrix turnover.

Interaction of Electromagnetic Fields with Chondrocytes in Gel Culture

DTIC Science & Technology

1992-01-14

presence of matrix was not required for the stimulatory response to be observed with Swarm rat chondrosarcoma cells. la OISTIGUTION/AVALgAGILeTY O0...and in rat chondrosarcoma cells (a continuous cell line). To address these goals, the specific objectives of this research period were: (1) to quantify...of models of physical mechanisms. The results of these studies suggest that: (1) both normal chondrocytes and Swarm rat chondrosarcoma cells in

Treatment of extraskeletal osteosarcoma at a previous injection site resulting in prolonged survival in 1 dog

PubMed Central

Selmic, Laura E.; Griffin, Lynn R.; Rector, Megan H.; Lafferty, Mary; Pool, Roy; Ehrhart, Nicole P.

2016-01-01

A rare presentation of an extraskeletal osteosarcoma at a previous interscapular injection site in a dog is described. Treatment included surgical excision of the tumor followed by 6 rounds of intravenous carboplatin, oral toceranib, and cyclophosphamide. The dog survived for 20.5 months after diagnosis despite early development of pulmonary metastases. PMID:27587886

Extraskeletal actions of vitamin D

PubMed Central

Bikle, Daniel D.

2016-01-01

The vitamin D receptor (VDR) is found in nearly all, if not all, cells in the body. The enzyme that produces the active metabolite of vitamin D and ligand for VDR, namely CYP27B1, likewise is widely expressed in many cells of the body. These observations indicate that the role of vitamin D is not limited to regulation of bone and mineral homeostasis, as important as that is. Rather, the study of its extraskeletal actions has become the major driving force behind the significant increase in research articles on vitamin D published over the past several decades. A great deal of information has accumulated from cell culture studies, in vivo animal studies, and clinical association studies that confirms that extraskeletal effects of vitamin D are truly widespread and substantial. However, randomized, placebo controlled clinical trials, when done, have by and large not produced the benefits anticipated by the in vitro cell culture and in vivo animal studies. In this review, I will examine the role of vitamin D signaling in a number of extraskeletal tissues, and assess the success of translating these findings into treatments of human diseases affecting those extracellular tissues. PMID:27649525

Imaging of rare appendicular non-acral soft-tissue chondromas in adults with histopathologic correlation.

PubMed

Nouh, Mohamed Ragab; Amr, Hanan Abd El-Aziz; Ali, Rola H

2018-06-01

Background Soft-tissue chondroma (STC) is a rare benign soft tissue tumor that arises primarily in acral extra-skeletal locations. Occasionally, STCs may arise in more proximal non-acral locations, accompanied by non-classic features that label them as indeterminate lesions and pose diagnostic challenge for both radiologists and pathologists alike. Purpose To explicate the potential of diagnostic imaging in the identification and characterization of appendicular non-acral STCs with emphasis on their morphologic magnetic resonance imaging (MRI) enhancement. Material and Methods Our clinical database records were searched for patients with histologically proven primary soft-tissue chondroid lesions over a five-year period. Two musculoskeletal (MSK) trained radiologists evaluated the imaging studies and an MSK pathologist revised the pathological findings. Results The study included six cases of appendicular non-acral STCs (mean age = 40.5 years). The mean size of the tumors was 5.6 cm, with four localized to the knee region, one in the thigh, and one in the sternoclavicular region. All cases showed high signal intensity matrix with low-signal intensity septa on T2-weighted MRI and post-contrast marginal/septal enhancement. The lesions were lobulated and lacked host tissue reaction except for one showing subjacent mild soft-tissue edema. Histologically, the cases lacked overt features of malignancy although one was originally misdiagnosed as chondrosarcoma. Conclusion Non-acral STCs are benign cartilaginous tumors that may pose a diagnostic challenge, both radiologically and pathologically. Collaborative imaging and pathologic workup is needed for better characterization of non-aggression of these lesions, and to avoid diagnostic pitfalls and unnecessary radical resections.

[Hemothorax caused by primary pleural chondrosarcoma: a case report and review of literatureYuan].

PubMed

Yuan, Y Q; Zhu, L Y; Zeng, H H; Zhou, R; Chen, P

2016-11-12

Objective: To analyze the clinical features of one case of spontaneous hemothorax caused by primary pleural chondrosarcoma and therefore to improve the understanding of this disease. Methods: The clinical features of a case with primary pleural chondrosarcoma were analyzed retrospectively and the related literatures were reviewed.The literature review was carried out with "primary pleural, chondrosarcoma" in Chinese and English respectively, as the search terms in Wanfang Data, CNKI and PubMed database from January 1980 to October 2015. A total of 6 articales, 1 in Chinese and 5 in English, were reviewed. Results: A 29 year-old male patient was admitted to the hospital because of fever, chest tightness, shortness of breath for 20 days. CT scan of the chest showed a mass near the right posterior fourth rib and right pleural effusion.Routine examination of the pleural effusion confirmed the presence of hemothorax. Thoracotomy was performed and revealed hemothorax in the right thorax, and a mass near the pleural apex. The tumor was removed by surgery and pleural decortication was also performed. Pathology study confirmed the diagnosis of high-differentiated chondrosarcoma. The patient was followed and there was no recurrence until now. A total of 6 case reports were retrieved from Wanfang Data, CNKI and PubMed. Five cases had complete data, including 2 males and 3 females(age from 28 to70), and another (a 78-year old male) without adequate data. Conclusions: Primary pleural chondrosarcoma is a rare disease, and hemothorax as the first manifestation is even rare. It is easily to be misdiagnosed due to nonspecific clinical symptoms.The final diagnosis depends ultimately on pathological biopsy. Thoracotomy is the most effective method for treatment of primary pleural chondrosarcoma.

MiR-129-5p Inhibits Proliferation and Invasion of Chondrosarcoma Cells by Regulating SOX4/Wnt/β-Catenin Signaling Pathway.

PubMed

Zhang, Peng; Li, Jifeng; Song, Yuze; Wang, Xiao

2017-01-01

Recently, microRNAs (miRNA) have been identified as novel regulators in Chondrosarcoma (CHS). This study was aimed to identify the roles of miR-129-5p-5p in regulation of SOX4 and Wnt/β-catenin signaling pathway, as well as cell proliferation and apoptosis in chondrosarcomas. Tissue samples were obtained from chondrosarcoma patients. Immunohistochemistry, real-time quantitative RT-PCR (RT-qPCR) and western blot analysis were performed to detect the expressions of miR-129-5p and SOX4. Luciferase assay was conducted to confirm that miR-129-5p directly targeted SOX4 mRNA. Manipulations of miR-129-5p and SOX4 expression were achieved through cell transfection. Cell proliferation, migration and apoptosis were evaluated by CCK-8 assay, colony forming assay, wound healing assay and flow cytometry in vitro. For in vivo experiment, the tumor xenograft model was established to evaluate the effects of miR-129-5p and SOX4 on chondrosarcomas. The expression of miR-129-5p was significantly down-regulated in chondrosarcoma tissues as well as cells in comparison with normal ones, while SOX4 was over-activated. Further studies suggested that miR-129-5p suppressed cell proliferation, migration and promoted apoptosis by inhibiting SOX4 and Wnt/β-catenin pathway. MiR-129-5p inhibits the Wnt/β-catenin signaling pathway by targeting SOX4 and further suppresses cell proliferation, migration and promotes apoptosis in chondrosarcomas. © 2017 The Author(s). Published by S. Karger AG, Basel.

Can imaging criteria distinguish enchondroma from grade 1 chondrosarcoma?

PubMed

Crim, Julia; Schmidt, Robert; Layfield, Lester; Hanrahan, Christopher; Manaster, Betty Jean

2015-11-01

To minimize systematic bias and optimize agreement on imaging criteria in order to better define the accuracy of imaging criteria in the diagnosis of grade 1 chondrosarcoma. Study was IRB-approved and HIPAA compliant; informed consent was waived. Records were reviewed and disclosed 53 cases (38 women, 15 men ages 21-76) which were diagnosed as enchondroma or grade 1 chondrosarcoma and had available radiographs, contrast-enhanced MRI, and definitive diagnosis by histology or 5-year follow-up. 2 MSK radiologists read the studies independently after a session where they agreed on criteria for malignancy. Interobserver variability was determined as raw variability and with the kappa statistic. Accuracy was determined compared to final diagnosis. Reliability of imaging features of chondrosarcoma was determined using regression analysis. The correct diagnosis of enchondroma was made on radiographs in 43 (67.2%) of readings, and on MRI in 37/64 (57.8%). The correct diagnosis of chondrosarcoma was made on radiographs in 5/24 (20.8%) of readings, and on MRI in 14/24 (57.8%). A diagnosis of borderline lesion was made in 19/64 (29.7%) of enchondromas on radiographs and 18/64 (28.1%) on MRI. The false positive rate of radiographs for chondrosarcoma was 2/64 (3.1%) and the false positive rate of MRI was 9/64 (14.1%). There was substantial interobserver variability. Cortical thickening and bone expansion were rare but specific signs of chondrosarcoma. Both radiographs and MRI have limitations in the evaluation of low-grade cartilage lesions. MRI has an increased rate of both true-positive and false-positive diagnosis compared to radiographs. Differences in the findings of this study compared to previous literature may reflect the influence of systematic biases. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Conservative cricoid surgery for chondrosarcoma: a case report.

PubMed

Gaio, Elena; Maggiore, Giandomenico; Canesso, Alessandra; Artico, Riccardo

2014-02-01

We present the case of a 39-year-old man who presented with hoarseness and progressively worsening dyspnea. Findings on laryngoscopy and computed tomography strongly suggested the presence of a chondrosarcoma. The patient underwent open surgery for removal of the lesion with wide margins. Reconstruction was carried out with two segments of costal cartilage. Laryngeal chondrosarcomas are rare, malignant, usually well-differentiated neoplasms that should be treated with conservative surgery. Recurrences should be treated more aggressively.

Inhibition of mutant IDH1 decreases D-2-HG levels without affecting tumorigenic properties of chondrosarcoma cell lines.

PubMed

Suijker, Johnny; Oosting, Jan; Koornneef, Annemarie; Struys, Eduard A; Salomons, Gajja S; Schaap, Frank G; Waaijer, Cathelijn J F; Wijers-Koster, Pauline M; Briaire-de Bruijn, Inge H; Haazen, Lizette; Riester, Scott M; Dudakovic, Amel; Danen, Erik; Cleton-Jansen, Anne-Marie; van Wijnen, Andre J; Bovée, Judith V M G

2015-05-20

Mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 are found in a subset of benign and malignant cartilage tumors, gliomas and leukaemias. The mutant enzyme causes the production of D-2-hydroxyglutarate (D-2-HG), affecting CpG island and histone methylation. While mutations in IDH1/2 are early events in benign cartilage tumors, we evaluated whether these mutations play a role in malignant chondrosarcomas. Compared to IDH1/2 wildtype cell lines, chondrosarcoma cell lines harboring an endogenous IDH1 (n=3) or IDH2 mutation (n=2) showed up to a 100-fold increase in intracellular and extracellular D-2-HG levels. Specific inhibition of mutant IDH1 using AGI-5198 decreased levels of D-2-HG in a dose dependent manner. After 72 hours of treatment one out of three mutant IDH1 cell lines showed a moderate decrease in viability , while D-2-HG levels decreased >90%. Likewise, prolonged treatment (up to 20 passages) did not affect proliferation and migration. Furthermore, global gene expression, CpG island methylation as well as histone H3K4, -9, and -27 trimethylation levels remained unchanged. Thus, while IDH1/2 mutations cause enchondroma, malignant progression towards central chondrosarcoma renders chondrosarcoma growth independent of these mutations. Thus, monotherapy based on inhibition of mutant IDH1 appears insufficient for treatment of inoperable or metastasized chondrosarcoma patients.

Dedifferentiated chondrosarcoma with telangiectatic osteosarcoma-like features.

PubMed

Okada, K; Hasegawa, T; Tateishi, U; Endo, M; Itoi, E

2006-11-01

A 35-year-old Japanese man was admitted to the National Cancer Center, Tokyo, Japan, in December 2000, with a 2-month history of pain around the left thigh. Radiographs showed a poorly demarcated osteolytic lesion with focal mineralisation and endosteal scalloping in the left proximal femur. Biopsy showed a proliferation of highly anaplastic cells without any cartilaginous component. A wide excision of the left proximal femur with a replacement by endoprosthesis was carried out in February 2001 after treatment with methotrexate and 20 Gy radiation therapy. Pathological examination of the surgical specimen showed a focus of low-grade chondrosarcoma and the coexistence of telangiectatic osteosarcoma-like features. The patient was diagnosed with dedifferentiated chondrosarcoma with telangiectatic osteosarcoma-like features. Lung metastasis appeared in July 2001 despite an adjuvant chemotherapy including methotrexate, cis-platinum and doxorubicin. The latest follow-up study in June 2004 showed multiple lung metastases. Establishing a definitive diagnosis of dedifferentiated chondrosarcoma may be difficult with limited small biopsy specimens. Dedifferentiated chondrosarcoma should be included in the differential diagnosis of osteolytic tumours with focal calcification and endosteal scalloping even if an extraosseous tumour component is not identified.

A High-Grade Chondrosarcoma of Calcaneum Mimicking as a Benign Pathology: Delayed Diagnosis and Management.

PubMed

Baba, Muzamil Ahmad; Nazir, Naila; Shabeer, Maajid; Mir, Bashir Ahmed; Kawoosa, Altaf Ahmad

2016-10-01

This case is presented to highlight a rare case of chondrosarcoma of calcaneum in a young adult mimicking as a benign pathology and to highlight the diagnosis and early management of such cases to prevent complications and even death. Chondrosarcoma constitutes less than 10% of all primary malignancies of bone and occurs mostly in proximal locations such as pelvis, proximal femur, and proximal humerus. We present a case of high-grade chondrosarcoma at a very rare site, calcaneum of a 40-year-old male that was mimicking as a benign pathology. This case report highlights the importance of proper clinical examination, evaluation, and suspicion for benign occurring lesions to prevent complications related to a delay in diagnosis. Therapeutic, Level IV: Case study. © 2016 The Author(s).

Primary extra-skeletal Ewing's sarcoma mimicking a disc protrusion.

PubMed

Ruelle, A; Boccardo, M

1987-07-01

One of the rarest cases of primary epidural neoplasm is a soft tissue sarcoma histologically similar to Ewing's sarcoma of the bone. In the literature only eleven cases of such an extra-skeletal Ewing's sarcoma have been described. The authors report an additional case presenting as a disc protrusion in a young male. The authors include some diagnostic, prognostic and nosologic remarks about this condition.

[Extra-skeletal Ewing's sarcoma. A case report with detailed review of the literature].

PubMed

Auge, B; Pusel, J

1990-01-01

Extra-skeletal Ewing's Sarcoma (EES): a clinico-pathological entity described in 1975 by L. Angervall and F.M. Enzinger. This article reports a new case in which the primary was localized in the right forearm and metastasized to the left lung fourteen years later. A detailed review of the literature emphasized similarities and differences between osseous and extra-osseous Ewing's Sarcoma.

Genetics Home Reference: Maffucci syndrome

MedlinePlus

... particular, affected individuals may develop bone cancers called chondrosarcomas, especially in the skull. People with Maffucci syndrome ... into Enchondroma, Enchondromatosis and the risk of secondary Chondrosarcoma. Review of the literature with an emphasis on ...

Use of MicroRNA biomarkers to distinguish enchondroma from low-grade chondrosarcoma.

PubMed

Zhang, Liang; Yang, Maozhou; Mayer, Theodore; Johnstone, Brian; Les, Clifford; Frisch, Nicholas; Parsons, Theodore; Mi, Qing-Sheng; Gibson, Gary

2017-03-01

Establishing a definitive diagnosis between benign enchondroma versus low-grade chondrosarcoma presents a potential challenge to both clinicians and pathologists. microRNAs (small non-coding RNAs) have proven to be effective biomarkers for the identification of tumors and tumor progression. We present analysis, both array and quantitative PCR, that shows consistently and substantially increased expression of two microRNAs, miRs-181a and -138, in low-grade chondrosarcomas compared with enchondromas. The data suggest these microRNAs would provide an analytical distinction between the chondrosarcoma and benign neoplasms that can be performed in formalin-fixed paraffin-embedded specimens. Together with recent publications, these data indicate that miRs-181a and -138 also play a role in tumor development and homeostasis and may provide new targets for the development of much needed therapeutic intervention.

Fluid shear promotes chondrosarcoma cell invasion by activating matrix metalloproteinase 12 via IGF-2 and VEGF signaling pathways

PubMed Central

Wang, P; Chen, S-H; Hung, W-C; Paul, C; Zhu, F; Guan, P-P; Huso, DL; Kontrogianni-Konstantopoulos, A; Konstantopoulos, K

2015-01-01

Interstitial fluid flow in and around the tumor tissue is a physiologically relevant mechanical signal that regulates intracellular signaling pathways throughout the tumor. Yet, the effects of interstitial flow and associated fluid shear stress on the tumor cell function have been largely overlooked. Using in vitro bioengineering models in conjunction with molecular cell biology tools, we found that fluid shear (2 dyn/cm2) markedly upregulates matrix metalloproteinase 12 (MMP-12) expression and its activity in human chondrosarcoma cells. MMP-12 expression is induced in human chondrocytes during malignant transformation. However, the signaling pathway regulating MMP-12 expression and its potential role in human chondrosarcoma cell invasion and metastasis have yet to be delineated. We discovered that fluid shear stress induces the synthesis of insulin growth factor-2 (IGF-2) and vascular endothelial growth factor (VEGF) B and D, which in turn transactivate MMP-12 via PI3-K, p38 and JNK signaling pathways. IGF-2-, VEGF-B- or VEGF-D-stimulated chondrosarcoma cells display markedly higher migratory and invasive potentials in vitro, which are blocked by inhibiting MMP-12, PI3-K, p38 or JNK activity. Moreover, recombinant human MMP-12 or MMP-12 overexpression can potentiate chondrosarcoma cell invasion in vitro and the lung colonization in vivo. By reconstructing and delineating the signaling pathway regulating MMP-12 activation, potential therapeutic strategies that interfere with chondrosarcoma cell invasion may be identified. PMID:25435370

Fluid shear promotes chondrosarcoma cell invasion by activating matrix metalloproteinase 12 via IGF-2 and VEGF signaling pathways.

PubMed

Wang, P; Chen, S-H; Hung, W-C; Paul, C; Zhu, F; Guan, P-P; Huso, D L; Kontrogianni-Konstantopoulos, A; Konstantopoulos, K

2015-08-27

Interstitial fluid flow in and around the tumor tissue is a physiologically relevant mechanical signal that regulates intracellular signaling pathways throughout the tumor. Yet, the effects of interstitial flow and associated fluid shear stress on the tumor cell function have been largely overlooked. Using in vitro bioengineering models in conjunction with molecular cell biology tools, we found that fluid shear (2 dyn/cm(2)) markedly upregulates matrix metalloproteinase 12 (MMP-12) expression and its activity in human chondrosarcoma cells. MMP-12 expression is induced in human chondrocytes during malignant transformation. However, the signaling pathway regulating MMP-12 expression and its potential role in human chondrosarcoma cell invasion and metastasis have yet to be delineated. We discovered that fluid shear stress induces the synthesis of insulin growth factor-2 (IGF-2) and vascular endothelial growth factor (VEGF) B and D, which in turn transactivate MMP-12 via PI3-K, p38 and JNK signaling pathways. IGF-2-, VEGF-B- or VEGF-D-stimulated chondrosarcoma cells display markedly higher migratory and invasive potentials in vitro, which are blocked by inhibiting MMP-12, PI3-K, p38 or JNK activity. Moreover, recombinant human MMP-12 or MMP-12 overexpression can potentiate chondrosarcoma cell invasion in vitro and the lung colonization in vivo. By reconstructing and delineating the signaling pathway regulating MMP-12 activation, potential therapeutic strategies that interfere with chondrosarcoma cell invasion may be identified.

Dedifferentiated chondrosarcoma with telangiectatic osteosarcoma‐like features

PubMed Central

Okada, K; Hasegawa, T; Tateishi, U; Endo, M; Itoi, E

2006-01-01

A 35‐year‐old Japanese man was admitted to the National Cancer Center, Tokyo, Japan, in December 2000, with a 2‐month history of pain around the left thigh. Radiographs showed a poorly demarcated osteolytic lesion with focal mineralisation and endosteal scalloping in the left proximal femur. Biopsy showed a proliferation of highly anaplastic cells without any cartilaginous component. A wide excision of the left proximal femur with a replacement by endoprosthesis was carried out in February 2001 after treatment with methotrexate and 20 Gy radiation therapy. Pathological examination of the surgical specimen showed a focus of low‐grade chondrosarcoma and the coexistence of telangiectatic osteosarcoma‐like features. The patient was diagnosed with dedifferentiated chondrosarcoma with telangiectatic osteosarcoma‐like features. Lung metastasis appeared in July 2001 despite an adjuvant chemotherapy including methotrexate, cis‐platinum and doxorubicin. The latest follow‐up study in June 2004 showed multiple lung metastases. Establishing a definitive diagnosis of dedifferentiated chondrosarcoma may be difficult with limited small biopsy specimens. Dedifferentiated chondrosarcoma should be included in the differential diagnosis of osteolytic tumours with focal calcification and endosteal scalloping even if an extraosseous tumour component is not identified. PMID:17071806

Regulation and Biological Significance of Formation of Osteoclasts and Foreign Body Giant Cells in an Extraskeletal Implantation Model

PubMed Central

Ahmed, Gazi Jased; Tatsukawa, Eri; Morishita, Kota; Shibata, Yasuaki; Suehiro, Fumio; Kamitakahara, Masanobu; Yokoi, Taishi; Koji, Takehiko; Umeda, Masahiro; Nishimura, Masahiro; Ikeda, Tohru

2016-01-01

The implantation of biomaterials induces a granulomatous reaction accompanied by foreign body giant cells (FBGCs). The characterization of multinucleated giant cells (MNGCs) around bone substitutes implanted in bone defects is more complicated because of healing with bone admixed with residual bone substitutes and their hybrid, and the appearance of two kinds of MNGCs, osteoclasts and FBGCs. Furthermore, the clinical significance of osteoclasts and FBGCs in the healing of implanted regions remains unclear. The aim of the present study was to characterize MNGCs around bone substitutes using an extraskeletal implantation model and evaluate the clinical significance of osteoclasts and FBGCs. Beta-tricalcium phosphate (β-TCP) granules were implanted into rat subcutaneous tissue with or without bone marrow mesenchymal cells (BMMCs), which include osteogenic progenitor cells. We also compared the biological significance of plasma and purified fibrin, which were used as binders for implants. Twelve weeks after implantation, osteogenesis was only detected in specimens implanted with BMMCs. The expression of two typical osteoclast markers, tartrate-resistant acid phosphatase (TRAP) and cathepsin-K (CTSK), was analyzed, and TRAP-positive and CTSK-positive osteoclasts were only detected beside bone. In contrast, most of the MNGCs in specimens without the implantation of BMMCs were FBGCs that were negative for TRAP, whereas the degradation of β-TCP was detected. In the region implanted with β-TCP granules with plasma, FBGCs tested positive for CTSK, and when β-TCP granules were implanted with purified fibrin, FBGCs tested negative for CTSK. These results showed that osteogenesis was essential to osteoclastogenesis, two kinds of FBGCs, CTSK-positive and CTSK-negative, were induced, and the expression of CTSK was plasma-dependent. In addition, the implantation of BMMCs was suggested to contribute to osteogenesis and the replacement of implanted β-TCP granules to bone. PMID:27462135

Genomic and Expression Profiling of Benign & Malignant Nerve Sheath Tumors in Neurofibromatosis Patients

DTIC Science & Technology

2006-05-01

high grade chondrosarcoma (1/8), Ewing sarcoma (1/13 cases), MPNST (4/88), gastrointestinal stromal tumor (1/34) and leiomyosarcoma (1/41) were...Alveolar rhabdomyosarcoma; ASPS: Alveolar soft parts sarcoma; BS Benign schwannoma; CCS: Clear cell sarcoma; CSa: Chondrosarcoma ; DFSP...0 1 2 4 1 14 Clear Cell Sarcoma 7 1 0 1 5 1 14 Chondrosarcoma , high grade 8 0 1 0 7 1 13 Ewing Sarcoma 13 1 0 1 11 1 8 GIST 35 0 2 7 26 2 6

Severe Hypocalcemia in a Patient with Recurrent Chondrosarcoma.

PubMed

Eun, Jung Nam; Choi, Yoo Duk; Lee, Jeong Ho; Jeong, Yun Ah; Yoon, Jee Hee; Kim, Hee Kyung; Kang, Ho-Cheol

2017-01-01

Hypocalcemia is relatively uncommon paraneoplastic syndrome. Only one case of hypocalcemia has been reported in a patient with chondrosarcoma. We herein report a case of a 32-year-old woman with metastatic chondrosarcoma with tetany. Her imaging findings revealed multiple calcific metastatic lesions in the lungs, pancreas, left atrium, and pulmonary vein. A laboratory examination showed hypocalcemia with no evidence of any other disease that could induce hypocalcemia. On the basis of the laboratory and clinical findings, we concluded the etiology of her severe hypocalcemia to be excessive calcium consumption by the tumor itself.

Secondary Chondrosarcoma of the Upper Thoracic Costovertebral Junction with Neural Foraminal Extension and Compressing the Spinal Cord.

PubMed

Bouali, Sofiene; Bouhoula, Asma; Maatar, Nidhal; Abderrahmen, Khansa; Boubaker, Adnen; Kallel, Jalel; Jemel, Hafedh

2016-08-01

Chondrosarcoma is a rare malignant tumor of bone. This family of tumors can be primary malignant tumors or a secondary malignant transformation of an underlying benign cartilage tumor. Secondary chondrosarcoma arising from a benign solitary costal osteochondroma is extremely rare. Data show that the reported incidence of costal osteochondroma is very low and they are usually found in the anterior region at the costochondral junction. To our knowledge, however, there have been no previous reports, in English literature, describing osteochondroma malignant transformation located in the thoracic costovertebral junction. We report the case of a man with chondrosarcoma arising from the malignant degeneration of an osteochondroma at the right first thoracic costovertebral junction with neural foraminal extension and compressing the spinal cord. Although it is rare in solitary osteochondromas of rib, malignant transformation must always be considered. Copyright © 2016 Elsevier Inc. All rights reserved.

Endoscopic Endonasal Approach in Skull Base Chondrosarcoma Associated with Maffucci Syndrome: Case Series and Literature Review.

PubMed

Beer-Furlan, André; Balsalobre, Leonardo; Vellutini, Eduardo A S; Stamm, Aldo C

2016-01-01

Maffucci syndrome is a nonhereditary disorder in which patients develop multiple enchondromas and cutaneous, visceral, or soft tissue hemangiomas. The potential malignant progression of enchondroma into a secondary chondrosarcoma is a well-known fact. Nevertheless, chondrosarcoma located at the skull base in patients with Maffuci syndrome is a very rare condition, with only 18 cases reported in the literature. We report 2 other cases successfully treated through an expanded endoscopic endonasal approach and discuss the condition based on the literature review. Skull base chondrosarcoma associated with Maffucci syndrome is a rare condition. The disease cannot be cured, therefore surgical treatment should be performed in symptomatic patients aiming for maximal tumor resection with function preservation. The endoscopic endonasal approach is a safe and reliable alternative for the management of these tumors. Copyright © 2016 Elsevier Inc. All rights reserved.

Digital PCR analysis of circulating tumor DNA: a biomarker for chondrosarcoma diagnosis, prognostication, and residual disease detection.

PubMed

Gutteridge, Alice; Rathbone, Victoria M; Gibbons, Rebecca; Bi, Mark; Archard, Nicholas; Davies, Kate E J; Brown, Jake; Plagnol, Vincent; Pillay, Nischalan; Amary, Fernanda; O'Donnell, Paul; Gupta, Manu; Tirabosco, Roberto; Flanagan, Adrienne M; Forshew, Tim

2017-10-01

Conventional chondrosarcoma is the most common primary bone tumor in adults. Prognosis corresponds with tumor grade but remains variable, especially for individuals with grade (G) II disease. There are currently no biomarkers available for monitoring or prognostication of chondrosarcoma. Circulating tumor DNA (ctDNA) has recently emerged as a promising biomarker for a broad range of tumor types. To date, little has been done to study the presence of ctDNA and its potential utility in the management of sarcomas, including chondrosarcoma. In this study, we have assessed ctDNA levels in a cohort of 71 patients, 32 with sarcoma, including 29 individuals with central chondrosarcoma (CS) and 39 with locally aggressive and benign bone and soft tissue tumors, using digital PCR. In patients with CS, ctDNA was detected in pretreatment samples in 14/29 patients, which showed clear correlation with tumor grade as demonstrated by the detection of ctDNA in all patients with GIII and dedifferentiated disease (n = 6) and in 8/17 patients with GII disease, but never associated with GI CS. Notably detection of ctDNA preoperatively in GII disease was associated with a poor outcome. A total of 14 patients with CS had ctDNA levels assessed at multiple time points and in most patients there was a clear reduction following surgical removal. This research lays the foundation for larger studies to assess the utility of ctDNA for chondrosarcoma diagnosis, prognostication, early detection of residual disease and monitoring disease progression. © 2017 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Management of tracheal chondrosarcoma almost completely obstructing the airway: a case report.

PubMed

Andolfi, Marco; Vaccarili, Maurizio; Crisci, Roberto; Puma, Francesco

2016-07-11

Primary malignant tracheal tumors account for only 0.2 % of all malignancies of the respiratory tract. Tracheal chondrosarcoma is a rare condition and only 17 cases have been described in the literature from 1965 to date. Herein we report the very unusual case of a patient with a tracheal chondrosarcoma, electively treated by curative surgery despite the virtually complete obstruction of the airway. We present the case of a 79-year old Caucasian man with long-lasting wheezing misdiagnosed as asthma and affected by a tracheal chondrosarcoma almost completely obstructing the airway. Videobronchoscopy and imaging investigations revealed a well-circumscribed mass arising from the cartilaginous rings of the cervical trachea with a posterior residual respiratory space of about 1 mm. Because of the mobility and flaccidity of the uninvolved pars membranacea, the tiny respiratory space slightly expanded during inspiration and expiration allowing the patient to be treated without an essential emergency procedure. Standard tracheal intubation was impossible. Rigid bronchoscopy enabled placement of a small tracheal tube distally to the tumor. Successful cervical tracheal resection and reconstruction was then performed, achieving complete tumor excision. Histologically, the mass was characterized as a low-grade tracheal chondrosarcoma. Videobronchoscopy performed 9 months after surgery showed a wide, well healed tracheal anastomosis. Ten months after surgery, the patient is alive and disease free. Complete surgical resection is the treatment of choice for tracheal chondrosarcoma. Rigid bronchoscopy is an essential tool for diagnostic and therapeutic purposes. It allows the palliative maneuvers for obstruction relief but also, in resectable patients, the intraoperative safe and straightforward management of the obstructed airway.

Inhibiting ROS-TFEB-Dependent Autophagy Enhances Salidroside-Induced Apoptosis in Human Chondrosarcoma Cells.

PubMed

Zeng, Wei; Xiao, Tao; Cai, Anlie; Cai, Weiliang; Liu, Huanhuan; Liu, Jingling; Li, Jie; Tan, Miduo; Xie, Li; Liu, Ying; Yang, Xiangcheng; Long, Yi

2017-01-01

Autophagy modulation has been considered a potential therapeutic strategy for human chondrosarcoma, and a previous study indicated that salidroside exhibits significant anti-carcinogenic activity. However, the ability of salidroside to induce autophagy and its role in human chondrosarcoma cell death remains unclear. We exposed SW1353 cells to different concentrations of salidroside (0.5, 1 and 2 mM) for 24 h. RT-PCR, Western-blotting, Immunocytofluorescence, and Luciferase Reporter Assays were used to evaluate whether salidroside activated the TFEB-dependent autophagy. We show that salidroside induced significant apoptosis in the human chondrosarcoma cell line SW1353. In addition, we demonstrate that salidroside-induced an autophagic response in SW1353 cells, as evidenced by the upregulation of LC3-II and downregulation of P62. Moreover, pharmacological or genetic blocking of autophagy enhanced salidroside -induced apoptosis, indicating the cytoprotective role of autophagy in salidroside-treated SW1353 cells. Salidroside also induced TFEB (Ser142) dephosphorylation, subsequently to activated TFEB nuclear translocation and increase of TFEB reporter activity, which contributed to lysosomal biogenesis and the expression of autophagy-related genes. Importantly, we found that salidroside triggered the generation of ROS in SW1353 cells. Furthermore, NAC, a ROS scavenger, abrogated the effects of salidroside on TFEB-dependent autophagy. These data demonstrate that salidroside increased TFEB-dependent autophagy by activating ROS signaling pathways in human chondrosarcoma cells. These data also suggest that blocking ROS-TFEB-dependent autophagy to enhance the activity of salidroside warrants further attention in treatment of human chondrosarcoma cells. © 2017 The Author(s). Published by S. Karger AG, Basel.

TCF-1 participates in the occurrence of dedifferentiated chondrosarcoma.

PubMed

Xu, Xiaolong; Tang, Xiaodong; Guo, Wei; Yang, Kang; Ren, Tingting

2016-10-01

The present study demonstrated that T cell factor 1 (TCF-1) protein, a component of the canonical Wnt/β-catenin signaling pathway, can regulate the expression of runt-related transcription factor 2 (runx2) gene and Sry-related HMG box 9 (sox9) gene, which may participate in the differentiation of chondrosarcoma. Dedifferentiated chondrosarcoma (DDCS) is a special variant of conventional chondrosarcoma (CCS), associated with poor survival and high metastasis rate. However, little is known about the mechanism of its occurrence; thus, no effective treatment is available except surgery. Earlier, high expression of runx2 and low expression of sox9 were found in DDCS compared with CCS. Using Western blot to detect clinical tissue samples (including 8 CCS samples and 8 DDCS samples) and immunohistochemistry to detect 85 different-grade chondrosarcoma specimens, a high expression of TCF-1 in DDCS tissues was found compared with CCS tissues. This difference in expression was related to patients' prognosis. Results of luciferase, chromatin immunoprecipitation, and gel electrophoresis mobility shift assays demonstrated that TCF-1 protein could bind to the promoter of runx2 gene directly and sox9 gene indirectly. Hence, it could regulate expression of runx2 gene positively and sox9 gene negatively. Furthermore, in vitro and in vivo experiments showed that TCF-1 protein was closely related to the phenotype and aggressiveness of chondrosarcoma. In conclusion, this study proved that TCF-1 participates in the dedifferentiation of DDCS, which may be mediated by runx2 gene and sox9 gene. Also, TCF-1 can be of important prognostic value and a promising therapeutic target for DDCS patients.

Functional and oncological outcome after surgical resection of the scapula and clavicle for primary chondrosarcoma.

PubMed

Nota, S P F T; Russchen, M J A M; Raskin, K A; Mankin, H J; Hornicek, F J; Schwab, J H

2017-04-01

The scapula is a relatively common site for chondrosarcoma to develop in contrary to the clavicle, which is rarely affected by these tumors. The aim of this study is to determine the functional and oncological outcome for patients treated operatively for scapular or clavicular chondrosarcoma. In this single-center retrospective study, we included a sample of 20 patients that received the diagnosis of a primary chondrosarcoma of the scapula or clavicle. Of the surviving patients, the functional function was assessed using the DASH and the PROMIS Physical Function-Upper Extremity. Patients were longitudinally tracked for their oncological outcome. All patients were followed for at least 2 years or until death. The mean age of the cohort was 47 years. Eighteen patients suffered from a chondrosarcoma of the scapula, and in 2 patients, the tumor was located in the clavicle. Metastasis, local recurrence and a higher tumor grade were all associated with a decreased overall survival. For the patients with a chondrosarcoma of the scapula, the average DASH score was 16 ± 16 and the mean PROMIS Physical Function-Upper Extremity score was 48 ± 10. Patients with both an intact rotator cuff and glenoid had a better physical function. Upper extremity function after (partial) scapulectomy varied depending on whether the glenoid was spared and whether a functioning shoulder abductor remained. When the resection spared these structures, then excellent functional outcomes were reported. Oncologic outcomes depended upon the grade of the tumor and whether local recurrence and metastases occurred.

Activation of Hedgehog signaling by loss of GNAS causes heterotopic ossification

PubMed Central

Regard, Jean B.; Malhotra, Deepti; Gvozdenovic-Jeremic, Jelena; Josey, Michelle; Chen, Min; Weinstein, Lee S.; Lu, Jianming; Shore, Eileen M.; Kaplan, Frederick S.; Yang, Yingzi

2014-01-01

Bone formation is exquisitely controlled in space and time. Heterotopic ossification (HO), the pathologic formation of extra-skeletal bone, occurs as a common complication of trauma or in genetic disorders and can be disabling and lethal. However, the underlying molecular mechanisms are largely unknown. Here we demonstrate that Gαs restricts bone formation to the skeleton by inhibiting Hedgehog (Hh) signaling in mesenchymal progenitor cells. In progressive osseous heteroplasia (POH), a human disease caused by null mutations in GNAS that encodes Gαs, HH signaling is upregulated in ectopic osteoblasts and progenitor cells. Ectopic Hh signaling is sufficient to induce HO, while Hh signaling inhibition blocks HO in animal models. As our previous work has shown that GNAS gain of function mutations upregulate WNT/β-Catenin signaling in fibrous dysplasia (FD), our findings identify Gαs as a critical regulator of osteoblast differentiation by maintaining a balance between two key signaling pathways: Wnt/β-catenin and Hh. HH signaling inhibitors developed for cancer therapy may be repurposed to treat HO and other diseases caused by GNAS inactivation. PMID:24076664

Severe Hypocalcemia in a Patient with Recurrent Chondrosarcoma

PubMed Central

Eun, Jung Nam; Choi, Yoo Duk; Lee, Jeong Ho; Jeong, Yun Ah; Yoon, Jee Hee; Kim, Hee Kyung; Kang, Ho-Cheol

2017-01-01

Hypocalcemia is relatively uncommon paraneoplastic syndrome. Only one case of hypocalcemia has been reported in a patient with chondrosarcoma. We herein report a case of a 32-year-old woman with metastatic chondrosarcoma with tetany. Her imaging findings revealed multiple calcific metastatic lesions in the lungs, pancreas, left atrium, and pulmonary vein. A laboratory examination showed hypocalcemia with no evidence of any other disease that could induce hypocalcemia. On the basis of the laboratory and clinical findings, we concluded the etiology of her severe hypocalcemia to be excessive calcium consumption by the tumor itself. PMID:28717079

Unique mutation portraits and frequent COL2A1 gene alteration in chondrosarcoma

PubMed Central

Totoki, Yasushi; Yoshida, Akihiko; Hosoda, Fumie; Nakamura, Hiromi; Hama, Natsuko; Ogura, Koichi; Yoshida, Aki; Fujiwara, Tomohiro; Arai, Yasuhito; Toguchida, Junya; Tsuda, Hitoshi; Miyano, Satoru; Kawai, Akira

2014-01-01

Chondrosarcoma is the second most frequent malignant bone tumor. However, the etiological background of chondrosarcomagenesis remains largely unknown, along with details on molecular alterations and potential therapeutic targets. Massively parallel paired-end sequencing of whole genomes of 10 primary chondrosarcomas revealed that the process of accumulation of somatic mutations is homogeneous irrespective of the pathological subtype or the presence of IDH1 mutations, is unique among a range of cancer types, and shares significant commonalities with that of prostate cancer. Clusters of structural alterations localized within a single chromosome were observed in four cases. Combined with targeted resequencing of additional cartilaginous tumor cohorts, we identified somatic alterations of the COL2A1 gene, which encodes an essential extracellular matrix protein in chondroskeletal development, in 19.3% of chondrosarcoma and 31.7% of enchondroma cases. Epigenetic regulators (IDH1 and YEATS2) and an activin/BMP signal component (ACVR2A) were recurrently altered. Furthermore, a novel FN1-ACVR2A fusion transcript was observed in both chondrosarcoma and osteochondromatosis cases. With the characteristic accumulative process of somatic changes as a background, molecular defects in chondrogenesis and aberrant epigenetic control are primarily causative of both benign and malignant cartilaginous tumors. PMID:25024164

Comparison of clinical and functional outcome between surgical treatment and carbon ion radiotherapy for pelvic chondrosarcoma.

PubMed

Outani, Hidetatsu; Hamada, Kenichiro; Imura, Yoshinori; Oshima, Kazuya; Sotobori, Tsukasa; Demizu, Yusuke; Kakunaga, Shigeki; Joyama, Susumu; Imai, Reiko; Okimoto, Tomoaki; Naka, Norifumi; Kudawara, Ikuo; Ueda, Takafumi; Araki, Nobuhito; Kamada, Tadashi; Yoshikawa, Hideki

2016-02-01

As there are no reports of studies in patients with pelvic chondrosarcoma treated with carbon ion radiotherapy (CIRT), the aim of this study was to evaluate the applicability of CIRT for patients with chondrosarcoma of the pelvis. The medical records of 31 patients with chondrosarcoma of the pelvis treated either by surgical resection or by CIRT between 1983 and 2014 were reviewed. There were 22 males and 9 females with a median age of 43 years (range 16-77 years). The median duration of follow-up was 66 months (range 5-289 months). Twenty-four patients underwent surgery, and 7 patients received CIRT (70.4 GyE in 16 fractions over 4 weeks). The overall local recurrence rate was 32 %, and the estimated overall 5- and 10-year survival rates were 72 and 57 %, respectively. The mean Musculoskeletal Tumor Society functional score was 59 %. The treatment procedures (surgery or CIRT) did not affect overall survival (P = 0.347). However, the patients who underwent surgery had impaired function compared with those who received CIRT (P = 0.03). Although more patients need to be monitored to assess the clinical and functional outcomes of CIRT for patients with chondrosarcoma of the pelvis, this treatment might offer an acceptable alternative.

Pre- and postoperative radiotherapy for extremity soft tissue sarcoma: Evaluation of inter-observer target volume contouring variability among French sarcoma group radiation oncologists.

PubMed

Sargos, P; Charleux, T; Haas, R L; Michot, A; Llacer, C; Moureau-Zabotto, L; Vogin, G; Le Péchoux, C; Verry, C; Ducassou, A; Delannes, M; Mervoyer, A; Wiazzane, N; Thariat, J; Sunyach, M P; Benchalal, M; Laredo, J D; Kind, M; Gillon, P; Kantor, G

2018-04-01

The purpose of this study was to evaluate, during a national workshop, the inter-observer variability in target volume delineation for primary extremity soft tissue sarcoma radiation therapy. Six expert sarcoma radiation oncologists (members of French Sarcoma Group) received two extremity soft tissue sarcoma radiation therapy cases 1: one preoperative and one postoperative. They were distributed with instructions for contouring gross tumour volume or reconstructed gross tumour volume, clinical target volume and to propose a planning target volume. The preoperative radiation therapy case was a patient with a grade 1 extraskeletal myxoid chondrosarcoma of the thigh. The postoperative case was a patient with a grade 3 pleomorphic undifferentiated sarcoma of the thigh. Contour agreement analysis was performed using kappa statistics. For the preoperative case, contouring agreement regarding GTV, gross tumour volume GTV, clinical target volume and planning target volume were substantial (kappa between 0.68 and 0.77). In the postoperative case, the agreement was only fair for reconstructed gross tumour volume (kappa: 0.38) but moderate for clinical target volume and planning target volume (kappa: 0.42). During the workshop discussion, consensus was reached on most of the contour divergences especially clinical target volume longitudinal extension. The determination of a limited cutaneous cover was also discussed. Accurate delineation of target volume appears to be a crucial element to ensure multicenter clinical trial quality assessment, reproducibility and homogeneity in delivering RT. radiation therapy RT. Quality assessment process should be proposed in this setting. We have shown in our study that preoperative radiation therapy of extremity soft tissue sarcoma has less inter-observer contouring variability. Copyright © 2018 Société française de radiothérapie oncologique (SFRO). Published by Elsevier SAS. All rights reserved.

The potential role of free chitosan in bone trauma and bone cancer management.

PubMed

Tan, Mei L; Shao, Peng; Friedhuber, Anna M; van Moorst, Mallory; Elahy, Mina; Indumathy, Sivanjah; Dunstan, Dave E; Wei, Yongzhong; Dass, Crispin R

2014-09-01

Bone defects caused by fractures or cancer-mediated destruction are debilitating. Chitosan is commonly used in scaffold matrices for bone healing, but rarely as a free drug. We demonstrate that free chitosan promotes osteoblast proliferation and osteogenesis in mesenchymal stem cells, increases osteopontin and collagen I expression, and reduces osteoclastogenesis. Chitosan inhibits invasion of endothelial cells, downregulating uPA/R, MT1-MMP, cdc42 and Rac1. Better healing of bone fractures with greater trabecular bone formation was observed in mice treated with chitosan. Chitosan induces apoptosis in osteotropic prostate and breast cancer cells via caspase-2 and -3 activation, and reduces their establishment in bone. Chitosan is pro-apoptotic in osteosarcoma cells, but not their normal counterpart, osteoblasts, or chondrosarcoma cells. Systemic delivery of chitosan does not perturb angiogenesis, bone volume or instinctive behaviour in pregnant mice, but decreases foetal length and changes pancreatic secretory acini. With certain controls in place, chitosan could be useful for bone trauma management. Copyright © 2014 Elsevier Ltd. All rights reserved.

Development and characterization of a human three-dimensional chondrosarcoma culture for in vitro drug testing.

PubMed

Voissiere, Aurélien; Jouberton, Elodie; Maubert, Elise; Degoul, Françoise; Peyrode, Caroline; Chezal, Jean-Michel; Miot-Noirault, Élisabeth

2017-01-01

It has been suggested that chemoresistance of chondrosarcoma (CHS), the cartilage tumor, is caused by the phenotypic microenvironmental features of the tumor tissue, mainly the chondrogenic extracellular matrix (ECM), and hypoxia. We developed and characterized a multicellular tumor spheroid (MCTS) of human chondrosarcoma HEMC-SS cells to gain insight into tumor cell biology and drug response. At Day 7, HEMC-SS spheroids exhibited a homogeneous distribution of proliferative Ki-67 positive cells, whereas in larger spheroids (Day 14 and Day 20), proliferation was mainly localized in the periphery. In the core of larger spheroids, apoptotic cells were evidenced by TUNEL assay, and hypoxia by pimonidazole staining. Interestingly, VEGF excretion, evidenced by ELISA on culture media, was detectable from Day 14 spheroids, and increased as the spheroids grew in size. HEMC-SS spheroids synthesized a chondrogenic extracellular matrix rich in glycosaminoglycans and type-2 collagen. Finally, we investigated the sensitivity of Day 7 and Day 14 chondrosarcoma MCTS to hypoxia-activated prodrug TH-302 and doxorubicin compared with their 2D counterparts. As expected, TH-302 exhibited higher cytotoxic activity on larger hypoxic spheroids (Day 14) than on non-hypoxic spheroids (Day 7), with multicellular resistance index (MCRI) values of 7.7 and 9.1 respectively. For doxorubicin, the larger-sized spheroids exhibited higher drug resistance (MCRI of 5.0 for Day 7 and 18.3 for Day 14 spheroids), possibly due to impeded drug penetration into the deep layer of spheroids, evidenced by its auto-fluorescence property. We have developed a model of human chondrosarcoma MCTS that combines an ECM rich in glycosaminoglycans with a high hypoxic core associated with VEGF excretion. This model could offer a more predictive in vitro chondrosarcoma system for screening drugs targeting tumor cells and their microenvironment.

Proteoglycans as Target for an Innovative Therapeutic Approach in Chondrosarcoma: Preclinical Proof of Concept.

PubMed

Peyrode, Caroline; Weber, Valérie; Voissière, Aurélien; Maisonial-Besset, Aurélie; Vidal, Aurélien; Auzeloux, Philippe; Gaumet, Vincent; Borel, Michèle; Dauplat, Marie-Mélanie; Quintana, Mercedes; Degoul, Françoise; Rédini, Françoise; Chezal, Jean-Michel; Miot-Noirault, Elisabeth

2016-11-01

To date, surgery remains the only option for the treatment of chondrosarcoma, which is radio- and chemoresistant due in part to its large extracellular matrix (ECM) and poor vascularity. In case of unresectable locally advanced or metastatic diseases with a poor prognosis, improving the management of chondrosarcoma still remains a challenge. Our team developed an attractive approach of improvement of the therapeutic index of chemotherapy by targeting proteoglycan (PG)-rich tissues using a quaternary ammonium (QA) function conjugated to melphalan (Mel). First of all, we demonstrated the crucial role of the QA carrier for binding to aggrecan by surface plasmon resonance. In the orthotopic model of Swarm rat chondrosarcoma, an in vivo biodistribution study of Mel and its QA derivative (Mel-QA), radiolabeled with tritium, showed rapid radioactivity accumulation in healthy cartilaginous tissues and tumor after [ 3 H]-Mel-QA injection. The higher T/M ratio of the QA derivative suggests some advantage of QA-active targeting of chondrosarcoma. The antitumoral effects were characterized by tumor volume assessment, in vivo 99m Tc-NTP 15-5 scintigraphic imaging of PGs, 1 H-HRMAS NMR spectroscopy, and histology. The conjugation of a QA function to Mel did not hamper its in vivo efficiency and strongly improved the tolerability of Mel leading to a significant decrease of side effects (hematologic analyses and body weight monitoring). Thus, QA conjugation leads to a significant improvement of the therapeutic index, which is essential in oncology and enable repeated cycles of chemotherapy in patients with chondrosarcoma. Mol Cancer Ther; 15(11); 2575-85. ©2016 AACR. ©2016 American Association for Cancer Research.

Toll like receptors TLR1/2, TLR6 and MUC5B as binding interaction partners with cytostatic proline rich polypeptide 1 in human chondrosarcoma.

PubMed

Galoian, Karina; Abrahamyan, Silva; Chailyan, Gor; Qureshi, Amir; Patel, Parthik; Metser, Gil; Moran, Alexandra; Sahakyan, Inesa; Tumasyan, Narine; Lee, Albert; Davtyan, Tigran; Chailyan, Samvel; Galoyan, Armen

2018-01-01

Metastatic chondrosarcoma is a bone malignancy not responsive to conventional therapies; new approaches and therapies are urgently needed. We have previously reported that mTORC1 inhibitor, antitumorigenic cytostatic proline rich polypeptide 1 (PRP-1), galarmin caused a significant upregulation of tumor suppressors including TET1/2 and SOCS3 (known to be involved in inflammatory processes), downregulation of oncoproteins and embryonic stem cell marker miR-302C and its targets Nanog, c-Myc and Bmi-1 in human chondrosarcoma. To understand better the mechanism of PRP-1 action it was very important to identify the receptor it binds to. Nuclear pathway receptor and GPCR assays indicated that PRP-1 receptors are not G protein coupled, neither do they belong to family of nuclear or orphan receptors. In the present study, we have demonstrated that PRP-1 binding interacting partners belong to innate immunity pattern recognition toll like receptors TLR1/2 and TLR6 and gel forming secreted mucin MUC5B. MUC5B was identified as PRP-1 receptor in human chondrosarcoma JJ012 cell line using Ligand-receptor capture technology. Toll like receptors TLR1/2 and TLR6 were identified as binding interaction partners with PRP-1 by western blot analysis in human chondrosarcoma JJ012 cell line lysates. Immunocytochemistry experiments confirmed the finding and indicated the localization of PRP-1 receptors in the tumor nucleus predominantly. TLR1/2, TLR6 and MUC5B were downregulated in human chondrosarcoma and upregulated in dose-response manner upon PRP-1 treatment. Experimental data indicated that in this cellular context the mentioned receptors had tumor suppressive function.

AMP-activated protein kinase activation mediates CCL3-induced cell migration and matrix metalloproteinase-2 expression in human chondrosarcoma

PubMed Central

2013-01-01

Chemokine (C-C motif) ligand 3 (CCL3), also known as macrophage inflammatory protein-1α, is a cytokine involved in inflammation and activation of polymorphonuclear leukocytes. CCL3 has been detected in infiltrating cells and tumor cells. Chondrosarcoma is a highly malignant tumor that causes distant metastasis. However, the effect of CCL3 on human chondrosarcoma metastasis is still unknown. Here, we found that CCL3 increased cellular migration and expression of matrix metalloproteinase (MMP)-2 in human chondrosarcoma cells. Pre-treatment of cells with the MMP-2 inhibitor or transfection with MMP-2 specific siRNA abolished CCL3-induced cell migration. CCL3 has been reported to exert its effects through activation of its specific receptor, CC chemokine receptor 5 (CCR5). The CCR5 and AMP-activated protein kinase (AMPK) inhibitor or siRNA also attenuated CCL3-upregulated cell motility and MMP-2 expression. CCL3-induced expression of MMP-2 and migration were also inhibited by specific inhibitors, and inactive mutants of AMPK, p38 mitogen activated protein kinase (p38 or p38-MAPK), and nuclear factor κB (NF-κB) cascades. On the other hand, CCL3 treatment demonstrably activated AMPK, p38, and NF-κB signaling pathways. Furthermore, the expression levels of CCL3, CCR5, and MMP-2 were correlated in human chondrosarcoma specimens. Taken together, our results indicate that CCL3 enhances the migratory ability of human chondrosarcoma cells by increasing MMP-2 expression via the CCR5, AMPK, p38, and NF-κB pathways. PMID:24047437

Toll like receptors TLR1/2, TLR6 and MUC5B as binding interaction partners with cytostatic proline rich polypeptide 1 in human chondrosarcoma

PubMed Central

Galoian, Karina; Abrahamyan, Silva; Chailyan, Gor; Qureshi, Amir; Patel, Parthik; Metser, Gil; Moran, Alexandra; Sahakyan, Inesa; Tumasyan, Narine; Lee, Albert; Davtyan, Tigran; Chailyan, Samvel; Galoyan, Armen

2018-01-01

Metastatic chondrosarcoma is a bone malignancy not responsive to conventional therapies; new approaches and therapies are urgently needed. We have previously reported that mTORC1 inhibitor, antitumorigenic cytostatic proline rich polypeptide 1 (PRP-1), galarmin caused a significant upregulation of tumor suppressors including TET1/2 and SOCS3 (known to be involved in inflammatory processes), downregulation of oncoproteins and embryonic stem cell marker miR-302C and its targets Nanog, c-Myc and Bmi-1 in human chondrosarcoma. To understand better the mechanism of PRP-1 action it was very important to identify the receptor it binds to. Nuclear pathway receptor and GPCR assays indicated that PRP-1 receptors are not G protein coupled, neither do they belong to family of nuclear or orphan receptors. In the present study, we have demonstrated that PRP-1 binding interacting partners belong to innate immunity pattern recognition toll like receptors TLR1/2 and TLR6 and gel forming secreted mucin MUC5B. MUC5B was identified as PRP-1 receptor in human chondrosarcoma JJ012 cell line using Ligand-receptor capture technology. Toll like receptors TLR1/2 and TLR6 were identified as binding interaction partners with PRP-1 by western blot analysis in human chondrosarcoma JJ012 cell line lysates. Immunocytochemistry experiments confirmed the finding and indicated the localization of PRP-1 receptors in the tumor nucleus predominantly. TLR1/2, TLR6 and MUC5B were downregulated in human chondrosarcoma and upregulated in dose-response manner upon PRP-1 treatment. Experimental data indicated that in this cellular context the mentioned receptors had tumor suppressive function. PMID:29138803

Hyperkinetic transient ischemic attacks preceding deep ganglionic infarction in a patient with a treated parasellar chondrosarcoma.

PubMed

Ruff, Michael W; Bhargav, Adip G; English, Stephen W; Klaas, James P

2018-02-01

A 44-year-old right-handed female with a past medical history of parasellar chondrosarcoma status post-surgical debulking and proton beam therapy (70 Gy) three years prior to presentation experienced several hours of brief, repetitive episodes of transient hemiballism and dystonia; this was followed by abrupt onset of fixed hemiparesis and dysarthria weeks later, ipsilateral to her prior hyperkinetic movements. She was found to have total occlusion of the right middle cerebral artery with focal stenosis of the proximal right A-1 segment of the anterior cerebral artery adjacent to the remnants of the chondrosarcoma. These focal areas of narrowing were attributed to accelerated atherosclerotic disease, an adverse effect of the radiotherapy used to treat her chondrosarcoma. As treatments improve and mean survival increases for intracranial malignancy, radiation-induced atherosclerotic disease with protean manifestations such as those presented in this case may be encountered more frequently. Copyright © 2017 Elsevier Ltd. All rights reserved.

Dedifferentiated chondrosarcoma with "adamantinoma-like" features: A case report and review of literature.

PubMed

Gambarotti, M; Righi, A; Frisoni, T; Donati, D; Vanel, D; Sbaraglia, M; Dei Tos, A P

2017-06-01

Dedifferentiated chondrosarcoma is defined by the presence of a low grade malignant cartilaginous component juxtaposed to a high grade malignant non-cartilaginous sarcomatous components. Only 4 cases in which the high grade component showed epithelial differentiation have been reported in the literature; three featured a squamous and the one a glandular epithelial component. Here we describe a case of dedifferentiated chondrosarcoma exhibiting epithelial "adamantinoma-like" basaloid features. The patient underwent wide resection of the proximal tibia and post-operative chemotherapy and died 8 months after the diagnosis due to lung and bone metastases. Copyright © 2017 Elsevier GmbH. All rights reserved.

Biomarkers of Osteosarcoma, Chondrosarcoma, and Ewing Sarcoma.

PubMed

Evola, Francesco R; Costarella, Luciano; Pavone, Vito; Caff, Giuseppe; Cannavò, Luca; Sessa, Andrea; Avondo, Sergio; Sessa, Giuseppe

2017-01-01

Osteosarcoma is the most frequent malignant bone neoplasm, followed by chondrosarcoma and Ewing sarcoma. The diagnosis of bone neoplasms is generally made through histological evaluation of a biopsy. Clinical and radiological features are also important in aiding diagnosis and to complete the staging of bone cancer. In addition to these, there are several non-specific serological or specific molecular markers for bone neoplasms. In bone tumors, molecular markers increase the accuracy of the diagnosis and assist in subtyping bone tumors. Here, we review these markers and discuss their role in the diagnosis and prognosis of the three most frequent malignant bone neoplasms, namely osteosarcoma, chondrosarcoma, and Ewing sarcoma.

Doxycycline and its quaternary ammonium derivative for adjuvant therapies of chondrosarcoma.

