Mechanism of Twist1-Induced Invasion in Breast Cancer Metastasis

DTIC Science & Technology

2012-01-01

Breast Cancer Metastasis PRINCIPAL INVESTIGATOR: Mark Adam Eckert CONTRACTING...2011 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Mechanism of Twist1-Induced Invasion in Breast Cancer Metastasis 5b. GRANT NUMBER W81XWH-09-1...an important mediator of breast cancer metastasis by driving the epithelial-mesenchymal transition. We find that Twist1 promotes metastasis by

DLC1-dependent parathyroid hormone-like hormone inhibition suppresses breast cancer bone metastasis.

PubMed

Wang, Yufeng; Lei, Rong; Zhuang, Xueqian; Zhang, Ning; Pan, Hong; Li, Gang; Hu, Jing; Pan, Xiaoqi; Tao, Qian; Fu, Da; Xiao, Jianru; Chin, Y Eugene; Kang, Yibin; Yang, Qifeng; Hu, Guohong

2014-04-01

Bone metastasis is a frequent complication of breast cancer that is often accelerated by TGF-β signaling; however, little is known about how the TGF-β pathway is regulated during bone metastasis. Here we report that deleted in liver cancer 1 (DLC1) is an important regulator of TGF-β responses and osteolytic metastasis of breast cancer cells. In murine models, breast cancer cells lacking DLC1 expression exhibited enhanced capabilities of bone metastasis. Knockdown of DLC1 in cancer cells promoted bone metastasis, leading to manifested osteolysis and accelerated death in mice, while DLC1 overexpression suppressed bone metastasis. Activation of Rho-ROCK signaling in the absence of DLC1 mediated SMAD3 linker region phosphorylation and TGF-β-induced expression of parathyroid hormone-like hormone (PTHLH), leading to osteoclast maturation for osteolytic colonization. Furthermore, pharmacological inhibition of Rho-ROCK effectively reduced PTHLH production and breast cancer bone metastasis in vitro and in vivo. Evaluation of clinical breast tumor samples revealed that reduced DLC1 expression was linked to elevated PTHLH expression and organ-specific metastasis to bone. Overall, our findings define a stroma-dependent paradigm of Rho signaling in cancer and implicate Rho-TGF-β crosstalk in osteolytic bone metastasis.

Impact of Visceral Metastasis on Efficacy of Fulvestrant in Patients with Hormone Receptor-positive Recurrent Breast Cancer.

PubMed

Koi, Yumiko; Koga, Chinami; Akiyoshi, Sayuri; Masuda, Takanobu; Ijichi, Hideki; Nakamura, Yoshiaki; Ishida, Mayumi; Ohno, Shinji; Tokunaga, Eriko

2018-03-01

Previous studies have suggested that the presence of visceral metastasis is a parameter useful in predicting the treatment efficacy of fulvestrant in patients with advanced breast cancer. We retrospectively examined the association between treatment efficacy and presence of visceral metastasis in 75 patients with hormone receptor-positive recurrent breast cancer who were treated with fulvestrant or no more than five lines of other endocrine monotherapy after recurrence. Nineteen patients received fulvestrant, 10 of whom had visceral metastasis. The median time to progression was 4 months for the overall study population; it was significantly longer for patients with non-visceral metastasis (5.4 months; 95% confidence interval=3.7-11.2 months) than for those with visceral metastasis (3.3 months; 95% confidence interval, 0.4-5.3 months; p=0.01). No differences in time to progression were found between the groups of patients with visceral metastasis and non-visceral metastasis who underwent other endocrine therapies. Fulvestrant is more effective for patients with non-visceral metastasis of recurrent breast cancer with than for those with visceral metastasis. Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Predictors of metastasis to lymph nodes posterior to the right recurrent laryngeal nerve in differentiated thyroid carcinoma: A prospective study.

PubMed

Liu, Ziwen; Sun, Mengqing; Xiao, Yiding; Yang, Jing; Zhang, Taiping; Zhao, Yupei

2017-07-01

To study the clinicopathological characteristics and the risk factors of lymph nodes posterior to the right recurrent laryngeal nerve (LN-prRLN) metastasis in differentiated thyroid carcinoma; and to identify the indication for LN-prRLN dissection. We treated 145 patients with differentiated thyroid carcinoma with appropriate surgical intervention. The specimens were examined by the pathologists. The right paratracheal lymph nodes were divided into two groups: anterior or posterior to right recurrent laryngeal nerve (VIa or VIp compartment, respectively). We recorded the clinical characteristics, histopathological features of the primary tumors, and lymph node metastasis of the patients. The results were statistically analyzed. There were 85 patients (58.6%) with central lymph node metastasis, of whom 61 (42.1%) had metastasis in VIa compartment; 16 patients (11.0%) had VIp subdistrict metastasis; and 25 patients had lateral lymph node metastasis. Multiplicity, larger tumor (≥1 cm), and coexistence of central lymph node metastasis, VIa compartment metastasis, and lateral lymph node metastasis were all significantly related with LN-prRLN metastasis, while sex, age, location of the tumor, and extrathyroid extension of the tumor showed no significant relation (p > 0.05). The incidence of LN-prRLN metastasis was lower than other central lymph nodes, as well as lymph nodes anterior to right recurrent laryngeal nerve. When there were multiple foci of tumors, or the tumor was larger than 1 cm, or central or lateral LN metastasis was indicated by preoperative ultrasound or confirmed by intraoperative frozen sections, it is strongly recommended that exploration and dissection of the LN-prRLN should only be performed by experienced surgeons. Copyright © 2016. Published by Elsevier Taiwan.

A genome-wide shRNA screen identifies GAS1 as a novel melanoma metastasis suppressor gene.

PubMed

Gobeil, Stephane; Zhu, Xiaochun; Doillon, Charles J; Green, Michael R

2008-11-01

Metastasis suppressor genes inhibit one or more steps required for metastasis without affecting primary tumor formation. Due to the complexity of the metastatic process, the development of experimental approaches for identifying genes involved in metastasis prevention has been challenging. Here we describe a genome-wide RNAi screening strategy to identify candidate metastasis suppressor genes. Following expression in weakly metastatic B16-F0 mouse melanoma cells, shRNAs were selected based upon enhanced satellite