PubMed

Miladi, Imen; Vivier, Magali; Dauplat, Marie-Mélanie; Chatard, Morgane; Besse, Sophie; Vidal, Aurélien; Chassain, Karine; Jean, Betty; Forestier, Christiane; Chezal, Jean-Michel; Rédini, Francoise; Degoul, Francoise; Miot-Noirault, Elisabeth

2017-09-01

This study was conducted during the development of innovative treatment targeting the microenvironment of chondrosarcoma. In this context, MMP inhibitors were conjugated with a quaternary ammonium (QA) function as a targeting ligand to proteoglycans of chondrosarcoma extracellular matrix. Here we report the proof of concept of this strategy applied to the MMP13 inhibitor, doxycycline (Dox). A quaternary ammonium derivative of the MMP13 inhibitor doxycycline (QA-Dox) was synthesized, and its anticancer activity was evaluated in the Swarm rat chondrosarcoma (SRC) model compared with the parent drug doxycycline, in vitro and in vivo. In vivo, dox and QA-Dox efficiency was assessed at equimolar doses according to a q4dx4 schedule by monitoring tumour volume by MRI and PG-targeted scintigraphy. Molecular mechanism (MMP13 expression, proteoglycan level) and histology studies were performed on tumours. The link of QA targeting function to Dox maintained the MMP13 inhibitory activity in vitro. Interestingly, the bacteriostatic activity was lost. SRC cells incubated with both drugs were blocked in S and G2 M phases. Tumour growth inhibition (confirmed by histology) was observed for both Dox and QA-Dox. Undesirable blood effects (leukocyte decrease) were reduced when Dox was targeted to tumour tissue using the QA function. In the SRC model, the MMP13 inhibitor Dox and its QA derivative are promising as adjuvant therapies for chondrosarcoma management.

Periosteal chondrosarcoma: a histopathological and molecular analysis of a rare chondrosarcoma subtype.

PubMed

Cleven, Arjen H G; Zwartkruis, Evita; Hogendoorn, Pancras C W; Kroon, Herman M; Briaire-de Bruijn, Inge; Bovée, Judith V M G

2015-10-01

Periosteal chondrosarcoma is a rare, malignant cartilage-forming neoplasm originating from the periosteal surface of bone. We collected 38 cases from the archives of the Netherlands Committee on Bone Tumours, with the aim of studying histological features and evaluating the involvement of isocitrate dehydrogenase 1 (IDH1), EXT, Wnt/β-catenin, the pRB pathway (CDK4 and p16), and the TP53 pathway (p53 and MDM2). Histology showed a moderately cellular matrix with mucoid-myxoid changes and, in 42% of cases, formation of a neocortex. Occasional intramedullary extension (26%) and subsequent host bone entrapment (40%) were seen. Histological grading revealed grade 1 (53%) and grade 2 (45%). The EXT1 protein was normally expressed, and mutations in IDH1 were observed in only 15% of cases. pRb signalling was deregulated by loss of p16 expression in 50% of cases, and Wnt signalling was lost in 89%. No alterations were found in CDK4, p53, or MDM2. We report the first large histological and molecular study on periosteal chondrosarcoma showing that histopathological examination and molecular aberrations do not predict prognosis. Although the mutation frequency of IDH1 was low, we confirm the supposed relationship with central chondrosarcoma. Moreover, we identify loss of canonical Wnt signalling and deregulation of pRb signalling as possible events contributing to its histogenesis. © 2015 John Wiley & Sons Ltd.

Understanding Collagen Organization in Breast Tumors to Predict and Prevent Metastasis

DTIC Science & Technology

2011-09-01

mechanisms (for example TNF-α has also been shown to increase migration in human chondrosarcoma cells in vitro by upregulating αvβ3 integrin expression... chondrosarcoma cells. J Cell Physiol 2011, 226:792-799. Figure Legends Figure 1: E0771 breast cancer cells do not produce significant TNF-α in vitro

What Is New in the miRNA World Regarding Osteosarcoma and Chondrosarcoma?

PubMed

Palmini, Gaia; Marini, Francesca; Brandi, Maria Luisa

2017-03-07

Despite the availability of multimodal and aggressive therapies, currently patients with skeletal sarcomas, including osteosarcoma and chondrosarcoma, often have a poor prognosis. In recent decades, advances in sequencing technology have revealed the presence of RNAs without coding potential known as non-coding RNAs (ncRNAs), which provides evidence that protein-coding genes account for only a small percentage of the entire genome. This has suggested the influence of ncRNAs during development, apoptosis and cell proliferation. The discovery of microRNAs (miRNAs) in 1993 underscored the importance of these molecules in pathological diseases such as cancer. Increasing interest in this field has allowed researchers to study the role of miRNAs in cancer progression. Regarding skeletal sarcomas, the research surrounding which miRNAs are involved in the tumourigenesis of osteosarcoma and chondrosarcoma has rapidly gained traction, including the identification of which miRNAs act as tumour suppressors and which act as oncogenes. In this review, we will summarize what is new regarding the roles of miRNAs in chondrosarcoma as well as the latest discoveries of identified miRNAs in osteosarcoma.

Brain-derived neurotrophic factor promotes VEGF-C-dependent lymphangiogenesis by suppressing miR-624-3p in human chondrosarcoma cells.

PubMed

Lin, Chih-Yang; Wang, Shih-Wei; Chen, Yen-Ling; Chou, Wen-Yi; Lin, Ting-Yi; Chen, Wei-Cheng; Yang, Chen-Yu; Liu, Shih-Chia; Hsieh, Chia-Chu; Fong, Yi-Chin; Wang, Po-Chuan; Tang, Chih-Hsin

2017-08-03

Chondrosarcoma is the second most common primary malignancy of bone, and one of the most difficult bone tumors to diagnose and treat. It is well known that increased levels of vascular endothelial growth factor-C (VEGF-C) promote active tumor lymphangiogenesis and lymphatic tumor spread to regional lymph nodes. Brain-derived neurotrophic factor (BDNF) is known to promote metastasis in human chondrosarcoma cells. Knowing more about the mechanism of BDNF in VEGF-C expression and lymphangiogenesis in human chondrosarcoma would improve our understanding as how to prevent chondrosarcoma angiogenesis and metastasis, which currently lacks effective adjuvant treatment. Here, we found that BDNF expression was at least 2.5-fold higher in the highly migratory JJ012(S10) cell line as compared with the primordial cell line (JJ012). In addition, VEGF-C expression and secretion was markedly increased in JJ012(S10) cells. Conditioned medium from JJ012(S10) cells significantly promoted migration and tube formation of human lymphatic endothelial cells (LECs), whereas knockdown of BDNF attenuated LEC migration and tube formation by suppressing VEGF-C production in JJ012(S10) cells. Mechanistic investigations indicated that BDNF facilitated VEGF-C-dependent lymphangiogenesis through the MEK/ERK/mTOR signaling pathway. We also showed that microRNA (miR)-624-3p expression was negatively regulated by BDNF via the MEK/ERK/mTOR cascade. Importantly, BDNF knockdown profoundly inhibited tumor-associated lymphangiogenesis in vivo. Further analyses identified that BDNF promoted tumor lymphangiogenesis by downregulating miR-624-3p in human chondrosarcoma tissues. In conclusion, this study is the first to reveal the mechanism underlying BDNF-induced lymphangiogenesis. We suggest that BDNF may serve as a promising therapeutic target for the restriction of VEGF-C-mediated tumor lymphangiogenesis and lymphatic metastasis.

Brain-derived neurotrophic factor promotes VEGF-C-dependent lymphangiogenesis by suppressing miR-624-3p in human chondrosarcoma cells

PubMed Central

Lin, Chih-Yang; Wang, Shih-Wei; Chen, Yen-Ling; Chou, Wen-Yi; Lin, Ting-Yi; Chen, Wei-Cheng; Yang, Chen-Yu; Liu, Shih-Chia; Hsieh, Chia-Chu; Fong, Yi-Chin; Wang, Po-Chuan; Tang, Chih-Hsin

2017-01-01

Chondrosarcoma is the second most common primary malignancy of bone, and one of the most difficult bone tumors to diagnose and treat. It is well known that increased levels of vascular endothelial growth factor-C (VEGF-C) promote active tumor lymphangiogenesis and lymphatic tumor spread to regional lymph nodes. Brain-derived neurotrophic factor (BDNF) is known to promote metastasis in human chondrosarcoma cells. Knowing more about the mechanism of BDNF in VEGF-C expression and lymphangiogenesis in human chondrosarcoma would improve our understanding as how to prevent chondrosarcoma angiogenesis and metastasis, which currently lacks effective adjuvant treatment. Here, we found that BDNF expression was at least 2.5-fold higher in the highly migratory JJ012(S10) cell line as compared with the primordial cell line (JJ012). In addition, VEGF-C expression and secretion was markedly increased in JJ012(S10) cells. Conditioned medium from JJ012(S10) cells significantly promoted migration and tube formation of human lymphatic endothelial cells (LECs), whereas knockdown of BDNF attenuated LEC migration and tube formation by suppressing VEGF-C production in JJ012(S10) cells. Mechanistic investigations indicated that BDNF facilitated VEGF-C-dependent lymphangiogenesis through the MEK/ERK/mTOR signaling pathway. We also showed that microRNA (miR)-624-3p expression was negatively regulated by BDNF via the MEK/ERK/mTOR cascade. Importantly, BDNF knockdown profoundly inhibited tumor-associated lymphangiogenesis in vivo. Further analyses identified that BDNF promoted tumor lymphangiogenesis by downregulating miR-624-3p in human chondrosarcoma tissues. In conclusion, this study is the first to reveal the mechanism underlying BDNF-induced lymphangiogenesis. We suggest that BDNF may serve as a promising therapeutic target for the restriction of VEGF-C-mediated tumor lymphangiogenesis and lymphatic metastasis. PMID:28771226

Whole-body low-dose computed tomography in multiple myeloma staging: Superior diagnostic performance in the detection of bone lesions, vertebral compression fractures, rib fractures and extraskeletal findings compared to radiography with similar radiation exposure.

PubMed

Lambert, Lukas; Ourednicek, Petr; Meckova, Zuzana; Gavelli, Giampaolo; Straub, Jan; Spicka, Ivan

2017-04-01

The primary objective of the present prospective study was to compare the diagnostic performance of conventional radiography (CR) and whole-body low-dose computed tomography (WBLDCT) with a comparable radiation dose reconstructed using hybrid iterative reconstruction technique, in terms of the detection of bone lesions, skeletal fractures, vertebral compressions and extraskeletal findings. The secondary objective was to evaluate lesion attenuation in relation to its size. A total of 74 patients underwent same-day skeletal survey by CR and WBLDCT. In CR and WBLDCT, two readers assessed the number of osteolytic lesions at each region and stage according to the International Myeloma Working Group (IMWG) criteria. A single reader additionally assessed extraskeletal findings and their significance, the number of vertebral compressions and bone fractures. The radiation exposure was 2.7±0.9 mSv for WBLDCT and 2.5±0.9 mSv for CR (P=0.054). CR detected bone involvement in 127 out of 486 regions (26%; P<0.0001), confirmed by WBLDCT. CR underestimated the disease stage in 16% and overestimated it in 8% of the patients (P=0.0077). WBLDCT detected more rib fractures compared with CR (188 vs. 47; P<0.0001), vertebral compressions (93 vs. 67; P=0.010) and extraskeletal findings (194 vs. 52; P<0.0001). There was no correlation observed between lesion size (≥5 mm) and its attenuation (r=-0.006; P=0.93). The inter-observer agreement for the presence of osteolytic lesions was κ=0.76 for WBLDCT, and κ=0.55 for CR. The present study concluded that WBLDCT with hybrid iterative reconstruction technique demonstrates superiority to CR with an identical radiation dose in the detection of bone lesions, skeletal fractures, vertebral compressions and extraskeletal findings, which results in up- or downstaging in 24% patients according to the IMWG criteria. The attenuation of osteolytic lesions can be measured with the avoidance of the partial volume effect.

Extraskeletal Ewing's sarcoma family of tumors in adults: prognostic factors and clinical outcome.

PubMed

Tural, Deniz; Molinas Mandel, Nil; Dervisoglu, Sergulen; Oner Dincbas, Fazilet; Koca, Sedat; Colpan Oksuz, Didem; Kantarci, Fatih; Turna, Hande; Selcukbiricik, Fatih; Hiz, Murat

2012-05-01

The aim of this study was to evaluate prognostic factors, survival rate and the efficacy of the treatment modalities used in patients with extraskeletal Ewing's sarcoma. Data of patients with extraskeletal Ewing's sarcoma followed up at our center between 1997 and 2010 were retrospectively analyzed. The median age of 27 patients was 24 years (range, 16-54 years). The median follow-up was 31.8 months (range, 6-144 months). Tumor size was between 1.5 and 14 cm (median: 8 cm). Eighty-five percent of patients had localized disease at presentation and 15% had metastatic disease. Local therapy was surgery alone in 16% of patients, surgery combined with radiotherapy in 42% and radiotherapy alone in 27%. All patients were treated with vincristine, doxorubicin, cyclophosphamide and actinomycin-D, alternating with ifosfamide and etoposide every 3 weeks. In patients with localized disease at presentation, the 5-year event-free survival and overall survival were 59.7 and 64.5%, respectively. At univariate analysis, patients with tumor size ≥ 8 cm, high serum lactate dehydrogenase, metastasis at presentation, poor histological response to chemotherapy and positive surgical margin had significantly worse event-free survival. The significant predictors of worse overall survival at univariate analysis were tumor size 8 ≥ cm, high lactate dehydrogenase, metastasis at presentation, poor histological response to chemotherapy, radiotherapy only as local treatment and positive surgical margin. Prognostic factors were similar to primary osseous Ewing's sarcomas. Adequate surgical resection, aggressive chemotherapy (vincristine, doxorubicin, cyclophosphamide and actinomycin-D alternating with ifosfamide and etoposide) and radiotherapy if indicated are the recommended therapy for patients with extraskeletal Ewing's sarcoma.

Primary chondrosarcoma of the trachea with extensive extraluminal growth.

PubMed

Ryabov, Andrey; Pikin, Oleg; Sokolov, Victor; Volchenko, Nadezda

2017-09-01

Primary chondrosarcoma of the trachea is an extremely rare non-epithelial neoplasm with only few cases published in the literature. We present a rare case of tracheal chondrosarcoma with extensive extraluminal growth. We operated a patient with obstructive tumour of the upper third of the trachea via partial sternotomy. Before surgery, a Hanarostent was put into the trachea to treat a life-threatening stenosis. Postoperative period was uneventful. We discuss the incidence, clinical presentation and treatment options in patients with rare tracheal tumours. In some cases, a multidisciplinary approach (endoscopic intervention followed by surgical resection) is an effective treatment tool. © The Author 2017. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

Extraskeletal multiple myeloma presenting with an atrial mass: a case report and a review of the literature.

PubMed

Vigo, Federica; Ciammella, Patrizia; Valli, Riccardo; Cagni, Elisabetta; Iotti, Cinzia

2012-08-10

Extraskeletal presentation at diagnosis or during the course of multiple myeloma is a rare event. The prognosis is usually very poor. At the moment there is no agreed gold standard for the treatment of this presentation. A 79-year-old Caucasian woman was treated at our hospital for right atrial myeloma localization. Our patient showed the following signs and symptoms of congestive heart failure: dyspnea, hypotension, cyanosis and facial edema. Surgery was not considered feasible due to the extent of the disease. Our patient underwent external-beam radiation therapy using an intensity modulated technique, thus obtaining a persistent complete remission. Our patient has been in continuous complete local remission for 25 months since the end of radiotherapy. The role of radiotherapy is not defined in multiple myeloma with extraskeletal presentation. Our regimen seems to be effective in controlling the disease in this patient.This case report adds to the existing literature as it describes an unusual presentation of the disease and a new therapeutic approach to this rare presentation of multiple myeloma.

Is intralesional resection suitable for central grade 1 chondrosarcoma: A systematic review and updated meta-analysis.

PubMed

Chen, X; Yu, L J; Peng, H M; Jiang, C; Ye, C H; Zhu, S B; Qian, W W

2017-09-01

The surgical choice for grade 1 chondrosarcoma has been debated for decades. Intralesional resection can minimize the damage caused by surgery and offer better functional outcome. However, controversy remains about whether it will result in higher rates of local recurrence and metastasis, fewer complications, and better functional outcome compared with resection with wide margin. This systematic review and updated meta-analysis therefore compared intralesional resection and resection with wide margin in terms of local recurrence, metastasis, complications, and functional outcome. Medline, Embase, and the Cochrane Library were comprehensively searched in December 2016 to identify studies comparing intralesional resection and resection with wide margin for central grade 1 chondrosarcoma. Data of interest were extracted and analyzed using Review Manager 5.3. Ten studies involving 394 patients were included, with 214 patients who had intralesional resection and 180 patients who had resection with wide margin for grade 1 chondrosarcoma. Intralesional resection was associated with lower complication rates (P < 0.0001) and better Musculoskeletal Tumor Society score (MSTS). There were no significant differences in terms of overall local recurrence (P = 0.27), local recurrence based on adjuvant therapies (P = 0.22), local recurrence in studies that included lesions of the hand, foot, pelvis, and axial skeleton (P = 0.55), and metastasis (P = 0.74) between groups. Intralesional resection provides lower complications and better functional outcome with no significant increase in the risk of recurrence and metastasis. We think it is a suitable treatment for central grade 1 chondrosarcoma. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Retrotracheal Extraskeletal Ewing's Sarcoma: Case Report and Discussion on Airway Management.

PubMed

Van Der Meer, Graeme; Linkhorn, Hannah; Gruber, Maayan; Mahadevan, Murali; Barber, Colin

2017-03-01

Extraskeletal Ewing's sarcoma is a rare tumor, and the management of airway compromise in case of cervical Ewing's sarcoma has not been established. This report describes the case of a patient with retrotracheal Ewing's sarcoma and discusses a successful approach to airway management. A 12-year-old male presented with a 2-week history of sore throat and sleep-disordered breathing and 48 hours of stridor. Imaging confirmed a retrotracheal soft tissue mass with airway compromise. A planned and controlled approach to his airway management resulted in a secure airway prior to definitive treatment.

Extraskeletal effects of vitamin D: facts, uncertainties, and controversies.

PubMed

Bouvard, Béatrice; Annweiler, Cédric; Sallé, Agnès; Beauchet, Olivier; Chappard, Daniel; Audran, Maurice; Legrand, Erick

2011-01-01

Vitamin D was long viewed as a hormone acting chiefly to regulate calcium-phosphate metabolism and bone mineralization. Over the last decade, however, basic science and clinical researchers have produced a bewildering amount of information on the extraskeletal effects of vitamin D. This article is a review of the clinical and biological actions of vitamin D including effects on the immune system, auto-immune diseases, infections, cancer, metabolic syndrome, fall risk, cognitive function, and muscle function. Copyright © 2010 Société française de rhumatologie. Published by Elsevier SAS. All rights reserved.

Generation of Soluble Receptor Activator of NF-KappaB Ligand Is Critical for Osteolytic Bone Metastasis

DTIC Science & Technology

2010-10-01

including breast (15), head and neck squa- mous carcinoma (18), melanoma, and chondrosarcoma (42). A previous report suggests involvement of MMP13 in the...2003;88: 1318–26. 42. Uria JA, Balbin M, Lopez JM, et al. Collagenase-3 (MMP-13) expres- sion in chondrosarcoma cells and its regulation by basic

Conditional Mesenchymal Disruption of Pkd1 Results in Osteopenia and Polycystic Kidney Disease

PubMed Central

Cao, Li; David, Valentin; Quarles, Leigh Darryl

2012-01-01

Conditional deletion of Pkd1 in osteoblasts using either Osteocalcin(Oc)-Cre or Dmp1-Cre results in defective osteoblast-mediated postnatal bone formation and osteopenia. Pkd1 is also expressed in undifferentiated mesenchyme that gives rise to the osteoblast lineage. To examine the effects of Pkd1 on prenatal osteoblast development, we crossed Pkd1 flox/flox and Col1a1(3.6)-Cre mice, which has been used to achieve selective inactivation of Pkd1 earlier in the osteoblast lineage. Control Pkd1 flox/flox and Pkd1 flox/+, heterozygous Col1a1(3.6)-Cre;Pkd1 flox/+ and Pkd1 flox/null, and homozygous Col1a1(3.6)-Cre;Pkd1 flox/flox and Col1a1(3.6)-Cre;Pkd1 flox/null mice were analyzed at ages ranging from E14.5 to 8-weeks-old. Newborn Col1a1(3.6)-Cre;Pkd1 flox/null mice exhibited defective skeletogenesis in association with a greater reduction in Pkd1 expression in bone. Conditional Col1a1(3.6)-Cre;Pkd1 flox/+ and Col1a1(3.6)-Cre;Pkd1 flox/flox mice displayed a gene dose-dependent decrease in bone formation and increase in marrow fat at 6 weeks of age. Bone marrow stromal cell and primary osteoblast cultures from homozygous Col1a1(3.6)-Cre;Pkd1 flox/flox mice showed increased proliferation, impaired osteoblast development and enhanced adipogenesis ex vivo. Unexpectedly, we found evidence for Col1a1(3.6)-Cre mediated deletion of Pkd1 in extraskeletal tissues in Col1a1(3.6)-Cre;Pkd1 flox/flox mice. Deletion of Pkd1 in mesenchymal precursors resulted in pancreatic and renal, but not hepatic, cyst formation. The non-lethality of Col1a1(3.6)-Cre;Pkd1 flox/flox mice establishes a new model to study abnormalities in bone development and cyst formation in pancreas and kidney caused by Pkd1 gene inactivation. PMID:23029375

Clinical features and outcomes in patients with extraskeletal Ewing sarcoma

PubMed Central

Applebaum, Mark A.; Worch, Jennifer; Matthay, Katherine K.; Goldsby, Robert; Neuhaus, John; West, Daniel C.; DuBois, Steven G.

2010-01-01

Background Ewing sarcoma can arise in either bone or soft tissue locations. We sought to investigate if patient characteristics, treatment strategies, and outcomes differ between skeletal Ewing sarcoma and extraskeletal Ewing sarcoma (EES). Procedure Patients < 40 years of age with Ewing sarcoma or peripheral primitive neuroectodermal tumor (PNET) reported to the US SEER database from 1973 to 2007 were evaluated based on skeletal (n=1519) vs. extraskeletal (n=683) site of origin. Patient characteristics were compared using Fisher exact tests. Overall survival was estimated by Kaplan-Meier methods and compared using log-rank tests and Cox models. Results Patients with EES had a higher mean age (19.5 vs. 16.3 years; p < 0.001) and were less likely to be male (53.4% vs. 63.3%; p < 0.001) or white (84.8% vs. 92.5%; p < 0.001) compared to patients with skeletal tumors. Extraskeletal tumors were more likely to arise in axial locations (72.9% vs. 54.2%; p = 0.001), though less likely to arise specifically in the pelvis (19.8% vs. 26.6%; p < 0.001). Metastatic status or tumor size did not differ by group. Five-year overall survival was superior for localized EES compared to localized skeletal tumors (69.7% vs. 62.6%; p = 0.02). The hazard ratio for death in patients with localized skeletal tumors compared to localized EES was 2.36 (95% CI 1.61-3.44) beyond 24 months from initial diagnosis. Conclusions Patient characteristics and outcomes differ among patients with EES compared to patients with skeletal Ewing sarcoma. These findings may have important implications for patient care. PMID:21692057

Intralesional curettage of central low-grade chondrosarcoma: A midterm follow-up study.

PubMed

Chen, Yi-Chou; Wu, Po-Kuei; Chen, Cheng-Fong; Chen, Wei-Ming

2017-03-01

The aim of this study was to review the experience of surgical treatment of low-grade chondrosarcoma and to assess the long-term oncological and functional outcomes between intralesional curettage and wide excision. We included 11 patients with central low-grade chondrosarcoma lesions treated with intralesional curettage or wide excision from 1998 to 2013. Seven patients were treated with intralesional curettage and local adjuvant treatment (Group A), and four patients were treated with wide excision and reconstructive surgery (Group B). The mean age of patients was 43.8±17.6 years (range, 20-71 years), and the mean duration of follow-up was 84.4±47.6 months (range, 48-194 months). Group A had a significantly lower complication rate than Group B; three complications were documented in Group B (0% vs. 75%, p=0.024). The operative time (177.1 hours vs. 366.3 hours, p=0.010) and the hospital stay (6.6 days vs. 12.5 days, p=0.010) were significantly shorter in Group A. There was one local recurrence in Group A without statistical significance. Also, there were no differences between intralesional curettage and wide excision with respect to the blood loss. No metastasis disease occurred in either group during the follow-up period. The Musculoskeletal Tumor Society (MSTS) scores in Groups A and B were 99.0±2.5 and 94.2±4.2, respectively, with statistically significant difference (p=0.048). Extended intralesional curettage has the benefits of good MSTS score, shorter operative time, shorter hospital stay, and lower complication rate without increasing local recurrence in central low-grade chondrosarcoma. For central low-grade chondrosarcoma, we suggest extended curettage to decrease soft tissue damage and surgical risk. Copyright © 2016. Published by Elsevier Taiwan LLC.

Extended endoscopic endonasal surgery for clival chordoma and chondrosarcoma: Our experience in 14 cases.

PubMed

Culebras, Diego; Torales, Jorge; Reyes, Luis Alberto; Zapata, Luis; García, Sergio; Roldán, Pedro; Langdon, Cristóbal; Alobid, Issam; Enseñat, Joaquim

2018-04-21

To report our experience in the management of chordoma and chondrosarcoma with extended endoscopic endonasal surgery. We performed a retrospective analysis of a series of 14 patients with clival chordoma or chondrosarcoma who had extended endoscopic endonasal surgery from 2008 to 2016 performed by the same multidisciplinary team. We had fourteen patients (male/female 2:1), with a mean age of 49years for chordoma and 32 for chondrosarcoma. The most common clinical presentation was diplopia in 78.5% of cases, followed by dysphagia in 28.6%. Histologically, 71.4% were chordomas and 28.6% were chondrosarcomas. In addition, invasion of at least two thirds or more of the clivus was found in 81% of the cases; in 57.1% there was intradural invasion, and in 35.7% invasion of the sella turcica. In 42.8% of cases, the degree of resection was total and in 21.5% subtotal. The most common complication was CSF fistula, occurring in 28.6% of the cases, with only one case requiring surgery to repair it. Adjuvant treatment with Proton Beam was performed in 35.7% of cases and with conventional radiotherapy in 21.5%. Mean follow-up was 53.5months and tumour recurrence or progression was found in 21.5% of the cases, two of which had not received adjuvant treatment. There were no deaths. The extended endoscopic endonasal approach (EEEA) performed by an experienced team is a good alternative for the management of these lesions. Intradural invasion may be related to an increased risk of complications and worse clinical presentation, in addition to a lower rate of total resection. Copyright © 2018 Sociedad Española de Neurocirugía. Publicado por Elsevier España, S.L.U. All rights reserved.

Glandular differentiation in dedifferentiated chondrosarcoma: molecular evidence of a rare phenomenon.

PubMed

Jour, George; Liu, Yajuan; Ricciotti, Robert; Pritchard, Colin; Hoch, Benjamin L

2015-09-01

Epithelial glandular differentiation in dedifferentiated chondrosarcoma has not been described. Our patient was a 64-year-old man with a history of prostate cancer status post-radiation and hormonal therapy. On screening bone scan, he was found to have increased uptake in his right femoral shaft. Biopsy revealed intermediate-grade conventional chondrosarcoma. Subsequent femoral resection was remarkable for an intermediate-grade chondrosarcomatous component juxtaposed to an area composed of anastomosing nests and cords of malignant epithelial cells showing nuclear atypia and increased mitotic activity. A fibroblastic-appearing spindle cell population was intimately associated with the epithelial cells. The epithelial cells labeled with 34bE12, AE1/AE3, EMA, and Vimentin (both spindled and epithelial components) while being negative for prostate-specific antigen, prostate specific acid phosphatase, cytokeratin 20, thyroid transcription factor-1, and CDX2. The patient developed local recurrence 9 months after the initial resection but has had no metastatic disease and consistently undetectable prostate-specific antigen levels. Deep parallel sequencing of the dedifferentiated component showed a nonsynonymous mutation at exon 4 of IDH1 gene at codon R132 leading to a substitution of arginine, with serine confirming glandular differentiation in dedifferentiated chondrosarcoma. Copyright © 2015 Elsevier Inc. All rights reserved.

Oncologic outcome after local recurrence of chondrosarcoma: Analysis of prognostic factors.

PubMed

Kim, Han-Soo; Bindiganavile, Srimanth S; Han, Ilkyu

2015-06-01

Literature on outcome after local recurrence (LR) in chondrosarcoma is scarce and better appreciation of prognostic factors is needed. (1) To evaluate post-LR oncologic outcomes of disease-specific survival and subsequent LR and (2) to identify prognostic factors for post-LR oncologic outcomes. Review of 28 patients with locally recurrent chondrosarcoma from the original cohort of 150 patients, who were treated surgically with or without adjuvants between 1982 and 2011, was performed. Mean age was 46 years (range, 21-73) which included 20 males and 8 females with mean follow up of 8.4 ± 7.5 years (range, 1.2-31.0). Post-LR survival at 5 years was 58.6 ± 10.3%. Age greater than 50 years (P = 0.011) and LR occurring within 1 year of primary surgery (P = 0.011) independently predicted poor survival. Seven patients suffered subsequent LR, which was significantly affected by surgical margin for LR (P = 0.038). Long-term survival of locally recurrent chondrosarcoma is achievable in a substantial number of patients. Older age at onset of LR and shorter interval from primary surgery to LR identifies high risk patients for poor post-LR survival while, wide surgical margins at LR surgery reduces the risk of subsequent LR. © 2015 Wiley Periodicals, Inc.

High hydrostatic pressure-induced cell death in human chondrocytes and chondrosarcoma cells.

PubMed

Naal, Florian-Dominique; Mengele, Karin; Schauwecker, Johannes; Gollwitzer, Hans; Gerdesmeyer, Ludger; Reuning, Ute; Mittelmeier, Wolfram; Gradinger, Reiner; Schmitt, Manfred; Diehl, Peter

2005-01-01

In orthopedic surgery, sterilization of bone used for reconstruction of osteoarticular defects caused by malignant tumors is carried out in different ways. At present, to devitalize tumor-bearing osteochondral segments, extracorporal irradiation or autoclaving is mainly used, although both methods have substantial disadvantages, e.g. loss of biomechanical and/or biological integrity of the bone and destabilization of the articular surface. In this regard, high hydrostatic pressure (HHP) treatment of bone is a new, advancing technology, now being used in preclinical testing to inactivate tumor cells. To find out if this technique is also suited for extracorporal inactivation of chondrocytes and chondral tumor cells, the effect of HHP on cell viability and morphology of human chondrocytes / chondrosarcoma cells was investigated in the present study. SW1353 chondrosarcoma cells and chondrocytes were subjected to HHP in the range of 50 to 350 MPa (10 min, 37 degrees C) and, subsequently, cell viability and cell morphology assessed. After exposure at 350 MPa, all HHP-treated chondral cells showed explicit morphological changes, evident by membrane ruffling and bleb formation; chondrosarcoma cells treated this way were irreversibly damaged and not alive. We anticipate that, in orthopedic surgery, HHP eventually can serve as a novel, promising technical approach for cell inactivation (including tumor cells) and allow subsequent reimplantation of the osteoarticular autograft.

False-positive 18F-fluorodeoxyglucose positron emission tomography/computed tomography in a patient with metallic implants following chondrosarcoma resection

PubMed Central

ZHOU, PU; TANG, JINLIANG; ZHANG, DONG; LI, GUANGHUI

2016-01-01

Positron emission tomography (PET) with fluorine-18-labeled fluorodeoxyglucose (18F-FDG) has been used for the staging and evaluation of recurrence in cancer patients. We herein report a false-positive result of 18F-FDG PET/computed tomography (CT) scan in a patient following chondrosarcoma resection and metallic implanting. A 35-year-old male patient with chondrosarcoma of the left iliac bone underwent radical resection, metal brace implanting and radiotherapy. A high uptake of 18F-FDG was observed in the metallic implants and adjacent tissue during PET/CT scanning in the 5th year of follow-up. Tissue biopsy and follow-up examination identified no tumor recurrence or infection at these sites, suggesting that the results of 18F-FDG PET/CT must be interpreted with caution in cancer patients with metallic implants. PMID:27123290

False-positive 18F-fluorodeoxyglucose positron emission tomography/computed tomography in a patient with metallic implants following chondrosarcoma resection.

PubMed

Zhou, P U; Tang, Jinliang; Zhang, Dong; Li, Guanghui

2016-05-01

Positron emission tomography (PET) with fluorine-18-labeled fluorodeoxyglucose ( 18 F-FDG) has been used for the staging and evaluation of recurrence in cancer patients. We herein report a false-positive result of 18 F-FDG PET/computed tomography (CT) scan in a patient following chondrosarcoma resection and metallic implanting. A 35-year-old male patient with chondrosarcoma of the left iliac bone underwent radical resection, metal brace implanting and radiotherapy. A high uptake of 18 F-FDG was observed in the metallic implants and adjacent tissue during PET/CT scanning in the 5th year of follow-up. Tissue biopsy and follow-up examination identified no tumor recurrence or infection at these sites, suggesting that the results of 18 F-FDG PET/CT must be interpreted with caution in cancer patients with metallic implants.

Differential transactivation by orphan nuclear receptor NOR1 and its fusion gene product EWS/NOR1: possible involvement of poly(ADP-ribose) polymerase I, PARP-1.

PubMed

Ohkura, Naganari; Nagamura, Yuko; Tsukada, Toshihiko

2008-10-15

In extraskeletal myxoid chondrosarcoma, a chromosomal translocation creates a gene fusion between EWS and an orphan nuclear receptor, NOR1. The resulting fusion protein EWS/NOR1 has been believed to lead to malignant transformation by functioning as a transactivator for NOR1-target genes. By comparing the gene expression profiles of NOR1- and EWS/NOR1-overexpressing cells, we found that they largely shared up-regulated genes, but no significant correlation was observed with respect to the transactivation levels of each gene. In addition, the proteins associated with NOR1 and EWS/NOR1 were mostly the same in these cells. The results suggest that these proteins differentially transactivate overlapping target genes through a similar transcriptional machinery. To clarify the mechanisms underlying the transcriptional divergence between NOR1 and EWS/NOR1, we searched for alternatively associated proteins, and identified poly(ADP-ribose) polymerase I (PARP-1) as an NOR1-specific binding protein. Consistent with its binding properties, PARP-1 acted as a transcriptional repressor of NOR1, but not EWS/NOR1, in a luciferase reporter assay employing PARP-1(-/-) fibroblasts. Interestingly, suppressive activity of PARP-1 was observed in a DNA response element-specific manner, and in a subtype-specific manner toward the NR4A family (Nur77, Nurr1, and NOR1), suggesting that PARP-1 plays a role in the diversity of transcriptional regulation mediated by the NR4A family in normal cells. Altogether, our findings suggest that NOR1 and EWS/NOR1 regulate overlapping target genes differently by utilizing associated proteins, including PARP-1; and that EWS/NOR1 may acquire oncogenic activities by avoiding (or gaining) transcription factor-specific modulation by the associated proteins. (c) 2008 Wiley-Liss, Inc.

Rare extraskeletal Ewing's sarcoma mimicking as adenocarcinoma of the sigmoid.

PubMed

Mertens, Michelle; Haenen, Filip W N; Siozopoulou, Vasiliki; Van Cleemput, Marc

2017-06-01

Extraskeletal Ewing's sarcoma (EES) is a rare finding in comparison with Ewing's sarcoma of bone and usually manifests in young patients. However, even in older patients, one must consider the diagnosis. In this case, we describe a 52-year-old woman diagnosed with EES, mimicking as adenocarcinoma of the sigmoid. The tumor was not visualized by a multi-slice spiral computed tomography of the abdomen and pelvis with intravenous contrast, and eventually the diagnosis was made by positive immunohistochemical staining for CD99 and by molecular testing for EWSR1 translocation. This combination of the patient's age and the localization of the tumor mimicking an adenocarcinoma of the sigmoid has never been described before.

Extra-skeletal Ewing's sarcoma of the submandibular gland.

PubMed

Agir, Hakan; Brasch, Helen D; Tan, Swee T

2007-01-01

Extra-skeletal Ewing's sarcoma (EES) is an uncommon malignancy, especially in the head and neck region that may arise in various extra-osseous tissues. We report a 22-year-old male with an EES of the submandibular gland, which to the best of our knowledge, has not been described previously. The patient who underwent combined treatment with surgical resection and chemo-irradiation was disease free for 22 months but succumbed to multi-organ metastases 14 months later. This case highlights the combined diagnostic role of immunohistochemical, cytogenetic and radiological evaluation of EES. EES is an aggressive cancer that requires multidisciplinary management with wide surgical excision and adjunctive chemo-irradiation for the best outcome.

Intralesional curettage and cementation for low-grade chondrosarcoma of long bones: retrospective study and literature review.

PubMed

Mermerkaya, Musa Ugur; Bekmez, Senol; Karaaslan, Fatih; Danisman, Murat; Kosemehmetoglu, Kemal; Gedikoglu, Gokhan; Ayvaz, Mehmet; Tokgozoglu, Ahmet Mazhar

2014-11-10

Various treatment strategies for low-grade chondrosarcomas with variable outcomes have been reported in the literature. The aim of this study was to assess the oncological and functional outcomes associated with intralesional curettage followed by adjuvant therapy comprising high-speed burring, thermal cauterization, and bone cementation with polymethylmethacrylate. We performed a retrospective review of 21 consecutive patients with intramedullary low-grade chondrosarcoma of long bones treated by intralesional curettage and adjuvant therapy comprising high-speed burring, thermal cauterization, and cementation at our institution from 2007 to 2012. The average age of the patients was 48.7 (range, 18-71) years. There were 7 male and 14 female patients. The mean follow-up period was 58.4 (range, 26-85) months after surgery. The treated lesions were located in the proximal humerus (n=10), proximal tibia (n=6), and distal femur (n=5). At the average follow-up time point of 58.4 (range, 26-85) months, no patient had developed local recurrence and no distant metastases were observed. The average Musculoskeletal Tumor Society score among all 21 patients was 95% (84-100). The combination of intralesional curettage, application of high-speed burring, thermal cauterization, and cementation is an effective treatment strategy for low-grade intramedullary chondrosarcoma of long bones. Excellent oncological and functional results can be obtained.

McCune-Albright syndrome and the extraskeletal manifestations of fibrous dysplasia.

PubMed

Collins, Michael T; Singer, Frederick R; Eugster, Erica

2012-05-24

Fibrous dysplasia (FD) is sometimes accompanied by extraskeletal manifestations that can include any combination of café-au-lait macules, hyperfunctioning endocrinopathies, such as gonadotropin-independent precocious puberty, hyperthyroidism, growth hormone excess, FGF23-mediated renal phosphate wasting, and/or Cushing syndrome, as well as other less common features. The combination of any of these findings, with or without FD, is known as McCune-Albright syndrome (MAS). The broad spectrum of involved tissues and the unpredictable combination of findings owe to the fact that molecular defect is due to dominant activating mutations in the widely expressed signaling protein, Gsα, and the fact these mutations arises sporadically, often times early in development, prior to gastrulation, and can distribute across many or few tissues.The complexity can be mastered by a systematic screening of potentially involved tissues and cognizance that the pattern of involved tissues is established, to some degree, in utero. Thorough testing allows the clinician to establish, often times at presentation, the full extent of the disease, and importantly as well what tissues are unaffected. Treatment and follow-up can then be focused on affected systems and a meaningful prognosis can be offered to the patient and family. The authors outline screening and treatment strategies that allow for effective management of the extraskeletal manifestations of FD.

McCune-Albright syndrome and the extraskeletal manifestations of fibrous dysplasia

PubMed Central

2012-01-01

Fibrous dysplasia (FD) is sometimes accompanied by extraskeletal manifestations that can include any combination of café-au-lait macules, hyperfunctioning endocrinopathies, such as gonadotropin-independent precocious puberty, hyperthyroidism, growth hormone excess, FGF23-mediated renal phosphate wasting, and/or Cushing syndrome, as well as other less common features. The combination of any of these findings, with or without FD, is known as McCune-Albright syndrome (MAS). The broad spectrum of involved tissues and the unpredictable combination of findings owe to the fact that molecular defect is due to dominant activating mutations in the widely expressed signaling protein, Gsα, and the fact these mutations arises sporadically, often times early in development, prior to gastrulation, and can distribute across many or few tissues. The complexity can be mastered by a systematic screening of potentially involved tissues and cognizance that the pattern of involved tissues is established, to some degree, in utero. Thorough testing allows the clinician to establish, often times at presentation, the full extent of the disease, and importantly as well what tissues are unaffected. Treatment and follow-up can then be focused on affected systems and a meaningful prognosis can be offered to the patient and family. The authors outline screening and treatment strategies that allow for effective management of the extraskeletal manifestations of FD. PMID:22640971

Diagnostic investigations of DKK-1 and PDCD5 expression levels as independent prognostic markers of human chondrosarcoma.

PubMed

Zarea, Mojtaba; Mohammadian Bajgiran, Amirhossein; Sedaghati, Farnoush; Hatami, Negin; Taheriazam, Afshin; Yahaghi, Emad; Shakeri, Mohammadreza

2016-07-01

In this study, we investigated the expression levels of Dickkopf-1 (DKK-1) and programmed cell death 5 (PDCD5) by using quantitative real-time PCR and immunohistochemistry in patients with chondrosarcoma. The DKK-1 mRNA levels were significantly higher in chondrosarcoma when compared with the corresponding nontumor tissues (mean ± SD: 4.23 ± 1.54; 1.54 ± 0.87; P = 0.001). PDCD5 mRNA levels were remarkably deceased in tumor tissues when compared with corresponding nontumor tissues (mean ± SD: 1.94 ± 0.73; 5.42 ± 1.73; P = 0.001). The high and moderate DKK-1 expressions were observed for 60% of chondrosarcoma samples in comparison with 27.5% of corresponding nontumor tissues (P  =  0.001). Moreover, low expression of PDCD5 was found in 67.5% of the tumor tissues when compared with the nontumor tissues (32.5%; P = 0.002). The results of this study showed that high DKK-1 expression levels were strongly related to MSTS stage (P = 0.011) and the advancement of histological grade (P < 0.001). Furthermore, the PDCD5 expression levels were correlated with histological grade (P < 0.001), MSTS stage (P = 0.016), and distant metastasis (P = 0.001). Kaplan-Meier survival and log-rank survival showed that patients with high DKK-1 levels and low PDCD5 levels were correlated with shorter overall survival (log-rank test P < 0.001). PDCD5 levels, histological grade, and tumor stage were independent predictors of overall survival. In conclusion, DKK-1 and PDCD5 can be independent predictors of overall survival in patients suffering from chondrosarcoma. © 2016 IUBMB Life, 68(7):597-601, 2016. © 2016 International Union of Biochemistry and Molecular Biology.

Biological aspects of chondrosarcoma: Leaps and hurdles.

PubMed

Mery, Benoîte; Espenel, Sophie; Guy, Jean-Baptiste; Rancoule, Chloé; Vallard, Alexis; Aloy, Marie-Thérèse; Rodriguez-Lafrasse, Claire; Magné, Nicolas

2018-06-01

Chondrosarcomas are characterized by their chemo- and radioresistance leading to a therapeutic surgical approach which remains the only available treatment with a 10-year survival between 30% and 80% depending on the grade. Non-surgical treatments are under investigation and rely on an accurate biological understanding of drug resistance mechanisms. Novel targeted therapy which represents a new relevant therapeutic approach will open new treatment options by targeting several pathways responsible for processes of proliferation and invasion. Survival pathways such as PI3K, AKT, mTOR and VEGF have been shown to be involved in proliferation of chondrosarcoma cells and antiapoptotic proteins may also play a relevant role. Other proteins such as p53 or COX2 have been identified as potential new targets. This review provides an insight into the biological substantial treatment challenges of CHS and focuses on improving our understanding of CH biology through an overview of major signaling pathways that could represent targets for new therapeutic approaches. Copyright © 2018 Elsevier B.V. All rights reserved.

Laryngeal chondrosarcoma: A systematic review of 592 cases.

PubMed

Chin, Oliver Y; Dubal, Pariket M; Sheikh, Ahmed B; Unsal, Aykut A; Park, Richard Chan Woo; Baredes, Soly; Eloy, Jean Anderson

2017-02-01

Laryngeal chondrosarcomas are rare entities that arise from the cartilaginous structures of the larynx, including the cricoid, thyroid cartilage, epiglottis, and arytenoid cartilages. These tumors represent a minority of malignancies involving the larynx and can be mistaken for benign pathologies. The treatment has historically been surgical excision, often by total laryngectomy. This review investigates treatment modalities and patient outcomes. Systematic review using PubMed/MEDLINE and EMBASE database. The databases were used to identify articles reporting cases of chondrosarcomas occurring exclusively in the larynx. Variables analyzed included patient demographics, presenting symptoms, grade, therapeutic approach, patient outcomes, and follow-up. Five hundred and ninety-two cases were identified. The average age reported was 62.5 years. There was a 3:1 male to female ratio. The most common surgical approach was local excision in 178 cases, followed by total laryngectomy in 174 cases. Nonsurgical treatment such as radiotherapy and chemotherapy was only used in 0.8% and 0.2%, respectively. Disease-specific survival rates for 1, 5, 10, and 20 years were 97.7%, 91.4%, 81.8%, and 68.0%, respectively, with no differences when comparing 5-year survival rates for location, grade, and therapy. Laryngeal chondrosarcomas are rare with a good prognosis. Various surgical approaches exist, with no difference noted in 5-year survival outcomes. Nonsurgical approaches were rarely used for these lesions. N/A. Laryngoscope, 2016 127:430-439, 2017. © 2016 The American Laryngological, Rhinological and Otological Society, Inc.

Osteocalcin and Osteonectin Expression in Canine Osteosarcoma.

PubMed

Wehrle-Martinez, A S; Dittmer, K E; Aberdein, D; Thompson, K G

2016-07-01

Osteosarcoma (OSA) is a malignant heterogeneous primary bone tumor responsible for up to 90% of all primary bone tumors in dogs. In this study, osteocalcin (OC) and osteonectin (ON) immunoreactivity was evaluated in 23 canine OSAs, 4 chondrosarcomas, 4 fibrosarcomas, 2 hemangiosarcomas, and 4 histiocytic sarcomas. The effects of three different decalcification agents (ethylenediaminetetraetic acid [EDTA], formic acid and hydrochloric acid [HCl]) on the immunoreactivity for OC and ON was also assessed. Immunoreactivity to OC was present in 19/23 (83%) cases of OSA and all cases of chondrosarcoma. In three OSAs the extracellular matrix showed immunoreactivity to OC. None of the fibrosarcomas, histiocytic sarcomas or hemangiosarcomas showed immunoreactivity to OC. The sensitivity and specificity for OC in canine OSA in this study was 83% and 71% respectively. For ON, 100% of both OSAs (23/23) and non-OSAs (14/14) showed cytoplasmic immunoreactivity to this antibody, giving a sensitivity of 100% but a complete lack of specificity. There were no significant differences in immunoreactivity for OC and ON between the different decalcification agents used. In conclusion, OC showed high sensitivity for identifying OSA but it failed to distinguish between OSA and chondrosarcoma, and the osteoid produced by neoplastic cells in most cases did not show immunoreactivity to OC. These factors may limit the practical utility of OC in the diagnosis of OSA in dogs when chondrosarcoma is a differential diagnosis. ON showed no specificity in detecting OSA and has little practical application for the diagnosis of OSA in dogs. © The Author(s) 2016.

Chondrosarcoma of the Osseous Spine: An Analysis of Epidemiology, Patient Outcomes, and Prognostic Factors Using the SEER Registry From 1973 to 2012.

PubMed

Arshi, Armin; Sharim, Justin; Park, Don Y; Park, Howard Y; Bernthal, Nicholas M; Yazdanshenas, Hamed; Shamie, Arya N

2017-05-01

Retrospective analysis. To determine the epidemiology and prognostic indicators in patients with chondrosarcoma of the osseous spine. Chondrosarcoma of the spine is rare, with limited data on its epidemiology, clinicopathologic features, and treatment outcomes. Therapy centers on complete en bloc resection with radiotherapy reserved for subtotal resection or advanced disease. The Surveillance, Epidemiology, and End Results Registry was queried for patients with chondrosarcoma of the osseous spine from 1973 to 2012. Study variables included age, sex, race, year of diagnosis, size, grade, extent of disease, and treatment modality. The search identified 973 cases of spinal chondrosarcoma. Mean age at diagnosis was 51.6 years, and 627% of patients were males. Surgical resection and radiotherapy were performed in 75.2% and 21.3% of cases, respectively. Kaplan-Meier analysis demonstrated overall survival (OS) and disease-specific survival (DSS) of 53% and 64%, respectively, at 5 years. Multivariate Cox regression analysis showed that age (OS, P < 0.001; DSS, P = 0.007), grade (OS, P < 0.001; DSS, P < 0.001), surgical resection (OS, P < 0.001; DSS, P < 0.001), and extent of disease (OS, P < 0.001; DSS, P < 0.001) were independent survival determinants; tumor size was an independent predictor of OS (P = 0.006). For confined disease, age (P = 0.013), decade of diagnosis (P = 0.023), and surgery (P = 0.017) were independent determinants of OS. For locally invasive disease, grade (OS, P < 0.001; DSS, P = 0.003), surgery (OS, P = 0.013; DSS, P = 0.046), and size (OS, P = 0.001, DSS, P = 0.002) were independent determinants of OS and DSS. Radiotherapy was an independent indicator of worse OS for both confined (P = 0.004) and locally invasive disease (P = 0.002). For metastatic disease, grade (OS, P = 0.021; DSS, P = 0.012) and surgery (OS, P = 0.007; DSS, P = 0.004) were survival determinants for both OS and DSS, whereas radiotherapy predicted improved OS (P = 0.039). Surgical resection confers survival benefit in patients with chondrosarcoma of the spine independent of extent of disease. Radiotherapy improves survival in patients with metastatic disease and worsens outcomes in patients with confined and locally invasive disease. 4.

Spontaneous Extraskeletal Osteosarcoma in a Rabbit (Oryctolagus cuniculus): Histopathological and Immunohistochemical Findings

PubMed Central

Wijesundera, Kavindra Kumara; Izawa, Takeshi; Fujita, Daisuke; Denda, Yuki; Seto, Eiko; Sasai, Hiroshi; Kuwamura, Mitsuru; Yamate, Jyoji

2013-01-01

A spontaneously occurring subcutaneous mass in the left forelimb of a nine-year-old rabbit (Oryctolagus cuniculus) was examined histopathologically and immunohistochemically. Clinically, edema and hemorrhage were seen around the mass. No connection of the tumor mass to the appendicular skeleton was found. The tumor was arranged in a solid growth pattern and irregular bundles, and neoplastic cells were polygonal to spindle-shape. Osteoid (positive for osteocalcin) and multinucleated giant cells were diffusely or focally seen. Neoplastic cells were positive for vimentin, osterix and Ki-67, indicating the nature of osteoblasts with proliferating activity, but negative for α-smooth muscle actin, desmin or CD204. Based on these findings, a diagnosis of extraskeletal osteosarcoma was made, a very rare tumor both in laboratory and pet rabbits. PMID:24155564

Do Patients After Chondrosarcoma Treatment Have Age-appropriate Bone Mineral Density in the Long Term?

PubMed

Hobusch, Gerhard M; Tiefenboeck, Thomas M; Patsch, Janina; Krall, Christoph; Holzer, Gerold

2016-06-01

In long-term survivors of osteosarcoma and Ewing sarcoma treated with the addition of radio- and chemotherapy, low bone mineral density (BMD) and fractures have been observed, presumably resulting from these adjuvants. Because patients with chondrosarcoma usually are not treated with conventional adjuvant treatment, observation of low BMD in patients with chondrosarcoma presumably would be the result of other mechanisms. However, BMD in patients with a history of chondrosarcoma has not been well characterized. The aim of our study was to address the following questions: (1) Do long-term survivors of chondrosarcoma have normal BMD and, if not, which factors contribute to low BMD? (2) Is there a greater risk of fracture and does the Fracture Risk Assessment Tool (FRAX(®)) score reflect fracture likelihood? All known patients with a history of chondrosarcoma treated at our institution before 2006 were identified. Of 127 patients believed to be alive at the time of this study, 30 agreed to participate in this study (11 females, 19 males; mean age at surgery, 39 ± 12 years; mean followup, 12 ± 5 years). With the data available, the 30 participants were not different from the 97 nonparticipants in terms of age, sex, BMI, tumor grade, tumor location (axial versus appendicular, lower extremity versus elsewhere), and use of any treatment known to influence osteopenia (chemotherapy, lower extremity surgery). BMD was measured and history of fractures was assessed using a questionnaire. The patients´ BMD measurements in this study were sex- and age-matched with a normative sex- and age-categorized reference population reported by Kudlacek et al. Associations were tested by univariate regressions and ANOVAs of all measures of BMD and eligible oncologic and demographic factors. Eighteen of 30 (60%) patients had a pathologic BMD according to the WHO dual-energy x-ray absorptiometry definition, 15 (50%) had osteopenia, and three (10%) had osteoporosis. T-scores in the study cohort were lower than reference values for the femur neck (mean difference, 0.64; 95% CI, 0.27-1.01; p < 0.0015), but not for the spine (mean difference, 0.39; 95% CI, -0.06 to 0.84; p = 0.09). Thirteen patients (45%) reported a history of fractures not distinguishing between low and high impact. The incidence of fractures was 2.8 greater than expected from a comparison with a published microcensus survey of the Austrian population. No effect of the FRAX(®) score on fracture risk could be identified (p = 0.057). Long-term survivors of chondrosarcoma appear to be at greater risk for having low BMD develop than the healthy population. Although these results are preliminary and based on a very small sampling of patients, if they can be confirmed in larger studies, BMD assessment by dual-energy x-ray absorptiometry might be considered as these patients are followed posttreatment by sarcoma care units. The reasons for low BMD still must be elucidated. Level IV, prognostic study.

CRISPR/Cas9 mediated generation of stable chondrocyte cell lines with targeted gene knockouts; analysis of an aggrecan knockout cell line.

PubMed

Yang, Maozhou; Zhang, Liang; Stevens, Jeff; Gibson, Gary

2014-12-01

The Swarm rat chondrosarcoma (RCS) cell lines derived from a spontaneous neoplasm in a rat spine several decades ago have provided excellent models of chondrosarcoma tumor development. In addition the robust chondrocyte phenotype (expression of a large panel of genes identical to that seen in normal rat cartilage) and the ability to generate cell clones have facilitated their extensive use in the identification of chondrocyte proteins and genes. The clustered regularly interspersed short palindromic repeat (CRISPR) technology employing the RNA-guided nuclease Cas9 has rapidly dominated the genome engineering field as a unique and powerful gene editing tool. We have generated a stable RCS cell line (RCS Cas9) expressing the nuclease Cas9 that enables the editing of any target gene or non-coding RNA by simple transfection with a guide RNA. As proof of principle, stable cell lines with targeted ablation of aggrecan expression (Acan KO) were generated and characterized. The studies show that stable chondrocyte cell lines with targeted genome editing can be quickly generated from RCS Cas9 cells using this system. The Acan KO cell lines also provided a tool for characterizing the response of chondrocytes to aggrecan loss and the role of aggrecan in chondrosarcoma development. Loss of aggrecan expression while not affecting the chondrocyte phenotype resulted in a much firmer attachment of cells to their substrate in culture. Large changes in the expression of several genes were observed in response to the absence of the proteoglycan matrix, including those for several small leucine rich proteoglycans (SLRPs), transcription factors and membrane transporters. Acan KO cells failed to form a substantial chondrosarcoma when injected subcutaneously in nude mice consistent with previous suggestions that the glycosaminoglycan-rich matrix surrounding the chondrosarcoma protects it from destruction by the host immune system. The studies provide new understanding of aggrecan function and the RCS Cas9 cell line is expected to provide a very valuable tool for the study gene function in chondrocytes. Copyright © 2014 Elsevier Inc. All rights reserved.

Dosimetric comparison of photon and proton treatment techniques for chondrosarcoma of thoracic spine

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yadav, Poonam, E-mail: yadav@humonc.wisc.edu; Department of Medical Physics, University of Wisconsin, Madison, WI; University of Wisconsin Riverview Cancer Center, Wisconsin Rapids, WI

2013-10-01

Chondrosarcomas are relatively radiotherapy resistant, and also delivering high radiation doses is not feasible owing to anatomic constraints. In this study, the feasibility of helical tomotherapy for treatment of chondrosarcoma of thoracic spine is explored and compared with other available photon and proton radiotherapy techniques in the clinical setting. A patient was treated for high-grade chondrosarcoma of the thoracic spine using tomotherapy. Retrospectively, the tomotherapy plan was compared with intensity-modulated radiation therapy, dynamic arc photon therapy, and proton therapy. Two primary comparisons were made: (1) comparison of normal tissue sparing with comparable target volume coverage (plan-1), and (2) comparison ofmore » target volume coverage with a constrained maximum dose to the cord center (plan-2). With constrained target volume coverage, proton plans were found to yield lower mean doses for all organs at risk (spinal cord, esophagus, heart, and both lungs). Tomotherapy planning resulted in the lowest mean dose to all organs at risk amongst photon-based methods. For cord dose constrained plans, the static-field intensity-modulated radiation therapy and dynamic arc plans resulted target underdosing in 20% and 12% of planning target volume2 volumes, respectively, whereas both proton and tomotherapy plans provided clinically acceptable target volume coverage with no portion of planning target volume2 receiving less than 90% of the prescribed dose. Tomotherapy plans are comparable to proton plans and produce superior results compared with other photon modalities. This feasibility study suggests that tomotherapy is an attractive alternative to proton radiotherapy for delivering high doses to lesions in the thoracic spine.« less

Skeletal stem cell isolation: A review on the state-of-the-art microfluidic label-free sorting techniques.

PubMed

Xavier, Miguel; Oreffo, Richard O C; Morgan, Hywel

2016-01-01

Skeletal stem cells (SSC) are a sub-population of bone marrow stromal cells that reside in postnatal bone marrow with osteogenic, chondrogenic and adipogenic differentiation potential. SSCs reside only in the bone marrow and have organisational and regulatory functions in the bone marrow microenvironment and give rise to the haematopoiesis-supportive stroma. Their differentiation capacity is restricted to skeletal lineages and therefore the term SSC should be clearly distinguished from mesenchymal stem cells which are reported to exist in extra-skeletal tissues and, critically, do not contribute to skeletal development. SSCs are responsible for the unique regeneration capacity of bone and offer unlimited potential for application in bone regenerative therapies. A current unmet challenge is the isolation of homogeneous populations of SSCs, in vitro, with homogeneous regeneration and differentiation capacities. Challenges that limit SSC isolation include a) the scarcity of SSCs in bone marrow aspirates, estimated at between 1 in 10-100,000 mononuclear cells; b) the absence of specific markers and thus the phenotypic ambiguity of the SSC and c) the complexity of bone marrow tissue. Microfluidics provides innovative approaches for cell separation based on bio-physical features of single cells. Here we review the physical principles underlying label-free microfluidic sorting techniques and review their capacity for stem cell selection/sorting from complex (heterogeneous) samples. Copyright © 2016 Elsevier Inc. All rights reserved.

A well-known lesion in an unusual location: infantile myofibroma of the eyelid: a case report and review of literature.

PubMed

Asadi Amoli, Fahimeh; Sina, Amir Hossein; Kasai, Aboulfazl; Ayan, Zahra

2010-01-01

Myofibroma is a neoplasia of myofibroblasts that can be solitary or multiple and it is found most commonly in the head & neck region including scalp, forehead, parotid region and oral cavity. In the eyelid it is rarely reported. It has a benign course in the solitary form and fatal in its multiple form. A 4 month male infant referred to Farabi hospital -the referral center for eye diseases- with a 2 month history of a mass in his eyelid with gradual enlargement with no other complaints. The only abnormal physical finding was a 2.5 cm mass in the eyelid. This mass was excised and sent to the hospital pathology laboratory. When confronting a spindle cell lesion with a nodular or multinodular growth pattern which appears biphasic due to alteration of light and dark staining areas, the surgical pathologist should think to the possibility of myofibroma. Its pattern of growth and architecture rules out the other differential diagnoses like nodular fasciitis, fibrous histiocytoma, infantile fibromatosis, and peripheral primitive neuroectodermal tumor, mesenchymal chondrosarcoma, malignant hemangiopericytoma, juvenile fibrosarcoma and poorly differentiated synovial sarcoma. In difficult cases immunohistochemical staining is helpful that is Vimentin & Actin positivity & Desmin, CK, EMA & S100 negativity.

Small round blue cell tumors of the sinonasal tract: a differential diagnosis approach.

PubMed

Thompson, Lester Dr

2017-01-01

One of the most challenging diagnostic categories within tumors of the sinonasal tract is the small round blue cell tumors. Biopsies are usually small and limited, resulting in considerable diagnostic difficulty for practicing surgical pathologists. These tumors share several overlapping histologic and immunophenotypic findings while also showing considerable variation within and between cases. Specific tumor site of origin, imaging findings, and clinical findings must be combined with the histology and pertinent ancillary studies if the correct diagnosis is to be reached. Discrimination between neoplasms is critical as there are significant differences in therapy and overall outcome. It is important to have a well developed differential diagnosis for this category of tumors, where each of the diagnoses is considered, evaluated, and either confirmed or excluded from further consideration. In an undifferentiated tumor, showing a small round blue cell morphology, using the mnemonic 'MR SLEEP' helps to highlight tumors to consider: melanoma, mesenchymal chondrosarcoma, rhabdomyosarcoma, sinonasal undifferentiated carcinoma, squamous cell carcinoma (including NUT carcinoma), small cell osteosarcoma, lymphoma, esthesioneuroblastoma (olfactory neuroblastoma), Ewing sarcoma/primitive neuroectodermal tumor, pituitary adenoma, and plasmacytoma. A panel of pertinent immunohistochemistry studies, histochemistries and/or molecular tests should aid in reaching a diagnosis, especially when taking the pattern and intensity of reactions into consideration.

PIM-1 kinase expression in adipocytic neoplasms: diagnostic and biological implications

PubMed Central

Nga, Min En; Swe, Nu Nu Ma; Chen, Kang Ting; Shen, Liang; Lilly, Michael B; Chan, Siew Pang; Salto-Tellez, Manuel; Das, Kakoli

2010-01-01

The differential diagnosis of soft tissue tumours poses a considerable challenge for pathologists, especially adipocytic tumours, as these may show considerable overlap in clinical presentation and morphological features with many other mesenchymal neoplasms. Hence, a specific and reliable marker that identifies adipocytic differentiation is much sought. We investigated the immunohistochemical expression of PIM-1 kinase in 35 samples of soft tissue tumours using tissue microarray technology and 49 full sections of adipocytic (n = 26) and non-adipocytic tumours (n = 23). Benign and malignant adipocytic tumours showed strong expression of PIM-1 while the non-adipocytic tumours were either negative or showed only weak staining for the protein. In myxoid liposarcomas, PIM-1 showed a distinct, unique vacuolar staining pattern, clearly outlining fine cytoplasmic lipid vacuoles. By contrast, non-adipocytic myxoid tumours (myxoma, chordoma and myxoid chondrosarcoma) did not show this vacuolar pattern of PIM-1 staining, although vacuolated cells were present on H&E. This differential expression was confirmed at a gene expression level in selected cases. Our results indicate that the expression of PIM-1 in adipose tissue may be a useful marker of adipocytic differentiation, in particular if the staining is both of high intensity and present in a unique, vacuolar pattern. PMID:19878356

Efficacy and Safety of Adjuvant Proton Therapy Combined With Surgery for Chondrosarcoma of the Skull Base: A Retrospective, Population-Based Study.

PubMed

Feuvret, Loïc; Bracci, Stefano; Calugaru, Valentin; Bolle, Stéphanie; Mammar, Hamid; De Marzi, Ludovic; Bresson, Damien; Habrand, Jean-Louis; Mazeron, Jean-Jacques; Dendale, Rémi; Noël, Georges

2016-05-01

Chondrosarcoma is a rare malignant tumor of the cartilage affecting young adults. Surgery, followed by charged-particle irradiation, is considered the reference standard for the treatment of patients with grade I to II skull base chondrosarcoma. The present study was conducted to assess the effect of the quality of surgery and radiation therapy parameters on local control (LC) and overall survival (OS). From 1996 to 2013, 159 patients (median age 40 years, range 12-83) were treated with either protons alone or a combination of protons and photons. The median total dose delivered was 70.2 Gy (relative biologic effectiveness [RBE]; range 67-71). Debulking and biopsy were performed in 133 and 13 patients, respectively. With a median follow-up of 77 months (range 2-214), 5 tumors relapsed based on the initial gross tumor volume. The 5- and 10-year LC rates were 96.4% and 93.5%, respectively, and the 5- and 10-year OS rates were 94.9% and 87%, respectively. A total of 16 patients died (13 of intercurrent disease, 3 of disease progression). On multivariate analysis, age <40 years and primary disease status were independent favorable prognostic factors for progression-free survival and OS, and local tumor control was an independent favorable predictor of OS. In contrast, the extent of surgery, dosimetric parameters, and adjacent organs at risk were not prognostic factors for LC or OS. Systematic high-dose postoperative proton therapy for skull base chondrosarcoma can achieve a high LC rate with a low toxicity profile. Maximal safe surgery, followed by high-dose conformal proton therapy, is therefore recommended. Copyright © 2016 Elsevier Inc. All rights reserved.

Efficacy and Safety of Adjuvant Proton Therapy Combined With Surgery for Chondrosarcoma of the Skull Base: A Retrospective, Population-Based Study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Feuvret, Loïc, E-mail: loic.feuvret@psl.aphp.fr; Department of Radiation Oncology, Institut Curie–Centre de protonthérapie d'Orsay; Bracci, Stefano

Purpose: Chondrosarcoma is a rare malignant tumor of the cartilage affecting young adults. Surgery, followed by charged-particle irradiation, is considered the reference standard for the treatment of patients with grade I to II skull base chondrosarcoma. The present study was conducted to assess the effect of the quality of surgery and radiation therapy parameters on local control (LC) and overall survival (OS). Methods and Materials: From 1996 to 2013, 159 patients (median age 40 years, range 12-83) were treated with either protons alone or a combination of protons and photons. The median total dose delivered was 70.2 Gy (relative biologic effectiveness [RBE];more » range 67-71). Debulking and biopsy were performed in 133 and 13 patients, respectively. Results: With a median follow-up of 77 months (range 2-214), 5 tumors relapsed based on the initial gross tumor volume. The 5- and 10-year LC rates were 96.4% and 93.5%, respectively, and the 5- and 10-year OS rates were 94.9% and 87%, respectively. A total of 16 patients died (13 of intercurrent disease, 3 of disease progression). On multivariate analysis, age <40 years and primary disease status were independent favorable prognostic factors for progression-free survival and OS, and local tumor control was an independent favorable predictor of OS. In contrast, the extent of surgery, dosimetric parameters, and adjacent organs at risk were not prognostic factors for LC or OS. Conclusions: Systematic high-dose postoperative proton therapy for skull base chondrosarcoma can achieve a high LC rate with a low toxicity profile. Maximal safe surgery, followed by high-dose conformal proton therapy, is therefore recommended.« less

Familial solitary chondrosarcoma resulting from germline EXT2 mutation.

PubMed

Heddar, Abdelkader; Fermey, Pierre; Coutant, Sophie; Angot, Emilie; Sabourin, Jean-Christophe; Michelin, Paul; Parodi, Nathalie; Charbonnier, Françoise; Vezain, Myriam; Bougeard, Gaëlle; Baert-Desurmont, Stéphanie; Frébourg, Thierry; Tournier, Isabelle

2017-02-01

Germline mutations of EXT2, encoding Exostosin Glycosyltransferase 2, are associated with multiple osteochondromas (MO), an autosomal dominant disease characterized by the development of multiple peripheral cartilaginous benign tumors with a weak risk of malignant transformation. We report here a family with a remarkable clinical presentation characterized by the development of isolated chondrosarcomas, mostly located in ribs. Comparative analysis of exomes from two third-degree affected relatives led us to identify a single common disruptive variation, corresponding to a stop mutation (c.237G > A, p.Trp79*; (NM_000401.3); c.138G > A, p.Trp46*; (NM_207122.1)) within exon 2 of the EXT2 gene. Interestingly, no obvious sign of MO was detected in affected members by radiological examination. This report shows that germline mutations of EXT2 can result, not only in the development of multiple benign osteochondromas, but also in the development of isolated malignant cartilaginous tumors including central tumors, and that the presence of germline EXT2 mutation should be considered in patients suspected to have an inherited predisposition to chondrosarcoma, even in the absence of MO. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Paravertebral masses in blue-tailed monitor, Varanus dorianus, indicative of soft-tissue infection with associated osteomyelitis.

PubMed

Rothschild, Bruce M

2014-03-01

Paravertebral osseous masses in reptiles have been attributed to Paget's disease on the basis of histology. Histologically recognized mosaic architecture and cement lines, however, lack specificity. A Varanus dorianus with this condition was subjected to standard and computerized tomography. Because the masses were extraskeletal in nature, Paget's disease could be excluded. Although interpretation of the computed tomography suggested the process to be entirely extraskeletal, standard radiographs revealed disorganized vertebral architecture characteristic of osteomyelitis, crossing intervertebral spaces. Posttraumatic myositis ossificans and calcified hematoma were confidently excluded as diagnoses. The etiology of paraspinal masses in this V. dorianus appears attributable to infection, with infection of a puncture wound hypothesized as the underlying process. If one extrapolates the findings in this one animal, it seems reasonable to suggest that consideration be given to investigating the possibility of an infectious origin when similar masses are recognized in other reptiles.

Extraskeletal osteosarcoma, telangiectatic variant arising from the small bowel mesentery.

PubMed

Hussain, Muhammad I; Al-Akeely, Mohammed H; Alam, Mohammed K; Jasser, Nayel A

2011-09-01

Extraskeletal osteosarcoma (EOS) is a highly aggressive and rare malignant soft tissue tumor, characterized by the production of neoplastic osseous tissue without attachment to the bone or periosteum. It rarely involves the visceral organs. Only 3 cases of mesenteric EOS have been reported in English literature. Here, we describe a male patient of 40 years, who was diagnosed to have EOS arising from small bowel mesentery. This patient presented with lower gastrointestinal (GI) bleeding. Upper GI endoscopy and colonoscopy were normal. Computed tomography scan demonstrated a well defined multi-loculated mixed density mass lesion measuring about 13x7x7 cm in lower abdomen adjacent to small bowel loops with liver metastasis. Palliative en bloc resection of tumor with adjacent small bowel was performed. The histopathology revealed a telangiectatic type osteosarcoma of mesentery. Diagnosis of EOS, its management and the outcome in context of the current literature are discussed.

The role of metabolic enzymes in mesenchymal tumors and tumor syndromes: genetics, pathology, and molecular mechanisms.

PubMed

Schaefer, Inga-Marie; Hornick, Jason L; Bovée, Judith V M G

2018-04-01

The discovery of mutations in genes encoding the metabolic enzymes isocitrate dehydrogenase (IDH), succinate dehydrogenase (SDH), and fumarate hydratase (FH) has expanded our understanding not only of altered metabolic pathways but also epigenetic dysregulation in cancer. IDH1/2 mutations occur in enchondromas and chondrosarcomas in patients with the non-hereditary enchondromatosis syndromes Ollier disease and Maffucci syndrome and in sporadic tumors. IDH1/2 mutations result in excess production of the oncometabolite (D)-2-hydroxyglutarate. In contrast, SDH and FH act as tumor suppressors and genomic inactivation results in succinate and fumarate accumulation, respectively. SDH deficiency may result from germline SDHA, SDHB, SDHC, or SDHD mutations and is found in autosomal-dominant familial paraganglioma/pheochromocytoma and Carney-Stratakis syndrome, describing the combination of paraganglioma and gastrointestinal stromal tumor (GIST). In contrast, patients with the non-hereditary Carney triad, including paraganglioma, GIST, and pulmonary chondroma, usually lack germline SDH mutations and instead show epigenetic SDH complex inactivation through SDHC promoter methylation. Inactivating FH germline mutations are found in patients with hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome comprising benign cutaneous/uterine leiomyomas and renal cell carcinoma. Mutant IDH, SDH, and FH share common inhibition of α-ketoglutarate-dependent oxygenases such as the TET family of 5-methylcytosine hydroxylases preventing DNA demethylation, and Jumonji domain histone demethylases increasing histone methylation, which together inhibit cell differentiation. Ongoing studies aim to better characterize these complex alterations in cancer, the different clinical phenotypes, and variable penetrance of inherited and sporadic cancer predisposition syndromes. A better understanding of the roles of metabolic enzymes in cancer may foster the development of therapies that specifically target functional alterations in tumor cells in the future. Here, the physiologic functions of these metabolic enzymes, the mutational spectrum, and associated functional alterations will be discussed, with a focus on mesenchymal tumor predisposition syndromes.

Primary chondrosarcoma of the thyroid cartilage: Surgery-based management of a rare case

PubMed Central

Sun, Guo-Hua; Wang, Yuan-Jin; Gao, Li-Li; Qu, Ning; Mu, Xiang-Ming; Shi, Rong-Liang; Ji, Qing-Hai

2016-01-01

In this study, we present a case of a 52-year-old male with a chondrosarcoma of the left lamina of the thyroid cartilage. Pre-operative evaluations detected typical calcifications and delineated the extent of the tumor. The patient underwent a total laryngectomy to ensure the complete resection of the tumor. The tumor was histopathologically found to consist of chondrocytes in a hyaline cartilage matrix. The patient's post-operative course has been successful apart from the permanent tracheostomy. Herien, we discuss the methods and rationales for the diagnosis and management of and recovery from this rare tumor, and also provide a review of the literature. PMID:28101206

Mucopolysaccharide and Protein—Polysaccharide of a Transplantable Rat Chondrosarcoma

PubMed Central

Choi, Haing Ug; Meyer, Karl; Swarm, Richard

1971-01-01

Two mucopolysaccharides, chondroitin 4-sulfate (97.8%) and hyaluronic acid (1.2%), were isolated after exhaustive proteolysis of a transplantable chondrosarcoma of the rat. The chondroitin 4-sulfate was fractionated into three fractions of varying degrees of sulfation and chain length. Keratan sulfate and chondroitin 6-sulfate were absent. Extraction of the fresh tumor gave two protein—polysaccharides of similar carbohydrate composition, one soluble in 0.5 M NaCl, the other insoluble. The latter was solubilized in 4 M guanidine·HCl. A dialyzable fraction from the 4 M guanidine solution may be responsible for the insolubility. Both protein—polysaccharides were antigenic and cross-reacted with similar fractions of bovine and human cartilage. PMID:4252539

Tumoral, quasitumoral and pseudotumoral lesions of the superficial and somatic soft tissue: new entities and new variants of old entities recorded during the last 25 years. Part XII: appendix.

PubMed

Bisceglia, M; Spagnolo, D; Galliani, C; Fisher, C; Suster, S; Kazakov, D V; Cooper, K; Michal, M

2006-08-01

In an eleven part series published in Pathologica, we have presented various tumoral, quasitumoral and pseudotumoral lesions of the superficial and somatic soft tissue (ST), which emerged as new entities or as variants of established entities during the last quarter of a century. Detailed clinicomorphological and differential diagnostic features of approximately sixty entities were chosen on the basis of their clinical significance and morphologic distinctiveness. The series included fibrous and myofibroblastic tumors (e.g. solitary fibrous tumor, high grade classic and pigmented dermatofibrosarcoma protuberans, inflammatory myofibroblastic tumor and myofibrosarcomas), fibromyxoid and fibrohistiocytic neoplasms (e.g., Evans' tumor, phosphaturic mesenchymal tumor, inflammatory myxohyaline tumor), special adipocytic/vascular/and smooth muscle lesions (e.g., chondroid lipoma, Dabska's tumor, ST hemangioblastoma, lipoleiomyosarcoma), epithelioid mesenchymal malignancies of diverse lineages (e.g., epithelioid liposarcoma, proximal-type epithelioid sarcoma, neuroendocrine extraskeletal chondromyxoid sarcoma), ST Ewing's tumor and peripheral nerve sheath tumors (perineuriomas and pigmented and rosetting tumors of the schwannoma/neurofibroma group), extranodal dendritic or histiocytic proliferative processes (follicular dendritic cell sarcoma, Rosai-Dorfman disease, Castleman's disease, and plexiform xanthomatous tumor), and tumors with myoepithelial differentiation. The section devoted to selected pseudotumoral entities considered representatives of the hamartoma group (neural fibrolipomatous hamartoma, ectopic hamartomatous thymoma, rudimentary meningocele), metabolic diseases (amyloid tumor, nephrogenic fibrosing dermopathy, tophaceous pseudogout, pseudoinfiltrative parathyromatosis), stromal tissue reactions to trauma (fibroosseous pseudotumors of digits) and infections (bacillary angiomatosis), and normal organs (glomus coccygeum). To conclude the descriptive phase, supplementary material has now been collected and appended in an attempt to provide a quick digest of essential knowledge both for comparison and differential diagnosis. The data have been tailored to synthesize diverse sources, integrating clinical elements and references to articles that previously appeared in Part I ("Introduction"), Part II ("The List and Review of New Entities") and Parts III to XI ("Excerpta"). At the very least we hope this final part ("Appendix") will provide the reader with a useful tabular organization of ST lesions and a reference resource.

Common genetic determinants of vitamin D insufficiency: the sunlight consortium

USDA-ARS?s Scientific Manuscript database

Background: Vitamin D is crucial for maintaining musculoskeletal health. Recently, vitamin D insufficiency has been linked to a number of extraskeletal disorders, including diabetes, cancer, and cardiovascular disease. Determinants of circulating 25-hydroxyvitamin D (25-OH D) include sun exposure an...

Dedifferentiated chondrosarcoma: A survival analysis of 159 cases from the SEER database (2001-2011).

PubMed

Strotman, Patrick K; Reif, Taylor J; Kliethermes, Stephanie A; Sandhu, Jasmin K; Nystrom, Lukas M

2017-08-01

Dedifferentiated chondrosarcoma is a rare malignancy with reported 5-year overall survival rates ranging from 7% to 24%. The purpose of this investigation is to determine the overall survival of dedifferentiated chondrosarcoma in a modern patient series and how it is impacted by patient demographics, tumor characteristics, and surgical treatment factors. This is a retrospective review of the Surveillance, Epidemiology, and End Results (SEER) database from 2001 to 2011. Kaplan Meier analyses were used for overall and disease-specific survival. Univariable and multivariable cox regression models were used to identify prognostic factors. Five year overall- and disease-specific survival was 18% (95% CI: 12-26%) and 28% (95% CI: 18-37%), respectively. Individuals with extremity tumors had a worse prognosis than individuals with a primary tumor in the chest wall or axial skeleton (HR 0.20, 95% CI: 0.07-0.56; P = 0.002 and HR 0.60, 95% CI: 0.36-0.99; P = 0.04, respectively). Patients with AJCC stage III or IV disease (HR 2.51, 95% CI: 1.50-4.20; P = 0.001), tumors larger than 8 cm (HR 2.17, 95% CI: 1.11-4.27; P = 0.046), metastatic disease at diagnosis (HR 3.25, 95% CI: 1.98-5.33; P < 0.001), and those treated without surgical resection (amputation: HR 0.43, 95% CI 0.23-0.80; P = 0.01; limb salvage/non-amputation resection: HR 0.41, 95% CI: 0.24-0.69; P = 0.001) had a significant increase in risk of mortality. The overall prognosis of dedifferentiated chondrosarcoma is poor with a 5-year overall survival of 18%. Patients with a primary tumor located in the chest wall had a better prognosis. Tumors larger than 8 cm, presence of metastases at diagnosis, and treatment without surgical resection were significant predictors of mortality. © 2017 Wiley Periodicals, Inc.

Challenges in Linear Accelerator Radiotherapy for Chordomas and Chondrosarcomas of the Skull Base: Focus on Complications

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hauptman, Jason S., E-mail: jhauptman@mednet.ucla.edu; Barkhoudarian, Garni; Safaee, Michael

2012-06-01

Purpose: Intracranial chordomas and chondrosarcomas are histologically low-grade, locally invasive tumors that infiltrate the skull base. Currently, consensus therapy includes surgical resection and adjuvant radiotherapy. Radiation delivery is typically limited by the proximity of these tumors to critical skull base structures. Methods: This is a retrospective review of 13 cases of chordomas and 2 cases of chondroid chondrosarcomas of the skull based treated with linear accelerator stereotactic radiotherapy (SRT, n = 10) or stereotactic radiosurgery (SRS, n = 5). The average time to the most recent follow-up visit was 4.5 years. The tumor characteristics, treatment details, and outcomes were recorded.more » Each radiation plan was reviewed, and the dosage received by the brainstem, optic apparatus, and pituitary was calculated. Results: Of the 10 patients treated with SRT, 6 were found to have unchanged or decreased tumor size as determined from radiographic follow-up. Of the 5 patients treated with SRS, 3 were found to have stable or unchanged tumors at follow-up. The complications included 1 SRT patient who developed endocrinopathy, 2 patients (1 treated with SRS and the other with SRT), who developed cranial neuropathy, and 1 SRS patient who developed visual deficits. Additionally, 1 patient who received both SRS and SRT within 2 years for recurrence experienced transient medial temporal lobe radiation changes that resolved. Conclusions: Where proton beam therapy is unavailable, linear accelerator-based SRT or radiosurgery remains a safe option for adjuvant therapy of chordomas and chondrosarcomas of the skull base. The exposure of the optic apparatus, pituitary stalk, and brainstem must be considered during planning to minimize complications. If the optic apparatus is included in the 80% isodose line, it might be best to fractionate therapy. Exposure of the pituitary stalk should be kept to <30 Gy to minimize endocrine dysfunction. Brainstem exposure should be limited to <60 Gy in fractions.« less

Intradural extramedullary Ewing's sarcoma: A case report and review of the literature.

PubMed

Paterakis, Konstantinos; Brotis, Alexandros; Tasiou, Anastasia; Kotoula, Vasiliki; Kapsalaki, Eftychia; Vlychou, Marianna

Extra-skeletal Ewing's sarcomas are very rare lesions to the spine surgeon, with the intradural, extramedullary lesions being even rarer. Herein we present a patient with an intradural, extramedullary form of Ewing's sarcoma and review the relevant literature. The medical records, operative reports, radiographical studies and histological examinations of a single patient are retrospectively reviewed. A 31-year old male presented with back-pain, right-leg progressive paraparesis, and inability to walk. Both motor and sensory disturbances were revealed on the right leg at the clinical examination. Lumbar MRI showed two lesions. The first one was an intradural, extramedullary lesion at the L2-L3 level, while the second was smaller, located at the bottom of the dural sac. The patient underwent gross total resection of the L2-L3 lesion after a bilateral laminectomy. Histological examination was compatible with Ewing's sarcoma, and was verified by molecular analysis. No other extra-skeletal or skeletal lesion was found. A chemotherapy scheme was tailored to the patients' histological diagnosis. The patient presented with local recurrence and bone metastasis 2 years after his initial diagnosis. A second operation was performed and the follow up of the patient showed no disease progression 18 months after revision surgery. The spine surgeon should be aware of the existence of such rare entities, in order to timely fulfill the staging process and institute the proper therapy. The management of patients with extra-skeletal Ewing's sarcomas involves professionals as members of a multidisciplinary team, all of which should co-operate for the patient's optimal outcome. Copyright © 2016. Published by Elsevier Urban & Partner Sp. z o.o.

Low-grade extraskeletal osteosarcoma of the chest wall: case report and review of literature.

PubMed

Sabatier, Renaud; Bouvier, Corinne; de Pinieux, Gonzague; Sarran, Anthony; Brenot-Rossi, Isabelle; Pedeutour, Florence; Chetaille, Bruno; Viens, Patrice; Weiller, Pierre-Jean; Bertucci, François

2010-11-24

Low-grade extraskeletal osteosarcomas (ESOS) are extremely rare. We present the first case of low-grade ESOS of the chest wall, which occurred in a 30-year-old man. Because of initial misdiagnosis and patient's refusal of surgery, the diagnosis was done after a 4-year history of a slowly growing mass in soft tissues, leading to a huge (30-cm diameter) calcified mass locally extended over the left chest wall. Final diagnosis was helped by molecular analysis of MDM2 and CDK4 oncogenes. Unfortunately, at this time, no surgical treatment was possible due to loco-regional extension, and despite chemotherapy, the patient died one year after diagnosis, five years after the first symptoms. We describe the clinical, radiological and bio-pathological features of this unique case, and review the literature concerning low-grade ESOS. Our case highlights the diagnostic difficulties for such very rare tumours and the interest of molecular analysis in ambiguous cases.

Vitamin D: Current Guidelines and Future Outlook.

PubMed

Pilz, Stefan; Trummer, Christian; Pandis, Marlene; Schwetz, Verena; Aberer, Felix; Grübler, Martin; Verheyen, Nicolas; Tomaschitz, Andreas; März, Winfried

2018-02-01

Vitamin D is of public health interest because its deficiency is common and is associated with musculoskeletal diseases, as well as extraskeletal diseases, such as cancer, cardiovascular diseases, and infections. Several health authorities have reviewed the existing literature and published nutritional vitamin D guidelines for the general population. There was a wide consensus that serum 25-hydroxyvitamin D [25(OH)D] concentration should be used to assess vitamin D status and intake, and that musculoskeletal, and not extraskeletal, effects of vitamin D should be the basis for nutritional vitamin D guidelines. Recommended target levels for 25(OH)D range from 25 to 50 nmol/l (10 to 20 ng/ml), corresponding to a vitamin D intake of 400 to 800 International Units (10 to 20 μg) per day. It is of concern that significant sections of the general population do not meet these recommended vitamin D levels. This definitely requires action from a public health perspective. Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Trial of Dasatinib in Advanced Sarcomas

ClinicalTrials.gov

2017-03-20

Rhabdomyosarcoma; Malignant Peripheral Nerve Sheath Tumors; Chondrosarcoma; Sarcoma, Ewing's; Sarcoma, Alveolar Soft Part; Chordoma; Epithelioid Sarcoma; Giant Cell Tumor of Bone; Hemangiopericytoma; Gastrointestinal Stromal Tumor (GIST)

Synchronous glioblastoma multiforme and chondrosarcoma: A case report and review of the literature.

PubMed

Li, Charles Xin; Goldenberg, Yoni; McLean, Catriona; Savio Gomes, Keith

2018-06-01

This case report describes the rare occurrence of two individually uncommon tumours found in synchronous manner in an otherwise healthy patient with no history of malignancy. We believe this to be the first reported case of synchronous glioblastoma and chondrosarcoma. While primary rib lesions metastasising to brain are rarely reported and primary brain lesions metastasising to rib are even rarer still, there were no previous reports in the literature of synchronous brain and rib dual primary pathology that we could identify. Unrelated dual pathology, while rare, must be considered amongst the list of differential diagnoses in patients who present with multiple lesions, and highlights the importance of separate histological confirmation prior to integrated management. Copyright © 2018 Elsevier Ltd. All rights reserved.

Computed tomographic diagnosis of unilateral cavernous sinus syndrome caused by a chondrosarcoma in a dog: a case report.

PubMed

Hernández-Guerra, Angel María; Del Mar López-Murcia, María; Planells, Alicia; Corpa, Juan Manuel; Liste, Fernando

2007-07-01

An eight-year old Rottweiler dog was presented with signs of enophthalmia, ptosis, anisocoria and mydriasis of the right eye, which showed visual disturbance, reduced or absent reflexes, and ophthalmoplegia. Consensual pupillary light reflex was also absent in the left eye. These neurological deficits were compatible with cavernous sinus syndrome. Computed tomography images of the cavernous sinus and the optical fissure revealed a mildly calcified mass arising from the right presphenoid bone extending further caudally into the orbital foramina. This extension of the mass affected the normal function of several cranial nerves. The dog was euthanased within one year of the initial presentation following development of forebrain signs. A chondrosarcoma was diagnosed histologically after necropsy.

Gene expression profiles in chondrosarcoma cells subjected to cyclic stretching and hydrostatic pressure. A cDNA array study.

PubMed

Karjalainen, Hannu M; Sironen, Reijo K; Elo, Mika A; Kaarniranta, Kai; Takigawa, Masaharu; Helminen, Heikki J; Lammi, Mikko J

2003-01-01

Mechanical forces have a profound effect on cartilage tissue and chondrocyte metabolism. Strenuous loading inhibits the cellular metabolism, while optimal level of loading at correct frequency raises an anabolic response in chondrocytes. In this study, we used Atlas Human Cancer cDNA array to investigate mRNA expression profiles in human chondrosarcoma cells stretched 8% for 6 hours at a frequency of 0.5 Hz. In addition, cultures were exposed to continuous and cyclic (0.5 Hz) 5 MPa hydrostatic pressure. Cyclic stretch had a more profound effect on the gene expression profiles than 5 MPa hydrostatic pressure. Several genes involved with the regulation of cell cycle were increased in stretched cells, as well as mRNAs for PDGF-B, glucose-1-phosphate uridylyltransferase, Tiam1, cdc37 homolog, Gem, integrin alpha6, and matrix metalloproteinase-3. Among down-regulated genes were plakoglobin, TGF-alpha, retinoic acid receptor-alpha and Wnt8b. A smaller number of changes was detected after pressure treatments. Plakoglobin was increased under cyclic and continuous 5 MPa hydrostatic pressure, while mitogen-activated protein kinase-9, proliferating cell nuclear antigen, Rad6, CD9 antigen, integrins alphaE and beta8, and vimentin were decreased. Cyclic and continuous pressurization induces a number of specific changes. In conclusion, a different set of genes were affected by three different types of mechanical stimuli applied on chondrosarcoma cells.

Chondrosarcoma

MedlinePlus

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Solitary extra-skeletal sinonasal metastasis from a primary skeletal Ewing's sarcoma.

PubMed

Hayes, S M; Jani, T N; Rahman, S M; Jogai, S; Harries, P G; Salib, R J

2011-08-01

Ewing's sarcoma is a rare, malignant tumour predominantly affecting young adolescent males. We describe a unique case of an isolated extra-skeletal metastasis from a skeletal Ewing's sarcoma primary, arising in the right sinonasal cavity of a young man who presented with severe epistaxis and periorbital cellulitis. Histologically, the lesion comprised closely packed, slightly diffuse, atypical cells with round, hyperchromatic nuclei, scant cytoplasm and occasional mitotic figures, arranged in a sheet-like pattern. Immunohistochemical analysis showed positive staining only for cluster of differentiation 99 glycoprotein. Fluorescent in situ hybridisation identified the Ewing's sarcoma gene, confirming the diagnosis. Complete surgical resection was achieved via a minimally invasive endoscopic transnasal approach; post-operative radiotherapy. Ten months post-operatively, there were no endoscopic or radiological signs of disease. Metastatic Ewing's sarcoma within the head and neck is incredibly rare and can pose significant diagnostic and therapeutic challenges. An awareness of different clinical presentations and distinct histopathological features is important to enable early diagnosis. This case illustrates one potential management strategy, and reinforces the evolving role of endoscopic transnasal approaches in managing sinonasal cavity and anterior skull base tumours.

[A rare tumor of the parapharyngeal space: myxoid chondrosarcoma].

PubMed

Bahri, I; Boudawara, T; Sellami, A; Khabir, A; Ghorgel, M; Drira, M; Daoud, J; Jlidi, R

2002-01-01

Extrasqueletal myxoid chondrosarcoma (EMC) is an uncommon soft tissue malignant tumor, locally aggressive with a high incidence of distant metastasis. It has distinctive clinical, immunophenotypic, cytogenetic and ultrastructural features. Most EMC are associated with the translocation t(9;22) (q22;q12). Their occurrence in the parapharyngeal space is extremely rare. Our objective is to discuss the difficulties of the histological diagnosis of EMC and to describe its immunophenotypic, cytogenetic features and clinical behavior. We report a case of a 67 years old woman who presented with a five months history of dysphagia. The oral examination found a mass displacing the posterior and left walls of the pharynx. Surgical resection of the tumor was undertaken. The pathologic examination concluded to the diagnosis of an EMC of the left parapharygeal space. Now, the patient is receiving an adjuvant radiotherapy.

A multiplanar complex resection of a low-grade chondrosarcoma of the distal femur guided by K-wires previously inserted under CT-guide: a case report.

PubMed

Zoccali, Carmine; Rossi, Barbara; Ferraresi, Virginia; Anelli, Vincenzo; Rita, Alessandro

2014-08-13

In muscular skeletal oncology aiming to achieve wide surgical margin is one of the main factors influencing patient prognosis. In cases where lesions are either meta or epiphyseal, surgery most often compromises joint integrity and stability because muscles, tendons and ligaments are involved in wide resection. When lesions are well circumscribed they can be completely resected by performing multi-planar osteotomies guided by computer-assisted navigation. We describe a case of low-grade chondrosarcoma of the distal femur where a simple but effective technique was useful to perform complex multiplanar osteotomies. No similar techniques are reported in the literature. A 57 year-old Caucasian female was referred to our department for the presence of a distal femur chondrosarcoma. A resection with the presenting technique was scheduled. The first step consists of inserting several K-wires under CT-scan control to delimitate the tumor; the second step consists of tumor removal: in operative theatre, following surgical access, k-wires are used as guide positioning; scalpels are externally placed to k-wires to perform a safe osteotomy. Computed assisted resections can be considered the most advantageous method to reach the best surgical outcome; unfortunately navigation systems are only available in specialized centres. The present technique allows for a multiplanar complex resection when navigation systems are not available. This technique can be applied in low-grade tumours where a minimal wide margin can be considered sufficient.

The 2011 Report on Dietary Reference Intakes for Calcium and Vitamin D from the Institute of Medicine: What Clinicians Need to Know

PubMed Central

Ross, A. Catharine; Manson, JoAnn E.; Abrams, Steven A.; Aloia, John F.; Brannon, Patsy M.; Clinton, Steven K.; Durazo-Arvizu, Ramon A.; Gallagher, J. Christopher; Gallo, Richard L.; Jones, Glenville; Kovacs, Christopher S.; Mayne, Susan T.; Rosen, Clifford J.; Shapses, Sue A.

2011-01-01

This article summarizes the new 2011 report on dietary requirements for calcium and vitamin D from the Institute of Medicine (IOM). An IOM Committee charged with determining the population needs for these nutrients in North America conducted a comprehensive review of the evidence for both skeletal and extraskeletal outcomes. The Committee concluded that available scientific evidence supports a key role of calcium and vitamin D in skeletal health, consistent with a cause-and-effect relationship and providing a sound basis for determination of intake requirements. For extraskeletal outcomes, including cancer, cardiovascular disease, diabetes, and autoimmune disorders, the evidence was inconsistent, inconclusive as to causality, and insufficient to inform nutritional requirements. Randomized clinical trial evidence for extraskeletal outcomes was limited and generally uninformative. Based on bone health, Recommended Dietary Allowances (RDAs; covering requirements of ≥97.5% of the population) for calcium range from 700 to 1300 mg/d for life-stage groups at least 1 yr of age. For vitamin D, RDAs of 600 IU/d for ages 1–70 yr and 800 IU/d for ages 71 yr and older, corresponding to a serum 25-hydroxyvitamin D level of at least 20 ng/ml (50 nmol/liter), meet the requirements of at least 97.5% of the population. RDAs for vitamin D were derived based on conditions of minimal sun exposure due to wide variability in vitamin D synthesis from ultraviolet light and the risks of skin cancer. Higher values were not consistently associated with greater benefit, and for some outcomes U-shaped associations were observed, with risks at both low and high levels. The Committee concluded that the prevalence of vitamin D inadequacy in North America has been overestimated. Urgent research and clinical priorities were identified, including reassessment of laboratory ranges for 25-hydroxyvitamin D, to avoid problems of both undertreatment and overtreatment. PMID:21118827

DOE Office of Scientific and Technical Information (OSTI.GOV)

Greenspan, A.; Norman, A.

Five cases of a rare developmental anomaly involving extraskeletal bone formation are described - four in the pelvis and one arising from the 12th rib. Three of these bony growths, called 'Pelvic digits' had well developed 'joints' or pseudoarticulations. The similarity of this anomaly to posttraumatic myositis ossificans and avulsion injuries of the pelvis (rectus femoris) is pointed out and a differential diagnosis offered.

Stereotactic Body Radiotherapy for Head and Neck Tumors

ClinicalTrials.gov

2016-04-18

Squamous Cell Carcinoma of the Head and Neck; Nasopharyngeal Carcinoma; Salivary Gland Cancer; Head and Neck Sarcoma; Paraganglioma of Head and Neck; Chordoma of Head and Neck; Chondrosarcoma of Head and Neck; Angiofibroma of Head and Neck

[Demographic Analysis of Patients with Osteosarcoma, Chonddrosarcoma, Ewing's Sarcoma from one Sarcoma Center in Switzerland].

PubMed

Hodel, Sandro; Seeli, Franziska; Fuchs, Bruno

2015-06-17

Retrospective analysis of presentation, diagnosis and outcome of patients with osteosarcoma, chondrosarcoma and Ewing's sarcoma was performed for a single Sarcoma Center in Zurich at the University Hospital Balgrist. 201 patients were included. Overall survival at five and ten years were 74 ± 6%, 69 ± 7% for osteosarcoma (n = 85, since 2000), 85 ± 7%, 80 ± 9% for Ewing's sarcoma (n = 43, since 1990) and 86 ± 5%, 78 ± 9% for chondrosarcoma (n = 73, since 2000). The here presented overall survival rates from a single Sarcoma Center in Switzerland appear to be equivalent to other large international monocenter studies. The presentation and epidemiology of these patients are in accordance with large multicenter epidemiological studies. A nationwide sarcoma database (SwissSARCOS; www.sarcoma.ch) seems indispensable for more detailed analysis and quality management in such rare diseases.

Sarcomas of nasal cavity and paranasal sinuses: chondrosarcoma, osteosarcoma and fibrosarcoma.

PubMed

Koka, V; Vericel, R; Lartigau, E; Lusinchi, A; Schwaab, G

1994-11-01

Forty-two patients were treated for sarcoma of the nasal cavity and paranasal sinuses at the Institut Gustave Roussy, Paris, between 1960 and 1993. Twelve patients had chondrosarcoma (CS), 14 had osteosarcoma (OS) and 16 had fibrosarcoma (FS). Ten patients had grade I, six grade II and 26 grade III tumours. All but 10 patients had surgery for the primary tumour. A significantly increased risk of local failure was associated with the male sex (p < 0.01), grade III tumours (p < 0.02) and patients excluded from surgery (p < 0.04). The overall incidence of local and distant failure was 76 and 12 per cent respectively. Overall survival was 28 per cent at three years and 23 per cent at five years. Eight patients (20 per cent) were alive more than 10 years later. The factors significantly influencing survival were sex (p < 0.01), grade (p < 0.05) and local failure (p < 0.01).

Dedifferentiated chondrosarcoma: Radiological features, prognostic factors and survival statistics in 23 patients

PubMed Central

Liu, Chenglei; Xi, Yan; Li, Mei; Jiao, Qiong; Zhang, Huizhen; Yang, Qingcheng; Yao, Weiwu

2017-01-01

Background Dedifferentiated chondrosarcoma is a rare, highly malignant tumor with a poor survival. There are many confusing issues concerning the imaging feature that can facilitate early diagnosis and the factors that might be related to outcomes. Methods Twenty-three patients with dedifferentiated chondrosarcoma confirmed by pathology were retrospectively reviewed from 2008 to 2015. The patients’ clinical information, images from radiographs (n = 17), CT (n = 19), and MRI (n = 17), histological features, treatment and prognosis were analyzed. Results There were 12 males and 11 females, and the mean age was 50.39 years old. Fourteen cases affected the axial bone (pelvis, spine), and 9 cases involved the appendicular bone. Seven (41.17%), 9 (47.36), and 12 (66.66%) lesions showed a biphasic nature on radiograph, CT and MRI, respectively. Of the lesions, 17.39% (4/23) were accompanied by pathological fractures. Histologically, the cartilage component was considered histological Grade1 in 12 patients and Grade 2 in 11 patients. The dedifferentiated component showed features of osteosarcoma in 8 cases, malignant fibrous histiocytoma in3 cases, myofibroblastic sarcoma in 1 case and spindle cell sarcoma in 11cases. Twenty-two cases were treated with surgical resection, and 17 cases achieved adequate (wide or radical) surgical margin. In 8 cases, surgery was combined with adjuvant chemotherapy. The overall median survival time was nine months; 17.4% of patients survived to five years. Conclusion Axial bone location, lung metastasis at diagnosis, inadequate surgical margin, incorrect diagnosis before surgery and pathological fractures was related to poorer outcome. Pre- or postoperative chemotherapy had no definitively effect on improved survival. PMID:28301537

The human chondrosarcoma HCS-2/8 cell line is responsive to BMP-7, but not to IL-1beta.

PubMed

Saas, Joachim; Gebauer, Matthias; Jacobi, Carsten; Haag, Jochen; Takigawa, Masaharu; Aigner, Thomas

2005-05-01

Cultures of primary chondrocytes as in vitro model systems for studying the cellular behavior of chondrocytes are notoriously difficult to cultivate and propagate. One way to circumvent these problems appears to be the use of immortalized/immortal chondrocytic cell lines. In the present study, we were interested whether the chondrosarcoma derived HCS-2/8 cells are suitable for studying major cellular reaction pattern in response to key anabolic (BMP-7) and catabolic (IL-1beta) factors. Therefore, we used cDNA array and real-time PCR technology in order to evaluate gene expression triggered by stimulation with IL-1beta (0,1-100 ng/ml) and BMP-7 in confluent monolayer cultures. HCS-2/8 cells hardly responded to IL-1beta, but showed good responsiveness to BMP-7. We found 12 genes up- and 17 significantly down-regulated by BMP-7 (out of 340 investigated genes). Besides the expected activation of anabolic genes chondrocytic cells after BMP-stimulation try to neutralize activation of the BMP-signalling cascade by expressing intra- and extracellular BMP-antagonists. Chondrosarcoma derived cell lines are a potential substitute for primary articular chondrocytes promising consistent expression of a differentiated chondrocyte phenotype with sufficient proliferative capacity. However, as shown by this study one needs to carefully select the cell line depending on the effects which one intends to study. In this respect, HCS-2/8 cells are a validated tool for studying BMP-effects on chondrocytes, but not e.g. effects of interleukin-1.

A multiplanar complex resection of a low-grade chondrosarcoma of the distal femur guided by K-wires previously inserted under CT-guide: a case report

PubMed Central

2014-01-01

Background In muscular skeletal oncology aiming to achieve wide surgical margin is one of the main factors influencing patient prognosis. In cases where lesions are either meta or epiphyseal, surgery most often compromises joint integrity and stability because muscles, tendons and ligaments are involved in wide resection. When lesions are well circumscribed they can be completely resected by performing multi-planar osteotomies guided by computer-assisted navigation. We describe a case of low-grade chondrosarcoma of the distal femur where a simple but effective technique was useful to perform complex multiplanar osteotomies. No similar techniques are reported in the literature. Case presentation A 57 year-old Caucasian female was referred to our department for the presence of a distal femur chondrosarcoma. A resection with the presenting technique was scheduled. The first step consists of inserting several K-wires under CT-scan control to delimitate the tumor; the second step consists of tumor removal: in operative theatre, following surgical access, k-wires are used as guide positioning; scalpels are externally placed to k-wires to perform a safe osteotomy. Conclusions Computed assisted resections can be considered the most advantageous method to reach the best surgical outcome; unfortunately navigation systems are only available in specialized centres. The present technique allows for a multiplanar complex resection when navigation systems are not available. This technique can be applied in low-grade tumours where a minimal wide margin can be considered sufficient. PMID:25123066

Study protocol of a phase IB/II clinical trial of metformin and chloroquine in patients with IDH1-mutated or IDH2-mutated solid tumours.

PubMed

Molenaar, Remco J; Coelen, Robert J S; Khurshed, Mohammed; Roos, Eva; Caan, Matthan W A; van Linde, Myra E; Kouwenhoven, Mathilde; Bramer, Jos A M; Bovée, Judith V M G; Mathôt, Ron A; Klümpen, Heinz-Josef; van Laarhoven, Hanneke W M; van Noorden, Cornelis J F; Vandertop, W Peter; Gelderblom, Hans; van Gulik, Thomas M; Wilmink, Johanna W

2017-06-10

High-grade chondrosarcoma, high-grade glioma and intrahepatic cholangiocarcinoma are aggressive types of cancer with a dismal outcome. This is due to the lack of effective treatment options, emphasising the need for novel therapies. Mutations in the genes IDH1 and IDH2 (isocitrate dehydrogenase 1 and 2) occur in 60% of chondrosarcoma, 80% of WHO grade II-IV glioma and 20% of intrahepatic cholangiocarcinoma. IDH1/2 -mutated cancer cells produce the oncometabolite D -2-hydroxyglutarate ( D -2HG) and are metabolically vulnerable to treatment with the oral antidiabetic metformin and the oral antimalarial drug chloroquine. We describe a dose-finding phase Ib/II clinical trial, in which patients with IDH1/2 -mutated chondrosarcoma, glioma and intrahepatic cholangiocarcinoma are treated with a combination of metformin and chloroquine. Dose escalation is performed according to a 3+3 dose-escalation scheme. The primary objective is to determine the maximum tolerated dose to establish the recommended dose for a phase II clinical trial. Secondary objectives of the study include (1) determination of pharmacokinetics and toxic effects of the study therapy, for which metformin and chloroquine serum levels will be determined over time; (2) investigation of tumour responses to metformin plus chloroquine in IDH1/2 -mutated cancers using CT/MRI scans; and (3) whether tumour responses can be measured by non-invasive D -2HG measurements (mass spectrometry and magnetic resonance spectroscopy) of tumour tissue, serum, urine, and/or bile or next-generation sequencing of circulating tumour DNA (liquid biopsies). This study may open a novel treatment avenue for IDH1/2 -mutated high-grade chondrosarcoma, glioma and intrahepatic cholangiocarcinoma by repurposing the combination of two inexpensive drugs that are already approved for other indications. This study has been approved by the medical-ethical review committee of the Academic Medical Center, Amsterdam, The Netherlands. The report will be submitted to a peer-reviewed journal. This article was registered at ClinicalTrials.gov identifier (NCT02496741): Pre-results. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

A Prospective Outcomes Study of Proton Therapy for Chordomas and Chondrosarcomas of the Spine

DOE Office of Scientific and Technical Information (OSTI.GOV)

Indelicato, Daniel J., E-mail: dindelicato@floridaproton.org; Rotondo, Ronny L.; Begosh-Mayne, Dustin

Purpose: To evaluate the effectiveness of definitive or adjuvant external beam proton therapy on survival in patients with chordomas and chondrosarcomas of the spine. Methods and Materials: Between March 2007 and May 2013, 51 patients with a median age of 58 years (range, 22-83 years) with chordoma (n=34) or chondrosarcomas (n=17) of the sacrum (n=21), the cervical spine (n=20), and the thoracolumbar spine (n=10) were treated with external beam proton therapy to a median dose of 70.2 Gy(RBE) [range, 64.2-75.6 Gy(RBE)] at our institution. Distant metastases, overall survival, cause-specific survival, local control, and disease-free survival were calculated. Results: The mean follow-up time was 3.7 yearsmore » (range, 0.3-7.7 years). Across all time points, 25 patients experienced disease recurrence: 18 local recurrences, 6 local and distant recurrences, and 1 distant metastasis. The 4-year rates of overall survival and cause-specific survival were 72%; disease-free survival was 57%, local control was 58%, and freedom from distant metastases was 86%. The median time to local progression was 1.7 years (range, 0.2-6.0 years), and the median time to distant progression was 1.6 years (range, 0.2-6.0 years). The risk factors for local recurrence were age ≤58 years (62% vs 26%; P=.04) and recurrence after prior surgery (29% vs 81%; P=.01). Secondary cancers developed in 2 patients: B-cell lymphoma 5.5 years after treatment and bladder cancer 2 years after treatment. We observed the following toxicities: sacral soft tissue necrosis requiring surgery (n=2), T1 vertebral fracture requiring fusion surgery (n=1), chronic urinary tract infections (n=1), surgery for necrotic bone cyst (n=1), and grade 2 bilateral radiation nephritis (n=1). Conclusion: High-dose proton therapy controls more than half of spinal chordomas and chondrosarcomas and compares favorably with historic photon data. Local progression is the dominant mode of treatment failure and may be reduced by treating patients at the time of initial diagnosis. The impact of age is a novel finding of this study.« less

Extra-skeletal Ewing's sarcoma in adults: presentation of two cases.

PubMed

Lipski, Samuel M; Cermak, Katia; Shumelinsky, Felix; Gil, Thierry; Gebhart, Michael J

2010-12-01

Extraosseous Ewing's sarcoma represents about 5% of the Ewing family of tumours. Two cases in adult patients are presented, emphasizing the complexity of a multi-modality treatment approach of this tumour. Clinical presentation, chemotherapeutical, surgical and radiotherapeutical approaches are discussed. A thorough literature search was done to correlate our therapeutic attitude with current knowledge of this very rare disease.

Extra-skeletal Ewing sarcoma of the lumbosacral region in an adult pregnant patient: a case report.

PubMed

Al Khawaja, Darweesh; Vescovi, Cristina; Dower, Ashraf; Thiruvilangam, Vallapan; Mahasneh, Tamadur

2017-03-01

Extra-skeletal Ewing sarcoma in pregnancy is rare. There is thus limited scientific evidence to guide clinicians in its complicated management, particularly within the context of early gestation. We therefore share our successful outcome in a 32-year-old pregnant patient, following a unique management strategy of complete aggressive surgical resection prior to neo-adjuvant therapy. The case involved a 2-month history of right-sided back and gluteal pain, with associated paraesthesia. Lumbosacral magnetic resonance imaging (MRI) revealed an approximate 40×50 mm indeterminate mass in the lower right paraspinal musculature. The mass extended into the first right sacral foramen and the central canal; and also impinged on the S2 exiting nerve. After considering the patients' rapid deterioration, pregnant status and other clinical factors, it was elected to proceed with complete surgical resection prior to any other therapeutic modality. Following surgery, the patient experienced immediate resolution of her pain and by 6 weeks was able to cease the use of all analgesics. At 32-weeks' gestation she underwent an uncomplicated vaginal delivery. At 9 months follow up, she remains disease free and has experienced complete resolution of her back pain and radiculopathy.

Extra-skeletal Ewing sarcoma of the lumbosacral region in an adult pregnant patient: a case report

PubMed Central

Al Khawaja, Darweesh; Dower, Ashraf; Thiruvilangam, Vallapan; Mahasneh, Tamadur

2017-01-01

Extra-skeletal Ewing sarcoma in pregnancy is rare. There is thus limited scientific evidence to guide clinicians in its complicated management, particularly within the context of early gestation. We therefore share our successful outcome in a 32-year-old pregnant patient, following a unique management strategy of complete aggressive surgical resection prior to neo-adjuvant therapy. The case involved a 2-month history of right-sided back and gluteal pain, with associated paraesthesia. Lumbosacral magnetic resonance imaging (MRI) revealed an approximate 40×50 mm indeterminate mass in the lower right paraspinal musculature. The mass extended into the first right sacral foramen and the central canal; and also impinged on the S2 exiting nerve. After considering the patients’ rapid deterioration, pregnant status and other clinical factors, it was elected to proceed with complete surgical resection prior to any other therapeutic modality. Following surgery, the patient experienced immediate resolution of her pain and by 6 weeks was able to cease the use of all analgesics. At 32-weeks’ gestation she underwent an uncomplicated vaginal delivery. At 9 months follow up, she remains disease free and has experienced complete resolution of her back pain and radiculopathy. PMID:28435928

18F-FDG PET/CT in Diagnostic and Prognostic Evaluation of Patients With Suspected Recurrence of Chondrosarcoma.

PubMed

Vadi, Shelvin Kumar; Mittal, Bhagwant Rai; Gorla, Arun Kumar Reddy; Sood, Ashwani; Basher, Rajender Kumar; Sood, Apurva; Kakkar, Nandita; Sen, Ramesh K

2018-02-01

The aim of the study was to analyze the diagnostic and prognostic utility of F-FDG PET/CT to predict the disease-specific survival (DSS) with FDG uptake and tumor grade in recurrent chondrosarcoma. Retrospective analysis of FDG PET/CT findings in 31 previously treated patients (46 studies) with mean follow-up period of 40.7 ± 23.9 months (range, 3-77 months) from the date of first PET/CT study was done. Kaplan-Meier DSS analysis was made with respect to tumor grade, FDG uptake at the recurrent primary sites, and a combination of grade and FDG uptake as parameters. Recurrence (local and distant) was shown in 28 (60.8%) of 46 FDG PET/CT studies with sensitivity and specificity of 88.9% and 78.9%, respectively. The median SUVmax at the recurrent primary sites differed significantly (P = 0.008) among 3 tumor grade groups, with higher median SUVmax in higher grades. There was significant difference in median SUVmax among different grade groups except between grade II and grade III. Recurrent primary site SUVmax cutoff at 6.15 derived from the receiver operating characteristic curve yielded significant difference (P < 0.001) in mean DSS time. Significant difference in survival was noted between 3 different tumor grade groups (P = 0.016). The combination of SUVmax and grade improved the survival prediction than with grade alone. In recurrent chondrosarcoma, the recurrent primary site FDG uptake and grade were found to be reliable prognostic factors with respect to DSS. PET/CT in recurrence setting has the potential to predict tumor grade and survival and may assist in clinical management.

Bayesian pretest probability estimation for primary malignant bone tumors based on the Surveillance, Epidemiology and End Results Program (SEER) database.

PubMed

Benndorf, Matthias; Neubauer, Jakob; Langer, Mathias; Kotter, Elmar

2017-03-01

In the diagnostic process of primary bone tumors, patient age, tumor localization and to a lesser extent sex affect the differential diagnosis. We therefore aim to develop a pretest probability calculator for primary malignant bone tumors based on population data taking these variables into account. We access the SEER (Surveillance, Epidemiology and End Results Program of the National Cancer Institute, 2015 release) database and analyze data of all primary malignant bone tumors diagnosed between 1973 and 2012. We record age at diagnosis, tumor localization according to the International Classification of Diseases (ICD-O-3) and sex. We take relative probability of the single tumor entity as a surrogate parameter for unadjusted pretest probability. We build a probabilistic (naïve Bayes) classifier to calculate pretest probabilities adjusted for age, tumor localization and sex. We analyze data from 12,931 patients (647 chondroblastic osteosarcomas, 3659 chondrosarcomas, 1080 chordomas, 185 dedifferentiated chondrosarcomas, 2006 Ewing's sarcomas, 281 fibroblastic osteosarcomas, 129 fibrosarcomas, 291 fibrous malignant histiocytomas, 289 malignant giant cell tumors, 238 myxoid chondrosarcomas, 3730 osteosarcomas, 252 parosteal osteosarcomas, 144 telangiectatic osteosarcomas). We make our probability calculator accessible at http://ebm-radiology.com/bayesbone/index.html . We provide exhaustive tables for age and localization data. Results from tenfold cross-validation show that in 79.8 % of cases the pretest probability is correctly raised. Our approach employs population data to calculate relative pretest probabilities for primary malignant bone tumors. The calculator is not diagnostic in nature. However, resulting probabilities might serve as an initial evaluation of probabilities of tumors on the differential diagnosis list.

Vitamin D supplementation in the prevention and management of major chronic diseases not related to mineral homeostasis in adults: research for evidence and a scientific statement from the European society for clinical and economic aspects of osteoporosis and osteoarthritis (ESCEO).

PubMed

Cianferotti, Luisella; Bertoldo, Francesco; Bischoff-Ferrari, Heike A; Bruyere, Olivier; Cooper, Cyrus; Cutolo, Maurizio; Kanis, John A; Kaufman, Jean-Marc; Reginster, Jean-Yves; Rizzoli, Rene; Brandi, Maria Luisa

2017-05-01

Optimal vitamin D status promotes skeletal health and is recommended with specific treatment in individuals at high risk for fragility fractures. A growing body of literature has provided indirect and some direct evidence for possible extraskeletal vitamin D-related effects. Members of the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis have reviewed the main evidence for possible proven benefits of vitamin D supplementation in adults at risk of or with overt chronic extra-skeletal diseases, providing recommendations and guidelines for future studies in this field. Robust mechanistic evidence is available from in vitro studies and in vivo animal studies, usually employing cholecalciferol, calcidiol or calcitriol in pharmacologic rather than physiologic doses. Although many cross-sectional and prospective association studies in humans have shown that low 25-hydroxyvitamin D levels (i.e., <50 nmol/L) are consistently associated with chronic diseases, further strengthened by a dose-response relationship, several meta-analyses of clinical trials have shown contradictory results. Overall, large randomized controlled trials with sufficient doses of vitamin D are missing, and available small to moderate-size trials often included people with baseline levels of serum 25-hydroxyvitamin D levels >50 nmol/L, did not simultaneously assess multiple outcomes, and did not report overall safety (e.g., falls). Thus, no recommendations can be made to date for the use of vitamin D supplementation in general, parental compounds, or non-hypercalcemic vitamin D analogs in the prevention and treatment of extra-skeletal chronic diseases. Moreover, attainment of serum 25-hydroxyvitamin D levels well above the threshold desired for bone health cannot be recommended based on current evidence, since safety has yet to be confirmed. Finally, the promising findings from mechanistic studies, large cohort studies, and small clinical trials obtained for autoimmune diseases (including type 1 diabetes, multiple sclerosis, and systemic lupus erythematosus), cardiovascular disorders, and overall reduction in mortality require further confirmation.

Carcinosarcoma of the upper urinary tract with an aggressive angiosarcoma component.

PubMed

Cuadra-Urteaga, José Luis; Font, Albert; Tapia, Gustavo; Areal, Juan; Taron, Miquel

2016-01-01

Carcinosarcomas (CS) are biphasic tumors with malignant epithelial and mesenchymal elements. The sarcomatoid elements of CS can include chondrosarcoma, malignant fibrous histiocytoma, osteosarcoma, leiomyosarcoma, fibrosarcoma, or liposarcoma. CS of the upper urinary tract are extremely rare but are associated with a poor prognosis. We report a case of a 44-year-old man with a localized right renal pelvis mass treated with a right nephroureterectomy. The pathological examination showed a high-grade urothelial carcinoma of the renal pelvis, stage III (pT3aNxM0). A few days later, he developed lower back pain, hematuria, cough with hemoptoic sputum and progressive dyspnea. Radiological explorations showed multiple bilateral lung nodules and a retroperitoneal mass. A CT-guided biopsy of the retroperitoneal mass revealed a high-grade angiosarcoma. A review of the nephrectomy specimen showed a microscopic focus of angiosarcoma in the urothelial carcinoma. Therefore, the initial diagnosis was changed to CS of the renal pelvis with an angiosarcoma component. The patient developed progressive respiratory failure and died 8 weeks after surgery. An autopsy revealed a large retroperitoneal mass with metastatic nodules to the abdominal wall, diaphragm, small intestine, liver, spleen, and lung. All lesions were angiosarcoma, with no evidence of urothelial carcinoma. This is the first case reported of a patient with CS of the upper urinary tract with an angiosarcoma component with a very aggressive course that caused the immediate appearance of multiple angiosarcoma metastases. We also describe the clinical and molecular characteristics of CS, which will help to contribute to a better understanding of this type of tumor.

Carcinosarcoma of the upper urinary tract with an aggressive angiosarcoma component

PubMed Central

Cuadra-Urteaga, José Luis; Font, Albert; Tapia, Gustavo; Areal, Juan; Taron, Miquel

2016-01-01

ABSTRACT Carcinosarcomas (CS) are biphasic tumors with malignant epithelial and mesenchymal elements. The sarcomatoid elements of CS can include chondrosarcoma, malignant fibrous histiocytoma, osteosarcoma, leiomyosarcoma, fibrosarcoma, or liposarcoma. CS of the upper urinary tract are extremely rare but are associated with a poor prognosis. We report a case of a 44-year-old man with a localized right renal pelvis mass treated with a right nephroureterectomy. The pathological examination showed a high-grade urothelial carcinoma of the renal pelvis, stage III (pT3aNxM0). A few days later, he developed lower back pain, hematuria, cough with hemoptoic sputum and progressive dyspnea. Radiological explorations showed multiple bilateral lung nodules and a retroperitoneal mass. A CT-guided biopsy of the retroperitoneal mass revealed a high-grade angiosarcoma. A review of the nephrectomy specimen showed a microscopic focus of angiosarcoma in the urothelial carcinoma. Therefore, the initial diagnosis was changed to CS of the renal pelvis with an angiosarcoma component. The patient developed progressive respiratory failure and died 8 weeks after surgery. An autopsy revealed a large retroperitoneal mass with metastatic nodules to the abdominal wall, diaphragm, small intestine, liver, spleen, and lung. All lesions were angiosarcoma, with no evidence of urothelial carcinoma. This is the first case reported of a patient with CS of the upper urinary tract with an angiosarcoma component with a very aggressive course that caused the immediate appearance of multiple angiosarcoma metastases. We also describe the clinical and molecular characteristics of CS, which will help to contribute to a better understanding of this type of tumor. PMID:26891233

Computer-aided designed, three dimensional-printed hemipelvic prosthesis for peri-acetabular malignant bone tumour.

PubMed

Wang, Baichuan; Hao, Yongqiang; Pu, Feifei; Jiang, Wenbo; Shao, Zengwu

2018-03-01

Prosthetic reconstruction may be a promising treatment for peri-acetabular malignant bone tumour; however, it is associated with a high complication rate. Therefore, prosthetic design and approach of prosthetic reconstruction after tumour resection warrant study. We retrospectively analyzed 11 patients with peri-acetabular malignant bone tumours treated by personalized 3D-printed hemipelvic prostheses after en bloc resection between 2015 and 2016. Pre-operative and post-operative pain at rest was assessed according to a 10-cm VAS score. The results of functional improvement were evaluated using the MSTS-93 score at the final follow-up. We also analyzed tumour recurrence, metastases, and complications associated with the reconstruction procedure. All patients were observed for six to 24 months with an average follow-up of 15.5 months. One patient had occasional pain of the involved hip at the final follow-up (VAS, pre vs. post 8 months: 3 vs. 2). The mean MSTS-93 score was 19.2 (range, 13-25). Hip dislocation was detected in two patients, while delayed wound healing occurred in one patient. One patient with mesenchymal chondrosarcoma had a left iliac bone metastasis. Local tumour recurrence was not observed. Reconstruction of bony defect after tumour resection using personalized 3D-printed hemipelvic prostheses can obtain acceptable functional results without severe complications. Based on previous reports and our results, we believe that reconstruction arthroplasty using 3D-printed hemipelvic prostheses will provide a promising alternative for those patients with peri-acetabular malignant bone tumours. Level IV, therapeutic study.

Bilateral chondrosarcoma of the jugular foramen: literature review and personal experience.

PubMed

Zanoletti, Elisabetta; Faccioli, Chiara; Cazzador, Diego; Mazzoni, Antonio; Martini, Alessandro

2015-10-01

Chondrosarcomas (CS) are slow-growing malignant cartilaginous tumors with locally invasive behavior. They account for only 0.15% head and neck neoplasia. There have been no reports in the management of bilateral skull base CS in the literature to date. The synchronous presentation of bilateral CS of the jugular foramen (JF) was diagnosed in a 22-year-old woman with right abducens nerve palsy. Once evaluated the collateral intracranial venous discharge, the lesions were removed in two surgical stages through a bilateral petro-occipital trans-sigmoid (POTS) approach performing a bilateral closure of sigmoid sinus. The patient is disease free 15 years after surgery. No complications occurred. Diplopia improved after excision of the tumor on the right side. A review of relevant English literature was performed. The POTS approach to the JF proved to be safe and effective. Staged radical surgery alone, assessing intracranial venous flow at all stages of surgery, was a valid strategy for bilateral CS, achieving long-term disease control, avoiding early adjuvant radiotherapy, and carrying no complications.

Vitamin D and rheumatic diseases.

PubMed

Rossini, M; Gatti, D; Viapiana, O; Caimmi, C; Idolazzi, L; Fracassi, E; Adami, S

2014-07-28

Vitamin D has some well-known effects on calcium, phosphate and bone metabolism, but it has recently shown to have many other effects, which may potentially be relevant to patients with extra-skeletal rheumatic diseases. Such effects may be justified by: 1) the presence of the vitamin D receptors also on extra-osseous cells, such as cartilage cells, sinoviocytes, muscle cells; 2) the proven role of vitamin D in the control of the transcription of genes involved in rheumatic diseases; 3) the evidence that vitamin D has multiple endocrine effects not only on calcium homeostasis; 4) the activation of vitamin D not only in the kidneys, but also in monocyte-macrophage and lymphocytic cell lines and in some epithelial cells with additional intracrine and paracrine effects. Vitamin D deficiency has been reported in numerous metabolic, degenerative, inflammatory and autoimmune rheumatic diseases. In some cases this association was also related to the risk of developing a rheumatic disease or the degree of disease activity. However there is no conclusive evidence of the efficacy of a preventive or therapeutic strategy based on vitamin D supplementation in extra-skeletal rheumatic diseases. This review aims to provide an overview of the latest evidence concerning the relationship between vitamin D and the most relevant rheumatic diseases.

Blue Cell Tumour at Unusual Site: Retropritoneal Ewings Sarcoma.

PubMed

Javalgi, Anita P; Karigoudar, Mahesh H; Palur, Katyayani

2016-04-01

Ewing's sarcoma is a highly malignant tumour of osseous or non-osseous origin, tremed as extra-skeletal Ewings sarcoma if arising from soft tissue. It is rare occurrence tumor most commonly occurring in paravertebral area, chest wall, head & neck and retroperitoneum. Reporting an interesting case of retroperitoneal Ewing's sarcoma in 39 years old female. Patient had complains of abdominal discomfort & vague pain since 2 months, following weakness in lower limb and loss of weight. On detail history and examination she was further referred to detail pathological and radiological investigations. Haematological profile, renal function test and liver function test were in normal limits. USG abdomen was normal, MRI showed a mass in pelvis retroperitoneum measuring 10x10cms, bilateral ovaries and tubes were normal. Because of retroperitoneal nature of tumor and suspicion of uterine sarcoma, laparotomy was performed. The large retroperitoneal mass adherent to posterior of uterus was excised and send for histopathological diagnosis. On gross and microscopy examination the diagnosis of blue cell tumor with PAS positivity, possibility of extraskeletal Ewing's sarcoma/primitive neuro-ectodermal tumor was made which was further confirmed by immunohistochemistry, positive for S100, Vementin and CD99 and negative for desmin and CK. Confirmed diagnosis help in accurate management and improves survival rate.

Primary Adult Renal Ewing's Sarcoma: A Rare Entity

PubMed Central

Mukkunda, Ravindra; Venkitaraman, Ramachandran; Thway, Khin; Min, Toon; Fisher, Cyril; Horwich, Alan; Judson, Ian

2009-01-01

Background. Ewing's sarcoma of extraskeletal origin is uncommon and that is of primary renal origin in adults are rare. There is no consensus on the optimal management of Ewing's tumors of renal origin. Methods. A retrospective review of the clinical features, treatment, and outcome of adult patients with primary renal extra-skeletal Ewing's sarcoma who were treated at the Royal Marsden hospital from January 1993–December 2007 is reported. Results. Seven adult patients with primary renal Ewing's sarcoma were identified. All four patients with nonmetastatic disease had radical nephrectomy and received adjuvant chemotherapy +/− radiotherapy. Two developed metastatic disease while on adjuvant chemotherapy, and one patient relapsed after 55 months. The three patients with metastatic disease at presentation did not have nephrectomy and were treated with chemotherapy. All three patients had disease progression with a dismal outcome. Only one patient in the whole group is alive and disease free. The median overall survival was 62.8 months, and the median disease-free survival in patients with nonmetastatic disease after combined modality treatment was 30.3 months. Conclusion. Primary adult renal Ewing's sarcoma is an aggressive tumor with a propensity for early metastasis. Radical nephrectomy with adjuvant combination chemotherapy produced the best results but the outlook remained poor with only one patient experiencing long disease-free survival. PMID:19478963

Association between dental pulp stones and calcifying nanoparticles.

PubMed

Zeng, Jinfeng; Yang, Fang; Zhang, Wei; Gong, Qimei; Du, Yu; Ling, Junqi

2011-01-07

The etiology of dental pulp stones, one type of extraskeletal calcification disease, remains elusive to date. Calcifying nanoparticles (CNPs), formerly referred to as nanobacteria, were reported to be one etiological factor in a number of extraskeletal calcification diseases. We hypothesized that CNPs are involved in the calcification of the dental pulp tissue, and therefore investigated the link between CNPs and dental pulp stones. Sixty-five freshly collected dental pulp stones, each from a different patient, were analyzed. Thirteen of the pulp stones were examined for the existence of CNPs in situ by immunohistochemical staining (IHS), indirect immunofluorescence staining (IIFS), and transmission electron microscope (TEM). The remaining 52 pulp stones were used for isolation and cultivation of CNPs; the cultured CNPs were identified and confirmed via their shape and growth characteristics. Among the dental pulp stones examined in situ, 84.6% of the tissue samples staines positive for CNPs antigen by IHS; the corresponding rate by IIFS was 92.3 %. In 88.2% of the cultured samples, CNPs were isolated and cultivated successfully. The CNPs were visible under TEM as 200-400 nm diameter spherical particles surrounded by a compact crust. CNPs could be detected and isolated from a high percentage of dental pulp stones, suggesting that CNPs might play an important role in the calcification of dental pulp.

Hypovitaminosis D3, Leukopenia, and Human Serotonin Transporter Polymorphism in Anorexia Nervosa and Bulimia Nervosa.

PubMed

Tasegian, Anna; Curcio, Francesco; Dalla Ragione, Laura; Rossetti, Francesca; Cataldi, Samuela; Codini, Michela; Ambesi-Impiombato, Francesco Saverio; Beccari, Tommaso; Albi, Elisabetta

2016-01-01

Vitamin D3 has been described to have different extraskeletal roles by acting as parahormone in obesity, diabetes, cancer, cognitive impairment, and dementia and to have important regulatory functions in innate immunity. There are no studies showing extraskeletal changes associated with hypovitaminosis D3 in eating disorders. Methods. We have analyzed the blood of 18 patients affected by anorexia nervosa and bulimia nervosa collected over a 15-month period. We performed a panel of chemical and clinical analyses: the assay of vitamin D3, the immunoblotting of vitamin D receptor and peroxisome proliferator-activated receptor gamma, and the genotyping of 5-hydroxytryptamine transporter linked polymorphic region. Results. We choose 18 patients with a normal blood test profile such as thyroid hormones, hepatic and renal parameters, triglycerides, proteins, vitamin B12, and folic acid. Among these emerged the case of a woman with long-term anorexia nervosa and the case of a woman with long-term bulimia nervosa both complicated by anxiety and depression, severe hypovitaminosis D3, decrease of vitamin D receptor, leukopenia, and 5-hydroxytryptamine transporter linked polymorphic region short allele. Conclusion. The results induce hypothesising that the severe hypovitaminosis D3 might be responsible for the lack of the inflammatory response and the depressive symptoms in patients with long-term eating disorders.

Orbital extraskeletal osteosarcoma following enucleation in a cat: a case report.

PubMed

Groskopf, Brooke S; Dubielzig, Richard R; Beaumont, Stephanie L

2010-05-01

We present a unique case of a feline orbital extraskeletal osteosarcoma that developed 5 years post-enucleation. In 2002, an ophthalmologist enucleated the left eye of a 2-year-old neutered male DSH and submitted it to the Comparative Ocular Pathology Laboratory of Wisconsin (COPLOW). COPLOW diagnosed the left eye with feline diffuse iris melanoma. In June 2007, the cat presented to another veterinarian for moderate swelling of the enucleation site. Palpation suggested a firm mass along the lateral orbital rim and an exploratory orbitotomy revealed a cyst with a mass adhered to it and the ventrolateral orbital rim. The cyst and mass were excised by the veterinarian and submitted to COPLOW. COPLOW diagnosed the tissue as an orbital conjunctival inclusion cyst and an acquired orbital osteosarcoma. Following the enucleation, retained conjunctival epithelium became embedded in the connective tissue of the orbit and caused a cyst to develop. The cyst wall consisted of a myofibroblastic collagen-rich matrix and acted as a nidus of chronic irritation and tumor growth. This orbital osteosarcoma resembles feline vaccine-associated sarcomas (VAS), feline post-traumatic ocular sarcomas, and microchip-associated sarcomas in terms of it histopathology and its hypothesized pathogenesis related to exposure to antigenic material such as implanted epithelium, lens protein, vaccine components, and microchips as foreign bodies.

Therapeutic Angiotensin-(1-7) in Treating Patients With Metastatic Sarcoma That Cannot Be Removed By Surgery

ClinicalTrials.gov

2018-02-27

Bone Cancer; Chondrosarcoma; Clear Cell Sarcoma of the Kidney; Metastatic Osteosarcoma; Ovarian Sarcoma; Recurrent Adult Soft Tissue Sarcoma; Recurrent Osteosarcoma; Recurrent Uterine Sarcoma; Stage III Adult Soft Tissue Sarcoma; Stage III Uterine Sarcoma; Stage IV Adult Soft Tissue Sarcoma; Stage IV Uterine Sarcoma

A broad spectrum of genomic changes in latinamerican patients with EXT1/EXT2-CDG

PubMed Central

Delgado, M. A.; Martinez-Domenech, G.; Sarrión, P.; Urreizti, R.; Zecchini, L.; Robledo, H. H.; Segura, F.; de Kremer, R. Dodelson; Balcells, S.; Grinberg, D.; Asteggiano, C. G.

2014-01-01

Multiple osteochondromatosis (MO), or EXT1/EXT2-CDG, is an autosomal dominant O-linked glycosylation disorder characterized by the formation of multiple cartilage-capped tumors (osteochondromas). In contrast, solitary osteochondroma (SO) is a non-hereditary condition. EXT1 and EXT2, are tumor suppressor genes that encode glycosyltransferases involved in heparan sulfate elongation. We present the clinical and molecular analysis of 33 unrelated Latin American patients (27 MO and 6 SO). Sixty-three percent of all MO cases presented severe phenotype and two malignant transformations to chondrosarcoma (7%). We found the mutant allele in 78% of MO patients. Ten mutations were novel. The disease-causing mutations remained unknown in 22% of the MO patients and in all SO patients. No second mutational hit was detected in the DNA of the secondary chondrosarcoma from a patient who carried a nonsense EXT1 mutation. Neither EXT1 nor EXT2 protein could be detected in this sample. This is the first Latin American research program on EXT1/EXT2-CDG. PMID:25230886

A broad spectrum of genomic changes in latinamerican patients with EXT1/EXT2-CDG.

PubMed

Delgado, M A; Martinez-Domenech, G; Sarrión, P; Urreizti, R; Zecchini, L; Robledo, H H; Segura, F; de Kremer, R Dodelson; Balcells, S; Grinberg, D; Asteggiano, C G

2014-09-18

Multiple osteochondromatosis (MO), or EXT1/EXT2-CDG, is an autosomal dominant O-linked glycosylation disorder characterized by the formation of multiple cartilage-capped tumors (osteochondromas). In contrast, solitary osteochondroma (SO) is a non-hereditary condition. EXT1 and EXT2, are tumor suppressor genes that encode glycosyltransferases involved in heparan sulfate elongation. We present the clinical and molecular analysis of 33 unrelated Latin American patients (27 MO and 6 SO). Sixty-three percent of all MO cases presented severe phenotype and two malignant transformations to chondrosarcoma (7%). We found the mutant allele in 78% of MO patients. Ten mutations were novel. The disease-causing mutations remained unknown in 22% of the MO patients and in all SO patients. No second mutational hit was detected in the DNA of the secondary chondrosarcoma from a patient who carried a nonsense EXT1 mutation. Neither EXT1 nor EXT2 protein could be detected in this sample. This is the first Latin American research program on EXT1/EXT2-CDG.

V-ATPase as an effective therapeutic target for sarcomas

DOE Office of Scientific and Technical Information (OSTI.GOV)

Perut, Francesca, E-mail: francesca.perut@ior.it; Avnet, Sofia; Fotia, Caterina

2014-01-01

Malignant tumors show intense glycolysis and, as a consequence, high lactate production and proton efflux activity. We investigated proton dynamics in osteosarcoma, rhabdomyosarcoma, and chondrosarcoma, and evaluated the effects of esomeprazole as a therapeutic agent interfering with tumor acidic microenvironment. All sarcomas were able to survive in an acidic microenvironment (up to 5.9–6.0 pH) and abundant acidic lysosomes were found in all sarcoma subtypes. V-ATPase, a proton pump that acidifies intracellular compartments and transports protons across the plasma membrane, was detected in all cell types with a histotype-specific expression pattern. Esomeprazole administration interfered with proton compartmentalization in acidic organelles andmore » induced a significant dose-dependent toxicity. Among the different histotypes, rhabdomyosarcoma, expressing the highest levels of V-ATPase and whose lysosomes are most acidic, was mostly susceptible to ESOM treatment. - Highlights: • Osteosarcoma, rhabdomyosarcoma, and chondrosarcoma survive in acidic microenvironment. • At acidic extracellular pH, sarcoma survival is dependent on V-ATPase expression. • Esomeprazole administration induce a significant dose-dependent toxicity.« less

[Microsurgical transplantation of bone tumors of uncertain prognosis in athymic nude mice].

PubMed

Duprez, A; Féry, A; Sommelet, J

1986-01-01

Eight cases of human bone or soft tissue tumours were transplanted to nude mice. After such transplants to nude mice which are immunologically deficient, the malignant tumors developed like benign tumours, but maintaining malignant cytological characteristics. The transplants of normal human tissues or of benign tumours decreased in size or remained stable. The technique allowed a change of an original diagnosis of osteosarcoma to a final diagnosis of chondrosarcoma. It made it possible to diagnose a benign osteoblastoma, the diagnosis of which was doubtful before the transplant between osteosarcoma and chondroblastoma. It was possible to diagnose the malignancy of a haemangiopericytoma of muscle. Two aggressive tumours--a non-ossifying fibroma and a giant-cell tumour--were rated as benign after transplantation. This technique also allowed a more precise diagnosis of the grade of one chondrosarcoma and one osteosarcoma. Finally, transplantation also made it possible to test the efficacy of chemotherapy. In a patient so treated, the extreme cell proliferation after transplantation to the nude mouse led to a change in the drugs administered.

Epidemiological data and case load spectrum of patients presenting to bone and soft tissue disease management group at a tertiary cancer center.

PubMed

Gulia, A; Puri, A; Chorge, S; Panda, P K

2016-01-01

This study was conducted to know the spectrum and number of bone and soft tissue (BST) tumors presenting to our institute. We needed to assess the gap between the number of patients seen and infrastructure available, and based on this information, help formulate guidelines for optimum utilization of resources and to provide best possible evidence-based cancer care. This is a prospective observational study (epidemiological). This study included all new patients seen in BST-disease management group (DMG) in the year 2010. An audit form was devised to capture all the relevant information. A comparison of our data with other national and international studies was also done. Out of total 31,951 new patients registered at our institute, 2007 patients availed BST-DMG services. Sixty percent were bone tumors and 36% were soft tissue tumors. In bone tumor, 66% were malignant, 15% were benign, and 19% were non-neoplastic. Osteosarcoma (43%) was the most common malignant tumor followed by primitive neuroectodermal tumor/Ewing's (27%) and chondrosarcoma (11%). Giant cell tumor was the most common benign bone tumor. Eighty-one percent of all soft tissue lesions were malignant, of which 75% were of mesenchymal origin and 25% were of cutaneous origin. This is an attempt to document the epidemiology of musculoskeletal tumors presenting to our institution while guiding the institute to frame and implement disease-specific protocols and generate further research questions. Continued data collection and follow-up can provide valuable information on long-term survival and treatment-related toxicities. This data (within limitations) may be extrapolated to national level to identify the need for infrastructure and human resources.

PHOX2B reliably distinguishes neuroblastoma among small round blue cell tumours.

PubMed

Hung, Yin P; Lee, John P; Bellizzi, Andrew M; Hornick, Jason L

2017-11-01

Neuroblastoma shows considerable histological overlap with other small round blue cell tumours. PHOX2B, a transcription factor that is essential for autonomic nervous system development, has been reported as an immunohistochemical marker for neuroblastoma. The aim of this study was to validate the specificity and diagnostic utility of PHOX2B for peripheral neuroblastic tumours. We evaluated 240 cases (133 in whole-tissue sections; 107 in tissue microarrays), including 76 peripheral neuroblastic tumours (median age 2 years; including four adults) and 164 other tumours: 44 Wilms tumours; 20 Ewing sarcomas; 10 each of CIC-rearranged round cell sarcomas, poorly differentiated synovial sarcomas, lymphoblastic lymphomas, alveolar rhabdomyosarcomas, embryonal rhabdomyosarcomas, mesenchymal chondrosarcomas, Merkel cell carcinomas, olfactory neuroblastomas, and melanomas; and five each of NUT midline carcinomas and desmoplastic small round cell tumours. Immunohistochemistry for PHOX2B was performed with a rabbit monoclonal antibody. PHOX2B positivity was defined as the presence of nuclear immunoreactivity in ≥5% of cells. PHOX2B was positive in 70 (92%) peripheral neuroblastic tumours, including 68 of 72 (94%) paediatric and two of four (50%) adult cases. Furthermore, PHOX2B was consistently negative in all non-peripheral neuroblastic tumours, with staining being absent in 160 cases and limited in four cases. PHOX2B is a highly sensitive and specific immunohistochemical marker for peripheral neuroblastic tumours, including neuroblastoma. PHOX2B reliably distinguishes neuroblastoma from histological mimics such as Wilms tumour, Ewing sarcoma, and CIC-rearranged round cell sarcoma. PHOX2B negativity in two of four adult neuroblastoma cases raises the possibility that some adult neuroblastomas are of a different lineage than paediatric cases. © 2017 John Wiley & Sons Ltd.

NKX2.2 is a useful immunohistochemical marker for Ewing sarcoma.

PubMed

Yoshida, Akihiko; Sekine, Shigeki; Tsuta, Koji; Fukayama, Masashi; Furuta, Koh; Tsuda, Hitoshi

2012-07-01

Ewing sarcoma is a high-grade round cell sarcoma that affects bones and soft tissues in children and young adults. Its diagnosis can be challenging, and the differential diagnoses include a wide variety of small round cell tumors. CD99 and FLI-1 are the currently accepted immunohistochemical markers for Ewing sarcoma, but their accuracy has been controversial. NKX2.2 is a homeodomain-containing transcription factor that plays a critical role in neuroendocrine/glial differentiation. The NKX2.2 gene was recently identified as a target of EWS-FLI-1, the fusion protein specific to Ewing sarcoma, and was shown to be differentially upregulated in Ewing sarcoma on the basis of array-based gene expression analysis. However, the immunohistochemical diagnostic potential of this marker has not been tested. We immunostained representative sections of 30 genetically confirmed Ewing sarcomas and 130 non-Ewing small round cell tumors by using an antibody to NKX2.2. Nuclear staining in at least 5% of the cells was deemed positive. Twenty-eight (93%) of the 30 Ewing sarcomas were positive for NKX2.2. The staining was diffuse (>50%) in all the positive cases and was moderate or strong in intensity for most cases (25 of 28). NKX2.2 was also positive in 14 non-Ewing tumors, including all the olfactory neuroblastomas and a minor subset of small cell carcinomas, synovial sarcomas, mesenchymal chondrosarcomas, and malignant melanomas. All the other non-Ewing tumors tested were negative for this marker. NKX2.2 is a valuable marker for Ewing sarcoma, with a sensitivity of 93% and a specificity of 89%, and aids in the differential diagnosis of small round cell tumors.

Spot Scanning Proton Therapy for Malignancies of the Base of Skull: Treatment Planning, Acute Toxicities, and Preliminary Clinical Outcomes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Grosshans, David R., E-mail: dgrossha@mdanderson.org; Zhu, X. Ronald; Melancon, Adam

2014-11-01

Purpose: To describe treatment planning techniques and early clinical outcomes in patients treated with spot scanning proton therapy for chordoma or chondrosarcoma of the skull base. Methods and Materials: From June 2010 through August 2011, 15 patients were treated with spot scanning proton therapy for chordoma (n=10) or chondrosarcoma (n=5) at a single institution. Toxicity was prospectively evaluated and scored weekly and at all follow-up visits according to Common Terminology Criteria for Adverse Events, version 3.0. Treatment planning techniques and dosimetric data were recorded and compared with those of passive scattering plans created with clinically applicable dose constraints. Results: Tenmore » patients were treated with single-field-optimized scanning beam plans and 5 with multifield-optimized intensity modulated proton therapy. All but 2 patients received a simultaneous integrated boost as well. The mean prescribed radiation doses were 69.8 Gy (relative biological effectiveness [RBE]; range, 68-70 Gy [RBE]) for chordoma and 68.4 Gy (RBE) (range, 66-70) for chondrosarcoma. In comparison with passive scattering plans, spot scanning plans demonstrated improved high-dose conformality and sparing of temporal lobes and brainstem. Clinically, the most common acute toxicities included fatigue (grade 2 for 2 patients, grade 1 for 8 patients) and nausea (grade 2 for 2 patients, grade 1 for 6 patients). No toxicities of grades 3 to 5 were recorded. At a median follow-up time of 27 months (range, 13-42 months), 1 patient had experienced local recurrence and a second developed distant metastatic disease. Two patients had magnetic resonance imaging-documented temporal lobe changes, and a third patient developed facial numbness. No other subacute or late effects were recorded. Conclusions: In comparison to passive scattering, treatment plans for spot scanning proton therapy displayed improved high-dose conformality. Clinically, the treatment was well tolerated, and with short-term follow-up, disease control rates and toxicity profiles were favorable.« less

Stage IV breast cancer: clinical course and survival of patients with osseous versus extraosseous metastases at initial diagnosis. The GOCS (Grupo Oncológico Cooperativo del Sur) experience.

PubMed

Leone, B A; Romero, A; Rabinovich, M G; Vallejo, C T; Bianco, A; Perez, J E; Machiavelli, M; Rodriguez, R; Alvarez, L A

1988-12-01

The medical records of 414 patients with metastatic breast carcinoma treated between 1978 and 1986 were reviewed and 44 women were identified as having stage IV disease when the primary breast lesion was detected. Of these 44 women, 25 had metastatic disease limited to the skeleton while 19 had extraosseous lesions only. The clinical features, response to therapy, and survival were analyzed and compared for both groups. The median survival of those patients with bone-only metastases was 52 months as compared with 13 months for those with extraskeletal lesions (p = 0.0025). The response rate to first-line systemic therapy was similar for both groups (47% for bone metastases and 44% for extraosseous metastases). The median duration of response was 14 months (range, 3-55 months) for patients with bone disease and 8 months (range, 4-43 months) for those with extraskeletal lesions. We conclude that patients with metastatic breast cancer confined to the skeleton at initial diagnosis tend to follow an indolent, chronic course with prolonged survival. Therefore the increase in response rate with aggressive chemotherapy should be balanced against its higher morbidity. Further studies are needed to confirm whether the better prognosis of these patients is determined by the anatomical confinement of the disease to the skeleton or merely reflects the influence of other prognostic factors.

Ewing's Sarcoma of the Adrenal Gland.

PubMed

Pal, Dilip Kumar; Chandra, Vipin; Ranjan, Kumar Rajiv; Chakrabortty, Debasis; Banerjee, Manju

2016-01-01

Ewing's sarcoma (ES) or primitive neuro-ectodermal tumor (PNET) typically occurs in long or flat bones, the chest wall, extra-skeletal soft tissue, and rarely in solid organs. Incidence of adrenal Ewing's sarcoma is very rare. Here we report a case of Ewing's sarcoma of the right adrenal gland in an 8-year-old girl who presented with an abdominal mass. The huge tumor was managed by preoperative neo-adjuvant chemotherapy followed by surgical resection. She died due to metastasis after five months of surgery.

High hydrostatic pressure induces ERK and PI3 kinase phosphorylation in human HCS-2/8 chondrosarcoma cells.

PubMed

Kopakkala-Tani, M; Elo, M A; Sironen, R K; Helminen, H J; Lammi, M J

2004-06-01

High continuous hydrostatic pressure has been shown to affect many cellular functions within the pressurised cells, for instance, accumulation of heat shock protein 70 occurs during pressurisation. Various signal transduction pathways are likely to mediate these changes, however, at the present time our knowledge of the pathways involved is rather limited. The aim of this study was to investigate whether some of the well known transduction pathways are activated by the exposure of human chondrosarcoma cells to 15-30 MPa hydrostatic pressure. The results showed an increased presence of the active, phosphorylated forms of extracellular signal-related kinase (ERK) and phosphoinositide 3-kinase (PI3K) in cells exposed to 15 and 30 MPa continuous hydrostatic pressure, while 0.5 Hz cyclic loading had weaker effects. Inhibition of ERK-pathway with UO126 did not prevent the accumulation of heat shock protein 70. No activation of c-Jun N-terminal protein kinase (JNK) or p38 could be noticed in pressurised cells. In conclusion, we could identify at least two different signal transduction pathways that are activated under high continuous hydrostatic pressure. Accumulation of heat shock protein 70 was independent of ERK-activation.

A case of McCune-Albright syndrome associated with pituitary GH adenoma: therapeutic process and autopsy.

PubMed

Liu, Fuyi; Li, Wenting; Yao, Yong; Li, Guilin; Yang, Yi; Dou, Wanchen; Zhong, Dingrong; Wang, Lin; Zhu, Xiangdong; Hu, Hua; Zhang, Jianmin; Wang, Renzhi; Chen, Gao

2011-01-01

McCune-Albright syndrome (MAS) is a clinical syndrome with low incidence, and its concurrence with pituitary GH adenoma is rare. Little of the history, treatment and outcome has been studied. Follow-up of a 37-year-old male patient of MAS associated with pituitary GH adenoma was performed continuously recording the disease development and the treatment process until death, after which an autopsy was performed. Radiation therapy (RT) efficaciously controlled GH hypersecretion, however, it may have been the cause of the malignant transformation of the dysplastic bone tissue, which eventually caused brain hernia and death; autopsy demonstrated that the cranium had significant thickening (as much as 10 cm), the pathological diagnosis was fibrous dysplasia of bone associated with chondrosarcoma; and undifferentiated chondrosarcoma with malignant fibrous histocytoma subtype in the sellar region; nodular goiter with the thyroid gland, one nodus was pathologically demonstrated as papillary carcinoma. GH adenoma, present in a patient with MAS, might be cured by RT; but the risk of malignant transformation of the dysplastic bone tissue in the field of irradiation make it controversial. Lessons from the case reported here told us that we should take great caution when recommending RT for patients like this.

Sex Steroid Actions in Male Bone

PubMed Central

Laurent, Michaël R.; Claessens, Frank; Gielen, Evelien; Lagerquist, Marie K.; Vandenput, Liesbeth; Börjesson, Anna E.; Ohlsson, Claes

2014-01-01

Sex steroids are chief regulators of gender differences in the skeleton, and male gender is one of the strongest protective factors against osteoporotic fractures. This advantage in bone strength relies mainly on greater cortical bone expansion during pubertal peak bone mass acquisition and superior skeletal maintenance during aging. During both these phases, estrogens acting via estrogen receptor-α in osteoblast lineage cells are crucial for male cortical and trabecular bone, as evident from conditional genetic mouse models, epidemiological studies, rare genetic conditions, genome-wide meta-analyses, and recent interventional trials. Genetic mouse models have also demonstrated a direct role for androgens independent of aromatization on trabecular bone via the androgen receptor in osteoblasts and osteocytes, although the target cell for their key effects on periosteal bone formation remains elusive. Low serum estradiol predicts incident fractures, but the highest risk occurs in men with additionally low T and high SHBG. Still, the possible clinical utility of serum sex steroids for fracture prediction is unknown. It is likely that sex steroid actions on male bone metabolism rely also on extraskeletal mechanisms and cross talk with other signaling pathways. We propose that estrogens influence fracture risk in aging men via direct effects on bone, whereas androgens exert an additional antifracture effect mainly via extraskeletal parameters such as muscle mass and propensity to fall. Given the demographic trends of increased longevity and consequent rise of osteoporosis, an increased understanding of how sex steroids influence male bone health remains a high research priority. PMID:25202834

Chronic Vitamin D Intoxication in Captive Iberian Lynx (Lynx pardinus)

PubMed Central

Muñoz, Luis; Raya, Ana; Lopez, Guillermo; Aguilera-Tejero, Escolástico

2016-01-01

To document the biochemical and pathologic features of vitamin D intoxication in lynx and to characterize mineral metabolism in healthy lynx, blood samples were obtained from 40 captive lynx that had been receiving excessive (approximately 30 times the recommended dose) vitamin D3 in the diet, and from 29 healthy free ranging lynx. Tissue samples (kidney, stomach, lung, heart and aorta) were collected from 13 captive lynx that died as a result of renal disease and from 3 controls. Vitamin D intoxication resulted in renal failure in most lynx (n = 28), and widespread extraskeletal calcification was most severe in the kidneys and less prominent in cardiovascular tissues. Blood minerals and calciotropic hormones in healthy lynx were similar to values reported in domestic cats except for calcitriol which was higher in healthy lynx. Changes in mineral metabolism after vitamin D intoxication included hypercalcemia (12.0 ± 0.3 mg/dL), hyperphosphatemia (6.3 ± 0.4 mg/dL), increased plasma calcidiol (381.5 ± 28.2 ng/mL) and decreased plasma parathyroid hormone (1.2 ± 0.7 pg/mL). Hypercalcemia and, particularly, hyperphosphatemia were of lower magnitude that what has been previously reported in the course of vitamin D intoxication in other species. However, extraskeletal calcifications were severe. The data suggest that lynx are sensitive to excessive vitamin D and extreme care should be taken when supplementing this vitamin in captive lynx diets. PMID:27243456

The spectrum of EWSR1-rearranged neoplasms at a tertiary sarcoma centre; assessing 772 tumour specimens and the value of current ancillary molecular diagnostic modalities

PubMed Central

Noujaim, Jonathan; Jones, Robin L; Swansbury, John; Gonzalez, David; Benson, Charlotte; Judson, Ian; Fisher, Cyril; Thway, Khin

2017-01-01

Background: EWSR1 rearrangements were first identified in Ewing sarcoma, but the spectrum of EWSR1-rearranged neoplasms now includes many soft tissue tumour subtypes including desmoplastic small round cell tumour (DSRCT), myxoid liposarcoma (MLPS), extraskeletal myxoid chondrosarcoma (EMC), angiomatoid fibrous histiocytoma (AFH), clear cell sarcoma (CCS) and myoepithelial neoplasms. We analysed the spectrum of EWSR1-rearranged soft tissue neoplasms at our tertiary sarcoma centre, by assessing ancillary molecular diagnostic modalities identifying EWSR1-rearranged tumours and reviewing the results in light of our current knowledge of these and other Ewing sarcoma-like neoplasms. Methods: We retrospectively analysed all specimens tested for EWSR1 rearrangements by fluorescence in situ hybridisation (FISH) and/or reverse transcription–PCR (RT–PCR) over a 7-year period. Results: There was a total of 772 specimens. FISH was performed more often than RT–PCR (n=753, 97.5% vs n=445, 57.6%). In total, 210 (27.9%) specimens were FISH-positive for EWSR1 rearrangement compared to 111 (14.4%) that showed EWSR1 fusion transcripts with RT–PCR. Failure rates for FISH and RT–PCR were 2.5% and 18.0%. Of 109 round cell tumours with pathology consistent with Ewing sarcoma, 15 (13.8 %) cases were FISH-positive without an identifiable EWSR1 fusion transcript, 4 (3.7%) were FISH-negative but RT–PCR positive and 4 (3.7%) were negative for both. FISH positivity for DSRCT, MLPS, EMC, AFH and CCS was 86.3%, 4.3%, 58.5%, 60.0% and 87.9%, respectively. A positive FISH result led to diagnostic change in 40 (19.0%) EWSR1-rearranged cases. 13 FISH-positive cases remained unclassifiable. Conclusions: FISH is more sensitive for identifying EWSR1 rearrangements than RT–PCR. However, there can be significant morphologic and immunohistochemical overlap between groups of EWSR1-rearranged neoplasms, with important prognostic and therapeutic implications. FISH and RT–PCR should be used as complementary modalities in diagnosing EWSR1-rearranged neoplasms, but as tumour groups harbouring EWSR1 rearrangements are increasingly characterised and because given translocations involving EWSR1 and its partner genes are not always specific for tumour types, it is critical that these are evaluated by specialist soft tissue surgical pathologists noting the morphologic and immunohistochemical context. As RT–PCR using commercial primers is limited to only the most prevalent EWSR1 fusion transcripts, the incorporation of high-throughput sequencing technologies into the standard diagnostic repertoire to assess for multiple molecular abnormalities of soft tissue tumours in parallel (including detection of newly characterised Ewing sarcoma-like tumours) might be the most effective and efficient means of ancillary diagnosis in future. PMID:28141799

Clinical Indications for Carbon Ion Radiotherapy and Radiation Therapy with Other Heavier Ions

NASA Astrophysics Data System (ADS)

Combs, Stephanie E.

A number of studies have shown excellent and convincing clinical results for various indications after treatment with ions heavier than protons. These include skull base chordomas and chondrosarcomas, hepatocellular carcinomas, recurrent rectal cancer, high-risk meningiomas, or soft-tissue and bone sarcomas. This chapter outlines these trials and provides a medical rationale for their choice before they are discussed in depth in subsequent chapters.

Differential marker expression by cultures rich in mesenchymal stem cells

PubMed Central

2013-01-01

Background Mesenchymal stem cells have properties that make them amenable to therapeutic use. However, the acceptance of mesenchymal stem cells in clinical practice requires standardized techniques for their specific isolation. To date, there are no conclusive marker (s) for the exclusive isolation of mesenchymal stem cells. Our aim was to identify markers differentially expressed between mesenchymal stem cell and non-stem cell mesenchymal cell cultures. We compared and contrasted the phenotype of tissue cultures in which mesenchymal stem cells are rich and rare. By initially assessing mesenchymal stem cell differentiation, we established that bone marrow and breast adipose cultures are rich in mesenchymal stem cells while, in our hands, foreskin fibroblast and olfactory tissue cultures contain rare mesenchymal stem cells. In particular, olfactory tissue cells represent non-stem cell mesenchymal cells. Subsequently, the phenotype of the tissue cultures were thoroughly assessed using immuno-fluorescence, flow-cytometry, proteomics, antibody arrays and qPCR. Results Our analysis revealed that all tissue cultures, regardless of differentiation potential, demonstrated remarkably similar phenotypes. Importantly, it was also observed that common mesenchymal stem cell markers, and fibroblast-associated markers, do not discriminate between mesenchymal stem cell and non-stem cell mesenchymal cell cultures. Examination and comparison of the phenotypes of mesenchymal stem cell and non-stem cell mesenchymal cell cultures revealed three differentially expressed markers – CD24, CD108 and CD40. Conclusion We indicate the importance of establishing differential marker expression between mesenchymal stem cells and non-stem cell mesenchymal cells in order to determine stem cell specific markers. PMID:24304471

Fluoxetine ameliorates cartilage degradation in osteoarthritis by inhibiting Wnt/β-catenin signaling.

PubMed

Miyamoto, Kentaro; Ohkawara, Bisei; Ito, Mikako; Masuda, Akio; Hirakawa, Akihiro; Sakai, Tadahiro; Hiraiwa, Hideki; Hamada, Takashi; Ishiguro, Naoki; Ohno, Kinji

2017-01-01

Abnormal activation of the Wnt/β-catenin signaling is implicated in the osteoarthritis (OA) pathology. We searched for a pre-approved drug that suppresses abnormally activated Wnt/β-catenin signaling and has a potency to reduce joint pathology in OA. We introduced the TOPFlash reporter plasmid into HCS-2/8 human chondrosarcoma cells to estimate the Wnt/β-catenin activity in the presence of 10 μM each compound in a panel of pre-approved drugs. We found that fluoxetine, an antidepressant in the class of selective serotonin reuptake inhibitors (SSRI), down-regulated Wnt/β-catenin signaling in human chondrosarcoma cells. Fluoxetine inhibited both Wnt3A- and LiCl-induced loss of proteoglycans in chondrogenically differentiated ATDC5 cells. Fluoxetine increased expression of Sox9 (the chondrogenic master regulator), and decreased expressions of Axin2 (a marker for Wnt/β-catenin signaling) and Mmp13 (matrix metalloproteinase 13). Fluoxetine suppressed a LiCl-induced increase of total β-catenin and a LiCl-induced decrease of phosphorylated β-catenin in a dose-dependent manner. An in vitro protein-binding assay showed that fluoxetine enhanced binding of β-catenin with Axin1, which is a scaffold protein forming the degradation complex for β-catenin. Fluoxetine suppressed LiCl-induced β-catenin accumulation in human OA chondrocytes. Intraarticular injection of fluoxetine in a rat OA model ameliorated OA progression and suppressed β-catenin accumulation.

Fluoxetine ameliorates cartilage degradation in osteoarthritis by inhibiting Wnt/β-catenin signaling

PubMed Central

Miyamoto, Kentaro; Ito, Mikako; Masuda, Akio; Hirakawa, Akihiro; Sakai, Tadahiro; Hiraiwa, Hideki; Hamada, Takashi; Ishiguro, Naoki; Ohno, Kinji

2017-01-01

Abnormal activation of the Wnt/β-catenin signaling is implicated in the osteoarthritis (OA) pathology. We searched for a pre-approved drug that suppresses abnormally activated Wnt/β-catenin signaling and has a potency to reduce joint pathology in OA. We introduced the TOPFlash reporter plasmid into HCS-2/8 human chondrosarcoma cells to estimate the Wnt/β-catenin activity in the presence of 10 μM each compound in a panel of pre-approved drugs. We found that fluoxetine, an antidepressant in the class of selective serotonin reuptake inhibitors (SSRI), down-regulated Wnt/β-catenin signaling in human chondrosarcoma cells. Fluoxetine inhibited both Wnt3A- and LiCl-induced loss of proteoglycans in chondrogenically differentiated ATDC5 cells. Fluoxetine increased expression of Sox9 (the chondrogenic master regulator), and decreased expressions of Axin2 (a marker for Wnt/β-catenin signaling) and Mmp13 (matrix metalloproteinase 13). Fluoxetine suppressed a LiCl-induced increase of total β-catenin and a LiCl-induced decrease of phosphorylated β-catenin in a dose-dependent manner. An in vitro protein-binding assay showed that fluoxetine enhanced binding of β-catenin with Axin1, which is a scaffold protein forming the degradation complex for β-catenin. Fluoxetine suppressed LiCl-induced β-catenin accumulation in human OA chondrocytes. Intraarticular injection of fluoxetine in a rat OA model ameliorated OA progression and suppressed β-catenin accumulation. PMID:28926590

The impact of vitamin D in pregnancy on extraskeletal health in children: a systematic review.

PubMed

Christesen, Henrik T; Elvander, Claes; Lamont, Ronald F; Jørgensen, Jan S

2012-12-01

The impact of maternal vitamin D status in pregnancy on the extraskeletal health of the offspring has become a "hot topic" with a potential for cost-beneficial prevention. The objective of this study was to systematically review the level I and II evidence. PubMed, Embase and Cochrane databases were searched using the MeSH terms "vitamin D" AND "pregnancy" until 1 January 2012. The search was limited to randomized controlled trials (evidence level I) and observational studies (evidence level II) in humans and in the English language. Papers reporting on vitamin D supplementation in combination with other supplements, or not reporting on 25OHD or outcomes of the offspring were excluded. Six randomized controlled trials and 24 observational studies were finally included. In randomized controlled studies, vitamin D supplementation resulted in increased birthweight in one study, but showed no effect in five other studies. In cohort and case-control studies, higher vitamin D intake, or higher 25OHD, was associated with increased birthweight in large studies only, and modified by vitamin D receptor polymorphisms and by race (U-shaped in Caucasians in one unconfirmed study). The risks of HIV mother-to-child transmission, rhinitis symptoms and eczema were lower. Data were conflicting on the effect on respiratory infections and wheezing, whereas U-shaped associations to inhalant allergen-specific IgE at five years and to schizophrenia were reported in unconfirmed studies. The risk of type 1 diabetes at 15 years was lower or unchanged. It is concluded that observational studies suggest an effect of vitamin D on several outcomes. U-Shaped associations warrant caution. © 2012 The Authors Acta Obstetricia et Gynecologica Scandinavica© 2012 Nordic Federation of Societies of Obstetrics and Gynecology.

Characteristics and Outcomes of Patients with Ewing Sarcoma Over 40 Years of Age at Diagnosis

PubMed Central

Karski, Erin E.; Matthay, Katherine K.; Neuhaus, John M.; Goldsby, Robert E.; DuBois, Steven G.

2012-01-01

Background The peak incidence of Ewing sarcoma (EWS) is in adolescence, with little known about patients who are ≥ 40 years at diagnosis. We describe the clinical characteristics and survival of this rare group. Methods This retrospective cohort study utilized the Surveillance Epidemiology and End Results database. 2780 patients were identified; including 383 patients diagnosed ≥ 40 years. Patient characteristics between age groups were compared using chi-squared tests. Survival from diagnosis to death was estimated via Kaplan-Meier methods, compared with log-rank tests, and modeled using multivariable Cox methods. A competing risks analysis was performed to evaluate death due to cancer. Results Patients ≥ 40 years of age were more likely to have extra-skeletal tumors (66.1% v 31.7%; p<0.001), axial tumors (64.0% v 57.2%; p=0.01), and metastatic disease at diagnosis (35.5% v 30.0%; p=0.04) compared to younger patients. Five-year survival for those age ≥ 40 and age < 40 were 40.6% and 54.3%, respectively (p<0.0001). A Cox multivariable model controlling for differences between groups confirmed inferior survival for older patients (hazard ratio for death of 2.04; 95% CI 1.63 - 2.54; p < 0.0001); though treatment data were unavailable and not controlled for in the model. A competing risks analysis confirmed increased risk of cancer-related death in older patients. Conclusion Patients ≥ 40 years at diagnosis with EWS are more likely to have extra-skeletal tumors, metastatic disease, and axial primary tumors suggesting a difference in tumor biology. Independent of differences in these characteristics, older patients also have a lower survival rate. PMID:22959474

Characteristics and outcomes of patients with Ewing sarcoma over 40 years of age at diagnosis.

PubMed

Karski, Erin E; Matthay, Katherine K; Neuhaus, John M; Goldsby, Robert E; Dubois, Steven G

2013-02-01

The peak incidence of Ewing sarcoma (EWS) is in adolescence, with little known about patients who are ≥40 years at diagnosis. We describe the clinical characteristics and survival of this rare group. This retrospective cohort study utilized the Surveillance Epidemiology and End Results database. 2780 patients were identified; including 383 patients diagnosed ≥40 years. Patient characteristics between age groups were compared using chi-squared tests. Survival from diagnosis to death was estimated via Kaplan-Meier methods, compared with log-rank tests, and modeled using multivariable Cox methods. A competing risks analysis was performed to evaluate death due to cancer. Patients ≥40 years of age were more likely to have extra-skeletal tumors (66.1% vs. 31.7%; p < 0.001), axial tumors (64.0% vs. 57.2%; p = 0.01), and metastatic disease at diagnosis (35.5% vs. 30.0%; p = 0.04) compared to younger patients. Five-year survival for those age ≥40 and age <40 were 40.6% and 54.3%, respectively (p < 0.0001). A Cox multivariable model controlling for differences between groups confirmed inferior survival for older patients (hazard ratio for death of 2.04; 95% CI 1.63-2.54; p < 0.0001); though treatment data were unavailable and not controlled for in the model. A competing risks analysis confirmed increased risk of cancer-related death in older patients. Patients ≥40 years at diagnosis with EWS are more likely to have extra-skeletal tumors, metastatic disease, and axial primary tumors suggesting a difference in tumor biology. Independent of differences in these characteristics, older patients also have a lower survival rate. Copyright © 2012 Elsevier Ltd. All rights reserved.

Effect of vitamin D deficiency in developed countries.

PubMed

Hassan-Smith, Zaki K; Hewison, Martin; Gittoes, Neil J

2017-06-01

Vitamin D deficiency is common worldwide with adverse effects on skeletal health. In recent years, there has been great interest in non-classical actions of vitamin D. Basic research has uncovered actions in a range of non-skeletal tissues, and observational studies have identified inverse relationships with risk of a number of disease states including sarcopenia, obesity, the metabolic syndrome, cardiovascular disease, cancer and autoimmune diseases. PubMed, Medline and Cochrane Systematic Reviews. Current evidence supports the use of vitamin D supplementation in deficiency to improve skeletal outcomes such as falls/fracture risk and bone mineral density. There is debate reflected in guidelines on optimal thresholds for circulating levels of vitamin D. Further studies are required to refine dosing regimens and treatment target levels of vitamin D. A number of studies have investigated the extra-skeletal effects of vitamin D deficiency but causality in humans has yet to be confirmed. Large-scale randomized controlled trials incorporating data on vitamin D status at baseline and follow up, adverse events, and comparison of dosing regimens are required. It is imperative that studies are carried out with a diverse range of participants (age, gender and ethnicity), and settings to allow for a more individualized approach. In addition, we would advocate incorporating cutting-edge research tools into human studies to advance our understanding of the mechanisms of vitamin D action in extra-skeletal disease. This may involve multi-metabolite analysis of vitamin D metabolites, or unbiased approaches to assess regulation of gene/protein expression in tissues of interest. © The Author 2017. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

Flagellin preconditioning enhances the efficacy of mesenchymal stem cells in an irradiation-induced proctitis model.

PubMed

Linard, Christine; Strup-Perrot, Carine; Lacave-Lapalun, Jean-Victor; Benderitter, Marc

2016-09-01

The success of mesenchymal stem cell transplantation for proctitis depends not only on cell donors but also on host microenvironmental factors, which play a major role in conditioning mesenchymal stem cell immunosuppressive action and repair. This study sought to determine if flagellin, a TLR5 ligand, can enhance the mesenchymal stem cell treatment efficacy in radiation-induced proctitis. With the use of a colorectal model of 27 Gy irradiation in rats, we investigated and compared the effects on immune capacity and remodeling at 28 d after irradiation of the following: 1) systemic mesenchymal stem cell (5 × 10(6)) administration at d 7 after irradiation, 2) administration of flagellin at d 3 and systemic mesenchymal stem cell administration at d 7, and 3) in vitro preconditioning of mesenchymal stem cells with flagellin, 24 h before their administration on d 7. The mucosal CD8(+) T cell population was normalized after treatment with flagellin-preconditioned mesenchymal stem cells or flagellin plus mesenchymal stem cells, whereas mesenchymal stem cells alone did not alter the radiation-induced elevation of CD8(+) T cell frequency. Mesenchymal stem cell treatment returned the irradiation-elevated frequency of CD25(+) cells in the mucosa-to-control levels, whereas both flagellin-preconditioned mesenchymal stem cell and flagellin-plus-mesenchymal stem cell treatment each significantly increased not only CD25(+) cell frequency but also forkhead box p3 and IL-2Rα expression. Specifically, IL-10 was overexpressed after flagellin-preconditioned mesenchymal stem cell treatment. Analysis of collagen expression showed that the collagen type 1/collagen type 3 ratio, an indicator of wound-healing maturation, was low in the irradiated and mesenchymal stem cell-treated groups and returned to the normal level only after the flagellin-preconditioned mesenchymal stem cell treatment. This was associated with a reduction in myofibroblast accumulation. In a proctitis model, flagellin-preconditioned mesenchymal stem cells improved colonic immune capacity and enhanced tissue remodeling. © Society for Leukocyte Biology.

UNUSUAL BONE TUMORS AFTER ROENTGEN THERAPY OF CHILDREN. Two Case Reports

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cohen, J.; D'Angio, G.J.

1961-09-01

In a selected series of 207 children who received x-ray therapy with 1000 r or more delivered to bone, 2 subsequently developed neoplasms of bone. Both bone tumors occurred in normal ribs included in the field of treatment. The tumors were atypical; one resembled a chondrosarcoma, the other an osteoblastoma. The latent periods were thirteen and two years, respectively. Both children had postirradiation scoliosis and hypoplasia of the ilium. One also developed an osteochondroma of the ilium. (auth)

Report of a man with heterotopic ossification of the legs.

PubMed

García-Arpa, Mónica; Flores-Terry, Miguel A; Franco-Muñoz, Monserrat; Villasanti-Rivas, Natalia; González-Ruiz, Lucía; Banegas-Illescas, M Eugenia

2018-05-21

Heterotopic ossification is an uncommon disorder that consists of deposition of ectopic bone outside the extraskeletal tissues. In the skin, it can be primary, in association with genetic syndromes, or be secondary to different disorders. The latter include subcutaneous ossification of the legs in chronic venousinsufficiency, an infrequent and unrecognized complication. We report the case of a patient with subcutaneous ossification of both legs secondary to venous insufficiency and review the literature. Copyright © 2018 Sociedad Española de Reumatologña y Colegio Mexicano de Reumatologña. Publicado por Elsevier España, S.L.U. All rights reserved.

Mesothelial- and epithelial-derived FGF9 have distinct functions in the regulation of lung development

PubMed Central

Yin, Yongjun; Wang, Fen; Ornitz, David M.

2011-01-01

Fibroblast growth factor (FGF) 9 is a secreted signaling molecule that is expressed in lung mesothelium and epithelium and is required for lung development. Embryos lacking FGF9 show mesenchymal hypoplasia, decreased epithelial branching and, by the end of gestation, hypoplastic lungs that cannot support life. Mesenchymal FGF signaling interacts with β-catenin-mediated WNT signaling in a feed-forward loop that functions to sustain mesenchymal FGF responsiveness and mesenchymal WNT/β-catenin signaling. During pseudoglandular stages of lung development, Wnt2a and Wnt7b are the canonical WNT ligands that activate mesenchymal WNT/β-catenin signaling, whereas FGF9 is the only known ligand that signals to mesenchymal FGF receptors (FGFRs). Here, we demonstrate that mesothelial- and epithelial-derived FGF9, mesenchymal Wnt2a and epithelial Wnt7b have unique functions in lung development in mouse. Mesothelial FGF9 and mesenchymal WNT2A are principally responsible for maintaining mesenchymal FGF-WNT/β-catenin signaling, whereas epithelial FGF9 primarily affects epithelial branching. We show that FGF signaling is primarily responsible for regulating mesenchymal proliferation, whereas β-catenin signaling is a required permissive factor for mesenchymal FGF signaling. PMID:21750028

I.V. infusion of brain-derived neurotrophic factor gene-modified human mesenchymal stem cells protects against injury in a cerebral ischemia model in adult rat.

PubMed

Nomura, T; Honmou, O; Harada, K; Houkin, K; Hamada, H; Kocsis, J D

2005-01-01

I.V. delivery of mesenchymal stem cells prepared from adult bone marrow reduces infarction size and ameliorates functional deficits in rat cerebral ischemia models. Administration of the brain-derived neurotrophic factor to the infarction site has also been demonstrated to be neuroprotective. To test the hypothesis that brain-derived neurotrophic factor contributes to the therapeutic benefits of mesenchymal stem cell delivery, we compared the efficacy of systemic delivery of human mesenchymal stem cells and human mesenchymal stem cells transfected with a fiber-mutant F/RGD adenovirus vector with a brain-derived neurotrophic factor gene (brain-derived neurotrophic factor-human mesenchymal stem cells). A permanent middle cerebral artery occlusion was induced by intraluminal vascular occlusion with a microfilament. Human mesenchymal stem cells and brain-derived neurotrophic factor-human mesenchymal stem cells were i.v. injected into the rats 6 h after middle cerebral artery occlusion. Lesion size was assessed at 6 h, 1, 3 and 7 days using MR imaging, and histological methods. Functional outcome was assessed using the treadmill stress test. Both human mesenchymal stem cells and brain-derived neurotrophic factor-human mesenchymal stem cells reduced lesion volume and elicited functional improvement compared with the control sham group, but the effect was greater in the brain-derived neurotrophic factor-human mesenchymal stem cell group. ELISA analysis of the infarcted hemisphere revealed an increase in brain-derived neurotrophic factor in the human mesenchymal stem cell groups, but a greater increase in the brain-derived neurotrophic factor-human mesenchymal stem cell group. These data support the hypothesis that brain-derived neurotrophic factor contributes to neuroprotection in cerebral ischemia and cellular delivery of brain-derived neurotrophic factor can be achieved by i.v. delivery of human mesenchymal stem cells.

Mesenchymal-epithelial interaction techniques

PubMed Central

Baskin, Lawrence

2016-01-01

This paper reviews the importance of mesenchymal-epithelial interactions in development and gives detailed technical protocols for investigating these interactions. Successful analysis of mesenchymal-epithelial interactions requires knowing the ages in which embryonic, neonatal and adult organs can be separated into mesenchymal and epithelial tissues. Methods for separation of mesenchymal and epithelial and preparation of tissue recombinants are described. PMID:26610327

Distinct requirements for cranial ectoderm and mesenchyme-derived wnts in specification and differentiation of osteoblast and dermal progenitors.

PubMed

Goodnough, L Henry; Dinuoscio, Gregg J; Ferguson, James W; Williams, Trevor; Lang, Richard A; Atit, Radhika P

2014-02-01

The cranial bones and dermis differentiate from mesenchyme beneath the surface ectoderm. Fate selection in cranial mesenchyme requires the canonical Wnt effector molecule β-catenin, but the relative contribution of Wnt ligand sources in this process remains unknown. Here we show Wnt ligands are expressed in cranial surface ectoderm and underlying supraorbital mesenchyme during dermal and osteoblast fate selection. Using conditional genetics, we eliminate secretion of all Wnt ligands from cranial surface ectoderm or undifferentiated mesenchyme, to uncover distinct roles for ectoderm- and mesenchyme-derived Wnts. Ectoderm Wnt ligands induce osteoblast and dermal fibroblast progenitor specification while initiating expression of a subset of mesenchymal Wnts. Mesenchyme Wnt ligands are subsequently essential during differentiation of dermal and osteoblast progenitors. Finally, ectoderm-derived Wnt ligands provide an inductive cue to the cranial mesenchyme for the fate selection of dermal fibroblast and osteoblast lineages. Thus two sources of Wnt ligands perform distinct functions during osteoblast and dermal fibroblast formation.

Mesenchymal Stem Cell Therapy for Nerve Regeneration and Immunomodulation after Composite Tissue Allotransplantation

DTIC Science & Technology

2012-02-01

10-1-0927 TITLE: Mesenchymal Stem Cell Therapy for Nerve Regeneration and Immunomodulation after Composite Tissue Allotransplantation...immunosuppression. Bone Marrow Derived Mesenchymal stem cells (BM-MSCs) are pluripotent cells, capable of differentiation along multiple mesenchymal lineages into...As part of implemented transition from University of Pittsburgh to Johns Hopkins University, we optimized our mesenchymal stem cell (MSC) isolation

Mesenchymal stem cells induce dermal fibroblast responses to injury

PubMed Central

Smith, Andria N.; Willis, Elise; Chan, Vincent T.; Muffley, Lara A.; Isik, F. Frank; Gibran, Nicole S.; Hocking, Anne M.

2009-01-01

Although bone marrow-derived mesenchymal stem cells have been shown to promote repair when applied to cutaneous wounds, the mechanism for this response remains to be determined. The aim of this study was to determine the effects of paracrine signaling from mesenchymal stem cells on dermal fibroblast responses to injury including proliferation, migration and expression of genes important in wound repair. Dermal fibroblasts were co-cultured with bone marrow-derived mesenchymal stem cells grown in inserts, which allowed for paracrine interactions without direct cell contact. In this co-culture model, bone marrow-derived mesenchymal stem cells regulate dermal fibroblast proliferation, migration and gene expression. When co-cultured with mesenchymal stem cells, dermal fibroblasts show increased proliferation and accelerated migration in a scratch assay. A chemotaxis assay also demonstrated that dermal fibroblasts migrate towards bone marrow-derived mesenchymal stem cells. A PCR array was used to analyze the effect of mesenchymal stem cells on dermal fibroblast gene expression. In response to mesenchymal stem cells, dermal fibroblasts up-regulate integrin alpha 7 expression and down-regulate expression of ICAM1, VCAM1 and MMP11. These observations suggest that mesenchymal stem cells may provide an important early signal for dermal fibroblast responses to cutaneous injury. PMID:19666021

Vγ9Vδ2 T cells and zoledronate mediate antitumor activity in an orthotopic mouse model of human chondrosarcoma.

PubMed

Sun, L; Li, Y; Jiang, Z; Zhang, J; Li, H; Li, B; Ye, Z

2016-06-01

Chondrosarcoma (CS) is a cartilaginous malignant neoplasm characterized by resistance to conventional adjuvant therapy. The prognosis of unresectable or metastatic CS is poor. Therefore, it is imperative to explore novel therapeutic approaches to improve the treatment efficacy for those CS patients. Emerging data has implicated the synergistic antitumor activity of zoledronate (ZOL) and Vγ9Vδ2 T cells. However, whether ZOL-stimulated Vγ9Vδ2 T cells could infiltrate bone sarcoma and inhibit tumor growth has not been thoroughly answered yet. In this study, Vγ9Vδ2 T cells from healthy donors and CS patients were expanded in the presence of ZOL (1 μM) and IL-2 (400 IU/ml). The antitumor activity of Vγ9Vδ2 T cells to ZOL-pretreated human CS was examined both in vitro and in vivo. ZOL pretreatment substantially enhanced the cytotoxicity of Vγ9Vδ2 T cells to SW1353 and primary CS cells. ZOL potentiated the migration and cytotoxicity of Vγ9Vδ2 T cells to SW1353 in dose- and time-dependent manner. Moreover, weekly intravenous ZOL followed by Vγ9Vδ2 T cells inhibited subcutaneous xenograft growth. Thus, Vγ9Vδ2 T cells were able to infiltrate bone tumor and significantly suppressed the development of orthotopic SW1353 xenografts. Altogether, the study raises the possibility of combining ZOL with Vγ9Vδ2 T cells for CS treatment.

Spot-Scanning Proton Radiation Therapy for Pediatric Chordoma and Chondrosarcoma: Clinical Outcome of 26 Patients Treated at Paul Scherrer Institute

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rombi, Barbara; ATreP; Ares, Carmen, E-mail: carmen.ares@psi.ch

Purpose: To evaluate the clinical results of fractionated spot-scanning proton radiation therapy (PT) in 26 pediatric patients treated at Paul Scherrer Institute for chordoma (CH) or chondrosarcoma (CS) of the skull base or axial skeleton. Methods and Materials: Between June 2000 and June 2010, 19 CH and 7 CS patients with tumors originating from the skull base (17) and the axial skeleton (9) were treated with PT. Mean age at the time of PT was 13.2 years. The mean prescribed dose was 74 Gy (relative biological effectiveness [RBE]) for CH and 66 Gy (RBE) for CS, at a dose ofmore » 1.8-2.0 Gy (RBE) per fraction. Results: Mean follow-up was 46 months. Actuarial 5-year local control (LC) rates were 81% for CH and 80% for CS. Actuarial 5-year overall survival (OS) was 89% for CH and 75% for CS. Two CH patients had local failures: one is alive with evidence of disease, while the other patient succumbed to local recurrence in the surgical pathway. One CS patient died of local progression of the disease. No high-grade late toxicities were observed. Conclusions: Spot-scanning PT for pediatric CH and CS patients resulted in excellent clinical outcomes with acceptable rates of late toxicity. Longer follow-up time and larger cohort are needed to fully assess tumor control and late effects of treatment.« less

Mesenchymal Progenitors Residing Close to the Bone Surface Are Functionally Distinct from Those in the Central Bone Marrow

PubMed Central

Siclari, Valerie A.; Zhu, Ji; Akiyama, Kentaro; Liu, Fei; Zhang, Xianrong; Chandra, Abhishek; Nah-Cederquist, Hyun-Duck; Shi, Songtao; Qin, Ling

2013-01-01

Long bone is an anatomically complicated tissue with trabecular-rich metaphyses at two ends and cortical-rich diaphysis at the center. The traditional flushing method only isolates mesenchymal progenitor cells from the central region of long bones and these cells are distant from the bone surface. We propose that mesenchymal progenitors residing in endosteal bone marrow that is close to the sites of bone formation, such as trabecular bone and endosteum, behave differently from those in the central bone marrow. In this report, we separately isolated endosteal bone marrow using a unique enzymatic digestion approach and demonstrated that it contained a much higher frequency of mesenchymal progenitors than the central bone marrow. Endosteal mesenchymal progenitors express traditional mesenchymal stem cell markers and are capable of multi-lineage differentiation. However, we found that mesenchymal progenitors isolated from different anatomical regions of the marrow did exhibit important functional differences. Compared to their central marrow counterparts, endosteal mesenchymal progenitors have superior proliferative ability with reduced expression of cell cycle inhibitors. They showed greater immunosuppressive activity in culture and in a mouse model of inflammatory bowel disease. Aging is a major contributing factor for trabecular bone loss. We found that old mice have a dramatically decreased number of endosteal mesenchymal progenitors compared to young mice. Parathyroid hormone (PTH) treatment potently stimulates bone formation. A single PTH injection greatly increased the number of endosteal mesenchymal progenitors, particularly those located at the metaphyseal bone, but had no effect on their central counterparts. In summary, endosteal mesenchymal progenitors are more metabolically active and relevant to physiological bone formation than central mesenchymal progenitors. Hence, they represent a biologically important target for future mesenchymal stem cell studies. PMID:23274348

Long noncoding RNAs related to the odontogenic potential of dental mesenchymal cells in mice.

PubMed

Zheng, Yunfei; Jia, Lingfei

2016-07-01

The purpose of this study is to identify the lncRNAs that are associated with the odontogenic potential in mouse dental mesenchymal cells. The odontogenic potential of dental mesenchymal cells was found to be lost in the course of in vitro culture, so the lncRNA profiles were subsequently compared between freshly-isolated and cultured dental mesenchymal cells using RNA-sequencing. A co-expression analysis of differentially expressed lncRNAs and coding RNAs was performed to understand their potential functions. The expression of several selected lncRNAs was also examined in developing tooth germs. Compared with cultured dental mesenchymal cells, 108 lncRNAs were upregulated and 36 lncRNAs were downregulated in freshly-isolated dental mesenchymal cells. Coding genes correlated with the lncRNAs were mainly associated with DNA and protein metabolic processes and cytoskeletal anchorage. Meg3, Malat1, Xist, and Dlx1as were significantly downregulated in cultured dental mesenchymal cells but were upregulated in odontogenic dental mesenchymal tissues. Moreover, the levels of Dlx1as were negatively correlated with that of Dlx1 in dental mesenchymal cells and dental mesenchymal tissues. The lncRNA profiles of dental mesenchymal cells are significantly changed during culturing, and the dysregulation of lncRNAs is associated with the loss of odontogenic potential. Copyright © 2016. Published by Elsevier Ltd.

Monolayered mesenchymal stem cells repair scarred myocardium after myocardial infarction.

PubMed

Miyahara, Yoshinori; Nagaya, Noritoshi; Kataoka, Masaharu; Yanagawa, Bobby; Tanaka, Koichi; Hao, Hiroyuki; Ishino, Kozo; Ishida, Hideyuki; Shimizu, Tatsuya; Kangawa, Kenji; Sano, Shunji; Okano, Teruo; Kitamura, Soichiro; Mori, Hidezo

2006-04-01

Mesenchymal stem cells are multipotent cells that can differentiate into cardiomyocytes and vascular endothelial cells. Here we show, using cell sheet technology, that monolayered mesenchymal stem cells have multipotent and self-propagating properties after transplantation into infarcted rat hearts. We cultured adipose tissue-derived mesenchymal stem cells characterized by flow cytometry using temperature-responsive culture dishes. Four weeks after coronary ligation, we transplanted the monolayered mesenchymal stem cells onto the scarred myocardium. After transplantation, the engrafted sheet gradually grew to form a thick stratum that included newly formed vessels, undifferentiated cells and few cardiomyocytes. The mesenchymal stem cell sheet also acted through paracrine pathways to trigger angiogenesis. Unlike a fibroblast cell sheet, the monolayered mesenchymal stem cells reversed wall thinning in the scar area and improved cardiac function in rats with myocardial infarction. Thus, transplantation of monolayered mesenchymal stem cells may be a new therapeutic strategy for cardiac tissue regeneration.

Mesenchymal stem cells induce dermal fibroblast responses to injury

DOE Office of Scientific and Technical Information (OSTI.GOV)

Smith, Andria N., E-mail: snosmith@u.washington.edu; Willis, Elise, E-mail: elise.willis@gmail.com; Chan, Vincent T.

2010-01-01

Although bone marrow-derived mesenchymal stem cells have been shown to promote repair when applied to cutaneous wounds, the mechanism for this response remains to be determined. The aim of this study was to determine the effects of paracrine signaling from mesenchymal stem cells on dermal fibroblast responses to injury including proliferation, migration and expression of genes important in wound repair. Dermal fibroblasts were co-cultured with bone marrow-derived mesenchymal stem cells grown in inserts, which allowed for paracrine interactions without direct cell contact. In this co-culture model, bone marrow-derived mesenchymal stem cells regulate dermal fibroblast proliferation, migration and gene expression. Whenmore » co-cultured with mesenchymal stem cells, dermal fibroblasts show increased proliferation and accelerated migration in a scratch assay. A chemotaxis assay also demonstrated that dermal fibroblasts migrate towards bone marrow-derived mesenchymal stem cells. A PCR array was used to analyze the effect of mesenchymal stem cells on dermal fibroblast gene expression. In response to mesenchymal stem cells, dermal fibroblasts up-regulate integrin alpha 7 expression and down-regulate expression of ICAM1, VCAM1 and MMP11. These observations suggest that mesenchymal stem cells may provide an important early signal for dermal fibroblast responses to cutaneous injury.« less

Epithelial-to-mesenchymal transition in penile squamous cell carcinoma.

PubMed

Masferrer, Emili; Ferrándiz-Pulido, Carla; Masferrer-Niubò, Magalí; Rodríguez-Rodríguez, Alfredo; Gil, Inmaculada; Pont, Antoni; Servitje, Octavi; García de Herreros, Antonio; Lloveras, Belen; García-Patos, Vicenç; Pujol, Ramon M; Toll, Agustí; Hernández-Muñoz, Inmaculada

2015-02-01

Epithelial-to-mesenchymal transition is a phenomenon in epithelial tumors that involves loss of intercellular adhesion, mesenchymal phenotype acquisition and enhanced migratory potential. While the epithelial-to-mesenchymal transition process has been extensively linked to metastatic progression of squamous cell carcinoma, studies of the role of epithelial-to-mesenchymal transition in squamous cell carcinoma containing high risk human papillomaviruses are scarce. Moreover, to our knowledge epithelial-to-mesenchymal transition involvement in human penile squamous cell carcinoma, which can arise through transforming HPV infections or independently of HPV, has not been investigated. We evaluated the presence of epithelial-to-mesenchymal transition markers and their relationship to HPV in penile squamous cell carcinoma. We assessed the expression of E-cadherin, vimentin and the epithelial-to-mesenchymal transition related transcription factors Twist, Zeb1 and Snail by immunohistochemical staining in 64 penile squamous cell carcinoma cases. HPV was detected by polymerase chain reaction amplification. Simultaneous loss of membranous E-cadherin expression and vimentin over expression were noted in 43.5% of penile squamous cell carcinoma cases. HPV was significantly associated with loss of membranous E-cadherin but not with epithelial-to-mesenchymal transition. Recurrence and mortality rates were significantly higher in cases showing epithelial-to-mesenchymal transition. Our findings indicate that in penile squamous cell carcinoma epithelial-to-mesenchymal transition is associated with poor prognosis but not with the presence of HPV. Copyright © 2015 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

Multiple intracranial calcifications and spinal compressions: rare complications of type la pseudohypoparathyroidism.

PubMed

Chen, H; Tseng, F; Su, D; Chen, H; Tsai, K

2005-01-01

Type la pseudohypoparathyroidism (PHP la) is an unusual inherited disease. PHP la often causes extraskeletal calcifications and even soft tissue ossifications. Patients may present neurologic symptoms and signs related to hypocalcemia and hyperphosphatemia. We report here a 38-yr-old woman with PHP la who had two uncommon neurologic complications. One was involuntary movements related to basal ganglia calcification, and the other was myelopathy owing to ossifications of the posterior longitudinal ligament and multiple herniated intervertebral disks. Aggressive body weight control and corrections of hypocalcemia, hyperphosphatemia, and elevated PTH may be important to prevent these unusual neurologic complications. Regular and careful neurologic examinations should be performed for early diagnosis and treatments of these spinal lesions.

Primary Pulmonary Ewing's Sarcoma/Primitive Neuroectodermal Tumor in a 67-year-old Man

PubMed Central

Lee, Yoon Young; Kim, Do Hoon; Lee, Ji Hye; Choi, Jong Sang; In, Kwang Ho; Oh, Yu Whan; Cho, Kyung Hwan

2007-01-01

Extraskeletal Ewing's sarcoma (EES) is a branch of neuroectodermal tumor (PNET), which is very rare soft tissue sarcoma. We report a case of EES/PNET arising is the lung of a 67-yr-old man. Computed tomography, bone scintigraphy, and positron emission tomography confirmed the mass to have a primary pulmonary origin. The mass showed positive reactivity in the Periodic Acid Schiff (PAS) stain and MIC-2 immunoreactivity in immunohistochemical stain. Fluorescence in situ hybridization (FISH) was performed, which revealed an EWSR1 (Ewing sarcoma breakpoint region 1) 22q12 rearrangement. The diagnosis was confirmed both pathologically and genetically. The mass lesion was resected, and the patient is currently undergoing chemotherapy. PMID:17923745

[Intraocular osteosarcoma in a dog].

PubMed

Wiesner, L; Schröder, S; Gralla, S; Goeck, D; Kramer, M; Ondreka, N

2014-01-01

The present case describes the diagnostic and therapeutic procedure of a dog with an intraocular osteosarcoma. According to the results of the diagnostic imaging studies, the tentative diagnosis of an intraocular neoplasm with perforation of the globe and orbital invasion of the tumour was made and an orbital exenteration was performed. The histopathological diagnosis of the extracted organ implied an intraocular, extraskeletal osteosarcoma. Seventy-seven days later the patient displayed an acute paraparesis. Clinical and diagnostic reevaluation using magnetic resonance imaging (MRI) was performed and the dog was euthanized at the owner's request. By means of MRI and necropsy, an additional axial osteosarcoma of the 6th lumbar vertebra and a malignant melanoma of the right tonsil were diagnosed.

PHD-2 Suppression in Mesenchymal Stromal Cells Enhances Wound Healing.

PubMed

Ko, Sae Hee; Nauta, Allison C; Morrison, Shane D; Hu, Michael S; Zimmermann, Andrew S; Chung, Michael T; Glotzbach, Jason P; Wong, Victor W; Walmsley, Graham G; Peter Lorenz, H; Chan, Denise A; Gurtner, Geoffrey C; Giaccia, Amato J; Longaker, Michael T

2018-01-01

Cell therapy with mesenchymal stromal cells is a promising strategy for tissue repair. Restoration of blood flow to ischemic tissues is a key step in wound repair, and mesenchymal stromal cells have been shown to be proangiogenic. Angiogenesis is critically regulated by the hypoxia-inducible factor (HIF) superfamily, consisting of transcription factors targeted for degradation by prolyl hydroxylase domain (PHD)-2. The aim of this study was to enhance the proangiogenic capability of mesenchymal stromal cells and to use these modified cells to promote wound healing. Mesenchymal stromal cells harvested from mouse bone marrow were transduced with short hairpin RNA (shRNA) against PHD-2; control cells were transduced with scrambled shRNA (shScramble) construct. Gene expression quantification, human umbilical vein endothelial cell tube formation assays, and wound healing assays were used to assess the effect of PHD knockdown mesenchymal stromal cells on wound healing dynamics. PHD-2 knockdown mesenchymal stromal cells overexpressed HIF-1α and multiple angiogenic factors compared to control (p < 0.05). Human umbilical vein endothelial cells treated with conditioned medium from PHD-2 knockdown mesenchymal stromal cells exhibited increased formation of capillary-like structures and enhanced migration compared with human umbilical vein endothelial cells treated with conditioned medium from shScramble-transduced mesenchymal stromal cells (p < 0.05). Wounds treated with PHD-2 knockdown mesenchymal stromal cells healed at a significantly accelerated rate compared with wounds treated with shScramble mesenchymal stromal cells (p < 0.05). Histologic studies revealed increased blood vessel density and increased cellularity in the wounds treated with PHD-2 knockdown mesenchymal stromal cells (p < 0.05). Silencing PHD-2 in mesenchymal stromal cells augments their proangiogenic potential in wound healing therapy. This effect appears to be mediated by overexpression of HIF family transcription factors and up-regulation of multiple downstream angiogenic factors.

IL-17B activated mesenchymal stem cells enhance proliferation and migration of gastric cancer cells.

PubMed

Bie, Qingli; Zhang, Bin; Sun, Caixia; Ji, Xiaoyun; Barnie, Prince Amoah; Qi, Chen; Peng, Jingjing; Zhang, Danyi; Zheng, Dong; Su, Zhaoliang; Wang, Shengjun; Xu, Huaxi

2017-03-21

Mesenchymal stem cells are important cells in tumor microenvironment. We have previously demonstrated that IL-17B/IL-17RB signal promoted progression of gastric cancer. In this study, we further explored the effect of IL-17B on mesenchymal stem cells in tumor microenvironment and its impact on the tumor progression. The results showed that IL-17B induced the expression of stemness-related genes Nanog, Sox2, and Oct4 in mesenchymal stem cells and enhanced its tumor-promoting effect. The supernatant from cultured mesenchymal stem cells after treating with exogenous rIL-17B promoted the proliferation and migration of MGC-803, therefor suggesting that rIL-17B might promote mesenchymal stem cells to produce soluble factors. In addition, rIL-17B also activated the NF-κΒ, STAT3, β-catenin pathway in mesenchymal stem cells. Our data revealed a new mechanism that IL-17B enhanced the progression of gastric cancer by activating mesenchymal stem cells.

Proliferation of Peripheral Blood Lymphocytes and Mesenchymal Stromal Cells Derived from Wharton's Jelly in Mixed and Membrane-Separated Cultures.

PubMed

Poltavtsev, A M; Poltavtseva, R A; Yushina, M N; Pavlovich, S V; Svirshchevskaya, E V

2017-08-01

We studied the effect of mesenchymal stromal cells on proliferation of CFSE-stained T cells in mixed and membrane-separated (Transwell) cultures and in 3D culture of mesenchymal stromal cells from Wharton's jelly. The interaction of mesenchymal stromal cells with mitogen-activated peripheral blood lymphocytes from an allogeneic donor was followed by suppression of T-cell proliferation in a wide range of cell proportions. Culturing in the Transwell system showed the absence of suppression assessed by the fraction of proliferating cells and by the cell cycle analysis. In 3D cultures, contact interaction of mesenchymal stromal cells and lymphocytes was demonstrated that led to accumulation of G2/M phase lymphocytes and G0/G1 phase mesenchymal stromal cells. The suppressive effect of mesenchymal stromal cells from Wharton's jelly is mediated by two mechanisms. The effects are realized within 6 days, which suggests that the therapeutic effects of mesenchymal stromal cells persist until their complete elimination from the body.

An unusual case of lumbar paravertebral miositis ossificans mimicking muscular skeletal tumor.

PubMed

Zoccali, C; Chichierchia, G; Covello, R

2013-12-01

Several lesions have clinical and radiological characteristics mimicking muscular skeletal tumor. Myositis ossificans usually presents a typical pattern making biopsy unnecessary; nevertheless, in rare cases, neoplasm must be ruled out. Biopsy is often sufficient to allow a diagnosis and a correct related treatment, but, unfortunately, sometimes it may lead to erroneous treatment. We report an unusual case of a lumbar paravertebral mass that had an MRI aspect similar to a chondrosarcoma, a histology pattern based on biopsy compatible with neurinoma and a definitive diagnosis of myosistis ossificans.

Cytology of Bone.

PubMed

Barger, Anne M

2017-01-01

Cytology of bone is a useful diagnostic tool. Aspiration of lytic or proliferative lesions can assist with the diagnosis of inflammatory or neoplastic processes. Bacterial, fungal, and protozoal organisms can result in significant osteomyelitis, and these organisms can be identified on cytology. Neoplasms of bone including primary bone tumors such as osteosarcoma, chondrosarcoma, fibrosarcoma, synovial cell sarcoma, and histiocytic sarcoma and tumors of bone marrow including plasma cell neoplasia and lymphoma and metastatic neoplasia can result in significant bone lysis or proliferation and can be diagnosed effectively with cytology. Copyright © 2016 Elsevier Inc. All rights reserved.

Mesenchymal Stem Cells From Bone Marrow, Adipose Tissue, and Lung Tissue Differentially Mitigate Lung and Distal Organ Damage in Experimental Acute Respiratory Distress Syndrome.

PubMed

Silva, Johnatas D; Lopes-Pacheco, Miquéias; Paz, Ana H R; Cruz, Fernanda F; Melo, Elga B; de Oliveira, Milena V; Xisto, Débora G; Capelozzi, Vera L; Morales, Marcelo M; Pelosi, Paolo; Cirne-Lima, Elizabeth; Rocco, Patricia R M

2018-02-01

Mesenchymal stem cells-based therapies have shown promising effects in experimental acute respiratory distress syndrome. Different mesenchymal stem cells sources may result in diverse effects in respiratory diseases; however, there is no information regarding the best source of mesenchymal stem cells to treat pulmonary acute respiratory distress syndrome. We tested the hypothesis that mesenchymal stem cells derived from bone marrow, adipose tissue, and lung tissue would lead to different beneficial effects on lung and distal organ damage in experimental pulmonary acute respiratory distress syndrome. Animal study and primary cell culture. Laboratory investigation. Seventy-five Wistar rats. Wistar rats received saline (control) or Escherichia coli lipopolysaccharide (acute respiratory distress syndrome) intratracheally. On day 2, acute respiratory distress syndrome animals were further randomized to receive saline or bone marrow, adipose tissue, or lung tissue mesenchymal stem cells (1 × 10 cells) IV. Lung mechanics, histology, and protein levels of inflammatory mediators and growth factors were analyzed 5 days after mesenchymal stem cells administration. RAW 264.7 cells (a macrophage cell line) were incubated with lipopolysaccharide followed by coculture or not with bone marrow, adipose tissue, and lung tissue mesenchymal stem cells (10 cells/mL medium). Regardless of mesenchymal stem cells source, cells administration improved lung function and reduced alveolar collapse, tissue cellularity, collagen, and elastic fiber content in lung tissue, as well as decreased apoptotic cell counts in liver. Bone marrow and adipose tissue mesenchymal stem cells administration also reduced levels of tumor necrosis factor-α, interleukin-1β, keratinocyte-derived chemokine, transforming growth factor-β, and vascular endothelial growth factor, as well as apoptotic cell counts in lung and kidney, while increasing expression of keratinocyte growth factor in lung tissue. Additionally, mesenchymal stem cells differently modulated the secretion of biomarkers by macrophages depending on their source. Mesenchymal stem cells from different sources led to variable responses in lungs and distal organs. Bone marrow and adipose tissue mesenchymal stem cells yielded greater beneficial effects than lung tissue mesenchymal stem cells. These findings may be regarded as promising in clinical trials.

Cryopreserved, Xeno-Free Human Umbilical Cord Mesenchymal Stromal Cells Reduce Lung Injury Severity and Bacterial Burden in Rodent Escherichia coli-Induced Acute Respiratory Distress Syndrome.

PubMed

Curley, Gerard F; Jerkic, Mirjana; Dixon, Steve; Hogan, Grace; Masterson, Claire; O'Toole, Daniel; Devaney, James; Laffey, John G

2017-02-01

Although mesenchymal stem/stromal cells represent a promising therapeutic strategy for acute respiratory distress syndrome, clinical translation faces challenges, including scarcity of bone marrow donors, and reliance on bovine serum during mesenchymal stem/stromal cell proliferation. We wished to compare mesenchymal stem/stromal cells from human umbilical cord, grown in xeno-free conditions, with mesenchymal stem/stromal cells from human bone marrow, in a rat model of Escherichia coli pneumonia. In addition, we wished to determine the potential for umbilical cord-mesenchymal stem/stromal cells to reduce E. coli-induced oxidant injury. Randomized animal study. University research laboratory. Male Sprague-Dawley rats. Acute respiratory distress syndrome was induced in rats by intratracheal instillation of E. coli (1.5-2 × 10 CFU/kg). "Series 1" compared the effects of freshly thawed cryopreserved umbilical cord-mesenchymal stem/stromal cells with bone marrow-mesenchymal stem/stromal cells on physiologic indices of lung injury, cellular infiltration, and E. coli colony counts in bronchoalveolar lavage. "Series 2" examined the effects of cryopreserved umbilical cord-mesenchymal stem/stromal cells on survival, as well as measures of injury, inflammation and oxidant stress, including production of reactive oxidative species, reactive oxidative species scavenging by superoxide dismutase-1 and superoxide dismutase-2. In "Series 1," animals subjected to E. coli pneumonia who received umbilical cord-mesenchymal stem/stromal cells had improvements in oxygenation, respiratory static compliance, and wet-to-dry ratios comparable to bone marrow-mesenchymal stem/stromal cell treatment. E. coli colony-forming units in bronchoalveolar lavage were reduced in both cell therapy groups, despite a reduction in bronchoalveolar lavage neutrophils. In series 2, umbilical cord-mesenchymal stem/stromal cells enhanced animal survival and decreased alveolar protein and proinflammatory cytokine concentrations, whereas increasing interleukin-10 concentrations. Umbilical cord-mesenchymal stem/stromal cell therapy decreased nicotinamide adenine dinucleotide phosphate-oxidase 2 and inducible nitric oxide synthase and enhanced lung concentrations of superoxide dismutase-2, thereby reducing lung tissue reactive oxidative species concentrations. Our results demonstrate that freshly thawed cryopreserved xeno-free human umbilical cord-mesenchymal stem/stromal cells reduce the severity of rodent E. coli-induced acute respiratory distress syndrome. Umbilical cord-mesenchymal stem/stromal cells, therefore, represent an attractive option for future clinical trials in acute respiratory distress syndrome.

Evolutionary modification of mesenchyme cells in sand dollars in the transition from indirect to direct development.

PubMed

Yajima, Mamiko

2007-01-01

Peronella japonica, an intermediate type of direct-developing sand dollar, forms an abbreviated pluteus, followed by metamorphosis within 3 days without feeding. In this species, ingression of mesenchyme cells starts before hatching and continues until gastrulation, but no typical secondary mesenchyme cells (SMCs) migrate from the tip of the archenteron. Here, I investigated the cell lineage of mesenchyme cells through metamorphosis in P. japonica and found that mesenchyme cells migrating before hatching (early mesenchyme cells [EMCs]) were exclusively derived from micromeres and became larval skeletogenic cells, whereas cells migrating after hatching (late mesenchyme cells [LMCs]) appeared to contain several nonskeletogenic cells. Thus, it is likely that EMCs are homologous to primary mesenchyme cells (PMCs) and LMCs are similar to the SMCs of typical indirect developers, suggesting that heterochrony in the timing of mesenchyme cell ingression may have occurred in this species. EMCs disappeared after metamorphosis and LMCs were involved in adult skeletogenesis. Embryos from which micromeres were removed at the 16-cell stage formed armless plutei that went on to form adult skeletons and resulted in juveniles with normal morphology. These results suggest that in P. japonica, LMCs form adult skeletal elements, whereas EMCs are specialized for larval spicule formation. The occurrence of evolutionary modifications in mesenchyme cells in the transition from indirect to direct development of sand dollars is discussed.

Endodermal Hedgehog signals modulate Notch pathway activity in the developing digestive tract mesenchyme

PubMed Central

Kim, Tae-Hee; Kim, Byeong-Moo; Mao, Junhao; Rowan, Sheldon; Shivdasani, Ramesh A.

2011-01-01

The digestive tract epithelium and its adjoining mesenchyme undergo coordinated patterning and growth during development. The signals they exchange in the process are not fully characterized but include ligands of the Hedgehog (Hh) family, which originate in the epithelium and are necessary for mesenchymal cells to expand in number and drive elongation of the developing gut tube. The Notch signaling pathway has known requirements in fetal and adult intestinal epithelial progenitors. We detected Notch pathway activity in the embryonic gut mesenchyme and used conditional knockout mice to study its function. Selective disruption of the Notch effector gene RBP-Jκ (Rbpj) in the mesenchyme caused progressive loss of subepithelial fibroblasts and abbreviated gut length, revealing an unexpected requirement in this compartment. Surprisingly, constitutive Notch activity also induced rapid mesenchymal cell loss and impaired organogenesis, probably resulting from increased cell death and suggesting the need for a delicate balance in Notch signaling. Because digestive tract anomalies in mouse embryos with excess Notch activity phenocopy the absence of Hh signaling, we postulated that endodermal Hh restrains mesenchymal Notch pathway activity. Indeed, Hh-deficient embryos showed Notch overactivity in their defective gut mesenchyme and exposure to recombinant sonic hedgehog could override Notch-induced death of cultured fetal gut mesenchymal cells. These results reveal unexpected interactions between prominent signals in gastrointestinal development and provide a coherent explanation for Hh requirements in mesenchymal cell survival and organ growth. PMID:21750033

Three cell recognition changes accompany the ingression of sea urchin primary mesenchyme cells.

PubMed

Fink, R D; McClay, D R

1985-01-01

At gastrulation the primary mesenchyme cells of sea urchin embryos lose contact with the extracellular hyaline layer and with neighboring blastomeres as they pass through the basal lamina and enter the blastocoel. This delamination process was examined using a cell-binding assay to follow changes in affinities between mesenchyme cells and their three substrates: hyalin, early gastrula cells, and basal lamina. Sixteen-cell-stage micromeres (the precursors of primary mesenchyme cells), and mesenchyme cells obtained from mesenchyme-blastula-stage embryos were used in conjunction with micromeres raised in culture to intermediate ages. The micromeres exhibited an affinity for hyalin, but the affinity was lost at the time of mesenchyme ingression in vivo. Similarly, micromeres had an affinity for monolayers of gastrula cells but the older mesenchyme cells lost much of their cell-to-cell affinity. Presumptive ectoderm and endoderm cells tested against the gastrula monolayers showed no decrease in binding over the same time interval. When micromeres and primary mesenchyme cells were tested against basal lamina preparations, there was an increase in affinity that was associated with developmental time. Presumptive ectoderm and endoderm cells showed no change in affinity over the same interval. Binding measurements using isolated basal laminar components identified fibronectin as one molecule for which the wandering primary mesenchyme cells acquired a specific affinity. The data indicate that as the presumptive mesenchyme cells leave the vegetal plate of the embryo they lose affinities for hyalin and for neighboring cells, and gain an affinity for fibronectin associated with the basal lamina and extracellular matrix that lines the blastocoel.

Mesenchymal stem cells for acute lung injury: Preclinical evidence

PubMed Central

Matthay, Michael A.; Goolaerts, Arnaud; Howard, James P.; Lee, Jae Woo

2013-01-01

Several experimental studies have suggested that mesenchymal stem cells may have value for the treatment of clinical disorders, including myocardial infarction, diabetes, acute renal failure, sepsis, and acute lung injury. In preclinical studies, mesenchymal stem cells have been effective in reducing lung injury from endotoxin, live bacteria, bleomycin, and hyperoxia. In some studies, the cultured medium from mesenchymal stem cells has been as effective as the mesenchymal stem cells themselves. Several paracrine mediators that can mediate the effect of mesenchymal stem cells have been identified, including interleukin-10, interleukin-1ra, keratinocyte growth factor, and prostaglandin E2. Further preclinical studies are needed, as is planning for clinical trials for acute lung injury. PMID:21164399

Mesenchymal progenitor cells for the osteogenic lineage.

PubMed

Ono, Noriaki; Kronenberg, Henry M

2015-09-01

Mesenchymal progenitors of the osteogenic lineage provide the flexibility for bone to grow, maintain its function and homeostasis. Traditionally, colony-forming-unit fibroblasts (CFU-Fs) have been regarded as surrogates for mesenchymal progenitors; however, this definition cannot address the function of these progenitors in their native setting. Transgenic murine models including lineage-tracing technologies based on the cre-lox system have proven to be useful in delineating mesenchymal progenitors in their native environment. Although heterogeneity of cell populations of interest marked by a promoter-based approach complicates overall interpretation, an emerging complexity of mesenchymal progenitors has been revealed. Current literatures suggest two distinct types of bone progenitor cells; growth-associated mesenchymal progenitors contribute to explosive growth of bone in early life, whereas bone marrow mesenchymal progenitors contribute to the much slower remodeling process and response to injury that occurs mainly in adulthood. More detailed relationships of these progenitors need to be studied through further experimentation.

Co-Culturing of Multipotent Mesenchymal Stromal Cells with Autological and Allogenic Lymphocytes.

PubMed

Kapranov, N M; Davydova, Yu O; Gal'tseva, I V; Petinati, N A; Bakshinskaitė, M V; Drize, N I; Kuz'mina, L A; Parovichnikova, E N; Savchenko, V G

2018-03-01

We studied the effect of autologous and allogeneic lymphocytes on multipotent mesenchymal stromal cells in co-culture. It is shown that changes in multipotent mesenchymal stromal cells and in lymphocytes did not depend on the source of lymphocytes. Contact with lymphocytes triggers expression of HLA-DR molecules on multipotent mesenchymal stromal cells and these cells lose their immune privilege. In multipotent mesenchymal stromal cells, the relative level of expression of factors involved in immunomodulation (IDO1, PTGES, and IL-6) and expression of adhesion molecule ICAM1 increased, while expression of genes involved in the differentiation of multipotent mesenchymal stromal cells remained unchanged. Priming of multipotent mesenchymal stromal cells with IFN did not affect these changes. In turn, lymphocytes underwent activation, expression of HLA-DR increased, subpopulation composition of lymphocytes changed towards the increase in the content of naïve T cells. These findings are important for cell therapy.

Activation of NK Cells in Mixed Cultures of Wharton's Jelly Mesenchymal Stromal Cells and Peripheral Blood Lymphocytes.

PubMed

Svirshchevskaya, E V; Poltavtsev, A M; Os'mak, G Zh; Poltavtseva, R A

2018-01-01

Mesenchymal stromal cells possess immunosuppressive properties that might be used for the therapy of inflammatory diseases of various geneses. The effects of mesenchymal stromal cells depend on their lifetime in the recipient tissues. During heterologous transplantation, mesenchymal stromal cells are eliminated by NK cells. We studied NK cell formation in mixed cultures of Wharton's jelly mesenchymal stromal cells and peripheral blood lymphocytes from an autologous donor. Lymphocytes were activated by a mitogen or IL-2. The lifetime of mesenchymal stromal cells was estimated by MTT test. Cytotoxic activity and phenotype of NK cells were evaluated by flow cytometry. It was found that activation of NK cells depended on IL-2 and was registered on day 2 of incubation with IL-2. In cultures with mitogen-activated lymphocytes, cytotoxicity was observed after 5-6 days. Cytotoxicity of NK correlated with significant decrease in CD16+ and increase in CD56+ NK and with reduction of mesenchymal stromal cell viability. Thus, the main mechanism of elimination of mesenchymal stromal cells is cytotoxicity of NK cells that depended on IL-2 production.

Exosomes derived from mesenchymal non-small cell lung cancer cells promote chemoresistance.

PubMed

Lobb, Richard J; van Amerongen, Rosa; Wiegmans, Adrian; Ham, Sunyoung; Larsen, Jill E; Möller, Andreas

2017-08-01

Non-small cell lung cancer (NSCLC) is the most common lung cancer type and the most common cause of mortality in lung cancer patients. NSCLC is often associated with resistance to chemotherapeutics and together with rapid metastatic spread, results in limited treatment options and poor patient survival. NSCLCs are heterogeneous, and consist of epithelial and mesenchymal NSCLC cells. Mesenchymal NSCLC cells are thought to be responsible for the chemoresistance phenotype, but if and how this phenotype can be transferred to other NSCLC cells is currently not known. We hypothesised that small extracellular vesicles, exosomes, secreted by mesenchymal NSCLC cells could potentially transfer the chemoresistance phenotype to surrounding epithelial NSCLC cells. To explore this possibility, we used a unique human bronchial epithelial cell (HBEC) model in which the parental cells were transformed from an epithelial to mesenchymal phenotype by introducing oncogenic alterations common in NSCLC. We found that exosomes derived from the oncogenically transformed, mesenchymal HBECs could transfer chemoresistance to the parental, epithelial HBECs and increase ZEB1 mRNA, a master EMT transcription factor, in the recipient cells. Additionally, we demonstrate that exosomes from mesenchymal, but not epithelial HBECs contain the ZEB1 mRNA, thereby providing a potential mechanism for the induction of a mesenchymal phenotype in recipient cells. Together, this work demonstrates for the first time that exosomes derived from mesenchymal, oncogenically transformed lung cells can transfer chemoresistance and mesenchymal phenotypes to recipient cells, likely via the transfer of ZEB1 mRNA in exosomes. © 2017 UICC.

Integrin-β4 identifies cancer stem cell-enriched populations of partially mesenchymal carcinoma cells

PubMed Central

Bierie, Brian; Pierce, Sarah E.; Kroeger, Cornelia; Stover, Daniel G.; Pattabiraman, Diwakar R.; Thiru, Prathapan; Liu Donaher, Joana; Reinhardt, Ferenc; Chaffer, Christine L.; Keckesova, Zuzana; Weinberg, Robert A.

2017-01-01

Neoplastic cells within individual carcinomas often exhibit considerable phenotypic heterogeneity in their epithelial versus mesenchymal-like cell states. Because carcinoma cells with mesenchymal features are often more resistant to therapy and may serve as a source of relapse, we sought to determine whether such cells could be further stratified into functionally distinct subtypes. Indeed, we find that a basal epithelial marker, integrin-β4 (ITGB4), can be used to enable stratification of mesenchymal-like triple-negative breast cancer (TNBC) cells that differ from one another in their relative tumorigenic abilities. Notably, we demonstrate that ITGB4+ cancer stem cell (CSC)-enriched mesenchymal cells reside in an intermediate epithelial/mesenchymal phenotypic state. Among patients with TNBC who received chemotherapy, elevated ITGB4 expression was associated with a worse 5-year probability of relapse-free survival. Mechanistically, we find that the ZEB1 (zinc finger E-box binding homeobox 1) transcription factor activity in highly mesenchymal SUM159 TNBC cells can repress expression of the epithelial transcription factor TAp63α (tumor protein 63 isoform 1), a protein that promotes ITGB4 expression. In addition, we demonstrate that ZEB1 and ITGB4 are important in modulating the histopathological phenotypes of tumors derived from mesenchymal TNBC cells. Hence, mesenchymal carcinoma cell populations are internally heterogeneous, and ITGB4 is a mechanistically driven prognostic biomarker that can be used to identify the more aggressive subtypes of mesenchymal carcinoma cells in TNBC. The ability to rapidly isolate and mechanistically interrogate the CSC-enriched, partially mesenchymal carcinoma cells should further enable identification of novel therapeutic opportunities to improve the prognosis for high-risk patients with TNBC. PMID:28270621

Tracking and Functional Characterization of Epithelial-Mesenchymal Transition and Mesenchymal Tumor Cells During Prostate Cancer Metastasis

PubMed Central

Ruscetti, Marcus; Quach, Bill; Dadashian, Eman L.; Mulholland, David J.; Wu, Hong

2015-01-01

The epithelial-mesenchymal transition (EMT) has been postulated as a mechanism by which cancer cells acquire the invasive and stem-like traits necessary for distant metastasis. However, direct in vivo evidence for the role of EMT in the formation of cancer stem-like cells (CSC) and the metastatic cascade remains lacking. Here we report the first isolation and characterization of mesenchymal and EMT tumor cells, which harbor both epithelial and mesenchymal characteristics, in an autochthonous murine model of prostate cancer. By crossing the established Pb-Cre+/−;PtenL/L;KrasG12D/+ prostate cancer model with a vimentin-GFP reporter strain, generating CPKV mice, we were able to isolate epithelial, EMT and mesenchymal cancer cells based on expression of vimentin and EpCAM. CPKV mice (but not mice with Pten deletion alone) exhibited expansion of cells with EMT (EpCAM+/Vim-GFP+) and mesenchymal (EpCAM−/Vim-GFP+) characteristics at the primary tumor site and in circulation. These EMT and mesenchymal tumor cells displayed enhanced stemness and invasive character compared to epithelial tumor cells. Moreover, they displayed an enriched tumor-initiating capacity and could regenerate epithelial glandular structures in vivo, indicative of epithelia-mesenchyme plasticity. Interestingly, while mesenchymal tumor cells could persist in circulation and survive in the lung following intravenous injection, only epithelial and EMT tumor cells could form macrometastases. Our work extends the evidence that mesenchymal and epithelial states in cancer cells contribute differentially to their capacities for tumor initiation and metastatic seeding, respectively, and that EMT tumor cells exist with plasticity that can contribute to multiple stages of the metastatic cascade. PMID:25948589

Metastatic extraskeletal Ewing's sarcoma treated with trabectedin: A case report.

PubMed

Hernando-Cubero, Jorge; Sanz-Moncasi, Pilar; Hernández-García, Alba; Pajares-Bernard, Isabel; Martínez-Trufero, Javier

2016-10-01

The Ewing's sarcoma family of tumors (ESFT) comprises a number of rare malignant tumors. Standard first-line treatment for patients with these tumors includes chemotherapy with a five-drug regimen of vincristine, doxorubicin (Adriamycin ® ) and cyclophosphamide, alternating with ifosfamide and etoposide (VAC/IE). In cases of inadequate response, there are a number of second-line regimens available. However, further treatment options are required for those patients with disease unresponsive to standard treatment. Trabectedin is a novel treatment option for patients with ESFT. The present study reports the case of a Caucasian 69-year-old female patient who presented with a soft tissue mass on the chest wall that had developed 7 months earlier. A computed tomography scan revealed a 9×8×7-cm mass on the anterior chest wall above the pectoral muscle. Histopathological evaluations and molecular analysis indicated that it was consistent with a metastatic extraskeletal Ewing's sarcoma. The patient was treated with an alternating VAC/IE regimen; however, an inadequate response was observed. The patient received second-line treatment with a gemcitabine and dacarbazine combination regimen, but the disease progressed. Subsequently, treatment with trabectedin (1.5 mg/m 2 as a 24-h continuous infusion every 3 weeks) was initiated. Trabectedin treatment resulted in long-lasting (18 months) progression-free survival. It is vital that novel drugs continue to being developed for patients with ESFT following progression subsequent to standard chemotherapy. The current report presents a case of a patient with metastatic, pre-treated Ewing's sarcoma achieving disease stabilization with trabectedin. Based on these results and the observed tolerability profile, trabectedin represents an alternative treatment for patients with ESFT. Further studies are required in order to determine the efficacy of trabectedin as monotherapy or in combination with other drugs. It is also important to identify which tumor subtypes, specific translocations and patient profiles will benefit the most from treatment with trabectedin.

Generation of mesenchymal stromal cells in the presence of platelet lysate: a phenotypic and functional comparison of umbilical cord blood- and bone marrow-derived progenitors

PubMed Central

Avanzini, Maria Antonietta; Bernardo, Maria Ester; Cometa, Angela Maria; Perotti, Cesare; Zaffaroni, Nadia; Novara, Francesca; Visai, Livia; Moretta, Antonia; Del Fante, Claudia; Villa, Raffaella; Ball, Lynne M.; Fibbe, Willem E.; Maccario, Rita; Locatelli, Franco

2009-01-01

Background Mesenchymal stromal cells are employed in various different clinical settings in order to modulate immune response. However, relatively little is known about the mechanisms responsible for their immunomodulatory effects, which could be influenced by both the cell source and culture conditions. Design and Methods We tested the ability of a 5% platelet lysate-supplemented medium to support isolation and ex vivo expansion of mesenchymal stromal cells from full-term umbilical-cord blood. We also investigated the biological/functional properties of umbilical cord blood mesenchymal stromal cells, in comparison with platelet lysate-expanded bone marrow mesenchymal stromal cells. Results The success rate of isolation of mesenchymal stromal cells from umbilical cord blood was in the order of 20%. These cells exhibited typical morphology, immunophenotype and differentiation capacity. Although they have a low clonogenic efficiency, umbilical cord blood mesenchymal stromal cells may possess high proliferative potential. The genetic stability of these cells from umbilical cord blood was demonstrated by a normal molecular karyotype; in addition, these cells do not express hTERT and telomerase activity, do express p16ink4a protein and do not show anchorage-independent cell growth. Concerning alloantigen-specific immune responses, umbilical cord blood mesenchymal stromal cells were able to: (i) suppress T- and NK-lymphocyte proliferation, (ii) decrease cytotoxic activity and (iii) only slightly increase interleukin-10, while decreasing interferon-γ secretion, in mixed lymphocyte culture supernatants. While an indoleamine 2,3-dioxygenase-specific inhibitor did not reverse mesenchymal stromal cell-induced suppressive effects, a prostaglandin E2-specific inhibitor hampered the suppressive effect of both umbilical cord blood- and bone marrow-mesenchymal stromal cells on alloantigen-induced cytotoxic activity. Mesenchymal stromal cells from both sources expressed HLA-G. Conclusions Umbilical cord blood- and bone marrow-mesenchymal stromal cells may differ in terms of clonogenic efficiency, proliferative capacity and immunomodulatory properties; these differences may be relevant for clinical applications. PMID:19773264

Carbon Monoxide Improves Efficacy of Mesenchymal Stromal Cells During Sepsis by Production of Specialized Proresolving Lipid Mediators.

PubMed

Tsoyi, Konstantin; Hall, Sean R R; Dalli, Jesmond; Colas, Romain A; Ghanta, Sailaja; Ith, Bonna; Coronata, Anna; Fredenburgh, Laura E; Baron, Rebecca M; Choi, Augustine M K; Serhan, Charles N; Liu, Xiaoli; Perrella, Mark A

2016-12-01

Mesenchymal stromal cells are being investigated as a cell-based therapy for a number of disease processes, with promising results in animal models of systemic inflammation and sepsis. Studies are ongoing to determine ways to further improve the therapeutic potential of mesenchymal stromal cells. A gas molecule that improves outcome in experimental sepsis is carbon monoxide. We hypothesized that preconditioning of mesenchymal stromal cells with carbon monoxide ex vivo would promote further therapeutic benefit when cells are administered in vivo after the onset of polymicrobial sepsis in mice. Animal study and primary cell culture. Laboratory investigation. BALB/c mice. Polymicrobial sepsis was induced by cecal ligation and puncture. Mesenchymal stromal cells, mesenchymal stromal cells-conditioned with carbon monoxide, fibroblasts, or fibroblasts-conditioned with carbon monoxide were delivered by tail vein injections to septic mice. The mice were assessed for survival, bacterial clearance, and the inflammatory response during sepsis in each of the groups. Mesenchymal stromal cells were also assessed for their ability to promote bacterial phagocytosis by neutrophils, the production of specialized proresolving lipid mediators, and their importance for mesenchymal stromal cells function using gene silencing. Ex vivo preconditioning with carbon monoxide allowed mesenchymal stromal cells to be administered later after the onset of sepsis (6 hr), and yet maintain their therapeutic effect with increased survival. Carbon monoxide preconditioned mesenchymal stromal cells were also able to alleviate organ injury, improve bacterial clearance, and promote the resolution of inflammation. Mesenchymal stromal cells exposed to carbon monoxide, with docosahexaenoic acid substrate, produced specialized proresolving lipid mediators, particularly D-series resolvins, which promoted survival. Silencing of lipoxygenase pathways (5-lipoxygenase and 12/15-lipoxygenase), which are important enzymes for specialized proresolving lipid mediator biosynthesis, resulted in a loss of therapeutic benefit bestowed on mesenchymal stromal cells by carbon monoxide. Taken together, these data suggest that production of specialized proresolving lipid mediators contribute to improved mesenchymal stromal cell efficacy when exposed to carbon monoxide, resulting in an improved therapeutic response during sepsis.

Long-term culture and differentiation of porcine red bone marrow hematopoietic cells co-cultured with immortalized mesenchymal cells.

PubMed

Garba, Abubakar; Acar, Delphine D; Roukaerts, Inge D M; Desmarets, Lowiese M B; Devriendt, Bert; Nauwynck, Hans J

2017-09-01

Mesenchymal cells are multipotent stromal cells with self-renewal, differentiation and immunomodulatory capabilities. We aimed to develop a co-culture model for differentiating hematopoietic cells on top of immortalized mesenchymal cells for studying interactions between hematopoietic and mesenchymal cells, useful for adequately exploring the therapeutic potential of mesenchymal cells. In this study, we investigated the survival, proliferation and differentiation of porcine red bone marrow hematopoietic cells co-cultured with immortalized porcine bone marrow mesenchymal cells for a period of five weeks. Directly after collection, primary porcine bone marrow mesenchymal cells adhered firmly to the bottom of the culture plates and showed a fibroblast-like appearance, one week after isolation. Upon immortalization, porcine bone marrow mesenchymal cells were continuously proliferating. They were positive for simian virus 40 (SV40) large T antigen and the mesenchymal cell markers CD44 and CD55. Isolated red bone marrow cells were added to these immortalized mesenchymal cells. Five weeks post-seeding, 92±6% of the red bone marrow hematopoietic cells were still alive and their number increased 3-fold during five weekly subpassages on top of the immortalized mesenchymal cells. The red bone marrow hematopoietic cells were originally small and round; later, the cells increased in size. Some of them became elongated, while others remained round. Tiny dendrites appeared attaching hematopoietic cells to the underlying immortalized mesenchymal cells. Furthermore, weekly differential-quick staining of the cells indicated the presence of monoblasts, monocytes, macrophages and lymphocytes in the co-cultures. At three weeks of co-culture, flow cytometry analysis showed an increased surface expression of CD172a, CD14, CD163, CD169, CD4 and CD8 up to 37±0.8%, 40±8%, 41±4%, 23±3% and 19±5% of the hematopoietic cells, respectively. In conclusion, continuous mesenchymal cell cultures were successfully established and characterized and they supported the proliferation of red bone marrow hematopoietic cells, which finally differentiated into monocytic cells and CD4 + and CD8 + cells. Copyright © 2017. Published by Elsevier B.V.

Trabectedin for Soft Tissue Sarcoma: Current Status and Future Perspectives.

PubMed

Gordon, Erlinda M; Sankhala, K Kumar; Chawla, Neal; Chawla, Sant P

2016-07-01

Trabectedin (ET743, Yondelis(®), manufactured by Baxter Oncology GmbH, Halle/Westfalen, Germany, for Janssen Products, LP, Horsham, PA), derived from the marine ascidian, Ecteinascidia turbinata, is a natural alkaloid with multiple complex mechanisms of action. On 23 October 2015, 15 years after the results of the first Phase 1 clinical trial using trabectedin for chemotherapy-resistant solid malignancies was reported, and 8 years after its approval in Europe, the United States Food and Drug Administration (USFDA) finally approved trabectedin for the treatment of unresectable or metastatic liposarcoma or leiomyosarcoma that has failed a prior anthracycline-containing regimen. Approval was based on the results of a pivotal Phase 3 trial involving a 2:1 randomization of 518 patients (who were further stratified by soft tissue sarcoma subtype), in which a significant improvement in progression-free survival was reported in the trabectedin-treated group vs. the dacarbazine-treated group (p < 0.001). In this trial, the most common adverse reactions were nausea, fatigue, vomiting, constipation, anorexia, diarrhea, peripheral edema, dyspnea, and headache, while the most serious were neutropenic sepsis, rhabdomyolysis, cardiomyopathy, hepatotoxicity, and extravasation leading to tissue necrosis. The most common grade 3-4 adverse events were laboratory abnormalities of myelosuppression in both arms and transient transaminitis in the trabectedin arm. In a recent Phase 2 trial, trabectedin had a similar outcome as doxorubicin when given as a single agent in the first-line setting. Studies are also being conducted to expand the use of trabectedin not only as a first-line cancer drug, but also for a number of other clinical indications, for example, in the case of mesenchymal chondrosarcoma, for which trabectedin has been reported to be exceptionally active. The possibility of combining trabectedin with targeted therapies, immune checkpoint inhibitors or virotherapy would also be an interesting concept. In short, trabectedin is an old new drug with proven potential to impact the lives of patients with soft tissue sarcoma and other solid malignancies. Sarcoma Oncology Center, Santa Monica, CA 90405.

Kinetic mechanism of ATP-sulphurylase from rat chondrosarcoma.

PubMed Central

Lyle, S; Geller, D H; Ng, K; Westley, J; Schwartz, N B

1994-01-01

ATP-sulphurylase catalyses the production of adenosine 5'-phosphosulphate (APS) from ATP and free sulphate with the release of PPi. APS kinase phosphorylates the APS intermediate to produce adenosine 3'-phosphate 5'-phosphosulphate (PAPS). The kinetic mechanism of rat chondrosarcoma ATP-sulphurylase was investigated by steady-state methods in the physiologically forward direction as well as the reverse direction. The sulphurylase activity was coupled to APS kinase activity in order to overcome the thermodynamic constraints of the sulphurylase reaction in the forward direction. Double-reciprocal initial-velocity plots for the forward sulphurylase intersect to the left of the ordinate for this reaction. KmATP and Kmsulphate were found to be 200 and 97 microM respectively. Chlorate, a competitive inhibitor with respect to sulphate, showed uncompetitive inhibition with respect to ATP with an apparent Ki of 1.97 mM. Steady-state data from experiments in the physiologically reverse direction also yielded double-reciprocal initial-velocity patterns that intersect to the left of the ordinate axis, with a KmAPS of 39 microM and a Kmpyrophosphate of 18 microM. The results of steady-state experiments in which Mg2+ was varied indicated that the true substrate is the MgPPi complex. An analogue of APS, adenosine 5'-[beta-methylene]phosphosulphate, was a linear inhibitor competitive with APS and non-competitive with respect to MgPPi. The simplest formal mechanism that agrees with all the data is an ordered steady-state single displacement with MgATP as the leading substrate in the forward direction and APS as the leading substrate in the reverse direction. PMID:8042976

Hematopoietic-to-mesenchymal transition of adipose tissue macrophages is regulated by integrin β1 and fabricated fibrin matrices

PubMed Central

Majka, Susan M.; Kohrt, Wendy M.; Miller, Heidi L.; Sullivan, Timothy M.; Klemm, Dwight J.

2017-01-01

ABSTRACT Some bona fide adult adipocytes arise de novo from a bone marrow-derived myeloid lineage. These studies further demonstrate that adipose tissue stroma contains a resident population of myeloid cells capable of adipocyte and multilineage mesenchymal differentiation. These resident myeloid cells lack hematopoietic markers and express mesenchymal and progenitor cell markers. Because bone marrow mesenchymal progenitor cells have not been shown to enter the circulation, we hypothesized that myeloid cells acquire mesenchymal differentiation capacity in adipose tissue. We fabricated a 3-dimensional fibrin matrix culture system to define the adipose differentiation potential of adipose tissue-resident myeloid subpopulations, including macrophages, granulocytes and dendritic cells. Our data show that multilineage mesenchymal potential was limited to adipose tissue macrophages, characterized by the acquisition of adipocyte, osteoblast, chondrocyte and skeletal muscle myocyte phenotypes. Fibrin hydrogel matrices stimulated macrophage loss of hematopoietic cell lineage determinants and the expression of mesenchymal and progenitor cell markers, including integrin β1. Ablation of integrin β1 in macrophages inhibited adipocyte specification. Therefore, some bona fide adipocytes are specifically derived from adipose tissue-resident macrophages via an integrin β1-dependent hematopoietic-to-mesenchymal transition, whereby they become capable of multipotent mesenchymal differentiation. The requirement for integrin β1 highlights this molecule as a potential target for controlling the production of marrow-derived adipocytes and their contribution to adipose tissue development and function. PMID:28441086

The anti-fibrotic effects of mesenchymal stem cells on irradiated lungs via stimulating endogenous secretion of HGF and PGE2

PubMed Central

Dong, Li-Hua; Jiang, Yi-Yao; Liu, Yong-Jun; Cui, Shuang; Xia, Cheng-Cheng; Qu, Chao; Jiang, Xin; Qu, Ya-Qin; Chang, Peng-Yu; Liu, Feng

2015-01-01

Radiation-induced pulmonary fibrosis is a common disease and has a poor prognosis owing to the progressive breakdown of gas exchange regions in the lung. Recently, a novel strategy of administering mesenchymal stem cells for pulmonary fibrosis has achieved high therapeutic efficacy. In the present study, we attempted to use human adipose tissue-derived mesenchymal stem cells to prevent disease in Sprague-Dawley rats that received semi-thoracic irradiation (15 Gy). To investigate the specific roles of mesenchymal stem cells in ameliorating radiation-induced pulmonary fibrosis, we treated control groups of irradiated rats with human skin fibroblasts or phosphate-buffered saline. After mesenchymal stem cells were infused, host secretions of hepatocyte growth factor (HGF) and prostaglandin E2 (PGE2) were elevated compared with those of the controls. In contrast, tumour necrosis factor-alpha (TNF-α) and transforming growth factor-beta1 (TGF-β1) levels were decreased after infusion of mesenchymal stem cells. Consequently, the architecture of the irradiated lungs was preserved without marked activation of fibroblasts or collagen deposition within the injured sites. Moreover, mesenchymal stem cells were able to prevent the irradiated type II alveolar epithelial cells from undergoing epithelial-mesenchymal transition. Collectively, these data confirmed that mesenchymal stem cells have the potential to limit pulmonary fibrosis after exposure to ionising irradiation. PMID:25736907

Signaling pathways regulating the expression of Prx1 and Prx2 in the Chick Mandibular Mesenchyme

PubMed Central

Doufexi, Aikaterini-El; Mina, Mina

2009-01-01

Prx1 and Prx2 are members of the aristaless-related homeobox genes shown to play redundant but essential roles in morphogenesis of the mandibular processes. To gain insight into the signaling pathways that regulate expression of Prx genes in the mandibular mesenchyme, we used the chick as a model system. We examined the patterns of gene expression in the face and the roles of signals derived from the epithelium on the expression of Prx genes in the mandibular mesenchyme. Our results demonstrated stage-dependent roles of mandibular epithelium on the expression of Prx in the mandibular mesenchyme and provide evidence for positive roles of members of the fibroblast and hedgehog families derived from mandibular epithelium on the expression of Prx genes in the mandibular mesenchyme. Our studies suggest that endothelin-1 signaling derived from the mesenchyme is involved in restricting the expression of Prx2 to the medial mandibular mesenchyme. PMID:18942149

Mechanisms of the epithelial-to-mesenchymal transition in sea urchin embryos

PubMed Central

Katow, Hideki

2015-01-01

Sea urchin mesenchyme is composed of the large micromere-derived spiculogenetic primary mesenchyme cells (PMC), veg2-tier macromere-derived non-spiculogenetic mesenchyme cells, the small micromere-derived germ cells, and the macro- and mesomere-derived neuronal mesenchyme cells. They are formed through the epithelial-to-mesenchymal transition (EMT) and possess multipotency, except PMCs that solely differentiate larval spicules. The process of EMT is associated with modification of epithelial cell surface property that includes loss of affinity to the apical and basal extracellular matrices, inter-epithelial cell adherens junctions and epithelial cell surface-specific proteins. These cell surface structures and molecules are endocytosed during EMT and utilized as initiators of cytoplasmic signaling pathways that often initiate protein phosphorylation to activate the gene regulatory networks. Acquisition of cell motility after EMT in these mesenchyme cells is associated with the expression of proteins such as Lefty, Snail and Seawi. Structural simplicity and genomic database of this model will further promote detailed EMT research. PMID:26716069

Specific mesenchymal/epithelial induction of olfactory receptor, vomeronasal, and gonadotropin-releasing hormone (GnRH) neurons

PubMed Central

Rawson, N.E; Lischka, F. W.; Yee, K.K.; Peters, A.Z.; Tucker, E.S.; Meechan, D.W.; Zirlinger, M.; Maynard, T.M.; Burd, G.B.; Dulac, C.; Pevny, L.; LaMantia, A-S.

2013-01-01

We asked whether specific mesenchymal/epithelial (M/E) induction generates olfactory receptor neurons (ORNs), vomeronasal neurons (VRNs) and gonadotropin releasing hormone (GnRH) neurons—the major neuron classes associated with the olfactory epithelium (OE). To assess specificity of M/E-mediated neurogenesis, we compared the influence of frontonasal mesenchyme on frontonasal epithelium, which becomes the OE, with that of the forelimb bud. Despite differences in position, morphogenetic and cytogenic capacity, both mesenchymal tissues support neurogenesis, expression of several signaling molecules and neurogenic transcription factors in the frontonasal epithelium. Only frontonasal mesenchyme, however, supports OE-specific patterning and activity of a subset of signals and factors associated with OE differentiation. Moreover, only appropriate pairing of frontonasal epithelial and mesenchymal partners yields ORNs, VRNs, and GnRH neurons. Accordingly, the position and molecular identity of specialized frontonasal epithelia and mesenchyme early in gestation and subsequent inductive interactions, specifies the genesis and differentiation of peripheral chemosensory and neuroendocrine neurons. PMID:20503368

Hypoxia enhances the protective effects of placenta-derived mesenchymal stem cells against scar formation through hypoxia-inducible factor-1α.

PubMed

Du, Lili; Lv, Runxiao; Yang, Xiaoyi; Cheng, Shaohang; Xu, Jing; Ma, Tingxian

2016-06-01

To explore the effect of placenta-derived mesenchymal stem cells on scar formation as well as the underlying mechanism. The isolated placenta-derived mesenchymal stem cells from mice were distributed in the wounded areas of scalded mouse models, attenuated inflammatory responses and decreased the deposition of collagens, thus performing a beneficial effect against scar formation. Hypoxia enhanced the protective effect of placenta-derived mesenchymal stem cells and hypoxia-inducible factor-1α was involved in the protective effect of placenta-derived mesenchymal stem cells in hypoxic condition. Hypoxia enhanced the protective effect of placenta-derived mesenchymal stem cells through hypoxia-inducible factor-1α and PMSCs may have a potential application in the treatment of wound.

Distinct effects of EGFR inhibitors on epithelial- and mesenchymal-like esophageal squamous cell carcinoma cells.

PubMed

Yoshioka, Masahiro; Ohashi, Shinya; Ida, Tomomi; Nakai, Yukie; Kikuchi, Osamu; Amanuma, Yusuke; Matsubara, Junichi; Yamada, Atsushi; Miyamoto, Shin'ichi; Natsuizaka, Mitsuteru; Nakagawa, Hiroshi; Chiba, Tsutomu; Seno, Hiroshi; Muto, Manabu

2017-08-01

Epidermal growth factor receptor (EGFR) plays a pivotal role in the pathophysiology of esophageal squamous cell carcinoma (ESCC). However, the clinical effects of EGFR inhibitors on ESCC are controversial. This study sought to identify the factors determining the therapeutic efficacy of EGFR inhibitors in ESCC cells. Immortalized-human esophageal epithelial cells (EPC2-hTERT), transformed-human esophageal epithelial cells (T-Epi and T-Mes), and ESCC cells (TE-1, TE-5, TE-8, TE-11, TE-11R, and HCE4) were treated with the EGFR inhibitors erlotinib or cetuximab. Inhibitory effects on cell growth were assessed by cell counting or cell-cycle analysis. The expression levels of genes and proteins such as involucrin and cytokeratin13 (a squamous differentiation marker), E-cadherin, and vimentin were evaluated by real-time polymerase chain reaction or western blotting. To examine whether mesenchymal phenotype influenced the effects of EGFR inhibitors, we treated T-Epi cells with TGF-β1 to establish a mesenchymal phenotype (mesenchymal T-Epi cells). We then compared the effects of EGFR inhibitors on parental T-Epi cells and mesenchymal T-Epi cells. TE-8 (mesenchymal-like ESCC cells)- or TE-11R (epithelial-like ESCC cells)-derived xenograft tumors in mice were treated with cetuximab, and the antitumor effects of EGFR inhibitors were evaluated. Cells were classified as epithelial-like or mesenchymal-like phenotypes, determined by the expression levels of E-cadherin and vimentin. Both erlotinib and cetuximab reduced cell growth and the ratio of cells in cell-cycle S phase in epithelial-like but not mesenchymal-like cells. Additionally, EGFR inhibitors induced squamous cell differentiation (defined as increased expression of involucrin and cytokeratin13) in epithelial-like but not mesenchymal-like cells. We found that EGFR inhibitors did not suppress the phosphorylation of EGFR in mesenchymal-like cells, while EGFR dephosphorylation was observed after treatment with EGFR inhibitors in epithelial-like cells. Furthermore, mesenchymal T-Epi cells showed resistance to EGFR inhibitors by circumventing the dephosphorylation of EGFR signaling. Cetuximab consistently showed antitumor effects, and increased involucrin expression in TE-11R (epithelial-like)-derived xenograft tumors but not TE-8 (mesenchymal-like)-derived xenograft tumors. The factor determining the therapeutic effects of EGFR inhibitors in ESCC cells is the phenotype representing the epithelial-like or mesenchymal-like cells. Mesenchymal-like ESCC cells are resistant to EGFR inhibitors because EGFR signaling is not blocked. EGFR inhibitors show antitumor effects on epithelial-like ESCC cells accompanied by promotion of squamous cell differentiation.

Therapeutic Evaluation of Mesenchymal Stem Cells in Chronic Gut Inflammation

DTIC Science & Technology

2014-09-01

AWARD NUMBER: W81XWH-11-1-0666 TITLE: Therapeutic Evaluation of Mesenchymal Stem Cells in Chronic Gut Inflammation PRINCIPAL INVESTIGATOR...2014 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Therapeutic Evaluation of Mesenchymal Stem Cells in Chronic Gut Inflammation 5b. GRANT NUMBER...several different mouse tissues during the development of chronic gut inflammation. 5. SUBJECT TERMS inflammatory bowel disease; mesenchymal stem

Immortalized porcine mesenchymal cells derived from nasal mucosa, lungs, lymph nodes, spleen and bone marrow retain their stemness properties and trigger the expression of siglec-1 in co-cultured blood monocytic cells

PubMed Central

Garba, Abubakar; Desmarets, Lowiese M. B.; Acar, Delphine D.; Devriendt, Bert; Nauwynck, Hans J.

2017-01-01

Mesenchymal stromal cells have been isolated from different sources. They are multipotent cells capable of differentiating into many different cell types, including osteocytes, chondrocytes and adipocytes. They possess a therapeutic potential in the management of immune disorders and the repair of damaged tissues. Previous work in our laboratory showed an increase of the percentages of CD172a+, CD14+, CD163+, Siglec-1+, CD4+ and CD8+ hematopoietic cells, when co-cultured with immortalized mesenchymal cells derived from bone marrow. The present work aimed to demonstrate the stemness properties of SV40-immortalized mesenchymal cells derived from nasal mucosa, lungs, spleen, lymph nodes and red bone marrow and their immunomodulatory effect on blood monocytes. Mesenchymal cells from nasal mucosa, lungs, spleen, lymph nodes and red bone marrow were isolated and successfully immortalized using simian virus 40 large T antigen (SV40LT) and later, co-cultured with blood monocytes, in order to examine their differentiation stage (expression of Siglec-1). Flow cytometric analysis revealed that the five mesenchymal cell lines were positive for mesenchymal cell markers CD105, CD44, CD90 and CD29, but lacked the expression of myeloid cell markers CD16 and CD11b. Growth analysis of the cells demonstrated that bone marrow derived-mesenchymal cells proliferated faster compared with those derived from the other tissues. All five mesenchymal cell lines co-cultured with blood monocytes for 1, 2 and 7 days triggered the expression of siglec-1 in the monocytes. In contrast, no siglec-1+ cells were observed in monocyte cultures without mesenchymal cell lines. Mesenchymal cells isolated from nasal mucosa, lungs, spleen, lymph nodes and bone marrow were successfully immortalized and these cell lines retained their stemness properties and displayed immunomodulatory effects on blood monocytes. PMID:29036224

Immortalized porcine mesenchymal cells derived from nasal mucosa, lungs, lymph nodes, spleen and bone marrow retain their stemness properties and trigger the expression of siglec-1 in co-cultured blood monocytic cells.

PubMed

Garba, Abubakar; Desmarets, Lowiese M B; Acar, Delphine D; Devriendt, Bert; Nauwynck, Hans J

2017-01-01

Mesenchymal stromal cells have been isolated from different sources. They are multipotent cells capable of differentiating into many different cell types, including osteocytes, chondrocytes and adipocytes. They possess a therapeutic potential in the management of immune disorders and the repair of damaged tissues. Previous work in our laboratory showed an increase of the percentages of CD172a+, CD14+, CD163+, Siglec-1+, CD4+ and CD8+ hematopoietic cells, when co-cultured with immortalized mesenchymal cells derived from bone marrow. The present work aimed to demonstrate the stemness properties of SV40-immortalized mesenchymal cells derived from nasal mucosa, lungs, spleen, lymph nodes and red bone marrow and their immunomodulatory effect on blood monocytes. Mesenchymal cells from nasal mucosa, lungs, spleen, lymph nodes and red bone marrow were isolated and successfully immortalized using simian virus 40 large T antigen (SV40LT) and later, co-cultured with blood monocytes, in order to examine their differentiation stage (expression of Siglec-1). Flow cytometric analysis revealed that the five mesenchymal cell lines were positive for mesenchymal cell markers CD105, CD44, CD90 and CD29, but lacked the expression of myeloid cell markers CD16 and CD11b. Growth analysis of the cells demonstrated that bone marrow derived-mesenchymal cells proliferated faster compared with those derived from the other tissues. All five mesenchymal cell lines co-cultured with blood monocytes for 1, 2 and 7 days triggered the expression of siglec-1 in the monocytes. In contrast, no siglec-1+ cells were observed in monocyte cultures without mesenchymal cell lines. Mesenchymal cells isolated from nasal mucosa, lungs, spleen, lymph nodes and bone marrow were successfully immortalized and these cell lines retained their stemness properties and displayed immunomodulatory effects on blood monocytes.

Multiple myeloma involving the cricoid cartilage.

PubMed

Floré, B; Hermans, R

2013-01-01

We present the case of a man with dyspnea due to a mass in the cricoid cartilage that turns out to be an extramedullary plasmocytoma. Although the patient has a history of multiple myeloma, the disease only rarely affects the cricoid cartilage. Other subglottic lesions possibly involving the cricoid cartilage are squamous cell carcinoma, chondroma, chondrosarcoma and metastasis. The imaging characteristics suggesting extramedullary plasmocytoma arising from the cricoid consist of thinning and expansion of the cartilage laminae without mucosal lesions nor soft tissue mass adjacent to the cricoid cartilage. The patient was successfully treated with radiation therapy and peroral steroids.

Transplant of Hepatocytes, Undifferentiated Mesenchymal Stem Cells, and In Vitro Hepatocyte-Differentiated Mesenchymal Stem Cells in a Chronic Liver Failure Experimental Model: A Comparative Study.

PubMed

El Baz, Hanan; Demerdash, Zeinab; Kamel, Manal; Atta, Shimaa; Salah, Faten; Hassan, Salwa; Hammam, Olfat; Khalil, Heba; Meshaal, Safa; Raafat, Inas

2018-02-01

Liver transplant is the cornerstone line of treatment for chronic liver diseases; however, the long list of complications and obstacles stand against this operation. Searching for new modalities for treatment of chronic liver illness is a must. In the present research, we aimed to compare the effects of transplant of undifferentiated human mesenchymal stem cells, in vitro differentiated mesenchymal stem cells, and adult hepatocytes in an experimental model of chronic liver failure. Undifferentiated human cord blood mesenchymal stem cells were isolated, pro-pagated, and characterized by morphology, gene expression analysis, and flow cytometry of surface markers and in vitro differentiated into hepatocyte-like cells. Rat hepatocytes were isolated by double perfusion technique. An animal model of chronic liver failure was developed, and undifferentiated human cord blood mesenchymal stem cells, in vitro hepato-genically differentiated mesenchymal stem cells, or freshly isolated rat hepatocytes were transplanted into a CCL4 cirrhotic experimental model. Animals were killed 3 months after transplant, and liver functions and histopathology were assessed. Compared with the cirrhotic control group, the 3 cell-treated groups showed improved alanine aminotransferase, aspartate aminotransferase, albumin, and bilirubin levels, with best results shown in the hepatocyte-treated group. Histopathologic examination of the treated groups showed improved fibrosis, with best results obtained in the undifferentiated mesenchymal stem cell-treated group. Both adult hepatocytes and cord blood mesenchymal stem cells proved to be promising candidates for cell-based therapy in liver regeneration on an experimental level. Improved liver function was evident in the hepatocyte-treated group, and fibrosis control was more evident in the undifferentiated mesenchymal stem cell-treated group.

Mesenchymal stem cells attenuate blood-brain barrier leakage after cerebral ischemia in mice.

PubMed

Cheng, Zhuo; Wang, Liping; Qu, Meijie; Liang, Huaibin; Li, Wanlu; Li, Yongfang; Deng, Lidong; Zhang, Zhijun; Yang, Guo-Yuan

2018-05-03

Ischemic stroke induced matrixmetallo-proteinase-9 (MMP-9) upregulation, which increased blood-brain barrier permeability. Studies demonstrated that mesenchymal stem cell therapy protected blood-brain barrier disruption from several cerebrovascular diseases. However, the underlying mechanism was largely unknown. We therefore hypothesized that mesenchymal stem cells reduced blood-brain barrier destruction by inhibiting matrixmetallo-proteinase-9 and it was related to intercellular adhesion molecule-1 (ICAM-1). Adult ICR male mice (n = 118) underwent 90-min middle cerebral artery occlusion and received 2 × 10 5 mesenchymal stem cell transplantation. Neurobehavioral outcome, infarct volume, and blood-brain barrier permeability were measured after ischemia. The relationship between myeloperoxidase (MPO) activity and ICAM-1 release was further determined. We found that intracranial injection of mesenchymal stem cells reduced infarct volume and improved behavioral function in experimental stroke models (p < 0.05). IgG leakage, tight junction protein loss, and inflammatory cytokines IL-1β, IL-6, and TNF-α reduced in mesenchymal stem cell-treated mice compared to the control group following ischemia (p < 0.05). After transplantation, MMP-9 was decreased in protein and activity levels as compared with controls (p < 0.05). Furthermore, myeloperoxidase-positive cells and myeloperoxidase activity were decreased in mesenchymal stem cell-treated mice (p < 0.05). The results showed that mesenchymal stem cell therapy attenuated blood-brain barrier disruption in mice after ischemia. Mesenchymal stem cells attenuated the upward trend of MMP-9 and potentially via downregulating ICAM-1 in endothelial cells. Adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) pathway may influence MMP-9 expression of neutrophils and resident cells, and ICAM-1 acted as a key factor in the paracrine actions of mesenchymal stem cell.

Labeling mesenchymal cells with DMSA-coated gold and iron oxide nanoparticles: assessment of biocompatibility and potential applications.

PubMed

Silva, Luisa H A; da Silva, Jaqueline R; Ferreira, Guilherme A; Silva, Renata C; Lima, Emilia C D; Azevedo, Ricardo B; Oliveira, Daniela M

2016-07-18

Nanoparticles' unique features have been highly explored in cellular therapies. However, nanoparticles can be cytotoxic. The cytotoxicity can be overcome by coating the nanoparticles with an appropriated surface modification. Nanoparticle coating influences biocompatibility between nanoparticles and cells and may affect some cell properties. Here, we evaluated the biocompatibility of gold and maghemite nanoparticles functionalized with 2,3-dimercaptosuccinic acid (DMSA), Au-DMSA and γ-Fe2O3-DMSA respectively, with human mesenchymal stem cells. Also, we tested these nanoparticles as tracers for mesenchymal stem cells in vivo tracking by computed tomography and as agents for mesenchymal stem cells magnetic targeting. Significant cell death was not observed in MTT, Trypan Blue and light microscopy analyses. However, ultra-structural alterations as swollen and degenerated mitochondria, high amounts of myelin figures and structures similar to apoptotic bodies were detected in some mesenchymal stem cells. Au-DMSA and γ-Fe2O3-DMSA labeling did not affect mesenchymal stem cells adipogenesis and osteogenesis differentiation, proliferation rates or lymphocyte suppression capability. The uptake measurements indicated that both inorganic nanoparticles were well uptaken by mesenchymal stem cells. However, Au-DMSA could not be detected in microtomograph after being incorporated by mesenchymal stem cells. γ-Fe2O3-DMSA labeled cells were magnetically responsive in vitro and after infused in vivo in an experimental model of lung silicosis. In terms of biocompatibility, the use of γ-Fe2O3-DMSA and Au-DMSA as tracers for mesenchymal stem cells was assured. However, Au-DMSA shown to be not suitable for visualization and tracking of these cells in vivo by standard computed microtomography. Otherwise, γ-Fe2O3-DMSA shows to be a promising agent for mesenchymal stem cells magnetic targeting.

Mesenchymal stromal cells support the viability and differentiation of thymocytes through direct contact in autologous co-cultures.

PubMed

Azghadi, Seyed Mohammad Reza; Suciu, Maria; Gruia, Alexandra Teodora; Barbu-Tudoran, Lucian; Cristea, Mirabela Iustina; Mic, Ani Aurora; Muntean, Danina; Nica, Dragos Vasile; Mic, Felix Aurel

2016-08-01

The development of thymocytes and generation of mature T cells is a complex process that requires spatio-temporal interactions of thymocytes with the other cells of the thymus microenvironment. Recently, mesenchymal stromal cells were isolated from the neonatal human thymus and differentiated into chondrogenic, osteogenic, and adipogenic lineages, just like their bone marrow counterparts. However, their function in thymocyte homeostasis is unknown. In our autologous co-cultures of rat mesenchymal stromal cells and thymocytes, the stromal cells preserve the viability of cultured thymocytes and stimulate the development of CD4-CD8- double-negative and the maturation of mainly CD4+ single-positive thymocytes. Thymocytes also influence the stemness of bone marrow mesenchymal stromal cells, as their expression of CD44, a marker associated with cellular proliferation and migration, is reduced in co-cultures. Mesenchymal stromal cells' influence on thymocyte development requires direct physical contact between the two cells and is not mediated by a soluble factor. When the two types of cells were physically separated, the stimulative effects of mesenchymal stromal cells on thymocytes did not occur. Electron microscopy confirmed the close contact between the membranes of thymocytes and mesenchymal stromal cells. Our experiments suggest that membrane exchanges could occur between mesenchymal stromal cells and thymocytes, such as the transfer of CD44 from mesenchymal stromal cells to the thymocytes, but its functional significance for thymocytes development remains to be established. These results suggest that mesenchymal stromal cells could normally be a part of the in vivo thymic microenvironment and form a niche that could sustain and guide the development of thymocytes.

Large, stratified, and mechanically functional human cartilage grown in vitro by mesenchymal condensation

PubMed Central

Bhumiratana, Sarindr; Eton, Ryan E.; Oungoulian, Sevan R.; Wan, Leo Q.; Ateshian, Gerard A.; Vunjak-Novakovic, Gordana

2014-01-01

The efforts to grow mechanically functional cartilage from human mesenchymal stem cells have not been successful. We report that clinically sized pieces of human cartilage with physiologic stratification and biomechanics can be grown in vitro by recapitulating some aspects of the developmental process of mesenchymal condensation. By exposure to transforming growth factor-β, mesenchymal stem cells were induced to condense into cellular bodies, undergo chondrogenic differentiation, and form cartilagenous tissue, in a process designed to mimic mesenchymal condensation leading into chondrogenesis. We discovered that the condensed mesenchymal cell bodies (CMBs) formed in vitro set an outer boundary after 5 d of culture, as indicated by the expression of mesenchymal condensation genes and deposition of tenascin. Before setting of boundaries, the CMBs could be fused into homogenous cellular aggregates giving rise to well-differentiated and mechanically functional cartilage. We used the mesenchymal condensation and fusion of CMBs to grow centimeter-sized, anatomically shaped pieces of human articular cartilage over 5 wk of culture. For the first time to our knowledge biomechanical properties of cartilage derived from human mesenchymal cells were comparable to native cartilage, with the Young’s modulus of >800 kPa and equilibrium friction coeffcient of <0.3. We also demonstrate that CMBs have capability to form mechanically strong cartilage–cartilage interface in an in vitro cartilage defect model. The CMBs, which acted as “lego-like” blocks of neocartilage, were capable of assembling into human cartilage with physiologic-like structure and mechanical properties. PMID:24778247

Targeting the Prostate Cancer Microenvironment to Improve Therapeutic Outcomes

DTIC Science & Technology

2013-06-01

and Kim, S. -J. 2008. Isolation and Characterization of Mouse Mesenchymal Stem Cells . Transplantation Proceedings. 40: 2649–2654. Watson, P. A...of mesenchymal cell characteristics (epithelial to mesenchymal transition, EMT), that are known to 5 enhance resistance to growth arrest signals...Multipotential Mesenchymal Cells from the Mouse Synovium. PLoS One. 7: e45517. Gilbert, L. A. and Hemann, M. T. 2010. DNA damage-mediated induction of a

Cellular proliferation in the urorectal septation complex of the human embryo at Carnegie stages 13-18: a nuclear area-based morphometric analysis.

PubMed

Nebot-Cegarra, Josep; Fàbregas, Pere Jordi; Sánchez-Pérez, Inma

2005-10-01

In order to analyse the patterns of cellular proliferation both in the mesenchyme of the urorectal septum (URS) and in the adjacent territories (posterior urogenital mesenchyme, anterior intestinal mesenchyme and cloacal folds mesenchyme), as well as their contribution to the process of cloacal division, a computer-assisted method was used to obtain the nuclear area of 3874 mesenchymal cells from camera lucida drawings of nuclear contours of selected sections of human embryos [Carnegie stages (CSs) 13-18]. Based on changes in the size of the nucleus during the cellular cycle, we considered proliferating cells in each territory to be those with a nuclear area over the 75th percentile. The URS showed increasing cell proliferation, with proliferation patterns that coincided closely with cloacal folds mesenchyme, and with less overall proliferation than urogenital and intestinal mesenchymes. Furthermore, at CS 18, we observed the beginning of the rupture in the cloacal membrane; however, no fusion has been demonstrated either between the URS and the cloacal membrane or between the cloacal folds. The results suggest that cloacal division depends on a morphogenetic complex where the URS adjacent territories could determine septal displacement at the time that their mesenchymes could be partially incorporated within the proliferating URS.

Mesenchymal Stem Cell Therapy for the Treatment of Vocal Fold Scarring: A Systematic Review of Preclinical Studies

PubMed Central

Wingstrand, Vibe Lindeblad; Jensen, David H.; Bork, Kristian; Sebbesen, Lars; Balle, Jesper; Fischer-Nielsen, Anne; von Buchwald, Christian

2016-01-01

Objectives Therapy with mesenchymal stem cells exhibits potential for the development of novel interventions for many diseases and injuries. The use of mesenchymal stem cells in regenerative therapy for vocal fold scarring exhibited promising results to reduce stiffness and enhance the biomechanical properties of injured vocal folds. This study evaluated the biomechanical effects of mesenchymal stem cell therapy for the treatment of vocal fold scarring. Data Sources PubMed, Embase, the Cochrane Library and Google Scholar were searched. Methods Controlled studies that assessed the biomechanical effects of mesenchymal stem cell therapy for the treatment of vocal fold scarring were included. Primary outcomes were viscoelastic properties and mucosal wave amplitude. Results Seven preclinical animal studies (n = 152 single vocal folds) were eligible for inclusion. Evaluation of viscoelastic parameters revealed a decreased dynamic viscosity (η’) and elastic modulus (G’), i.e., decreased resistance and stiffness, in scarred vocal folds treated with mesenchymal stem cells compared to non-treated scarred vocal folds. Mucosal wave amplitude was increased in scarred vocal folds treated with mesenchymal stem cells vs. non-treated scarred vocal folds. Conclusion The results from these studies suggest an increased regenerative effect of therapy with mesenchymal stem cells for scarred vocal folds and are encouraging for further clinical studies. PMID:27631373

Mesenchymal Stem Cell Therapy for the Treatment of Vocal Fold Scarring: A Systematic Review of Preclinical Studies.

PubMed

Wingstrand, Vibe Lindeblad; Grønhøj Larsen, Christian; Jensen, David H; Bork, Kristian; Sebbesen, Lars; Balle, Jesper; Fischer-Nielsen, Anne; von Buchwald, Christian

2016-01-01

Therapy with mesenchymal stem cells exhibits potential for the development of novel interventions for many diseases and injuries. The use of mesenchymal stem cells in regenerative therapy for vocal fold scarring exhibited promising results to reduce stiffness and enhance the biomechanical properties of injured vocal folds. This study evaluated the biomechanical effects of mesenchymal stem cell therapy for the treatment of vocal fold scarring. PubMed, Embase, the Cochrane Library and Google Scholar were searched. Controlled studies that assessed the biomechanical effects of mesenchymal stem cell therapy for the treatment of vocal fold scarring were included. Primary outcomes were viscoelastic properties and mucosal wave amplitude. Seven preclinical animal studies (n = 152 single vocal folds) were eligible for inclusion. Evaluation of viscoelastic parameters revealed a decreased dynamic viscosity (η') and elastic modulus (G'), i.e., decreased resistance and stiffness, in scarred vocal folds treated with mesenchymal stem cells compared to non-treated scarred vocal folds. Mucosal wave amplitude was increased in scarred vocal folds treated with mesenchymal stem cells vs. non-treated scarred vocal folds. The results from these studies suggest an increased regenerative effect of therapy with mesenchymal stem cells for scarred vocal folds and are encouraging for further clinical studies.

Mesenchymal Stromal Cells for Antineoplastic Drug Loading and Delivery.

PubMed

Petrella, Francesco; Rimoldi, Isabella; Rizzo, Stefania; Spaggiari, Lorenzo

2017-11-23

Mesenchymal stromal cells are a population of undifferentiated multipotent adult cells possessing extensive self-renewal properties and the potential to differentiate into a variety of mesenchymal lineage cells. They express broad anti-inflammatory and immunomodulatory activity on the immune system and after transplantation can interact with the surrounding microenvironment, promoting tissue healing and regeneration. For this reason, mesenchymal stromal cells have been widely used in regenerative medicine, both in preclinical and clinical settings. Another clinical application of mesenchymal stromal cells is the targeted delivery of chemotherapeutic agents to neoplastic cells, maximizing the cytotoxic activity against cancer cells and minimizing collateral damage to non-neoplastic tissues. Mesenchymal stem cells are home to the stroma of several primary and metastatic neoplasms and hence can be used as vectors for targeted delivery of antineoplastic drugs to the tumour microenvironment, thereby reducing systemic toxicity and maximizing antitumour effects. Paclitaxel and gemcitabine are the chemotherapeutic drugs best loaded by mesenchymal stromal cells and delivered to neoplastic cells, whereas other agents, like pemetrexed, are not internalized by mesenchymal stromal cells and therefore are not suitable for advanced antineoplastic therapy. This review focuses on the state of the art of advanced antineoplastic cell therapy and its future perspectives, emphasizing in vitro and in vivo preclinical results and future clinical applications.

Cellular proliferation in the urorectal septation complex of the human embryo at Carnegie stages 13–18: a nuclear area-based morphometric analysis

PubMed Central

Nebot-Cegarra, Josep; Fàbregas, Pere Jordi; Sánchez-Pérez, Inma

2005-01-01

In order to analyse the patterns of cellular proliferation both in the mesenchyme of the urorectal septum (URS) and in the adjacent territories (posterior urogenital mesenchyme, anterior intestinal mesenchyme and cloacal folds mesenchyme), as well as their contribution to the process of cloacal division, a computer-assisted method was used to obtain the nuclear area of 3874 mesenchymal cells from camera lucida drawings of nuclear contours of selected sections of human embryos [Carnegie stages (CSs) 13–18]. Based on changes in the size of the nucleus during the cellular cycle, we considered proliferating cells in each territory to be those with a nuclear area over the 75th percentile. The URS showed increasing cell proliferation, with proliferation patterns that coincided closely with cloacal folds mesenchyme, and with less overall proliferation than urogenital and intestinal mesenchymes. Furthermore, at CS 18, we observed the beginning of the rupture in the cloacal membrane; however, no fusion has been demonstrated either between the URS and the cloacal membrane or between the cloacal folds. The results suggest that cloacal division depends on a morphogenetic complex where the URS adjacent territories could determine septal displacement at the time that their mesenchymes could be partially incorporated within the proliferating URS. PMID:16191164

RBFOX2 Is an Important Regulator of Mesenchymal Tissue-Specific Splicing in both Normal and Cancer Tissues

PubMed Central

Venables, Julian P.; Brosseau, Jean-Philippe; Gadea, Gilles; Klinck, Roscoe; Prinos, Panagiotis; Beaulieu, Jean-François; Lapointe, Elvy; Durand, Mathieu; Thibault, Philippe; Tremblay, Karine; Rousset, François; Tazi, Jamal; Abou Elela, Sherif

2013-01-01

Alternative splicing provides a critical and flexible layer of regulation intervening in many biological processes to regulate the diversity of proteins and impact cell phenotype. To identify alternative splicing differences that distinguish epithelial from mesenchymal tissues, we have investigated hundreds of cassette exons using a high-throughput reverse transcription-PCR (RT-PCR) platform. Extensive changes in splicing were noted between epithelial and mesenchymal tissues in both human colon and ovarian tissues, with many changes from mostly one splice variant to predominantly the other. Remarkably, many of the splicing differences that distinguish normal mesenchymal from normal epithelial tissues matched those that differentiate normal ovarian tissues from ovarian cancer. Furthermore, because splicing profiling could classify cancer cell lines according to their epithelial/mesenchymal characteristics, we used these cancer cell lines to identify regulators for these specific splicing signatures. By knocking down 78 potential splicing factors in five cell lines, we provide an extensive view of the complex regulatory landscape associated with the epithelial and mesenchymal states, thus revealing that RBFOX2 is an important driver of mesenchymal tissue-specific splicing. PMID:23149937

Neural Crest-Derived Mesenchymal Cells Require Wnt Signaling for Their Development and Drive Invagination of the Telencephalic Midline

PubMed Central

Choe, Youngshik; Zarbalis, Konstantinos S.; Pleasure, Samuel J.

2014-01-01

Embryonic neural crest cells contribute to the development of the craniofacial mesenchyme, forebrain meninges and perivascular cells. In this study, we investigated the function of ß-catenin signaling in neural crest cells abutting the dorsal forebrain during development. In the absence of ß-catenin signaling, neural crest cells failed to expand in the interhemispheric region and produced ectopic smooth muscle cells instead of generating dermal and calvarial mesenchyme. In contrast, constitutive expression of stabilized ß-catenin in neural crest cells increased the number of mesenchymal lineage precursors suggesting that ß-catenin signaling is necessary for the expansion of neural crest-derived mesenchymal cells. Interestingly, the loss of neural crest-derived mesenchymal stem cells (MSCs) leads to failure of telencephalic midline invagination and causes ventricular system defects. This study shows that ß-catenin signaling is required for the switch of neural crest cells to MSCs and mediates the expansion of MSCs to drive the formation of mesenchymal structures of the head. Furthermore, loss of these structures causes striking defects in forebrain morphogenesis. PMID:24516524

Dynamic relationship of the epithelium and mesenchyme during salivary gland initiation: the role of Fgf10

PubMed Central

Wells, Kirsty L.; Gaete, Marcia; Matalova, Eva; Deutsch, Danny; Rice, David; Tucker, Abigail S.

2013-01-01

Summary Salivary glands provide an excellent model for the study of epithelial–mesenchymal interactions. We have looked at the interactions involved in the early initiation and development of murine salivary glands using classic recombination experiments and knockout mice. We show that salivary gland epithelium, at thickening and initial bud stages, is able to direct salivary gland development in non-gland pharyngeal arch mesenchyme at early stages. The early salivary gland epithelium is therefore able to induce gland development in non-gland tissue. This ability later shifts to the mesenchyme, with non-gland epithelium, such as from the limb bud, able to form a branching gland when combined with pseudoglandular stage gland mesenchyme. This shift appears to involve Fgf signalling, with signals from the epithelium inducing Fgf10 in the mesenchyme. Fgf10 then signals back to the epithelium to direct gland down-growth and bud development. These experiments highlight the importance of epithelial–mesenchymal signalling in gland initiation, controlling where, when and how many salivary glands form. PMID:24167707

Mesenchymal Stem Cell Therapy for Acute Radiation Syndrome: Innovative Medical Approaches in Military Medicine

DTIC Science & Technology

2015-01-30

mesenchymal stem cells . Cytokine Growth Factor Rev. 2009;20:419–27. 8. Wang L, Li Y, Chen X, Chen J, Gautam SC, Xu Y, et al. MCP...Literature 3. DATES COVERED (From - To) 4. TITLE AND SUBTITLE Mesenchymal stem cell therapy for acute radiation syndrome: innovative medical...Independent Research Program 14. ABSTRACT See reprint. 15. SUBJECT TERMS Acute radiation syndrome, Mesenchymal stem cell , cell therapy,

An In Vitro Culture System for Long-Term Expansion of Epithelial and Mesenchymal Salivary Gland Cells: Role of TGF-β1 in Salivary Gland Epithelial and Mesenchymal Differentiation

PubMed Central

Janebodin, Kajohnkiart; Buranaphatthana, Worakanya; Ieronimakis, Nicholas; Hays, Aislinn L.; Reyes, Morayma

2013-01-01

Despite a pivotal role in salivary gland development, homeostasis, and disease, the role of salivary gland mesenchyme is not well understood. In this study, we used the Col1a1-GFP mouse model to characterize the salivary gland mesenchyme in vitro and in vivo. The Col1a1-GFP transgene was exclusively expressed in the salivary gland mesenchyme. Ex vivo culture of mixed salivary gland cells in DMEM plus serum medium allowed long-term expansion of salivary gland epithelial and mesenchymal cells. The role of TGF-β1 in salivary gland development and disease is complex. Therefore, we used this in vitro culture system to study the effects of TGF-β1 on salivary gland cell differentiation. TGF-β1 induced the expression of collagen, and inhibited the formation of acini-like structures in close proximity to mesenchymal cells, which adapted a fibroblastic phenotype. In contrast, TGF-βR1 inhibition increased acini genes and fibroblast growth factors (Fgf-7 and Fgf-10), decreased collagen and induced formation of larger, mature acini-like structures. Thus, inhibition of TGF-β signaling may be beneficial for salivary gland differentiation; however, due to differential effects of TGF-β1 in salivary gland epithelial versus mesenchymal cells, selective inhibition is desirable. In conclusion, this mixed salivary gland cell culture system can be used to study epithelial-mesenchymal interactions and the effects of differentiating inducers and inhibitors. PMID:23841093

Characterization and Classification of Mesenchymal Stem Cells in Several Species Using Surface Markers for Cell Therapy Purposes.

PubMed

Ghaneialvar, Hori; Soltani, Leila; Rahmani, Hamid Reza; Lotfi, Abbas Sahebghadam; Soleimani, Masoud

2018-01-01

Mesenchymal stem cells are multipotent cells capable of replicating as undifferentiated cells, and have the potential of differentiating into mesenchymal tissue lineages such as osteocytes, adipocytes and chondrocytes. Such lineages can then be used in cell therapy. The aim of present study was to characterize bone marrow derived mesenchymal stem cells in four different species, including: sheep, goat, human and mouse. Human bone-marrow mesenchymal stem cells were purchased, those of sheep and goat were isolated from fetal bone marrow, and those of mouse were collected by washing bone cavity of femur and tibia with DMEM/F12. Using flow-cytometry, they were characterized by CD surface antigens. Furthermore, cells of third passage were examined for their osteogenic and adipogenic differentiation potential by oil red and alizarin red staining respectively. According to the results, CD markers studied in the four groups of mesenchymal stem cells showed a different expression. Goat and sheep expressed CD44 and CD166, and weakly expressed CD34, CD45, CD105 and CD90. Similarly, human and mouse mesenchymal cells expressed CD44, CD166, CD105 and CD90 whereas the expression of CD34 and CD45 was negative. In conclusion, although all mesenchymal stem cells display plastic adherence and tri-lineage differentiation, not all express the same panel of surface antigens described for human mesenchymal stem cells. Additional panel of CD markers are necessary to characterize regenerative potential and possible application of these stem cells in regenerative medicine and implantology.

Immortalized Mouse Floxed Fam20c Dental Papillar Mesenchymal and Osteoblast Cell Lines Retain Their Primary Characteristics

PubMed Central

Liu, Chao; Wang, Xiaofang; Zhang, Hua; Xie, Xiaohua; Liu, Peihong; Liu, Ying; Jani, Priyam H.; Lu, Yongbo; Chen, Shuo; Qin, Chunlin

2016-01-01

Fam20c is essential for the normal mineralization of dentin and bone. The generation of odontoblast and osteoblast cell lines carrying floxed Fam20c allele can offer valuable tools for the study of the roles of Fam20c in the mineralization of dentin and bone. The limited capability of the primary odontoblasts and osteoblasts to proliferate necessitates the development of odontoblast and osteoblast cell lines serving as substitutes for the study of differentiation and mineralization of the odontoblasts and osteoblasts. In this study, we established and characterized immortalized mouse floxed Fam20c dental papilla mesenchymal and osteoblast cell lines. The isolated primary mouse floxed Fam20c dental papilla mesenchymal cells and osteoblasts were immortalized by the infection of lentivirus containing Simian Virus 40 T-antigen (SV40 T-Ag). The immortalization of floxed Fam20c dental papilla mesenchymal cells and osteoblasts was verified by the long-term passages and genomic integration of SV40 T-Ag. The immortalized floxed Fam20c dental papilla mesenchymal and osteoblast cell lines not only proliferated at a high rate and retained the morphology of their primary counterparts, but also preserved the dentin and bone specific gene expression as the primary dental papilla mesenchymal cells and osteoblasts did. Consistently, the capability of the primary floxed Fam20c dental papilla mesenchymal cells and osteoblasts to mineralize was also inherited by the immortalized dental papilla mesenchymal and osteoblast cell lines. Thus, we have successfully generated the immortalized mouse floxed Fam20c dental papilla mesenchymal and osteoblast cell lines. PMID:25833681

[Indication of chemotherapy according to histological type of musculoskeletal sarcomas].

PubMed

Goto, Takahiro; Okuma, Tomotake; Ogura, Koichi; Imanishi, Jungo; Hozumi, Takahiro; Kondo, Taiji

2009-02-01

In high-grade musculoskeletal sarcomas, adjuvant chemotherapy is often performed to prevent distant metastases. As the efficacy of chemotherapy varies according to the histological type of sarcoma, its indication is determined according to the histological type and the stage. Prognoses are poor in patients with osteosarcoma, Ewing's sarcoma, or rhabdomyosarcoma, when surgery alone is performed. However, because these sarcomas are chemosensitive, their prognoses are improved with adjuvant chemotherapy, so it is absolutely necessary. Drugs commonly used for osteosarcoma include adriamycin, cisplatin, methotrexate, vincristine, and ifosfamide. For Ewing's sarcoma and rhabdomyosarcoma, vincristine, actinomycin-D, cyclophosphamide, etoposide, and ifosfamide are commonly used. On the other hand, the efficacy of chemotherapy is unclear in most of the non-round cell sarcomas, e. g., malignant fibrous histiocytoma, pleomorphic liposarcoma, and leiomyosarcoma, so adjuvant chemotherapy is relatively indicated and often performed preoperatively. The efficacy is evaluated by reduction of the tumor volume as a surrogate marker. Postoperative chemotherapy is performed when the preoperative chemotherapy is effective. Nowadays, several kinds of antitumor agents are usually used for non-round cell sarcomas, and many authors have reported various kinds of regimens and their clinical results. Among them, the key drugs are adriamycin and ifosfamide. Recently, taxanes and gemcitabine are sometimes used. For chemoresistant sarcomas, e. g., chondrosarcoma, chordoma, alveolar soft part sarcoma, chemotherapy is rarely indicated, even if the tumor is histologically high grade and large. Low-grade musculoskeletal sarcomas, e. g., low-grade chondrosarcoma, central low-grade osteosarcoma, parosteal osteosarcoma, well-differentiated liposarcoma, and dermatofibrosarcoma protuberans, are well cured only by surgical excision, and adjuvant chemotherapy is therefore not indicated. Superficially-located, small-size non-round cell sarcomas, even though histologically high grade, are well healed only by surgical excision, and adjuvant chemotherapy is rarely indicated.

CRISPR/Cas9 knockout of HAS2 in rat chondrosarcoma chondrocytes demonstrates the requirement of hyaluronan for aggrecan retention

PubMed Central

Huang, Yi; Askew, Emily B.; Knudson, Cheryl B.; Knudson, Warren

2016-01-01

Hyaluronan (HA) plays an essential role in cartilage where it functions to retain aggrecan. Previous studies have suggested that aggrecan is anchored indirectly to the plasma membrane of chondrocytes via its binding to cell-associated HA. However, reagents used to test these observations such as hyaluronidase and HA oligosaccharides are short term and may have side activities that complicate interpretation. Using the CRISPR/Cas9 gene editing approach, a model system was developed by generating HA-deficient chondrocyte cell lines. HA synthase-2 (Has2)-specific single guide RNA was introduced into two different variant lines of rat chondrosarcoma chondrocytes; knockout clones were isolated and characterized. Two other members of the HA synthase gene family were expressed at very low relative copy number but showed no compensatory response in the Has2 knockouts. Wild type chondrocytes of both variants exhibited large pericellular matrices or coats extending from the plasma membrane. Addition of purified aggrecan monomer expanded the size of these coats as the proteoglycan became retained within the pericellular matrix. Has2 knockout chondrocytes lost all capacity to assemble a particle-excluding pericellular matrix and more importantly, no matrices formed around the knockout cells following the addition of purified aggrecan. When grown as pellet cultures so as to generate a bioengineered neocartilage tissue, the Has2 knockout chondrocytes assumed a tightly-compacted morphology as compared to the wild type cells. When knockout chondrocytes were transduced with Adeno-ZsGreen1-mycHas2, the cell-associated pericellular matrices were restored including the capacity to bind and incorporate additional exogenous aggrecan into the matrix. These results suggest that HA is essential for aggrecan retention and maintaining cell separation during tissue formation. PMID:27094859

Carbon ion radiotherapy performed as re-irradiation using active beam delivery in patients with tumors of the brain, skull base and sacral region.

PubMed

Combs, Stephanie E; Kalbe, Adriana; Nikoghosyan, Anna; Ackermann, Benjamin; Jäkel, Oliver; Haberer, Thomas; Debus, Jürgen

2011-01-01

To asses carbon ion radiation therapy (RT) performed as re-irradiation in 28 patients with recurrent tumors. Twenty-eight patients were treated with carbon ion RT as re-irradiation for recurrent chordoma and chondrosarcoma of the skull base (n=16 and n=2), one chordoma and one chondrosarcoma of the os sacrum, high-risk meningioma (n=3), adenoid-cystic carcinoma (n=4) as well as one SCCHN. All patients were treated using active raster scanning, and treatment planning was performed on CT- and MRI-basis. All patients were followed prospectively during follow-up. In all patients re-irradiation could be applied safely without interruptions. For skull base tumors, local tumor control after re-irradiation was 92% at 24 months and 64% at 36 months. Survival after re-irradiation was 86% at 24 months, and 43% at 60 months. In all three meningiomas treated with C12 for re-irradiation, the tumor recurrence was located within the former RT-field. Two patients developed tumor progression at 6 months, and in one patient the tumor remained stable for 67 months. In patients with head-and-neck tumors, three patients developed local tumor progression at 12, 24 and 29 months after re-irradiation. Median local progression-free survival was 24 months. For sacral tumors, re-irradiation offered palliation with tumor control for 24 and 36 months. Due to the physical characteristics particle therapy offers a new treatment modality in cases with tumor recurrences. With carbon ions, the additional biological benefits may be exploited for long-term tumor control. Further evaluation in a larger patients' cohort will be performed in the future. Copyright © 2010. Published by Elsevier Ireland Ltd.

Postnatal epithelium and mesenchyme stem/progenitor cells in bioengineered amelogenesis and dentinogenesis.

PubMed

Jiang, Nan; Zhou, Jian; Chen, Mo; Schiff, Michael D; Lee, Chang H; Kong, Kimi; Embree, Mildred C; Zhou, Yanheng; Mao, Jeremy J

2014-02-01

Rodent incisors provide a classic model for studying epithelial-mesenchymal interactions in development. However, postnatal stem/progenitor cells in rodent incisors have not been exploited for tooth regeneration. Here, we characterized postnatal rat incisor epithelium and mesenchyme stem/progenitor cells and found that they formed enamel- and dentin-like tissues in vivo. Epithelium and mesenchyme cells were harvested separately from the apical region of postnatal 4-5 day rat incisors. Epithelial and mesenchymal phenotypes were confirmed by immunocytochemistry, CFU assay and/or multi-lineage differentiation. CK14+, Sox2+ and Lgr5+ epithelium stem cells from the cervical loop enhanced amelogenin and ameloblastin expression upon BMP4 or FGF3 stimulation, signifying their differentiation towards ameloblast-like cells, whereas mesenchyme stem/progenitor cells upon BMP4, BMP7 and Wnt3a treatment robustly expressed Dspp, a hallmark of odontoblastic differentiation. We then control-released microencapsulated BMP4, BMP7 and Wnt3a in transplants of epithelium and mesenchyme stem/progenitor cells in the renal capsule of athymic mice in vivo. Enamel and dentin-like tissues were generated in two integrated layers with specific expression of amelogenin and ameloblastin in the newly formed, de novo enamel-like tissue, and DSP in dentin-like tissue. These findings suggest that postnatal epithelium and mesenchyme stem/progenitor cells can be primed towards bioengineered tooth regeneration. Copyright © 2013 Elsevier Ltd. All rights reserved.

RTVP-1 promotes mesenchymal transformation of glioma via a STAT-3/IL-6-dependent positive feedback loop

PubMed Central

Giladi, Nis David; Ziv-Av, Amotz; Lee, Hae Kyung; Finniss, Susan; Cazacu, Simona; Xiang, Cunli; Ben-Asher, Hiba Waldman; deCarvalho, Ana; Mikkelsen, Tom; Poisson, Laila; Brodie, Chaya

2015-01-01

Glioblastomas (GBMs), the most aggressive primary brain tumors, exhibit increased invasiveness and resistance to anti-tumor treatments. We explored the role of RTVP-1, a glioma-associated protein that promotes glioma cell migration, in the mesenchymal transformation of GBM. Analysis of The Cancer Genome Atlas (TCGA) demonstrated that RTVP-1 expression was higher in mesenchymal GBM and predicted tumor recurrence and poor clinical outcome. ChiP analysis revealed that the RTVP-1 promoter binds STAT3 and C/EBPβ, two master transcription factors that regulate mesenchymal transformation of GBM. In addition, IL-6 induced RTVP-1 expression in a STAT3-dependent manner. RTVP-1 increased the migration and mesenchymal transformation of glioma cells. Similarly, overexpression of RTVP-1 in human neural stem cells induced mesenchymal differentiation, whereas silencing of RTVP-1 in glioma stem cells (GSCs) decreased the mesenchymal transformation and stemness of these cells. Silencing of RTVP-1 also increased the survival of mice bearing GSC-derived xenografts. Using gene array analysis of RTVP-1 silenced glioma cells we identified IL-6 as a mediator of RTVP-1 effects on the mesenchymal transformation and migration of GSCs, therefore acting in a positive feedback loop by upregulating RTVP-1 expression via the STAT3 pathway. Collectively, these results implicate RTVP-1 as a novel prognostic marker and therapeutic target in GBM. PMID:26267319

Feasibility of mesenchymal stem cell culture expansion for a phase I clinical trial in multiple sclerosis.

PubMed

Planchon, Sarah M; Lingas, Karen T; Reese Koç, Jane; Hooper, Brittney M; Maitra, Basabi; Fox, Robert M; Imrey, Peter B; Drake, Kylie M; Aldred, Micheala A; Lazarus, Hillard M; Cohen, Jeffrey A

2018-01-01

Multiple sclerosis is an inflammatory, neurodegenerative disease of the central nervous system for which therapeutic mesenchymal stem cell transplantation is under study. Published experience of culture-expanding multiple sclerosis patients' mesenchymal stem cells for clinical trials is limited. To determine the feasibility of culture-expanding multiple sclerosis patients' mesenchymal stem cells for clinical use. In a phase I trial, autologous, bone marrow-derived mesenchymal stem cells were isolated from 25 trial participants with multiple sclerosis and eight matched controls, and culture-expanded to a target single dose of 1-2 × 10 6 cells/kg. Viability, cell product identity and sterility were assessed prior to infusion. Cytogenetic stability was assessed by single nucleotide polymorphism analysis of mesenchymal stem cells from 18 multiple sclerosis patients and five controls. One patient failed screening. Mesenchymal stem cell culture expansion was successful for 24 of 25 multiple sclerosis patients and six of eight controls. The target dose was achieved in 16-62 days, requiring two to three cell passages. Growth rate and culture success did not correlate with demographic or multiple sclerosis disease characteristics. Cytogenetic studies identified changes on one chromosome of one control (4.3%) after extended time in culture. Culture expansion of mesenchymal stem cells from multiple sclerosis patients as donors is feasible. However, culture time should be minimized for cell products designated for therapeutic administration.

The innate immune response in fetal lung mesenchymal cells targets VEGFR2 expression and activity.

PubMed

Medal, Rachel M; Im, Amanda M; Yamamoto, Yasutoshi; Lakhdari, Omar; Blackwell, Timothy S; Hoffman, Hal M; Sahoo, Debashis; Prince, Lawrence S

2017-06-01

In preterm infants, soluble inflammatory mediators target lung mesenchymal cells, disrupting airway and alveolar morphogenesis. However, how mesenchymal cells respond directly to microbial stimuli remains poorly characterized. Our objective was to measure the genome-wide innate immune response in fetal lung mesenchymal cells exposed to the bacterial endotoxin lipopolysaccharide (LPS). With the use of Affymetrix MoGene 1.0st arrays, we showed that LPS induced expression of unique innate immune transcripts heavily weighted toward CC and CXC family chemokines. The transcriptional response was different between cells from E11, E15, and E18 mouse lungs. In all cells tested, LPS inhibited expression of a small core group of genes including the VEGF receptor Vegfr2 Although best characterized in vascular endothelial populations, we demonstrated here that fetal mouse lung mesenchymal cells express Vegfr2 and respond to VEGF-A stimulation. In mesenchymal cells, VEGF-A increased cell migration, activated the ERK/AKT pathway, and promoted FOXO3A nuclear exclusion. With the use of an experimental coculture model of epithelial-mesenchymal interactions, we also showed that VEGFR2 inhibition prevented formation of three-dimensional structures. Both LPS and tyrosine kinase inhibition reduced three-dimensional structure formation. Our data suggest a novel mechanism for inflammation-mediated defects in lung development involving reduced VEGF signaling in lung mesenchyme. Copyright © 2017 the American Physiological Society.

Mesenchymal stromal cells from pooled mononuclear cells of multiple bone marrow donors as rescue therapy in pediatric severe steroid-refractory graft-versus-host disease: a multicenter survey

PubMed Central

Kuçi, Zyrafete; Bönig, Halvard; Kreyenberg, Hermann; Bunos, Milica; Jauch, Anna; Janssen, Johannes W.G.; Škifić, Marijana; Michel, Kristina; Eising, Ben; Lucchini, Giovanna; Bakhtiar, Shahrzad; Greil, Johann; Lang, Peter; Basu, Oliver; von Luettichau, Irene; Schulz, Ansgar; Sykora, Karl-Walter; Jarisch, Andrea; Soerensen, Jan; Salzmann-Manrique, Emilia; Seifried, Erhard; Klingebiel, Thomas; Bader, Peter; Kuçi, Selim

2016-01-01

To circumvent donor-to-donor heterogeneity which may lead to inconsistent results after treatment of acute graft-versus-host disease with mesenchymal stromal cells generated from single donors we developed a novel approach by generating these cells from pooled bone marrow mononuclear cells of 8 healthy “3rd-party” donors. Generated cells were frozen in 209 vials and designated as mesenchymal stromal cell bank. These vials served as a source for generation of clinical grade mesenchymal stromal cell end-products, which exhibited typical mesenchymal stromal cell phenotype, trilineage differentiation potential and at later passages expressed replicative senescence-related markers (p21 and p16). Genetic analysis demonstrated their genomic stability (normal karyotype and a diploid pattern). Importantly, clinical end-products exerted a significantly higher allosuppressive potential than the mean allosuppressive potential of mesenchymal stromal cells generated from the same donors individually. Administration of 81 mesenchymal stromal cell end-products to 26 patients with severe steroid-resistant acute graft-versus-host disease in 7 stem cell transplant centers who were refractory to many lines of treatment, induced a 77% overall response at the primary end point (day 28). Remarkably, although the cohort of patients was highly challenging (96% grade III/IV and only 4% grade II graft-versus-host disease), after treatment with mesenchymal stromal cell end-products the overall survival rate at two years follow up was 71±11% for the entire patient cohort, compared to 51.4±9.0% in graft-versus-host disease clinical studies, in which mesenchymal stromal cells were derived from single donors. Mesenchymal stromal cell end-products may, therefore, provide a novel therapeutic tool for the effective treatment of severe acute graft-versus-host disease. PMID:27175026

A SHH-FOXF1-BMP4 signaling axis regulating growth and differentiation of epithelial and mesenchymal tissues in ureter development.

PubMed

Bohnenpoll, Tobias; Wittern, Anna B; Mamo, Tamrat M; Weiss, Anna-Carina; Rudat, Carsten; Kleppa, Marc-Jens; Schuster-Gossler, Karin; Wojahn, Irina; Lüdtke, Timo H-W; Trowe, Mark-Oliver; Kispert, Andreas

2017-08-01

The differentiated cell types of the epithelial and mesenchymal tissue compartments of the mature ureter of the mouse arise in a precise temporal and spatial sequence from uncommitted precursor cells of the distal ureteric bud epithelium and its surrounding mesenchyme. Previous genetic efforts identified a member of the Hedgehog (HH) family of secreted proteins, Sonic hedgehog (SHH) as a crucial epithelial signal for growth and differentiation of the ureteric mesenchyme. Here, we used conditional loss- and gain-of-function experiments of the unique HH signal transducer Smoothened (SMO) to further characterize the cellular functions and unravel the effector genes of HH signaling in ureter development. We showed that HH signaling is not only required for proliferation and SMC differentiation of cells of the inner mesenchymal region but also for survival of cells of the outer mesenchymal region, and for epithelial proliferation and differentiation. We identified the Forkhead transcription factor gene Foxf1 as a target of HH signaling in the ureteric mesenchyme. Expression of a repressor version of FOXF1 in this tissue completely recapitulated the mesenchymal and epithelial proliferation and differentiation defects associated with loss of HH signaling while re-expression of a wildtype version of FOXF1 in the inner mesenchymal layer restored these cellular programs when HH signaling was inhibited. We further showed that expression of Bmp4 in the ureteric mesenchyme depends on HH signaling and Foxf1, and that exogenous BMP4 rescued cell proliferation and epithelial differentiation in ureters with abrogated HH signaling or FOXF1 function. We conclude that SHH uses a FOXF1-BMP4 module to coordinate the cellular programs for ureter elongation and differentiation, and suggest that deregulation of this signaling axis occurs in human congenital anomalies of the kidney and urinary tract (CAKUT).

Therapeutic effect of mesenchymal multipotent stromal cells on memory in animals with Alzheimer-type neurodegeneration.

PubMed

Bobkova, N V; Poltavtseva, R A; Samokhin, A N; Sukhikh, G T

2013-11-01

Transplantation of human mesenchymal multipotent stromal cells improved spatial memory in bulbectomized mice with Alzheimer-type neurodegeneration. The positive effect was observed in 1 month after intracerebral transplantation and in 3 months after systemic injection of mesenchymal multipotent stromal cells. No cases of malignant transformation were noted. These findings indicate prospects of using mesenchymal multipotent stromal cells for the therapy of Alzheimer disease and the possibility of their systemic administration for attaining the therapeutic effect.

The distribution and ultrastructure of the forming blood capillaries and the effect of apoptosis on vascularization in mouse embryonic molar mesenchyme.

PubMed

Yuan, Guohua; Zhang, Li; Yang, Guobin; Yang, Jingwen; Wan, Chunyan; Zhang, Lu; Song, Guangtai; Chen, Shuo; Chen, Zhi

2014-04-01

Vascularization is essential for organ and tissue development. Teeth develop through interactions between epithelium and mesenchyme. The developing capillaries in the enamel organ, the dental epithelial structure, occur simultaneously by mechanisms of vasculogenesis and angiogenesis at the onset of dentinogenesis. The vascular neoformation in the dental mesenchyme has been reported to start from the cap stage. However, the mechanisms of vascularization in the dental mesenchyme remain unknown. In the hope of understanding the mechanisms of the formation of dental mesenchymal vasculature, mouse lower molar germs from embryonic day (E) 13.5 to E16.5 were processed for immunostaining of CD31 and CD34, terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL) and transmission electron microscopy (TEM). In addition, the role of apoptosis for the vascularization in dental mesenchyme was examined by in vitro culture of E14.0 lower molars in the presence of the apoptosis inhibitor (z-VAD-fmk) and a subsequent subrenal culture. Our results showed that CD31- and CD34-positive cells progressively entered the central part of the dental papilla from the peridental mesenchyme. For TEM, angioblasts, young capillaries with thick endothelium and endothelial cells containing vacuoles were observed in peripheral dental mesenchyme, suggesting vasculogenesis was taking place. The presence of lateral sprouting, cytoplasmic filopodia and transluminal bridges in the dental papilla suggested angiogenesis was also occurring. Inhibition of apoptosis delayed the angiogenic vascularization of the dental papilla. Therefore, these data demonstrated that molar mesenchyme is progressively vascularized by mechanisms of both vasculogenesis and angiogenesis and apoptosis partially contributes to the vascularization of the dental papilla.

Antitumor Activity of Rat Mesenchymal Stem Cells during Direct or Indirect Co-Culturing with C6 Glioma Cells.

PubMed

Gabashvili, A N; Baklaushev, V P; Grinenko, N F; Mel'nikov, P A; Cherepanov, S A; Levinsky, A B; Chehonin, V P

2016-02-01

The tumor-suppressive effect of rat mesenchymal stem cells against low-differentiated rat C6 glioma cells during their direct and indirect co-culturing and during culturing of C6 glioma cells in the medium conditioned by mesenchymal stem cells was studied in an in vitro experiment. The most pronounced antitumor activity of mesenchymal stem cells was observed during direct co-culturing with C6 glioma cells. The number of live C6 glioma cells during indirect co-culturing and during culturing in conditioned medium was slightly higher than during direct co-culturing, but significantly differed from the control (C6 glioma cells cultured in medium conditioned by C6 glioma cells). The cytotoxic effect of medium conditioned by mesenchymal stem cells was not related to medium depletion by glioma cells during their growth. The medium conditioned by other "non-stem" cells (rat astrocytes and fibroblasts) produced no tumor-suppressive effect. Rat mesenchymal stem cells, similar to rat C6 glioma cells express connexin 43, the main astroglial gap junction protein. During co-culturing, mesenchymal stem cells and glioma C6 cells formed functionally active gap junctions. Gap junction blockade with connexon inhibitor carbenoxolone attenuated the antitumor effect observed during direct co-culturing of C6 glioma cells and mesenchymal stem cells to the level produced by conditioned medium. Cell-cell signaling mediated by gap junctions can be a mechanism of the tumor-suppressive effect of mesenchymal stem cells against C6 glioma cells. This phenomenon can be used for the development of new methods of cell therapy for high-grade malignant gliomas.

Identification of Regulatory Factors for Mesenchymal Stem Cell-Derived Salivary Epithelial Cells in a Co-Culture System

PubMed Central

Park, Yun-Jong; Koh, Jin; Gauna, Adrienne E.; Chen, Sixue; Cha, Seunghee

2014-01-01

Patients with Sjögren’s syndrome or head and neck cancer patients who have undergone radiation therapy suffer from severe dry mouth (xerostomia) due to salivary exocrine cell death. Regeneration of the salivary glands requires a better understanding of regulatory mechanisms by which stem cells differentiate into exocrine cells. In our study, bone marrow-derived mesenchymal stem cells were co-cultured with primary salivary epithelial cells from C57BL/6 mice. Co-cultured bone marrow-derived mesenchymal stem cells clearly resembled salivary epithelial cells, as confirmed by strong expression of salivary gland epithelial cell-specific markers, such as alpha-amylase, muscarinic type 3 receptor, aquaporin-5, and cytokeratin 19. To identify regulatory factors involved in this differentiation, transdifferentiated mesenchymal stem cells were analyzed temporarily by two-dimensional-gel-electrophoresis, which detected 58 protein spots (>1.5 fold change, p<0.05) that were further categorized into 12 temporal expression patterns. Of those proteins only induced in differentiated mesenchymal stem cells, ankryin-repeat-domain-containing-protein 56, high-mobility-group-protein 20B, and transcription factor E2a were selected as putative regulatory factors for mesenchymal stem cell transdifferentiation based on putative roles in salivary gland development. Induction of these molecules was confirmed by RT-PCR and western blotting on separate sets of co-cultured mesenchymal stem cells. In conclusion, our study is the first to identify differentially expressed proteins that are implicated in mesenchymal stem cell differentiation into salivary gland epithelial cells. Further investigation to elucidate regulatory roles of these three transcription factors in mesenchymal stem cell reprogramming will provide a critical foundation for a novel cell-based regenerative therapy for patients with xerostomia. PMID:25402494

Immortalized Mouse Floxed Fam20c Dental Papillar Mesenchymal and Osteoblast Cell Lines Retain Their Primary Characteristics.

PubMed

Liu, Chao; Wang, Xiaofang; Zhang, Hua; Xie, Xiaohua; Liu, Peihong; Liu, Ying; Jani, Priyam H; Lu, Yongbo; Chen, Shuo; Qin, Chunlin

2015-11-01

Fam20c is essential for the normal mineralization of dentin and bone. The generation of odontoblast and osteoblast cell lines carrying floxed Fam20c allele can offer valuable tools for the study of the roles of Fam20c in the mineralization of dentin and bone. The limited capability of the primary odontoblasts and osteoblasts to proliferate necessitates the development of odontoblast and osteoblast cell lines serving as substitutes for the study of differentiation and mineralization of the odontoblasts and osteoblasts. In this study, we established and characterized immortalized mouse floxed Fam20c dental papilla mesenchymal and osteoblast cell lines. The isolated primary mouse floxed Fam20c dental papilla mesenchymal cells and osteoblasts were immortalized by the infection of lentivirus containing Simian Virus 40 T-antigen (SV40 T-Ag). The immortalization of floxed Fam20c dental papilla mesenchymal cells and osteoblasts was verified by the long-term passages and genomic integration of SV40 T-Ag. The immortalized floxed Fam20c dental papilla mesenchymal and osteoblast cell lines not only proliferated at a high rate and retained the morphology of their primary counterparts, but also preserved the dentin and bone specific gene expression as the primary dental papilla mesenchymal cells and osteoblasts did. Consistently, the capability of the primary floxed Fam20c dental papilla mesenchymal cells and osteoblasts to mineralize was also inherited by the immortalized dental papilla mesenchymal and osteoblast cell lines. Thus, we have successfully generated the immortalized mouse floxed Fam20c dental papilla mesenchymal and osteoblast cell lines. © 2015 Wiley Periodicals, Inc.

Potential benefits of allogeneic bone marrow mesenchymal stem cells for wound healing

PubMed Central

Badiavas, Alexander R.; Badiavas, Evangelos V.

2011-01-01

Introduction It is becoming increasingly evident that select adult stem cells have the capacity to participate in repair and regeneration of damaged and/or diseased tissues. Mesenchymal stem cells have been among the most studied adult stem cells for the treatment of a variety of conditions including wound healing. Areas covered Mesenchymal stem cell features potentially beneficial to cutaneous wound healing applications are reviewed. Expert opinion Given their potential for in vitro expansion and immune modulatory effects, both autologous and allogeneic mesenchymal stem cells appear to be well suited as wound healing therapies. Allogeneic mesenchymal stem cells derived from young healthy donors could have particular advantage over autologous sources where age and systemic disease can be significant factors. PMID:21854302

Transplantation of neurotrophin-3-transfected bone marrow mesenchymal stem cells for the repair of spinal cord injury.

PubMed

Dong, Yuzhen; Yang, Libin; Yang, Lin; Zhao, Hongxing; Zhang, Chao; Wu, Dapeng

2014-08-15

Bone marrow mesenchymal stem cell transplantation has been shown to be therapeutic in the repair of spinal cord injury. However, the low survival rate of transplanted bone marrow mesenchymal stem cells in vivo remains a problem. Neurotrophin-3 promotes motor neuron survival and it is hypothesized that its transfection can enhance the therapeutic effect. We show that in vitro transfection of neurotrophin-3 gene increases the number of bone marrow mesenchymal stem cells in the region of spinal cord injury. These results indicate that neurotrophin-3 can promote the survival of bone marrow mesenchymal stem cells transplanted into the region of spinal cord injury and potentially enhance the therapeutic effect in the repair of spinal cord injury.

Spontaneous multicentric soft tissue sarcoma in a captive African pygmy hedgehog (Atelerix albiventris): case report and literature review.

PubMed

Díaz-Delgado, Josué; Pool, Roy; Hoppes, Sharman; Cerezo, Argine; Quesada-Canales, Óscar; Stoica, George

2017-05-18

This report describes the clinical, macroscopic, histopathological and immunohistochemical features of a spontaneous multicentric extraskeletal sarcoma in an adult male African hedgehog (Atelerix albiventris). It also provides a succinct up-to-date review on neoplasia in this species. On autopsy examination, main gross findings included a moderately demarcated cranial mass and a multilobulated, caudal intra-abdominal mass. The cranial mass had perforated the underlying temporal and occipital bones and had extended into the cranial vault and was compressing the surface of the cerebellum and cerebrum. Histologic, histochemical and immunohistochemical analyses supported a diagnosis of multicentric poorly differentiated spindle cell sarcoma with fibrosarcomatous, storiform and myxoid foci. The high incidence of neoplasia and cross similarities renders the African hedgehog a suitable species for comparative pathology studies.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Noda, Kazuo, E-mail: knoda@kuhp.kyoto-u.ac.jp; Nakamura, Tomoyuki; Komatsu, Yoshihiro

Craniofacial sutures govern the shape of the craniofacial skeleton during postnatal development. The differentiation of suture mesenchymal cells to osteoblasts is precisely regulated in part by signaling through cell surface receptors that interact with extracellular proteins. Here we report that fibulin-5, a key extracellular matrix protein, is important for craniofacial skeletal development in mice. Fibulin-5 is deposited as a fibrous matrix in cranial neural crest-derived mesenchymal tissues, including craniofacial sutures. Fibulin-5-null mice show decreased premaxillary bone outgrowth during postnatal stages. While premaxillo-maxillary suture mesenchymal cells in fibulin-5-null mice were capable of differentiating into osteoblasts, suture cells in mutant mice weremore » less proliferative. Our study provides the first evidence that fibulin-5 is indispensable for the regulation of facial suture mesenchymal cell proliferation required for craniofacial skeletal morphogenesis. - Highlights: • Fibulin-5 is deposited in cranial neural crest-derived mesenchymal tissues. • Fibulin-5-null mice show decreased premaxillary bone growth during postnatal stage. • Fibulin-5 is indispensable for facial suture mesenchymal cell proliferation.« less

Can mesenchymal cells undergo collective cell migration?

PubMed Central

Theveneau, Eric

2011-01-01

Cell migration is critical for proper development of the embryo and is also used by many cell types to perform their physiological function. For instance, cell migration is essential for immune cells to monitor the body and for epithelial cells to heal a wound whereas, in cancer cells, acquisition of migratory capabilities is a critical step toward malignancy. Migratory cells are often categorized into two groups: (1) mesenchymal cells, produced by an epithelium-to-mesenchyme transition, that undergo solitary migration and (2) epithelial-like cells which migrate collectively. However, on some occasions, mesenchymal cells may travel in large, dense groups and exhibit key features of collectively migrating cells such as coordination and cooperation. Here, using data published on neural crest cells, a highly invasive mesenchymal cell population that extensively migrate throughout the embryo, we explore the idea that mesenchymal cells, including cancer cells, might be able to undergo collective cell migration under certain conditions and discuss how they could do so. PMID:22274714

Apolar and polar transitions drive the conversion between amoeboid and mesenchymal shapes in melanoma cells

PubMed Central

Cooper, Sam; Sadok, Amine; Bousgouni, Vicky; Bakal, Chris

2015-01-01

Melanoma cells can adopt two functionally distinct forms, amoeboid and mesenchymal, which facilitates their ability to invade and colonize diverse environments during the metastatic process. Using quantitative imaging of single living tumor cells invading three-dimensional collagen matrices, in tandem with unsupervised computational analysis, we found that melanoma cells can switch between amoeboid and mesenchymal forms via two different routes in shape space—an apolar and polar route. We show that whereas particular Rho-family GTPases are required for the morphogenesis of amoeboid and mesenchymal forms, others are required for transitions via the apolar or polar route and not amoeboid or mesenchymal morphogenesis per se. Altering the transition rates between particular routes by depleting Rho-family GTPases can change the morphological heterogeneity of cell populations. The apolar and polar routes may have evolved in order to facilitate conversion between amoeboid and mesenchymal forms, as cells are either searching for, or attracted to, particular migratory cues, respectively. PMID:26310441

Chimaphilin inhibits human osteosarcoma cell invasion and metastasis through suppressing the TGF-β1-induced epithelial-to-mesenchymal transition markers via PI-3K/Akt, ERK1/2, and Smad signaling pathways.

PubMed

Dong, Feng; Liu, Tingting; Jin, Hao; Wang, Wenbo

2018-01-01

Epithelial-to-mesenchymal transition is a cellular process associated with cancer invasion and metastasis. However, the antimetastatic effects of chimaphilin remain elusive. In this study, we attempted to investigate the potential use of chimaphilin as an inhibitor of TGF-β1-induced epithelial-to-mesenchymal transition in U2OS cells. We found that TGF-β1 induced epithelial-to-mesenchymal transition to promote U2OS cell invasion and metastasis. Western blotting demonstrated that chimaphilin inhibited U2OS cell invasion and migration, increased the expression of the epithelial phenotype marker E-cadherin, repressed the expression of the mesenchymal phenotype marker vimentin, as well as decreased the level of epithelial-to-mesenchymal-inducing transcription factors Snail1 and Slug during the initiation of TGF-β1-induced epithelial-to-mesenchymal transition. In this study, we revealed that chimaphilin up-regulated the E-cadherin expression level and inhibited the production of vimentin, Snail1, and Slug in TGF-β1-induced U2OS cells by blocking PI-3K/Akt and ERK 1/2 signaling pathway. Additionally, the TGF-β1-mediated phosphorylated levels of Smad2/3 were inhibited by chimaphilin pretreatment. Above all, we conclude that chimaphilin represents an effective inhibitor of the metastatic potential of U2OS cells through suppression of TGF-β1-induced epithelial-to-mesenchymal transition.

Proliferation, apoptosis and expression of matrix metalloproteinase-9 in human fetal lung.

PubMed

Kraljevic, Daniela; Vukojevic, Katarina; Karan, Dragana; Rajic, Borko; Todorovic, Jelena; Miskovic, Josip; Tomic, Vajdana; Kordic, Mario; Soljic, Violeta

2015-01-01

Expression pattern of the Ki-67, caspase-3 and matrix metalloproteinases-9 (MMP-9) factors were immunohistochemically analyzed in 48 human fetal lungs from 12 to 40 weeks of gestation. The number of Ki-67 positive cells in the epithelium of canaliculare (88cells/mm(2)) and sacculare stage (93cells/mm(2)) were significantly higher than in the epithelium of pseudoglandular stage (12cells/mm(2)) (p=0.0008 vs. p=0.003). The number of Ki-67 positive cells in the mesenchyme of canaliculare stage (132cells/mm(2)) was significantly higher than in the mesenchyme of pseudoglandular stage (37cells/mm(2)) (p=0.001). The proliferation of mesenchymal cells was higher than the epithelial cells in all developmental stages, especially in the canaliculare stage (p=0.007). Similarly, the number of caspase-3 positive cells in the epithelium of canalicular stage (13cells/mm(2)) was significantly higher than in the epithelium of pseudoglandular stage (6cells/mm(2)) (p=0.002) with peaks in the conductive epithelium of canalicular stage. The number of caspase-3 positive cells in the mesenchyme of canaliculare stage (3cells/mm(2)) was significantly higher than in the mesenchyme of saccular stage (0cells/mm(2)) (p=0.05). There were no caspase-3 positive cells in the mesenchyme of pseudoglandular stage. However, unlike the Ki-67 expression, mesenchymal cells in comparison to epithelial cells express substantially less caspase-3 in all developmental stages. Up to the saccular stage, the expression of MMP-9 in mesenchymal cells showed a linear increase with most pronounced expression in that stage. The number of MMP-9 positive cells in the mesenchyme of canaliculare (20cells/mm(2)) and sacculare (39cells/mm(2)) stage were significantly higher than in the mesenchyme of pseudoglandular stage (12cells/mm(2)) (p=0.04 vs. p=0.004). The first epithelial cells that express MMP-9 were present only at the alveolar stage. Increased proliferation and apoptosis of the mesenchymal cells of canalicular stage is important for formation of definite structures within the stroma of the lung parenchyma. Although apoptosis in the epithelium is not pronounced as proliferation, it is important for thinning of the epithelium and consequent spread of respiratory tract. However in the saccular stage when mesenchyme disappears, MMP-9 expression is more important for primitive alveoli differentiation. Copyright © 2015 Elsevier GmbH. All rights reserved.

Isolation and purification of rabbit mesenchymal stem cells using an optimized protocol.

PubMed

Lin, Chunbo; Shen, Maorong; Chen, Weiping; Li, Xiaofeng; Luo, Daoming; Cai, Jinhong; Yang, Yuan

2015-11-01

Mesenchymal stem cells were first isolated and grown in vitro by Friedenstein over 40 yr ago; however, their isolation remains challenging as they lack unique markers for identification and are present in very small quantities in mesenchymal tissues and bone marrow. Using whole marrow samples, common methods for mesenchymal stem cell isolation are the adhesion method and density gradient fractionation. The whole marrow sample adhesion method still results in the nonspecific isolation of mononuclear cells, and activation and/or potential loss of target cells. Density gradient fractionation methods are complicated, and may result in contamination with toxic substances that affect cell viability. In the present study, we developed an optimized protocol for the isolation and purification of mesenchymal stem cells based on the principles of hypotonic lysis and natural sedimentation.

Mesenchymal-epithelial interactions during hair follicle morphogenesis and cycling

PubMed Central

Sennett, Rachel; Rendl, Michael

2012-01-01

Embryonic hair follicle induction and formation are regulated by mesenchymal-epithelial interactions between specialized dermal cells and epidermal stem cells that switch to a hair fate. Similarly, during postnatal hair growth, communication between mesenchymal dermal papilla cells and surrounding epithelial matrix cells coordinates hair shaft production. Adult hair follicle regeneration in the hair cycle again is thought to be controlled by activating signals originating from the mesenchymal compartment and acting on hair follicle stem cells. Although many signaling pathways are implicated in hair follicle formation and growth, the precise nature, timing, and intersection of these inductive and regulatory signals remains elusive. The goal of this review is to summarize our current understanding and to discuss recent new insights into mesenchymal-epithelial interactions during hair follicle morphogenesis and cycling. PMID:22960356

Cytokine Production in Mixed Cultures of Mesenchymal Stromal Cells from Wharton's Jelly and Peripheral Blood Lymphocytes.

PubMed

Poltavtsev, A M; Poltavtseva, R A; Yushina, M N; Volgina, N E; Svirshchevskaya, E V

2017-05-01

We compared the production of 19 humoral factors in mixed cultures of mesenchymal stromal cells from Wharton's jelly and allogenic peripheral blood lymphocytes. For evaluation of the specificity of immunosuppressive activity of mesenchymal stromal cells, comparative analysis of the production of these humoral factors in mixed cultures of lymphocytes and epithelial BxPC-3 cells was conducted. The production of soluble factors in both mono- and mixed cultures significantly correlated (p<0.05). The maximum production was found for proinflammatory chemokine IP-10 and IFN-γ and anti-inflammatory cytokine IL-10. The major difference of mesenchymal stromal cells from epithelial BxPC-3 cells was 7-fold higher production of IL-10, which can explain the immunosuppressive effect of mesenchymal stromal cells.

A Systematic Review of Mesenchymal Stem Cells in Spinal Cord Injury, Intervertebral Disc Repair and Spinal Fusion.

PubMed

Khan, Shujhat; Mafi, Pouya; Mafi, Reza; Khan, Wasim

2018-01-01

Spinal surgery presents a challenge for both neurosurgery and orthopaedic surgery. Due to the heterogeneous differentiation potential of mesenchymal stem cells, there is much interest in the treatment of spine surgery. Animal and human trials focussing on the efficacy of mesenchymal stem cells in spinal cord injury, spine fusion and disc degeneration were included in this systematic review. Published articles up to January 2016 from MEDLINE, PubMed and Ovid were used by searching for specific terms. Of the 2595 articles found, 53 met the selection criteria and were included for analysis (16 on spinal cord injury, 28 on intervertebral disc repair and 9 on spinal fusion). Numerous studies reported better results when the mesenchymal stem cells were used in co-culture with other cells or used in scaffolds. Mesenchymal stem cells were also found to have an immune-modulatory role, which can improve surgical outcome. This systematic review suggests that mesenchymal stem cells can be used safely and effectively for these spinal surgery treatments. Whilst, in certain studies, mesenchymal stem cells did not necessarily show improved results from existing treatments, they provide an alternative option. This can reduce morbidity that arises from current surgical treatment. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Wnt/β-Catenin Signaling Determines the Vasculogenic Fate of Postnatal Mesenchymal Stem Cells.

PubMed

Zhang, Zhaocheng; Nör, Felipe; Oh, Min; Cucco, Carolina; Shi, Songtao; Nör, Jacques E

2016-06-01

Vasculogenesis is the process of de novo blood vessel formation observed primarily during embryonic development. Emerging evidence suggest that postnatal mesenchymal stem cells are capable of recapitulating vasculogenesis when these cells are engaged in tissue regeneration. However, the mechanisms underlining the vasculogenic differentiation of mesenchymal stem cells remain unclear. Here, we used stem cells from human permanent teeth (dental pulp stem cells [DPSC]) or deciduous teeth (stem cells from human exfoliated deciduous teeth [SHED]) as models of postnatal primary human mesenchymal stem cells to understand mechanisms regulating their vasculogenic fate. GFP-tagged mesenchymal stem cells seeded in human tooth slice/scaffolds and transplanted into immunodeficient mice differentiate into human blood vessels that anastomize with the mouse vasculature. In vitro, vascular endothelial growth factor (VEGF) induced the vasculogenic differentiation of DPSC and SHED via potent activation of Wnt/β-catenin signaling. Further, activation of Wnt signaling is sufficient to induce the vasculogenic differentiation of postnatal mesenchymal stem cells, while Wnt inhibition blocked this process. Notably, β-catenin-silenced DPSC no longer differentiate into endothelial cells in vitro, and showed impaired vasculogenesis in vivo. Collectively, these data demonstrate that VEGF signaling through the canonical Wnt/β-catenin pathway defines the vasculogenic fate of postnatal mesenchymal stem cells. Stem Cells 2016;34:1576-1587. © 2016 AlphaMed Press.

Novel application of the published kinase inhibitor set to identify therapeutic targets and pathways in triple negative breast cancer subtypes

PubMed Central

Phamduy, Theresa B.; Chrisey, Douglas B.

2017-01-01

Triple negative breast cancers (TNBCs) have high recurrence and metastasis rates. Acquisition of a mesenchymal morphology and phenotype in addition to driving migration is a consequential process that promotes metastasis. Although some kinases are known to regulate a mesenchymal phenotype, the role for a substantial portion of the human kinome remains uncharacterized. Here we evaluated the Published Kinase Inhibitor Set (PKIS) and screened a panel of TNBC cell lines to evaluate the compounds’ effects on a mesenchymal phenotype. Our screen identified 36 hits representative of twelve kinase inhibitor chemotypes based on reversal of the mesenchymal cell morphology, which was then prioritized to twelve compounds based on gene expression and migratory behavior analyses. We selected the most active compound and confirmed mesenchymal reversal on transcript and protein levels with qRT-PCR and Western Blot. Finally, we utilized a kinase array to identify candidate kinases responsible for the EMT reversal. This investigation shows the novel application to identify previously unrecognized kinase pathways and targets in acquisition of a mesenchymal TNBC phenotype that warrant further investigation. Future studies will examine specific roles of the kinases in mechanisms responsible for acquisition of the mesenchymal and/or migratory phenotype. PMID:28771473

Hyaluronidase 2 Deficiency Causes Increased Mesenchymal Cells, Congenital Heart Defects, and Heart Failure.

PubMed

Chowdhury, Biswajit; Xiang, Bo; Liu, Michelle; Hemming, Richard; Dolinsky, Vernon W; Triggs-Raine, Barbara

2017-01-01

Hyaluronan (HA) is required for endothelial-to-mesenchymal transition and normal heart development in the mouse. Heart abnormalities in hyaluronidase 2 (HYAL2)-deficient ( Hyal2 - /- ) mice and humans suggested removal of HA is also important for normal heart development. We have performed longitudinal studies of heart structure and function in Hyal2 -/- mice to determine when, and how, HYAL2 deficiency leads to these abnormalities. Echocardiography revealed atrial enlargement, atrial tissue masses, and valvular thickening at 4 weeks of age, as well as diastolic dysfunction that progressed with age, in Hyal2 -/- mice. These abnormalities were associated with increased HA, vimentin-positive cells, and fibrosis in Hyal2 -/- compared with control mice. Based on the severity of heart dysfunction, acute and chronic groups of Hyal2 -/- mice that died at an average of 12 and 25 weeks respectively, were defined. Increased HA levels and mesenchymal cells, but not vascular endothelial growth factor in Hyal2 -/- embryonic hearts, suggest that HYAL2 is important to inhibit endothelial-to-mesenchymal transition. Consistent with this, in wild-type embryos, HYAL2 and HA were readily detected, and HA levels decreased with age. These data demonstrate that disruption of normal HA catabolism in Hyal2 -/- mice causes increased HA, which may promote endothelial-to-mesenchymal transition and proliferation of mesenchymal cells. Excess endothelial-to-mesenchymal transition, resulting in increased mesenchymal cells, is the likely cause of morphological heart abnormalities in both humans and mice. In mice, these abnormalities result in progressive and severe diastolic dysfunction, culminating in heart failure. © 2016 The Authors.

The potential of chondrogenic pre-differentiation of adipose-derived mesenchymal stem cells for regeneration in harsh nucleus pulposus microenvironment.

PubMed

Wang, Jingkai; Tao, Yiqing; Zhou, Xiaopeng; Li, Hao; Liang, Chengzhen; Li, Fangcai; Chen, Qi-Xin

2016-12-01

Recent studies indicated that cell-based therapy could be a promising approach to treat intervertebral disc degeneration. Though the harsh microenvironment in disc is still challenging to implanted cells, it could be overcome by pre-conditioning graft cells before transplantation, suggested by previous literatures. Therefore, we designed this study to identify the potential effect of chondrogenic pre-differentiation on adipose-derived mesenchymal stem cells in intervertebral disc-like microenvironment, characterized by limited nutrition, acidic, and high osmosis in vitro. Adipose-derived mesenchymal stem cells of rat were divided into five groups, embedded in type II collagen scaffold, and cultured in chondrogenic differentiation medium for 0, 3, 7, 10, and 14 days. Then, the adipose-derived mesenchymal stem cells were implanted and cultured in intervertebral disc-like condition. The proliferation and differentiation of adipose-derived mesenchymal stem cells were evaluated by cell counting kit-8 test, real-time quantitative polymerase chain reaction, and Western blotting and immunofluorescence analysis. Analyzed by the first week in intervertebral disc-like condition, the results showed relatively greater proliferative capability and extracellular matrix synthesis ability of the adipose-derived mesenchymal stem cells pre-differentiated for 7 and 10 days than the control. We concluded that pre-differentiation of rat adipose-derived mesenchymal stem cells in chondrogenic culture medium for 7 to 10 days could promote the regeneration effect of adipose-derived mesenchymal stem cells in intervertebral disc-like condition, and the pre-differentiated cells could be a promising cell source for disc regeneration medicine.

DHEA increases epithelial markers and decreases mesenchymal proteins in breast cancer cells and reduces xenograft growth.

PubMed

Colín-Val, Zaira; González-Puertos, Viridiana Yazmín; Mendoza-Milla, Criselda; Gómez, Erika Olivia; Huesca-Gómez, Claudia; López-Marure, Rebeca

2017-10-15

Breast cancer is one of the most common neoplasias and the leading cause of cancer death in women worldwide. Its high mortality rate is linked to a great metastatic capacity associated with the epithelial-mesenchymal transition (EMT). During this process, a decrease in epithelial proteins expression and an increase of mesenchymal proteins are observed. On the other hand, it has been shown that dehydroepiandrosterone (DHEA), the most abundant steroid in human plasma, inhibits migration of breast cancer cells; however, the underlying mechanisms have not been elucidated. In this study, the in vitro effect of DHEA on the expression pattern of some EMT-related proteins, such as E-cadherin (epithelial), N-cadherin, vimentin and Snail (mesenchymal) was measured by Western blot and immunofluorescence in MDA-MB-231 breast cancer cells with invasive, metastatic and mesenchymal phenotype. Also, the in vivo effect of DHEA on xenograft tumor growth in nude mice (nu - /nu - ) and on expression of the same epithelial and mesenchymal proteins in generated tumors was evaluated. We found that DHEA increased expression of E-cadherin and decreased N-cadherin, vimentin and Snail expression both in MD-MB-231 cells and in the formed tumors, possibly by DHEA-induced reversion of mesenchymal phenotype. These results were correlated with a tumor size reduction in mouse xenografts following DHEA administration either a week earlier or concurrent with breast cancer cells inoculation. In conclusion, DHEA could be useful in the treatment of breast cancer with mesenchymal phenotype. Copyright © 2017 Elsevier Inc. All rights reserved.

Multimodality imaging features, metastatic pattern and clinical outcome in adult extraskeletal Ewing sarcoma: experience in 26 patients

PubMed Central

Somarouthu, B S; Shinagare, A B; Rosenthal, M H; Hornick, J L; Ramaiya, N H

2014-01-01

Objective: To describe the multimodality imaging features, metastatic pattern and clinical outcome in adult extraskeletal Ewing sarcoma (EES). Methods: In this institutional review board–approved, health insurance portability and accountability act–compliant retrospective study, we included 26 patients (17 females and 9 males; mean age, 36 years; range, 18–85 years) with pathologically confirmed EES seen at our institute between 1999 and 2011, who had imaging of primary tumour. Imaging of primary tumour in all 26 patients and follow-up imaging in 23 was reviewed by two radiologists in consensus. Clinical data were extracted from electronic medical records. Results: The most common primary sites were the torso (n = 13), extremities (n = 10) and head and neck (HN) region (n = 3). The mean tumour size was 9 cm (range, 3–22 cm); tumours of the torso were larger than those of other areas (p > 0.05). Compared with the skeletal muscle, tumours were isodense on CT (21/21), hypointense (n = 5) to isointense (n = 14) on T1 weighted image, hyperintense on T2 weighted image (19/19) and were fluorine-18 fludeoxyglucose (18F-FDG)-avid [10/10; mean maximum standardized uptake value of 7 (range, 3–11)]. Necrosis (15/26), haemorrhage (5/26) and adjacent organ invasion (14/26) were present without calcification. Median follow-up was 16 months. 5 patients had local recurrence (torso, 3; extremity, 1; and HN, 1). Metastases developed in 11 patients (torso, 7; extremities, 3; and HN, 1; p > 0.05); 8 at presentation, most commonly to lung (9/11), peritoneum (4/11), muscles (4/11) and lymph nodes (4/11). Nine patients (torso, 7; extremity, 1; and HN, 1) died (10 months median survival) (p > 0.05). Conclusion: Adult EESs are large tumours, which frequently invade adjacent organs and metastasize to the lung. EESs of the torso are larger, have more frequent metastases and poorer outcomes. Advances in knowledge: Adult EESs of the torso have poor outcomes compared with other EESs. PMID:24734938

Probing Tumor Microenvironment with In Vivo Phage Display

DTIC Science & Technology

2013-07-01

include immune cells (macrophages polymorphonuclear neutrophils, lymphocytes, dendritic cells ), mesenchymal cells (fibroblasts, mesenchymal stem ... cells , immune cells , mesenchymal cells , and extracellular matrix, which are critical to tumor development and progression. Although various probes...example is the production of various growth factors and cytokines by tumor macrophages, which can promote tumor cell growth and angiogenesis

Mesenchymal Inflammation Drives Genotoxic Stress in Hematopoietic Stem Cells and Predicts Disease Evolution in Human Pre-leukemia.

PubMed

Zambetti, Noemi A; Ping, Zhen; Chen, Si; Kenswil, Keane J G; Mylona, Maria A; Sanders, Mathijs A; Hoogenboezem, Remco M; Bindels, Eric M J; Adisty, Maria N; Van Strien, Paulina M H; van der Leije, Cindy S; Westers, Theresia M; Cremers, Eline M P; Milanese, Chiara; Mastroberardino, Pier G; van Leeuwen, Johannes P T M; van der Eerden, Bram C J; Touw, Ivo P; Kuijpers, Taco W; Kanaar, Roland; van de Loosdrecht, Arjan A; Vogl, Thomas; Raaijmakers, Marc H G P

2016-11-03

Mesenchymal niche cells may drive tissue failure and malignant transformation in the hematopoietic system, but the underlying molecular mechanisms and relevance to human disease remain poorly defined. Here, we show that perturbation of mesenchymal cells in a mouse model of the pre-leukemic disorder Shwachman-Diamond syndrome (SDS) induces mitochondrial dysfunction, oxidative stress, and activation of DNA damage responses in hematopoietic stem and progenitor cells. Massive parallel RNA sequencing of highly purified mesenchymal cells in the SDS mouse model and a range of human pre-leukemic syndromes identified p53-S100A8/9-TLR inflammatory signaling as a common driving mechanism of genotoxic stress. Transcriptional activation of this signaling axis in the mesenchymal niche predicted leukemic evolution and progression-free survival in myelodysplastic syndrome (MDS), the principal leukemia predisposition syndrome. Collectively, our findings identify mesenchymal niche-induced genotoxic stress in heterotypic stem and progenitor cells through inflammatory signaling as a targetable determinant of disease outcome in human pre-leukemia. Copyright © 2016 Elsevier Inc. All rights reserved.

EGF does not induce Msx-1 and Msx-2 in dental mesenchyme.

PubMed

Wang, Y H; Kollar, E J; Upholt, W B; Mina, M

1998-01-01

Previous heterospecific tissue recombinations indicate that mandibular epithelium exerts the first known inductive signal for odontogenesis in mouse embryos. BMP-4 and EGF are two growth factors implicated as signaling molecules mediating the initial inductive epithelial-mesenchymal interactions during odontogenesis. The purpose of the present study was to examine and compare the effects of these growth factors and mouse mandibular epithelium on expression of Msx-1 and Msx-2 genes in molar-forming mesenchyme. Agarose beads soaked in growth factors or pieces of mouse mandibular epithelium (E11) were placed in contact with E11 molar-forming mesenchyme and cultured for 24 h. Whole-mount in situ hybridization analysis revealed that, in contrast to mouse mandibular epithelium and BMP-4-releasing beads, EGF-releasing beads did not induce the expression of Msx-1 and Msx-2 in E11 molar-forming mesenchyme. These observations suggest that whereas BMP-4 may be involved in activation of Msx-1 and Msx-2 in the underlying mesenchyme, EGF may regulate events involved in the formation of dental lamina.

[Pathological and immunohistochemical analysis of giant cells of pancreas].

PubMed

Miyake, T; Suda, K; Yamamura, A; Tada, Y

1997-10-01

Multinucleated giant cells in the pancreas (five giant cell carcinomas, a mucinous cystadenocarcinoma attended with many osteoclast-like giant cells, 42 invasive ductal carcinomas and 29 chronic pancreatitises) were examined. Three types of multinucleated giant cell were identified: epithelial type, coexpressive type, mesenchymal type. Epithelial type expressed epithelial markers, such as keratin and EMA in 23 ductal carcinomas. Coexpressive type expressed both epithelial markers and mesenchymal marker vimentin was in four ductal carcinomas. Mesenchymal type expressed mesenchymal markers, vimentin and CD68 in four osteoclastoid type giant cell carcinomas, the mucinous cystadenocarcinoma, six ductal carcinomas and ten chronic pancreatitises. Epithelial and coexpressive type were considered to be epithelial neoplastic origin, those had bizarre appearance and transitional area from definite adenocarcinoma area. Vimentin expression is associated with sarcomatous proliferation. Mesenchymal type was considered to be nonneoplastic and a certain type of macrophage polykaryons.

Establishment of human hair follicle mesenchymal stem cells with overexpressed human hepatocyte growth factor.

PubMed

Zhou, Dan; Cheng, Hongjing; Liu, Jinyu; Zhang, Lei

2017-06-01

Chronic liver disease has become a major health problem that causes serious damage to human health. Since the existing treatment effect was not ideal, we need to seek new treatment methods. We utilized the gene recombination technology to obtain the human hair mesenchymal stem cells which overexpression of human hepatocyte growth factor (hHGF). Furthermore, we verified the property of transfected cells through detecting surface marker by flow cytometry. We show here establishment of the hHGF-overexpressing lentivirus vector, and successfully transfection to human hair follicle mesenchymal stem cells. The verified experiments could demonstrate the human hair follicle mesenchymal stem cells which have been transfected still have the properties of stem cells. We successfully constructed human hair follicle mesenchymal stem cells which overexpression hHGF, and maintain the same properties compared with pro-transfected cells.

[Analysis of factors related to the number of mesenchymal stem cells derived from synovial fluid of the temporomandibular joint].

PubMed

Sun, Y P; Zheng, Y H; Zhang, Z G

2017-06-09

Objective: To analyze related factors on the number of mesenchymal stem cells in the synovial fluid of the temporomandibular joint (TMJ) and provide an research basis for understanding of the source and biological role of mesenchymal stem cells derived from synovial fluid in TMJ. Methods: One hundred and twenty-two synovial fluid samples from 91 temporomandibular disorders (TMD) patients who visited in Department of TMJ Center, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University from March 2013 to December 2013 were collected in this study, and 6 TMJ synovial fluid samples from 6 normal volunteers who were studying in the North Campus of Sun Yat-sen University were also collected, so did their clinical information. Then the relation between the number of mesenchymal stem cells derived from synovial fluid and the health status of the joints, age of donor, disc perforation, condylar bony destruction, blood containing and visual analogue scale score of pain were investigated using Mann-Whitney U test and Spearman rank correlation test. Results: The number of mesenchymal stem cells derived from synovial fluid had no significant relation with visual analogue scale score of pain ( r= 0.041, P= 0.672), blood containing ( P= 0.063), condylar bony destruction ( P= 0.371). Linear correlation between the number of mesenchymal stem cells derived from synovial fluid and age of donor was very week ( r= 0.186, P= 0.043). The number of mesenchymal stem cells up-regulated when the joint was in a disease state ( P= 0.001). The disc perforation group had more mesenchymal stem cells in synovial fluid than without disc perforation group ( P= 0.042). Conclusions: The number of mesenchymal stem cells derived from synovial fluid in TMJ has no correlation with peripheral blood circulation and condylar bony destruction, while has close relation with soft tissue structure damage of the joint.

Placental mesenchymal dysplasia complicated by hydrops fetalis and fetal death: a case report.

PubMed

Akbarzadeh-Jahromi, Mojgan; Sari Aslani, Fatemeh; Parvari, Shams

2013-09-01

Placental mesenchymal dysplasia is a rare condition of the placenta and its true incidence and underlying cause has remained unknown till now due to its rarity. Its accurate diagnosis is essential, because placental mesenchymal dysplasia is usually compatible with a good fetal and maternal outcome. A precise ultrasonographic evaluation can contribute to the identification of characteristic features, particularly to discriminate it from partial hydatidiform mole, its main differential diagnosis. We report an early third-trimester pathologically- diagnosed case of placental mesenchymal dysplasia. It was complicated by fetal hydrops and death. 

Synergetic effect of topological cue and periodic mechanical tension-stress on osteogenic differentiation of rat bone mesenchymal stem cells.

PubMed

Liu, Yao; Yang, Guang; Ji, Huanzhong; Xiang, Tao; Luo, En; Zhou, Shaobing

2017-06-01

Mesenchymal stem cells (MSCs) are able to self-renew and differentiate into tissues of mesenchymal origin, making them to be significant for cell-based therapies, such as metabolic bone diseases and bone repair. Regulating the differentiation of MSCs is significant for bone regeneration. Electrospun fibers mimicking natural extracellular matrix (ECM), is an effective artificial ECM to regulate the behaviors and fates of MSCs. The aligned electrospun fibers can modulate polar cell pattern of bone mesenchymal stem cells, which leads to more obvious osteogenic differentiation. Apart from the topographic effect of electrospun fibers, mechanical cues can also intervene the cell behaviors. In this study, the osteogenic differentiation of rat bone mesenchymal stem cells was evaluated, which were cultured on aligned/random electrospun fiber mats materials under mechanical tension intervention. Scanning electron microscope and immune-fluorescent staining were used to directly observe the polarity changing of cellular morphology and cytoskeleton. The results proved that aligned electrospun fibers could be more conducive to promote osteogenic differentiation of rat bone mesenchymal stem cells and this promotion of osteogenic differentiation was enhanced by tension intervention. These results were correlated to the quantitative real-time PCR assay. In general, culturing rat bone mesenchymal stem cells on electrospun fibers under the intervention of mechanical tension is an effective way to mimic a more real cellular microenvironment. Copyright © 2017 Elsevier B.V. All rights reserved.

Epithelial-mesenchymal transition can suppress major attributes of human epithelial tumor-initiating cells

PubMed Central

Celià-Terrassa, Toni; Meca-Cortés, Óscar; Mateo, Francesca; Martínez de Paz, Alexia; Rubio, Nuria; Arnal-Estapé, Anna; Ell, Brian J.; Bermudo, Raquel; Díaz, Alba; Guerra-Rebollo, Marta; Lozano, Juan José; Estarás, Conchi; Ulloa, Catalina; ρlvarez-Simón, Daniel; Milà, Jordi; Vilella, Ramón; Paciucci, Rosanna; Martínez-Balbás, Marian; García de Herreros, Antonio; Gomis, Roger R.; Kang, Yibin; Blanco, Jerónimo; Fernández, Pedro L.; Thomson, Timothy M.

2012-01-01

Malignant progression in cancer requires populations of tumor-initiating cells (TICs) endowed with unlimited self renewal, survival under stress, and establishment of distant metastases. Additionally, the acquisition of invasive properties driven by epithelial-mesenchymal transition (EMT) is critical for the evolution of neoplastic cells into fully metastatic populations. Here, we characterize 2 human cellular models derived from prostate and bladder cancer cell lines to better understand the relationship between TIC and EMT programs in local invasiveness and distant metastasis. The model tumor subpopulations that expressed a strong epithelial gene program were enriched in highly metastatic TICs, while a second subpopulation with stable mesenchymal traits was impoverished in TICs. Constitutive overexpression of the transcription factor Snai1 in the epithelial/TIC-enriched populations engaged a mesenchymal gene program and suppressed their self renewal and metastatic phenotypes. Conversely, knockdown of EMT factors in the mesenchymal-like prostate cancer cell subpopulation caused a gain in epithelial features and properties of TICs. Both tumor cell subpopulations cooperated so that the nonmetastatic mesenchymal-like prostate cancer subpopulation enhanced the in vitro invasiveness of the metastatic epithelial subpopulation and, in vivo, promoted the escape of the latter from primary implantation sites and accelerated their metastatic colonization. Our models provide new insights into how dynamic interactions among epithelial, self-renewal, and mesenchymal gene programs determine the plasticity of epithelial TICs. PMID:22505459

Biocompatibility of quantum dots (CdSe/ZnS ) in human amniotic membrane-derived mesenchymal stem cells in vitro.

PubMed

Wang, Gongping; Zeng, Guangwei; Wang, Caie; Wang, Huasheng; Yang, Bo; Guan, Fangxia; Li, Dongpeng; Feng, Xiaoshan

2015-06-01

Amniotic membrane-derived mesenchymal stem cells (hAM-dMSCs) are a potential source of mesenchymal stem cells which could be used to repair skin damage. The use of mesenchymal stem cells to repair skin damage requires safe, effective and biocompatible agents to evaluate the effectiveness of the result. Quantum dots (QDs) composed of CdSe/ZnS are semiconductor nanocrystals with broad excitation and narrow emission spectra, which have been considered as a new chemical and fluorescent substance for non-invasively labeling different cells in vitro and in vivo. This study investigated the cytotoxic effects of QDs on hAM-dMSCs at different times following labeling. Using 0.75, 1.5 and 3.0 μL between quantum dots, labeled human amniotic mesenchymal stem cells were collected on days 1, 2 and 4 and observed morphological changes, performed an MTT cell growth assay and flow cytometry for mesenchymal stem cells molecular markers. Quantum dot concentration 0.75 μg/mL labeled under a fluorescence microscope, cell morphology was observed, The MTT assay showed cells in the proliferative phase. Flow cytometry expression CD29, CD31, CD34, CD44, CD90, CD105 and CD106. Within a certain range of concentrations between quantum dots labeled human amniotic mesenchymal stem cells has good biocompatibility.

The increase of microRNA-21 during lung fibrosis and its contribution to epithelial-mesenchymal transition in pulmonary epithelial cells.

PubMed

Yamada, Mitsuhiro; Kubo, Hiroshi; Ota, Chiharu; Takahashi, Toru; Tando, Yukiko; Suzuki, Takaya; Fujino, Naoya; Makiguchi, Tomonori; Takagi, Kiyoshi; Suzuki, Takashi; Ichinose, Masakazu

2013-09-24

The excess and persistent accumulation of fibroblasts due to aberrant tissue repair results in fibrotic diseases such as idiopathic pulmonary fibrosis. Recent reports have revealed significant changes in microRNAs during idiopathic pulmonary fibrosis and evidence in support of a role for microRNAs in myofibroblast differentiation and the epithelial-mesenchymal transition in the context of fibrosis. It has been reported that microRNA-21 is up-regulated in myofibroblasts during fibrosis and promotes transforming growth factor-beta signaling by inhibiting Smad7. However, expression changes in microRNA-21 and the role of microRNA-21 in epithelial-mesenchymal transition during lung fibrosis have not yet been defined. Lungs from saline- or bleomycin-treated C57BL/6 J mice and lung specimens from patients with idiopathic pulmonary fibrosis were analyzed. Enzymatic digestions were performed to isolate single lung cells. Lung epithelial cells were isolated by flow cytometric cell sorting. The expression of microRNA-21 was analyzed using both quantitative PCR and in situ hybridization. To induce epithelial-mesenchymal transition in culture, isolated mouse lung alveolar type II cells were cultured on fibronectin-coated chamber slides in the presence of transforming growth factor-β, thus generating conditions that enhance epithelial-mesenchymal transition. To investigate the role of microRNA-21 in epithelial-mesenchymal transition, we transfected cells with a microRNA-21 inhibitor. Total RNA was isolated from the freshly isolated and cultured cells. MicroRNA-21, as well as mRNAs of genes that are markers of alveolar epithelial or mesenchymal cell differentiation, were quantified using quantitative PCR. The lung epithelial cells isolated from the bleomycin-induced lung fibrosis model system had decreased expression of epithelial marker genes, whereas the expression of mesenchymal marker genes was increased. MicroRNA-21 was significantly upregulated in isolated lung epithelial cells during bleomycin-induced lung fibrosis and human idiopathic pulmonary fibrosis. MicroRNA-21 was also upregulated in the cultured alveolar epithelial cells under the conditions that enhance epithelial-mesenchymal transition. Exogenous administration of a microRNA-21 inhibitor prevented the increased expression of vimentin and alpha-smooth muscle actin in cultured primary mouse alveolar type II cells under culture conditions that induce epithelial-mesenchymal transition. Our experiments demonstrate that microRNA-21 is increased in lung epithelial cells during lung fibrosis and that it promotes epithelial-mesenchymal transition.

Lower Oncogenic Potential of Human Mesenchymal Stem Cells Derived from Cord Blood Compared to Induced Pluripotent Stem Cells

PubMed Central

Foroutan, T.; Najmi, M.; Kazemi, N.; Hasanlou, M.; Pedram, A.

2015-01-01

Background: In regenerative medicine, use of each of the mesenchymal stem cells derived from bone marrow, cord blood, and adipose tissue, has several cons and pros. Mesenchymal stem cells derived from cord blood have been considered the best source for precursor transplantation. Direct reprogramming of a somatic cell into induced pluripotent stem cells by over-expression of 6 transcription factors Oct4, Sox2, Klf4, lin28, Nanog, and c-Myc has great potential for regenerative medicine, eliminating the ethical issues of embryonic stem cells and the rejection problems of using non-autologous cells. Objective: To compare reprogramming and pluripotent markers OCT4, Sox-2, c-Myc, Klf4, Nanog, and lin28 in mesenchymal stem cells derived from cord blood and induced pluripotent stem cells. Methods: We analyzed the expression level of OCT4, Sox-2, c-Myc, Klf4, Nanog and lin28 genes in human mesenchymal stem cells derived from cord blood and induced pluripotent stem cells by cell culture and RT-PCR. Results: The expression level of pluripotent genes OCT4 and Sox-2, Nanog and lin28 in mesenchymal stem cells derived from cord blood were significantly higher than those in induced pluripotent stem cells. In contrast to OCT-4A and Sox-2, Nanog and lin28, the expression level of oncogenic factors c-Myc and Klf4 were significantly higher in induced pluripotent stem cells than in mesenchymal stem cells derived from cord blood. Conclusion: It could be concluded that mesenchymal stem cells derived from human cord blood have lower oncogenic potential compared to induced pluripotent stem cells. PMID:26306155

Down-regulation of Wnt10a affects odontogenesis and proliferation in mesenchymal cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liu, Yang, E-mail: Ly10160624@163.com; Han, Dong, E-mail: Donghan@bjmu.edu.cn; Wang, Lei, E-mail: wanglei_dentist@163.com

Highlights: •Down-regulation of Wnt10a in dental mesenchymal cells impairs odontogenesis of reassociated tooth germs. •Dspp is down- and up-regulated after Wnt10a-knockdown and overexpression in dental mesenchymal cells. •Down-regulation of Wnt10a inhibits proliferation of dental mesenchymal cells. -- Abstract: The WNT10a mutation has been found in patients with abnormal odontogenesis. In mice, Wnt10a expression is found in the tooth germ, but its role has not yet been elucidated. We aimed to investigate the role of Wnt10a in odontogenesis. Mesenchymal cells of the first mandibular molar germ at the bell stage were isolated, transfected with Wnt10a SiRNA or plasmid, and reassociated withmore » epithelial part of the molar germ. Scrambled SiRNA or empty vector was used in the control group. The reassociated tooth germs were transplanted into mice subrenal capsules. After gene modification, dental mesenchymal cells cultured in vitro were checked for cell proliferation and the expression of Dspp was examined. All 12 reassociated tooth germs in the control group resumed odontogenesis, while only 5 of 12 in the Wnt10a knockdown group developed into teeth. After Wnt10a knockdown, the mesenchymal cells cultured in vitro presented repressed proliferation. Wnt10a knockdown and overexpression led to both down- and up-regulation of Dspp. We conclude that the down-regulation of Wnt10a impairs odontogensis and cell proliferation, and that Wnt10a regulates Dspp expression in mesenchymal cells. These findings help to elucidate the mechanism of abnormal tooth development in patients with the WNT10A mutation.« less

Sequential Ligand-Dependent Notch Signaling Activation Regulates Valve Primordium Formation and Morphogenesis.

PubMed

MacGrogan, Donal; D'Amato, Gaetano; Travisano, Stanislao; Martinez-Poveda, Beatriz; Luxán, Guillermo; Del Monte-Nieto, Gonzalo; Papoutsi, Tania; Sbroggio, Mauro; Bou, Vanesa; Gomez-Del Arco, Pablo; Gómez, Manuel Jose; Zhou, Bin; Redondo, Juan Miguel; Jiménez-Borreguero, Luis J; de la Pompa, José Luis

2016-05-13

The Notch signaling pathway is crucial for primitive cardiac valve formation by epithelial-mesenchymal transition, and NOTCH1 mutations cause bicuspid aortic valve; however, the temporal requirement for the various Notch ligands and receptors during valve ontogeny is poorly understood. The aim of this study is to determine the functional specificity of Notch in valve development. Using cardiac-specific conditional targeted mutant mice, we find that endothelial/endocardial deletion of Mib1-Dll4-Notch1 signaling, possibly favored by Manic-Fringe, is specifically required for cardiac epithelial-mesenchymal transition. Mice lacking endocardial Jag1, Notch1, or RBPJ displayed enlarged valve cusps, bicuspid aortic valve, and septal defects, indicating that endocardial Jag1 to Notch1 signaling is required for post-epithelial-mesenchymal transition valvulogenesis. Valve dysmorphology was associated with increased mesenchyme proliferation, indicating that Jag1-Notch1 signaling restricts mesenchyme cell proliferation non-cell autonomously. Gene profiling revealed upregulated Bmp signaling in Jag1-mutant valves, providing a molecular basis for the hyperproliferative phenotype. Significantly, the negative regulator of mesenchyme proliferation, Hbegf, was markedly reduced in Jag1-mutant valves. Hbegf expression in embryonic endocardial cells could be readily activated through a RBPJ-binding site, identifying Hbegf as an endocardial Notch target. Accordingly, addition of soluble heparin-binding EGF-like growth factor to Jag1-mutant outflow tract explant cultures rescued the hyperproliferative phenotype. During cardiac valve formation, Dll4-Notch1 signaling leads to epithelial-mesenchymal transition and cushion formation. Jag1-Notch1 signaling subsequently restrains Bmp-mediated valve mesenchyme proliferation by sustaining Hbegf-EGF receptor signaling. Our studies identify a mechanism of signaling cross talk during valve morphogenesis involved in the origin of congenital heart defects associated with reduced NOTCH function. © 2016 American Heart Association, Inc.

Carvacrol promotes angiogenic paracrine potential and endothelial differentiation of human mesenchymal stem cells at low concentrations.

PubMed

Matluobi, Danial; Araghi, Atefeh; Maragheh, Behnaz Faramarzian Azimi; Rezabakhsh, Aysa; Soltani, Sina; Khaksar, Majid; Siavashi, Vahid; Feyzi, Adel; Bagheri, Hesam Saghaei; Rahbarghazi, Reza; Montazersaheb, Soheila

2018-01-01

Phenolic monoterpene compound, named Carvacrol, has been found to exert different biological outcomes. It has been accepted that the angiogenic activity of human mesenchymal stem cells was crucial in the pursuit of appropriate regeneration. In the current experiment, we investigated the contribution of Carvacrol on the angiogenic behavior of primary human mesenchymal stem cells. Mesenchymal stem cells were exposed to Carvacrol in a dose ranging from 25 to 200μM for 48h. We measured cell survival rate by MTT assay and migration rate by a scratch test. The oxidative status was monitored by measuring SOD, GPx activity. The endothelial differentiation was studied by evaluating the level of VE-cadherin and vWF by real-time PCR and ELISA analyses. The content of VEGF and tubulogenesis behavior was monitored in vitro. We also conducted Matrigel plug in vivo CAM assay to assess the angiogenic potential of conditioned media from human mesenchymal stem cells after exposure to Carvacrol. Carvacrol was able to increase mesenchymal stem cell survival and migration rate (p<0.05). An increased activity of SOD was obtained while GPx activity unchanged or reduced. We confirmed the endothelial differentiation of stem cells by detecting vWF and VE-cadherin expression (p<0.05). The VEGF expression was increased and mesenchymal stem cells conditioned media improved angiogenesis tube formation in vitro (p<0.05). Moreover, histological analysis revealed an enhanced microvascular density at the site of Matrigel plug in CAM assay. Our data shed lights on the possibility of a Carvacrol to induce angiogenesis in human mesenchymal stem cells by modulating cell differentiation and paracrine angiogenic response. Copyright © 2017 Elsevier Inc. All rights reserved.

Insight into the Role of Long Non-coding RNAs During Osteogenesis in Mesenchymal Stem Cells.

PubMed

Huo, Sibei; Zhou, Yachuan; He, Xinyu; Wan, Mian; Du, Wei; Xu, Xin; Ye, Ling; Zhou, Xuedong; Zheng, Liwei

2018-01-01

Long non-coding RNAs (LncRNAs) are non-protein coding transcripts longer than 200 nucleotides in length. Instead of being "transcriptional noise", lncRNAs are emerging as a key modulator in various biological processes and disease development. Mesenchymal stem cells can be isolated from various adult tissues, such as bone marrow and dental tissues. The differentiation processes into multiple lineages, such as osteogenic differentiation, are precisely orchestrated by molecular signals in both genetic and epigenetic ways. Recently, several lines of evidence suggested the role of lncRNAs participating in cell differentiation through the regulation of gene transcriptions. And the involvement of lncRNAs may be associated with initiation and progression of mesenchymal stem cell-related diseases. We aimed at addressing the role of lncRNAs in the regulation of osteogenesis of mesenchymal stem cells derived from bone marrow and dental tissues, and discussing the potential utility of lncRNAs as biomarkers and therapeutic targets for mesenchymal stem cell-related diseases. Numerous lncRNAs were differentially expressed during osteogenesis or odontogenesis of mesenchymal stem cells, and some of them were confirmed to be able to regulate the differentiation processes through the modifications of chromatin, transcriptional and post-transcriptional processes. LncRNAs were also associated with some diseases related with pathologic differentiation of mesenchymal stem cells. LncRNAs involve in the osteogenic differentiation of bone marrow and dental tissuederived mesenchymal stem cells, and they could become promising therapeutic targets and prognosis parameters. However, the mechanisms of the role of lncRNAs are still enigmatic and require further investigation. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Implications of the Hybrid Epithelial/Mesenchymal Phenotype in Metastasis

PubMed Central

Jolly, Mohit Kumar; Boareto, Marcelo; Huang, Bin; Jia, Dongya; Lu, Mingyang; Ben-Jacob, Eshel; Onuchic, José N.; Levine, Herbert

2015-01-01

Transitions between epithelial and mesenchymal phenotypes – the epithelial to ­mesenchymal transition (EMT) and its reverse the mesenchymal to epithelial transition (MET) – are hallmarks of cancer metastasis. While transitioning between the epithelial and mesenchymal phenotypes, cells can also attain a hybrid epithelial/mesenchymal (E/M) (i.e., partial or intermediate EMT) phenotype. Cells in this phenotype have mixed epithelial (e.g., adhesion) and mesenchymal (e.g., migration) properties, thereby allowing them to move collectively as clusters. If these clusters reach the bloodstream intact, they can give rise to clusters of circulating tumor cells (CTCs), as have often been seen experimentally. Here, we review the operating principles of the core regulatory network for EMT/MET that acts as a “three-way” switch giving rise to three distinct phenotypes – E, M and hybrid E/M – and present a theoretical framework that can elucidate the role of many other players in regulating epithelial plasticity. Furthermore, we highlight recent studies on partial EMT and its association with drug resistance and tumor-initiating potential; and discuss how cell–cell communication between cells in a partial EMT phenotype can enable the formation of clusters of CTCs. These clusters can be more apoptosis-resistant and have more tumor-initiating potential than singly moving CTCs with a wholly mesenchymal (complete EMT) phenotype. Also, more such clusters can be formed under inflammatory conditions that are often generated by various therapies. Finally, we discuss the multiple advantages that the partial EMT or hybrid E/M phenotype have as compared to a complete EMT phenotype and argue that these collectively migrating cells are the primary “bad actors” of metastasis. PMID:26258068

Isolation and hepatocyte differentiation of mesenchymal stem cells from porcine bone marrow--"surgical waste" as a novel MSC source.

PubMed

Brückner, S; Tautenhahn, H-M; Winkler, S; Stock, P; Jonas, S; Dollinger, M; Christ, B

2013-06-01

Mesenchymal stem cells (MSC) isolated from bone marrow and differentiated into hepatocyte-like cells have increasingly gained attention for clinical cell therapy of liver diseases because of their high regenerative capacity. They are available from bone marrow aspirates of the os coxae after puncture of the crista iliaca or from bone marrow "surgical waste" gained from amputations or knee and hip operations. Thus, the aim of the study was to demonstrate whether these pBM-MSC (porcine bone marrow-derived mesenchymal stem cells) displayed mesenchymal features and hepatocyte differentiation potential. MSC were isolated either from crista iliaca punctures or after sampling and collagenase digestion of bone marrow from the os femoris. Mesenchymal features were assessed by flow cytometry for specific surface antigens and their ability to differentiate into at least 3 lineages. Functional properties, such as urea or glycogen synthesis and cytochrome P450 activity, as well as the cell morphology were examined during hepatocyte differentiation. pBM-MSC from both sources lacked the hematopoietic markers CD14 and CD45 but expressed the typical mesenchymal markers CD44, CD29, CD90, and CD105. Both cell types could differentiate into adipocyte, osteocyte, and hepatocyte lineages. After hepatocyte differentiation, CD105 expression decreased significantly and cells changed morphology from fibroblastoid into polygonal, displaying significantly increased glycogen storage, urea synthesis, and cytochrome activity. pBM-MSC from various sources were identical in respect to their mesenchymal features and their hepatocyte differentiation potential. Hence, long bones might be a particularly useful resource to isolate bone marrow mesenchymal stem cells for transplantation. Copyright © 2013 Elsevier Inc. All rights reserved.

Mesenchymal stem cells for bone repair and metabolic bone diseases.

PubMed

Undale, Anita H; Westendorf, Jennifer J; Yaszemski, Michael J; Khosla, Sundeep

2009-10-01

Human mesenchymal stem cells offer a potential alternative to embryonic stem cells in clinical applications. The ability of these cells to self-renew and differentiate into multiple tissues, including bone, cartilage, fat, and other tissues of mesenchymal origin, makes them an attractive candidate for clinical applications. Patients who experience fracture nonunion and metabolic bone diseases, such as osteogenesis imperfecta and hypophosphatasia, have benefited from human mesenchymal stem cell therapy. Because of their ability to modulate immune responses, allogeneic transplant of these cells may be feasible without a substantial risk of immune rejection. The field of regenerative medicine is still facing considerable challenges; however, with the progress achieved thus far, the promise of stem cell therapy as a viable option for fracture nonunion and metabolic bone diseases is closer to reality. In this review, we update the biology and clinical applicability of human mesenchymal stem cells for bone repair and metabolic bone diseases.

Mesenchymal stem cells in cardiac regeneration: a detailed progress report of the last 6 years (2010-2015).

PubMed

Singh, Aastha; Singh, Abhishek; Sen, Dwaipayan

2016-06-04

Mesenchymal stem cells have been used for cardiovascular regenerative therapy for decades. These cells have been established as one of the potential therapeutic agents, following several tests in animal models and clinical trials. In the process, various sources of mesenchymal stem cells have been identified which help in cardiac regeneration by either revitalizing the cardiac stem cells or revascularizing the arteries and veins of the heart. Although mesenchymal cell therapy has achieved considerable admiration, some challenges still remain that need to be overcome in order to establish it as a successful technique. This in-depth review is an attempt to summarize the major sources of mesenchymal stem cells involved in myocardial regeneration, the significant mechanisms involved in the process with a focus on studies (human and animal) conducted in the last 6 years and the challenges that remain to be addressed.

Histology and imaging of soft tissue sarcomas.

PubMed

Kind, Michèle; Stock, Nathalie; Coindre, Jean Michel

2009-10-01

Imaging and histology are two complementary morphological techniques which play a fundamental role in the diagnosis and management of soft tissue sarcomas. Imaging allows to identify some pseudosarcomatous benign lesions such as myositis ossificans, intramuscular hemangioma, angiomyolipoma, intramuscular lipoma, giant cell tumour of tendon sheath, desmoid tumour and elastofibroma. There is no formal criterion for diagnosing a sarcoma on magnetic resonance imaging (MRI) but malignancy is strongly suspected with the presence of necrosis and vascular, bone or joint invasion. Imaging may also suggest some histological types of sarcoma such as well-differentiated liposarcoma, dedifferentiated liposarcoma, synovial sarcoma or extraskeletal osteosarcoma. Imaging is also extremely helpful in determining the appropriate kind of sampling to carry out and in guiding the performance of a microbiopsy. The appearance observed on imaging should always be taken into consideration for the interpretation of the microbiopsy by the pathologist.

Ewing's Sarcoma of the Peritoneum: a Rare Location for Extraskeletal Ewing's Sarcoma.

PubMed

Saglam, Muzaffer; Ozdemir, Yavuz; Yigit, Taner; Kucukodaci, Zafer; Sonmez, Guner

2016-11-01

A 38-year-old male presented to the emergency department with abdominal pain and bulge. He had a history of irritable bowel syndrome for 1 year with complaint of dyspepsia. Physical examination revealed a distended abdomen with a huge palpable mass located in the paraumblical region. Laboratory findings revealed a high white blood cell count with neutrophil predominance. Contrast-enhanced computed tomography (CT) showed a 23-cm, oval-shaped, grossly necrotic, low-attenuation mass with peripherally located dominant vessels. Magnetic resonance imaging (MRI) with diffusion weighted imaging (DWI) suggested a highly malignant tumor with prominent diffusion restriction especially at the periphery of the mass. On surgery, macroscopic examination showed a macrolobulated, hypervascular, reddish brown mass attached to the parietal peritoneum with a stalk. Ewing's sarcoma (ES) was diagnosed on histopathological examination with small round cells.

Spontaneous multicentric soft tissue sarcoma in a captive African pygmy hedgehog (Atelerix albiventris): case report and literature review

PubMed Central

DÍAZ-DELGADO, Josué; POOL, Roy; HOPPES, Sharman; CEREZO, Argine; QUESADA-CANALES, Óscar; STOICA, George

2017-01-01

This report describes the clinical, macroscopic, histopathological and immunohistochemical features of a spontaneous multicentric extraskeletal sarcoma in an adult male African hedgehog (Atelerix albiventris). It also provides a succinct up-to-date review on neoplasia in this species. On autopsy examination, main gross findings included a moderately demarcated cranial mass and a multilobulated, caudal intra-abdominal mass. The cranial mass had perforated the underlying temporal and occipital bones and had extended into the cranial vault and was compressing the surface of the cerebellum and cerebrum. Histologic, histochemical and immunohistochemical analyses supported a diagnosis of multicentric poorly differentiated spindle cell sarcoma with fibrosarcomatous, storiform and myxoid foci. The high incidence of neoplasia and cross similarities renders the African hedgehog a suitable species for comparative pathology studies. PMID:28331115

Prevention and Treatment of Heterotopic Ossification

DTIC Science & Technology

2012-02-01

suggest that low oxygen tension critically influences chondrocyte differentiation by accelerating the growth of mesenchymal stem cells and promoting...ossification, we focused on the microenvironmental conditions needed to induce mesenchymal stem cells to differentiate to chondrocytes, which form the...this is due in part to the use of different family members in for extravasating lymphocytes versus mesenchymal stem cells . Since entry of

Effects of Combined Transplantation of Multipotent Mesenchymal Stromal and Hemopoietic Stem Cells on Regeneration of the Hemopoietic Tissue.

PubMed

Maklakova, I Yu; Grebnev, D Yu

2017-05-01

The effect of allogenic combined transplantation of placental multipotent mesenchymal stromal and hemopoietic stem cells on regeneration of the myeloid tissue and spleen after acute blood loss was studied in laboratory mice. Combined transplantation of these cells did not change the content of cytogenetically modified cells in the bone marrow under normal conditions, but reduced their levels after acute blood loss. Combined transplantation of multipotent mesenchymal stromal and hemopoietic stem cells promoted activation of erythropoiesis and granulocytopoiesis. The major morphometric and cytological parameters of the white pulp of the spleen decreased, presumably due to immunosuppressive effect of multipotent mesenchymal stromal cells.

Effect of Fibroblast-Like Cells of Mesenchymal Origin of Cytotoxic Activity of Lymphocytes against NK-Sensitive Target Cells.

PubMed

Lupatov, A Yu; Kim, Ya S; Bystrykh, O A; Vakhrushev, I V; Pavlovich, S V; Yarygin, K N; Sukhikh, G T

2017-02-01

We studied immunosuppressive properties of skin fibroblasts and mesenchymal stromal cells against NK cells. In vitro experiments showed that mesenchymal stromal cells isolated from human umbilical cord and human skin fibroblasts can considerably attenuate cytotoxic activity of NK cells against Jurkat cells sensitive to NK-mediated lysis. NK cells cultured in lymphocyte population exhibited higher cytotoxic activity than isolated NK cells. Mesenchymal stromal cells or fibroblasts added 1:1 to lymphocyte culture almost completely suppressed NK cell cytotoxicity. This suggests that fibroblast-like cells can suppress not only isolated NK cells, but also NK cells in natural cell microenvironment.

The efficacy of polycaprolactone/hydroxyapatite scaffold in combination with mesenchymal stem cells for bone tissue engineering.

PubMed

Chuenjitkuntaworn, Boontharika; Osathanon, Thanaphum; Nowwarote, Nunthawan; Supaphol, Pitt; Pavasant, Prasit

2016-01-01

Major drawbacks of using an autograft are the possibilities of insufficient bony source and patient's morbidity after operation. Bone tissue engineering technology, therefore, has been applied for repairing bony defects. Previous study showed that a novel fabricated 3D-Polycaprolactone/Hydroxyapatite (PCL/HAp) scaffold possessed a good biocompatibility for bone cells. This study aimed to determine the ability of PCL/HAp for supporting cell growth, gene expression, and osteogenic differentiation in three types of mesenchymal stem cells, including bone marrow-derived mesenchymal stem cells (BMSCs), dental pulp stem cells (DPSCs), and adiposed-derived mesenchymal stem cells (ADSCs). These were assessed by cell viability assay (MTT), reverse-transcription polymerase chain reaction (RT-PCR) analysis, alkaline phosphatase activity, and osteogenic differentiation by alizarin red-S staining. The results showed that PCL/HAp scaffold could support growth of all three types of mesenchymal stem cells. In addition, DPSCs with PCL/HAp showed the highest level of calcium deposition compared to other groups. In conclusion, DPSCs exhibited a better compatibility with these scaffolds compared to BMSCs and ADSCs. However, the PCL/HAp could be a good candidate scaffold for all tested mesenchymal stem cells in bone tissue engineering. © 2015 Wiley Periodicals, Inc.

Heparanase promotes myeloma progression by inducing mesenchymal features and motility of myeloma cells.

PubMed

Li, Juan; Pan, Qianying; Rowan, Patrick D; Trotter, Timothy N; Peker, Deniz; Regal, Kellie M; Javed, Amjad; Suva, Larry J; Yang, Yang

2016-03-08

Bone dissemination and bone disease occur in approximately 80% of patients with multiple myeloma (MM) and are a major cause of patient mortality. We previously demonstrated that MM cell-derived heparanase (HPSE) is a major driver of MM dissemination to and progression in new bone sites. However the mechanism(s) by which HPSE promotes MM progression remains unclear. In the present study, we investigated the involvement of mesenchymal features in HPSE-promoted MM progression in bone. Using a combination of molecular, biochemical, cellular, and in vivo approaches, we demonstrated that (1) HPSE enhanced the expression of mesenchymal markers in both MM and vascular endothelial cells; (2) HPSE expression in patient myeloma cells positively correlated with the expression of the mesenchymal markers vimentin and fibronectin. Additional mechanistic studies revealed that the enhanced mesenchymal-like phenotype induced by HPSE in MM cells is due, at least in part, to the stimulation of the ERK signaling pathway. Finally, knockdown of vimentin in HPSE expressing MM cells resulted in significantly attenuated MM cell dissemination and tumor growth in vivo. Collectively, these data demonstrate that the mesenchymal features induced by HPSE in MM cells contribute to enhanced tumor cell motility and bone-dissemination.

Epithelial-to-mesenchymal transition (EMT) induced by inflammatory priming elicits mesenchymal stromal cell-like immune-modulatory properties in cancer cells.

PubMed

Ricciardi, M; Zanotto, M; Malpeli, G; Bassi, G; Perbellini, O; Chilosi, M; Bifari, F; Krampera, M

2015-03-17

Epithelial-to-mesenchymal transition (EMT) has a central role in cancer progression and metastatic dissemination and may be induced by local inflammation. We asked whether the inflammation-induced acquisition of mesenchymal phenotype by neoplastic epithelial cells is associated with the onset of mesenchymal stromal cell-like immune-regulatory properties that may enhance tumour immune escape. Cell lines of lung adenocarcinoma (A549), breast cancer (MCF7) and hepatocellular carcinoma (HepG2) were co-cultured with T, B and NK cells before and after EMT induction by either the supernatant of mixed-lymphocyte reactions or inflammatory cytokines. EMT occurrence following inflammatory priming elicited multiple immune-regulatory effects in cancer cells resulting in NK and T-cell apoptosis, inhibition of lymphocyte proliferation and stimulation of regulatory T and B cells. Indoleamine 2,3-dioxygenase, but not Fas ligand pathway, was involved at least in part in these effects, as shown by the use of specific inhibitors. EMT induced by inflammatory stimuli confers to cancer cells some mesenchymal stromal cell-like immune-modulatory properties, which could be a cue for cancer progression and metastatic dissemination by favouring immune escape.

Mesenchymal Stem Cell Therapy for Nonhealing Cutaneous Wounds

PubMed Central

Hanson, Summer E.; Bentz, Michael L.; Hematti, Peiman

2014-01-01

Summary Chronic wounds remain a major challenge in modern medicine and represent a significant burden, affecting not only physical and mental health, but also productivity, health care expenditure, and long-term morbidity. Even under optimal conditions, the healing process leads to fibrosis or scar. One promising solution, cell therapy, involves the transplantation of progenitor/stem cells to patients through local or systemic delivery, and offers a novel approach to many chronic diseases, including nonhealing wounds. Mesenchymal stem cells are multipotent, adult progenitor cells of great interest because of their unique immunologic properties and regenerative potential. A variety of preclinical and clinical studies have shown that mesenchymal stem cells may have a useful role in wound-healing and tissue-engineering strategies and both aesthetic and reconstructive surgery. Recent advances in stem cell immunobiology can offer insight into the multiple mechanisms through which mesenchymal stem cells could affect underlying pathophysiologic processes associated with nonhealing mesenchymal stem cells. Critical evaluation of the current literature is necessary for understanding how mesenchymal stem cells could potentially revolutionize our approach to skin and soft-tissue defects and designing clinical trials to address their role in wound repair and regeneration. PMID:20124836

Glycosaminoglycan-dependent restriction of FGF diffusion is necessary for lacrimal gland development

PubMed Central

Qu, Xiuxia; Pan, Yi; Carbe, Christian; Powers, Andrea; Grobe, Kay; Zhang, Xin

2012-01-01

Glycosaminoglycans (GAGs) play a central role in embryonic development by regulating the movement and signaling of morphogens. We have previously demonstrated that GAGs are the co-receptors for Fgf10 signaling in the lacrimal gland epithelium, but their function in the Fgf10-producing periocular mesenchyme is still poorly understood. In this study, we have generated a mesenchymal ablation of UDP-glucose dehydrogenase (Ugdh), an essential biosynthetic enzyme for GAGs. Although Fgf10 RNA is expressed normally in the periocular mesenchyme, Ugdh mutation leads to excessive dispersion of Fgf10 protein, which fails to elicit an FGF signaling response or budding morphogenesis in the presumptive lacrimal gland epithelium. This is supported by genetic rescue experiments in which the Ugdh lacrimal gland defect is ameliorated by constitutive Ras activation in the epithelium but not in the mesenchyme. We further show that lacrimal gland development requires the mesenchymal expression of the heparan sulfate N-sulfation genes Ndst1 and Ndst2 but not the 6-O and 2-O-sulfation genes Hs6st1, Hs6st2 and Hs2st. Taken together, these results demonstrate that mesenchymal GAG controls lacrimal gland induction by restricting the diffusion of Fgf10. PMID:22745308

Immunohistochemical detection of FLI-1 protein expression: a study of 132 round cell tumors with emphasis on CD99-positive mimics of Ewing's sarcoma/primitive neuroectodermal tumor.

PubMed

Folpe, A L; Hill, C E; Parham, D M; O'Shea, P A; Weiss, S W

2000-12-01

The histologic and immunohistochemical differentiation of Ewing' s sarcoma/primitive neuroectodermal tumor (ES/PNET) from other small, blue, round cell tumors may be difficult. Despite initial promise, CD99 (MIC2) has not proven to be a specific marker. Approximately 90% of ES/PNET have a specific t(11; 22)(q24;q12) that results in fusion of the EWS and FLI-1 genes, and overexpression of FLI-1 protein. A recent study has shown immunohistochemical FLI-1 expression in five of seven of the ES/PNET cases tested. We evaluated FLI-1 expression in 132 well-characterized small, blue, round cell tumors. All tumors were immunostained for FLI-1 (1:40, Sc 356 polyclonal, Santa Cruz Biotechnology) using steam heat for epitope retrieval. Only nuclear staining was accepted as positive. Endothelial cells were strongly positive in all cases and served as an internal control. In many cases, a subset of lymphocytes also stained positive. No staining was seen in any other normal tissue. FLI-1 expression was seen in 29 of 41 (71%) ES/PNET, 7 of 8 (88%) lymphoblastic lymphomas, 0 of 8 poorly differentiated synovial sarcomas (PDSS), 0 of 32 rhabdomyosarcoma (RMS), 0 of 30 neuroblastomas, 0 of 8 esthesioneuroblastomas, 0 of 3 Wilms' tumors, 0 of 1 mesenchymal chondrosarcoma, and in 1 of 1 desmoplastic round cell tumor. This last case was known to have an EWS/WT-1 fusion. Although the EWS/FLI-1 fusion gene is specific for ES/PNET, FLI-1 protein expression is not. Significantly, the great majority of lymphoblastic lymphomas (also CD99-positive) are strongly FLI-1-positive. Immunohistochemical detection of FLI-1 may be valuable in confirming the diagnosis of ES/ PNET in cases in which molecular genetic evaluation is not feasible. FLI-1 protein expression is also helpful in distinguishing ES/PNET from other tumors that may be CD99-positive, such as PDSS and RMS. It is not surprising that some ES/ PNET are FLI-1-negative, because not all ES/PNET have the classic EWS/FLI-1, and some cases of ES/PNET may produce either low levels of protein or idiotypically different protein.

Stem cells for regenerative medicine: advances in the engineering of tissues and organs

NASA Astrophysics Data System (ADS)

Ringe, Jochen; Kaps, Christian; Burmester, Gerd-Rüdiger; Sittinger, Michael

2002-07-01

The adult bone marrow stroma contains a subset of nonhematopoietic cells referred to as mesenchymal stem or mesenchymal progenitor cells (MSC). These cells have the capacity to undergo extensive replication in an undifferentiated state ex vivo. In addition, MSC have the potential to develop either in vitro or in vivo into distinct mesenchymal tissues, including bone, cartilage, fat, tendon, muscle, and marrow stroma, which suggest these cells as an attractive cell source for tissue engineering approaches. The interest in modern biological technologies such as tissue engineering has dramatically increased since it is feasible to isolate living, healthy cells from the body, expand them under cell culture conditions, combine them with biocompatible carrier materials and retransplant them into patients. Therefore, tissue engineering gives the opportunity to generate living substitutes for tissues and organs, which may overcome the drawbacks of classical tissue reconstruction: lacking quality and quantity of autologous grafts, immunogenicity of allogenic grafts and loosening of alloplastic implants. Due to the prerequisite for tissue engineering to ensure a sufficient number of tissue specific cells without donor site morbidity, much attention has been drawn to multipotential progenitor cells such as embryonic stem cells, periosteal cells and mesenchymal stem cells. In this report we review the state of the art in tissue engineering with mesenchymal stem and mesenchymal progenitor cells with emphasis on bone and cartilage reconstruction. Furthermore, several issues of importance, especially with regard to the clinical application of mesenchymal stem cells, are discussed.

Identification and Characterization of Mesenchymal-Epithelial Progenitor-Like Cells in Normal and Injured Rat Liver

PubMed Central

Liu, Daqing; Yovchev, Mladen I.; Zhang, Jinghang; Alfieri, Alan A.; Tchaikovskaya, Tatyana; Laconi, Ezio; Dabeva, Mariana D.

2016-01-01

In normal rat liver, thymocyte antigen 1 (Thy1) is expressed in fibroblasts/myofibroblasts and in some blood progenitor cells. Thy1-expressing cells also accumulate in the liver during impaired liver regeneration. The origin and nature of these cells are not well understood. By using RT-PCR analysis and immunofluorescence microscopy, we describe the presence of rare Thy1+ cells in the liver lobule of normal animals, occasionally forming small collections of up to 20 cells. These cells constitute a small portion (1.7% to 1.8%) of nonparenchymal cells and reveal a mixed mesenchymal-epithelial phenotype, expressing E-cadherin, cytokeratin 18, and desmin. The most potent mitogens for mesenchymal-epithelial Thy1+ cells in vitro are the inflammatory cytokines interferon γ, IL-1, and platelet-derived growth factor-BB, which are not produced by Thy1+ cells. Thy1+ cells express all typical mesenchymal stem cell and hepatic progenitor cell markers and produce growth factor and cytokine mRNA (Hgf, Il6, Tgfa, and Tweak) for proteins that maintain oval cell growth and differentiation. Under appropriate conditions, mesenchymal-epithelial cells differentiate in vitro into hepatocyte-like cells. In this study, we show that the adult rat liver harbors a small pool of endogenous mesenchymal-epithelial cells not recognized previously. In the quiescent state, these cells express both mesenchymal and epithelial cell markers. They behave like hepatic stem cells/progenitors with dual phenotype, exhibiting high plasticity and long-lasting proliferative activity. PMID:25447047

Mesenchymal Stem Cells Suppress Chronic Rejection in Heterotopic Small Intestine Transplant Rat Models Via Inhibition of CD68, Transforming Growth Factor- β1, and Platelet-Derived Growth Factor Expression.

PubMed

Li, Fuxin; Cao, Jisen; Zhao, Zhicheng; Li, Chuan; Qi, Feng; Liu, Tong

2017-04-01

Mesenchymal stem cells are easy to obtain and expand, with characteristics of low immunogenicity and strong tissue repair capacity. In this study, our aim was to investigate the role of mesenchymal stem cells in chronic immune rejection of heterotopic small intestine transplant in rats. After successfully constructing a rat chronic immune rejection model of heterotopic small intestine transplant, we infused mesenchymal stem cells into the animal recipients. We observed mesenchymal stem cell location in the recipients, recipient survival, pathology changes, and the expression of CD68, transforming growth factor β1, and platelet-derived growth factor C in the donor intestine. Mesenchymal stem cells inhibited the lymphocyte proliferation caused by concanavalin A in vitro. After stem cells were infused into recipients, they were mainly located in the donor intestine, as well as in the spleen and thymus. Recovery after transplant and pathology changes of the donor intestine in rats with stem cell infusion were better than in the control group; however, we observed no differences in survival time, accompanied by downregulated expression of CD68, transforming growth factor β1, and platelet-derived growth factor C. Mesenchymal stem cells, to a certain extent, could inhibit the process of chronic rejection. The mechanisms may include the inhibited function of these cells on lymphocyte proliferation, reduced infiltration of macrophages, and reduced expression of transforming growth factor β1 and platelet-derived growth factor C.

A small population of resident limb bud mesenchymal cells express few MSC-associated markers, but the expression of these markers is increased immediately after cell culture.

PubMed

Marín-Llera, Jessica Cristina; Chimal-Monroy, Jesús

2018-05-01

Skeletal progenitors are derived from resident limb bud mesenchymal cells of the vertebrate embryos. However, it remains poorly understood if they represent stem cells, progenitors, or multipotent mesenchymal stromal cells (MSC). Derived-MSC of different adult tissues under in vitro experimental conditions can differentiate into the same cellular lineages that are present in the limb. Here, comparing non-cultured versus cultured mesenchymal limb bud cells, we determined the expression of MSC-associated markers, the in vitro differentiation capacity and their gene expression profile. Results showed that in freshly isolated limb bud mesenchymal cells, the proportion of cells expressing Sca1, CD44, CD105, CD90, and CD73 is very low and a low expression of lineage-specific genes was observed. However, recently seeded limb bud mesenchymal cells acquired Sca1 and CD44 markers and the expression of the key differentiation genes Runx2 and Sox9, while Scx and Pparg genes decreased. Also, their chondrogenic differentiation capacity decreased through cellular passages while the osteogenic increased. Our findings suggest that the modification of the cell adhesion process through the in vitro method changed the limb mesenchymal cell immunophenotype leading to the expression and maintenance of common MSC-associated markers. These findings could have a significant impact on MSC study and isolation strategy because they could explain common variations observed in the MSC immunophenotype in different tissues. © 2018 International Federation for Cell Biology.

Chicken homeobox gene Msx-1: structure, expression in limb buds and effect of retinoic acid.

PubMed

Yokouchi, Y; Ohsugi, K; Sasaki, H; Kuroiwa, A

1991-10-01

A chicken gene carrying a homeobox highly homologous to the Drosophila muscle segment homeobox (msh) gene was isolated and designated as Msx-1. Conceptual translation from the longest ORF gave a protein of 259 amino acids lacking the conserved hexapeptide. Northern analysis detected a single 2.6 kb transcript. As early as day 2 of incubation, the transcript was detected but was not found in adult tissue. In situ hybridization analysis revealed that Msx-1 expression is closely related to a particular mesenchymal cell lineage during limb bud formation. In early stage embryos, Msx-1 was expressed in the somatopleure. When primordial mesenchyme cells for limb bud were generated from the Wolffian ridge of the somatopleure, Msx-1 expression began to diminish in the posterior half of the limb bud then in the presumptive cartilage-forming mesenchyme. In developing limb buds, remarkable expression was seen in the apical ectodermal ridge (AER), which is responsible for the sustained outgrowth and development of the limb. The Msx-1 transcripts were found in the limb mesenchymal cells in the region covering the necrotic zone and ectodermal cells overlying such mesenchymal cells. Both ectodermal and mesenchymal expression in limb bud were rapidly suppressed by local treatment of retinoic acid which can generate mirror-image duplication of digits. This indicates that retinoic acid alters the marginal presumptive non-cartilage forming mesenchyme cell lineage through suppression of Msx-1 expression.

The response of breast cancer cells to mesenchymal stem cells: a possible role of inflammation by breast implants.

PubMed

Orciani, Monia; Lazzarini, Raffaella; Scartozzi, Mario; Bolletta, Elisa; Mattioli-Belmonte, Monica; Scalise, Alessandro; Di Benedetto, Giovanni; Di Primio, Roberto

2013-12-01

Breast implants are widely used and at times might cause inflammation as a foreign body, followed by fibrous capsule formation around the implant. In cancer, the inflamed stroma is essential for preservation of the tumor. Mesenchymal stem cells can be recruited to sites of inflammation, and their role in cancer development is debated. The authors assessed the effects of inflammation caused by breast implants' effects on tumor. Mesenchymal stem cells were isolated from the fibrous capsules of women who underwent a second operation after 1 year (presenting inflammation) or after 20 years (not presenting inflammation) since initial surgery. After characterization, cells were co-cultured with MCF7, a breast cancer cell line. The expression of genes involved in oncogenesis, proliferation, and epithelial-to-mesenchymal transition was investigated, followed by Western blot analyses. After co-culture with mesenchymal stem cells from the inflamed capsule, MCF7 induced a dose- and time-dependent increase in proliferation. Polymerase chain reaction analyses revealed a dysregulation of genes involved in oncogenesis, proliferation, and epithelial-to-mesenchymal transition. The subsequent evaluation by Western blot did not confirm these results, showing only a modest decrease in the expression of E-cadherin after co-culture with mesenchymal stem cells (both derived from inflamed or control capsules). These data indicate that inflammation caused by breast implants partially affects proliferation of MCF7 but does not influence key mechanisms of tumor development.

Localization of extracellular matrix components in developing mouse salivary glands by confocal microscopy

NASA Technical Reports Server (NTRS)

Hardman, P.; Spooner, B. S.

1992-01-01

The importance of the extracellular matrix (ECM) in epithelial-mesenchymal interactions in developing organisms is well established. Proteoglycans and interstitial collagens are required for the growth, morphogenesis, and differentiation of epithelial organs and the distribution of these molecules has been described. However, much less is known about other ECM macromolecules in developing epithelial organs. We used confocal microscopy to examine the distribution of laminin, heparan sulfate (BM-1) proteoglycan, fibronectin, and collagen types I, IV, and V, in mouse embryonic salivary glands. Organ rudiments were isolated from gestational day 13 mouse embryos and cultured for 24, 48, or 72 hours. Whole mounts were stained by indirect immunofluorescence and then examined using a Zeiss Laser Scan Microscope. We found that each ECM component examined had a distinct distribution and that the distribution of some molecules varied with culture time. Laminin was mainly restricted to the basement membrane. BM-1 proteoglycan was concentrated in the basement membrane and also formed a fine network throughout the mesenchyme. Type IV collagen was mainly located in the basement membrane of the epithelium, but it was also present throughout the mesenchyme. Type V collagen was distributed throughout the mesenchyme at 24 hours, but at 48 hours was principally located in the basement membrane. Type I collagen was distributed throughout the mesenchyme at all culture times, and accumulated in the clefts and particularly at the epithelial-mesenchymal interface as time in culture increased. Fibronectin was observed throughout the mesenchyme at all times.

[Tumorous space occupying lesions of the scapula. An analysis of preoperative assessment of invasion].

PubMed

Erlemann, R; Davies, A M; Edel, G; Wuisman, P; Peters, P E; Grundmann, E

1988-02-01

The radiographic and histological morphology of 38 tumors lesions of the scapula are analyzed. Osteochondromas (n = 12), chondrosarcomas (n = 7), plasmacytomas (n = 4) and Ewing's sarcomas (n = 3) were the most frequent neoplasms. The radiographically determined growth rates allowed an estimate of the dignity in all cases. Benign lesions were only observed in the first five decades of life, and were mostly located in the scapular blade. Most tumors found in the acromion and in the glenoid region and all lesions diagnosed in the 6th to the 8th decades of life were malignant. In 63.2% of cases correct diagnosis of the type of lesion present was possible on radiographic examination.

A New Approach to Implant-Based Midface Reconstruction Following Subtotal Maxillectomy.

PubMed

Dawood, Andrew; Kalavrezos, Nicholas; Tanner, Susan

2016-01-01

This case presentation describes the reconstruction of an extensive maxillary-orbital defect following subtotal resection of the maxilla en bloc with orbital exenteration in a young adult following the diagnosis of chondrosarcoma. A new approach to composite midface reconstruction with dental implants is described, in which computer-guided surgery (CGS) was used to obliquely position dental implants interradicularly in the residual maxilla, such that the implant tips lie in close proximity to the root apices of the remaining teeth. The implants were then used to fixate a milled-titanium bar, fabricated using computer-aided design and manufacture (CAD/CAM), and provided with attachments for the stabilization and retention of a maxillary obturator.

Design and development of a magnetic device for mesenchymal stem cell retaining in deep targets

NASA Astrophysics Data System (ADS)

Banis, G. C.

2017-12-01

This paper focuses on the retaining of mesenchymal stem cells in blood flow conditions using the appropriate magnetic field. Mesenchymal stem cells can be tagged with magnetic nanoparticles and thus, they can be manipulated from distance, through the application of an external magnetic field. In this paper the case of kidney as target of the therapy is being studied.

New Fluorescent Reporter Systems for Evaluation of the Expression of E- and N-Cadherins.

PubMed

Burmistrova, O A; Nikulin, S V; Zakharova, G S; Fomicheva, K A; Alekseev, B Ya; Shkurnikov, M Yu

2018-05-24

During metastatic growth, cells of solid tumors undergo phenotypical changes related to epithelial-mesenchymal transition. Epithelial-mesenchymal transition is regarded as a potential target for prospective antitumor drugs. Fluorescent reporter systems for evaluation of the expression of markers of epithelial and mesenchymal status (E- and N-cadherins) were created. The described approaches can be used for creation of analogous reporter systems.

Tissue Engineering Research

DTIC Science & Technology

2002-01-01

al. 1999; Petersen et al. 1999); the differentiation (Pittenger et al. 1999) and clinical use of mesenchymal stem cells (Osiris Therapeutics...endothelialization of vascular prostheses, and use of mesenchymal stem cells for bone repair. Current Condition Factors determining cell source and design...the use of mesenchymal stem cells for bone repair. The UK has taken an active interest in further research on the use of ES cells . This is aided by

Novel Therapy for Bone Regeneration in Large Segmental Defects

DTIC Science & Technology

2015-10-01

mesenchymal stem cells (MSCs). The in- flammatory... mesenchymal stem cells and the wound healing process. Cells 2013;2:621-34. 17. Kumar A, Salimath BP, Stark GB, Finkenzeller G. 22 K.M. Davis et al.: Muscle...Gao X, Usas A, Tang Y, et al. A comparison of bone re- generation with human mesenchymal stem cells and mus- cle-derived stem cells and the

A Unique Opportunity To Test Whether Cell Fusion Is a Mechanism of Breast Cancer Metastasis

DTIC Science & Technology

2016-08-01

mesenchymal stem cells are a potent fusion partner for breast cancer cells ...and hematopoietic stem cells were enriched. In addition, human mesenchymal stem cells were obtained from bone marrow. 2   Table 1...adherent cell types – mesenchymal stem cells and epithelial cell types. Thus, MSCs were mixed with each epithelial cell type  (i.e. MSCs with

Muscle Stem Cell Therapy for the Treatment of DMD Associated Cardiomyopathy

DTIC Science & Technology

2012-10-01

2009;27(8):1954-1962. 44. Abarbanell AM, Coffey AC, Fehrenbacher JW, et al. Proinflammatory cytokine effects on mesenchymal stem cell therapy for...signaling pathway functions as a commitment switch for osteogenic and adipogenic differentiation of mesenchymal stem cells (MSCs) (22). Activation...mediate reduced osteoblastogenesis and enhanced adipogenesis of human mesenchymal stem cells in modeled microgravity. J Bone Miner Res. 2005;20(10

The extracellular matrix architecture relating to myotendinous pattern formation in the distal part of the developing chick limb: an ultrastructural, histochemical and immunocytochemical analysis.

PubMed

Hurle, J M; Hinchliffe, J R; Ros, M A; Critchlow, M A; Genis-Galvez, J M

1989-07-01

In the later developmental stages (Hamburger and Hamilton, 25-34) the distal part of the chick leg possesses a distinctive extracellular matrix (ECM) architecture which relates to myotendinous patterning. There are two components: firstly, a system of dorsoventrally oriented fibrils which link the two ectodermal surfaces through the undifferentiated distal mesenchyme and secondly, a 'mesenchyme lamina' originates at the basement membrane distally, but proximally runs through the mesoderm, subjacent and parallel to the basement membrane. The 'mesenchyme lamina' appears to be a precursor of developing tendons and is spatially related to the distal tips of the myogenic blocks. As developing tendons form on the inner surface of the lamina at its proximal end, it becomes less distinct and disappears. Further dorsoventral fibrils run from the 'mesenchyme lamina' into the developing condensations and chondrogenic elements of the phalanges. The architecture of the ECM was revealed by silver and lectin staining (peanut and Ricinus communis agglutinins, PNA and RCA I), by immunocytochemistry (for fibronectin, tenascin, collagen type I) and by ultrastructural analysis. Both components stain with silver, PNA following neuraminidase digestion, RCA I, tenascin and collagen type I. However, the dorsoventral fibrils are positive for fibronectin and negative for PNA, while conversely the mesenchyme lamina is positive for PNA but much less so for fibronectin. Tenascin has been shown to be a specialized mesenchyme component of tendons and myotendinous junctions (Chiquet and Fambrough, 1984). Such a basement membrane forming a 'mesenchyme lamina' appears to be unique in epithelial-mesenchymal developing systems and points to an ectodermal role in tendon pattern formation within the mesenchyme. We discuss the possible role of mechanical force in converting the dorsoventral tenascin-positive fibrils into the localized pattern of tendon insertions into the proximal parts of the phalanges. Distally the dorsoventral fibrils may shape the digital plate by pulling together the two ectodermal surfaces. A similar ECM architecture is found in corresponding stages in the developing wing.

Adult human mesenchymal stem cells delivered via intra-articular injection to the knee following partial medial meniscectomy: a randomized, double-blind, controlled study.

PubMed

Vangsness, C Thomas; Farr, Jack; Boyd, Joel; Dellaero, David T; Mills, C Randal; LeRoux-Williams, Michelle

2014-01-15

There are limited treatment options for tissue restoration and the prevention of degenerative changes in the knee. Stem cells have been a focus of intense preclinical research into tissue regeneration but limited clinical investigation. In a randomized, double-blind, controlled study, the safety of the intra-articular injection of human mesenchymal stem cells into the knee, the ability of mesenchymal stem cells to promote meniscus regeneration following partial meniscectomy, and the effects of mesenchymal stem cells on osteoarthritic changes in the knee were investigated. A total of fifty-five patients at seven institutions underwent a partial medial meniscectomy. A single superolateral knee injection was given within seven to ten days after the meniscectomy. Patients were randomized to one of three treatment groups: Group A, in which patients received an injection of 50 × 10⁶ allogeneic mesenchymal stem cells; Group B, 150 × 10⁶ allogeneic mesenchymal stem cells; and the control group, a sodium hyaluronate (hyaluronic acid/hyaluronan) vehicle control. Patients were followed to evaluate safety, meniscus regeneration, the overall condition of the knee joint, and clinical outcomes at intervals through two years. Evaluations included sequential magnetic resonance imaging (MRI). No ectopic tissue formation or clinically important safety issues were identified. There was significantly increased meniscal volume (defined a priori as a 15% threshold) determined by quantitative MRI in 24% of patients in Group A and 6% in Group B at twelve months post meniscectomy (p = 0.022). No patients in the control group met the 15% threshold for increased meniscal volume. Patients with osteoarthritic changes who received mesenchymal stem cells experienced a significant reduction in pain compared with those who received the control, on the basis of visual analog scale assessments. There was evidence of meniscus regeneration and improvement in knee pain following treatment with allogeneic human mesenchymal stem cells. These results support the study of human mesenchymal stem cells for the apparent knee-tissue regeneration and protective effects.

Interactions between Bmp-4 and Msx-1 act to restrict gene expression to odontogenic mesenchyme.

PubMed

Tucker, A S; Al Khamis, A; Sharpe, P T

1998-08-01

Tooth development is regulated by a reciprocal series of epithelial-mesenchymal interactions. Bmp4 has been identified as a candidate signalling molecule in these interactions, initially as an epithelial signal and then later at the bud stage as a mesenchymal signal (Vainio et al. [1993] Cell 75:45-58). A target gene for Bmp4 signalling is the homeobox gene Msx-1, identified by the ability of recombinant Bmp4 protein to induce expression in mesenchyme. There is, however, no evidence that Bmp4 is the endogenous inducer of Msx-1 expression. Msx-1 and Bmp-4 show dynamic, interactive patterns of expression in oral epithelium and ectomesenchyme during the early stages of tooth development. In this study, we compare the temporal and spatial expression of these two genes to determine whether the changing expression patterns of these genes are consistent with interactions between the two molecules. We show that changes in Bmp-4 expression precede changes in Msx-1 expression. At embryonic day (E)10.5-E11.0, expression patterns are consistent with BMP4 from the epithelium, inducing or maintaining Msx-1 in underlying mesenchyme. At E11.5, Bmp-4 expression shifts from epithelium to mesenchyme and is rapidly followed by localised up-regulation of Msx-1 expression at the sites of Bmp-4 expression. Using cultured explants of developing mandibles, we confirm that exogenous BMP4 is capable of replacing the endogenous source in epithelium and inducing Msx-1 gene expression in mesenchyme. By using noggin, a BMP inhibitor, we show that endogenous Msx-1 expression can be inhibited at E10.5 and E11.5, providing the first evidence that endogenous Bmp-4 from the epithelium is responsible for regulating the early spatial expression of Msx-1. We also show that the mesenchymal shift in Bmp-4 is responsible for up-regulating Msx-1 specifically at the sites of future tooth formation. Thus, we establish that a reciprocal series of interactions act to restrict expression of both genes to future sites of tooth formation, creating a positive feedback loop that maintains expression of both genes in tooth mesenchymal cells.

The role of hesperetin on osteogenesis of human mesenchymal stem cells and its function in bone regeneration.

PubMed

Xue, Deting; Chen, Erman; Zhang, Wei; Gao, Xiang; Wang, Shengdong; Zheng, Qiang; Pan, Zhijun; Li, Hang; Liu, Ling

2017-03-28

Hesperetin has been suggested to be involved in bone strength. We aimed to investigate the effects of hesperetin on the osteogenic differentiation of human mesenchymal stem cells and its related mechanisms. We showed that hesperetin promoted osteogenic differentiation of human mesenchymal stem cells in vitro. It potentially exerts its effects via the ERK and Smad signaling pathways. Using a rat osteotomy model, we showed that human mesenchymal stem cells combined with a hesperetin/gelatin sponge scaffold resulted in accelerated fracture healing in vivo. Due to the low cost of hesperetin, it could be used as a growth factor for bone tissue engineering or surgical fracture treatment.

Pluripotent Stem Cells as a Robust Source of Mesenchymal Stem Cells.

PubMed

Luzzani, Carlos D; Miriuka, Santiago G

2017-02-01

Mesenchymal stem cells (MSC) have been extensively studied over the past years for the treatment of different diseases. Most of the ongoing clinical trials currently involve the use of MSC derived from adult tissues. This source may have some limitations, particularly with therapies that may require extensive and repetitive cell dosage. However, nowadays, there is a staggering growth in literature on a new source of MSC. There is now increasing evidence about the mesenchymal differentiation from pluripotent stem cell (PSC). Here, we summarize the current knowledge of pluripotent-derived mesenchymal stem cells (PD-MSC). We present a historical perspective on the subject, and then discuss some critical questions that remain unanswered.

The epithelial-mesenchymal transition in cancer: a potential critical topic for translational proteomic research.

PubMed

Bottoni, Patrizia; Isgrò, Maria Antonietta; Scatena, Roberto

2016-01-01

The epithelial-mesenchymal transition (EMT) is a morphogenetic process that results in a loss of epithelial characteristics and the acquisition of a mesenchymal phenotype. First described in embryogenesis, the EMT has been recently implicated in carcinogenesis and tumor progression. In addition, recent evidence has shown that stem-like cancer cells present the hallmarks of the EMT. Some of the molecular mechanisms related to the interrelationships between cancer pathophysiology and the EMT are well-defined. Nevertheless, the precise molecular mechanism by which epithelial cancer cells acquire the mesenchymal phenotype remains largely unknown. This review focuses on various proteomic strategies with the goal of better understanding the physiological and pathological mechanisms of the EMT process.

Craniofacial Tissue Engineering by Stem Cells

PubMed Central

Mao, J.J.; Giannobile, W.V.; Helms, J.A.; Hollister, S.J.; Krebsbach, P.H.; Longaker, M.T.; Shi, S.

2008-01-01

Craniofacial tissue engineering promises the regeneration or de novo formation of dental, oral, and craniofacial structures lost to congenital anomalies, trauma, and diseases. Virtually all craniofacial structures are derivatives of mesenchymal cells. Mesenchymal stem cells are the offspring of mesenchymal cells following asymmetrical division, and reside in various craniofacial structures in the adult. Cells with characteristics of adult stem cells have been isolated from the dental pulp, the deciduous tooth, and the periodontium. Several craniofacial structures—such as the mandibular condyle, calvarial bone, cranial suture, and subcutaneous adipose tissue—have been engineered from mesenchymal stem cells, growth factor, and/or gene therapy approaches. As a departure from the reliance of current clinical practice on durable materials such as amalgam, composites, and metallic alloys, biological therapies utilize mesenchymal stem cells, delivered or internally recruited, to generate craniofacial structures in temporary scaffolding biomaterials. Craniofacial tissue engineering is likely to be realized in the foreseeable future, and represents an opportunity that dentistry cannot afford to miss. PMID:17062735

Vitamin C treatment promotes mesenchymal stem cell sheet formation and tissue regeneration by elevating telomerase activity.

PubMed

Wei, Fulan; Qu, Cunye; Song, Tieli; Ding, Gang; Fan, Zhipeng; Liu, Dayong; Liu, Yi; Zhang, Chunmei; Shi, Songtao; Wang, Songlin

2012-09-01

Cell sheet engineering has been developed as an alternative approach to improve mesenchymal stem cell-mediated tissue regeneration. In this study, we found that vitamin C (Vc) was capable of inducing telomerase activity in periodontal ligament stem cells (PDLSCs), leading to the up-regulated expression of extracellular matrix type I collagen, fibronectin, and integrin β1, stem cell markers Oct4, Sox2, and Nanog as well as osteogenic markers RUNX2, ALP, OCN. Under Vc treatment, PDLSCs can form cell sheet structures because of increased cell matrix production. Interestingly, PDLSC sheets demonstrated a significant improvement in tissue regeneration compared with untreated control dissociated PDLSCs and offered an effective treatment for periodontal defects in a swine model. In addition, bone marrow mesenchymal stem cell sheets and umbilical cord mesenchymal stem cell sheets were also well constructed using this method. The development of Vc-mediated mesenchymal stem cell sheets may provide an easy and practical approach for cell-based tissue regeneration. Copyright © 2011 Wiley Periodicals, Inc.

A sea urchin in vivo model to evaluate Epithelial-Mesenchymal Transition.

PubMed

Romancino, Daniele P; Anello, Letizia; Lavanco, Antonella; Buffa, Valentina; Di Bernardo, Maria; Bongiovanni, Antonella

2017-04-01

Epithelial-mesenchymal transition (EMT) is an evolutionarily conserved cellular program, which is a prerequisite for the metastatic cascade in carcinoma progression. Here, we evaluate the EMT process using the sea urchin Paracentrotus lividus embryo. In sea urchin embryos, the earliest EMT event is related to the acquisition of a mesenchymal phenotype by the spiculogenetic primary mesenchyme cells (PMCs) and their migration into the blastocoel. We investigated the effect of inhibiting the epidermal growth factor (EGF) signaling pathway on this process, and we observed that mesenchyme cell differentiation was blocked. In order to extend and validate our studies, we investigated the migratory capability and the level of potential epidermal growth factor receptor (EGFr) targets in a breast cancer cell line after EGF modulation. Altogether, our data highlight the sensitivity of the sea urchin embryo to anti-EMT drugs and pinpoint the sea urchin embryo as a valuable in vivo model system for studying EMT and the screening of anti-EMT candidates. © 2017 Japanese Society of Developmental Biologists.

Isolation and evaluation of dental pulp stem cells from teeth with advanced periodontal disease.

PubMed

Derakhshani, Ali; Raoof, Maryam; Dabiri, Shahriar; Farsinejad, Ali Reza; Gorjestani, Hedayat; Yaghoobi, Mohammad Mehdi; Shokouhinejad, Noushin; Ehsani, Maryam

2015-04-01

Successful isolation of mesenchymal stem cells from waste tissues might be extremely promising for developing stem cell-based therapies. This study aimed to explore whether cells retrieved from teeth extracted due to advanced periodontal disease present mesenchymal stem cell-like properties. Pulp cells were isolated from 15 intact molars and 15 teeth with advanced periodontal disease. Cell proliferation and markers of mesenchymal stem cells were evaluated. Based on the RT-PCR and agarose gel electrophoresis, nucleostemin, Oct-4 and jmj2c, but not Nanog, were expressed in undifferentiated mesenchymal stem cells of both groups. Interestingly, diseased pulp exhibited higher gene expressions although it was not statistically significant. The average percentage of BrdU positive cells in the diseased group (84.4%, n = 5) was significantly higher than that of the control group (65.4%, n = 5) (t-test, P = 0.001). Our results indicate the successful isolation of mesenchymal stem cells from the pulp tissue of hopeless periodontally involved teeth.

Regulation of pulmonary inflammation by mesenchymal cells.

PubMed

Alkhouri, Hatem; Poppinga, Wilfred Jelco; Tania, Navessa Padma; Ammit, Alaina; Schuliga, Michael

2014-12-01

Pulmonary inflammation and tissue remodelling are common elements of chronic respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), and pulmonary hypertension (PH). In disease, pulmonary mesenchymal cells not only contribute to tissue remodelling, but also have an important role in pulmonary inflammation. This review will describe the immunomodulatory functions of pulmonary mesenchymal cells, such as airway smooth muscle (ASM) cells and lung fibroblasts, in chronic respiratory disease. An important theme of the review is that pulmonary mesenchymal cells not only respond to inflammatory mediators, but also produce their own mediators, whether pro-inflammatory or pro-resolving, which influence the quantity and quality of the lung immune response. The notion that defective pro-inflammatory or pro-resolving signalling in these cells potentially contributes to disease progression is also discussed. Finally, the concept of specifically targeting pulmonary mesenchymal cell immunomodulatory function to improve therapeutic control of chronic respiratory disease is considered. Copyright © 2014 Elsevier Ltd. All rights reserved.

Sources of adult mesenchymal stem cells for ligament and tendon tissue engineering.

PubMed

Dhinsa, Baljinder S; Mahapatra, Anant N; Khan, Wasim S

2015-01-01

Tendon and ligament injuries are common, and repair slowly with reduced biomechanical properties. With increasing financial demands on the health service and patients to recover from tendon and ligament injuries faster, and with less morbidity, health professionals are exploring new treatment options. Tissue engineering may provide the answer, with its unlimited source of natural cells that in the correct environment may improve repair and regeneration of tendon and ligament tissue. Mesenchymal stem cells have demonstrated the ability to self renew and have multilineage differentiation potential. The use of bone marrow-derived mesenchymal stem cells has been reported, however significant in vitro culture expansion is required due to the low yield of cells, which has financial implications. Harvesting of bone marrow cells also has associated morbidity. Several studies have looked at alternative sources for mesenchymal stem cells. Reports in literature from animal studies have been encouraging, however further work is required. This review assesses the potential sources of mesenchymal stem cells for tissue engineering in tendons and ligaments.

The Role of the Rab Coupling Protein in ErbB2-Driven Mammary Tumorigenesis and Metastasis

DTIC Science & Technology

2014-10-01

Coupling Protein/Rab11FIP1/RCP, Epithelial Mesenchymal Transition , Cell junctions , Cell Proliferation, Senescence. 16. SECURITY CLASSIFICATION OF: 17...Tyrosine Kinase, Her/ErbB2 signaling, Rab Coupling Protein/Rab11FIP1/RCP, Epithelial Mesenchymal Transition , Cell junctions , Cell Proliferation...lines included RCP condition to internalization and detection of E-cadherin, a well-known adherent junction and epithelial mesenchymal transition

Phosphaturic mesenchymal tumor of the tibia with oncogenic osteomalacia in a teenager.

PubMed

Farmakis, Shannon G; Siegel, Marilyn J

2015-08-01

Phosphaturic mesenchymal tumor is an uncommon cause of a paraneoplastic syndrome that can be associated with osteogenic osteomalacia. This tumor most commonly occurs in middle-aged men and women. We report a rare case of a phosphaturic mesenchymal tumor in a 16-year-old girl with multiple fractures as a result of severe osteoporosis. CT and MRI showed a mass arising from the tibia.

Mechanisms of Invariant Natural Killer T Cell-Mediated Immunoregulation in Cancer

DTIC Science & Technology

2012-05-01

by mesenchymal stem cells . Intriguingly, the increased metastatic ability was dependent on the production of CCL5 by mesenchymal stem cells , which...Tubo, R., &Weinberg, R.A.(2007) Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature. Vol. 449:pp557-563. Breast...can induce preferential secretion of immunosuppressive cytokines ; 2) iNKT cells inhibit effector T cell priming by killing dendritic cells that

Rg1 inhibits high glucose-induced mesenchymal activation and fibrosis via regulating miR-2113/RP11-982M15.8/Zeb1 pathway.

PubMed

Xue, Li-Ping; Fu, Xiao-Lin; Hu, Min; Zhang, Li-Wei; Li, Ya-Di; Peng, Ya-Li; Ding, Peng

2018-07-02

Recent study has showed that Ginsenoside Rg1, the mian active compound of Panax ginseng, could ameliorate oxidative stress and myocardial apoptosis in diabetes mellitus. However, the roles and mechanisms of Rg1 in proliferative diabetic retinopathy (PDR) are still unclear. In the present study, we aimed to investigate the effects of Rg1 on mesenchymal activation of high-glucose (HG) cultured müller cells. High glucose conditions up-regulate MMP-2, MMP-9 and down-regulate TIMP-2, and promote mesenchymal activation in Müller cells. And Rg1 inhibits the HG-induced mesenchymal activation and HG-increased MMP-2 and MMP-9 and HG-decreased TIMP-2 in Müller cells. HG up-regulates Zeb1 and lncRNA RP11-982M15.8, and down-regulates miR-2113, and Rg1 inhibits these effects of HG. Both inhibition of miR-2113 and over-expression of RP11-982M15.8 significantly restored the HG induced mesenchymal activasion. Taken together, our findings suggested that Rg1 inhibited HG-induced mesenchymal activation and fibrosis via regulating miR-2113/RP11-982M15.8/Zeb1 pathway. Copyright © 2018. Published by Elsevier Inc.

Bone marrow mesenchymal stem cells from patients with aplastic anemia maintain functional and immune properties and do not contribute to the pathogenesis of the disease.

PubMed

Bueno, Clara; Roldan, Mar; Anguita, Eduardo; Romero-Moya, Damia; Martín-Antonio, Beatriz; Rosu-Myles, Michael; del Cañizo, Consuelo; Campos, Francisco; García, Regina; Gómez-Casares, Maite; Fuster, Jose Luis; Jurado, Manuel; Delgado, Mario; Menendez, Pablo

2014-07-01

Aplastic anemia is a life-threatening bone marrow failure disorder characterized by peripheral pancytopenia and marrow hypoplasia. The majority of cases of aplastic anemia remain idiopathic, although hematopoietic stem cell deficiency and impaired immune responses are hallmarks underlying the bone marrow failure in this condition. Mesenchymal stem/stromal cells constitute an essential component of the bone marrow hematopoietic microenvironment because of their immunomodulatory properties and their ability to support hematopoiesis, and they have been involved in the pathogenesis of several hematologic malignancies. We investigated whether bone marrow mesenchymal stem cells contribute, directly or indirectly, to the pathogenesis of aplastic anemia. We found that mesenchymal stem cell cultures can be established from the bone marrow of aplastic anemia patients and display the same phenotype and differentiation potential as their counterparts from normal bone marrow. Mesenchymal stem cells from aplastic anemia patients support the in vitro homeostasis and the in vivo repopulating function of CD34(+) cells, and maintain their immunosuppressive and anti-inflammatory properties. These data demonstrate that bone marrow mesenchymal stem cells from patients with aplastic anemia do not have impaired functional and immunological properties, suggesting that they do not contribute to the pathogenesis of the disease. Copyright© Ferrata Storti Foundation.

Canonical WNT signalling determines lineage specificity in Wilms tumour.

PubMed

Fukuzawa, R; Anaka, M R; Weeks, R J; Morison, I M; Reeve, A E

2009-02-26

Wilms tumours (WTs) have two distinct types of histology with or without ectopic mesenchymal elements, suggesting that WTs arise from either the mesenchymal or epithelial nephrogenic lineages. Regardless of the presence or absence of CTNNB1 mutations, nuclear accumulation of beta-catenin is often observed in WTs with ectopic mesenchymal elements. Here, we addressed the relationship between the WNT-signalling pathway and lineage in WTs by examining CTNNB1 and WT1 mutations, nuclear accumulation of beta-catenin, tumour histology and gene expression profiles. In addition, we screened for mutations in WTX, which has been proposed to be a negative regulator of the canonical WNT-signalling pathway. Unsupervised clustering analysis identified two classes of tumours: mesenchymal lineage WNT-dependent tumours, and epithelial lineage WNT-independent tumours. In contrast to the mesenchymal lineage specificity of CTNNB1 mutations, WTX mutations were surprisingly observed in both lineages. WTX-mutant WTs with ectopic mesenchymal elements had nuclear accumulation of beta-catenin, upregulation of WNT target genes and an association with CTNNB1 mutations in exon 7 or 8. However, epithelial lineage WTs with WTX mutations had no indications of active WNT signalling, suggesting that the involvement of WTX in the WNT-signalling pathway may be lineage dependent, and that WTX may have an alternative function to its role in the canonical WNT-signalling pathway.

HMEC-1 adopt the mixed amoeboid-mesenchymal migration type during EndMT.

PubMed

Kryczka, Jakub; Przygodzka, Patrycja; Bogusz, Helena; Boncela, Joanna

2017-06-01

The contribution of endothelial cells to scar and fibrotic tissue formation is undisputedly connected to their ability to undergo the endothelial-to-mesenchymal transition (EndMT) towards fibroblast phenotype-resembling cells. The migration model of fibroblasts and fibroblast-resembling cells is still not fully understood. It may be either a Rho/ROCK-independent, an integrin- and MMP-correlated ECM degradation-dependent, a mesenchymal model or Rho/ROCK-dependent, integrin adhesion- and MMP activity-independent, an amoeboid model. Here, we hypothesized that microvascular endothelial cells (HMEC-1) undergoing EndMT adopt an intermediate state of drifting migration model between the mesenchymal and amoeboid protrusive types in the early stages of fibrosis. We characterized the response of HMEC-1 to TGF-β2, a well-known mediator of EndMT within the microvasculature. We observed that TGF-β2 induces up to an intermediate mesenchymal phenotype in HMEC-1. In parallel, MMP-2 is upregulated and is responsible for most proteolytic activity. Interestingly, the migration of HMEC-1 undergoing EndMT is dependent on both ECM degradation and invadosome formation associated with MMP-2 proteolytic activity and Rho/ROCK cytoskeleton contraction. In conclusion, the transition from mesenchymal towards amoeboid movement highlights a molecular plasticity mechanism in endothelial cell migration in skin fibrosis. Copyright © 2017 Elsevier GmbH. All rights reserved.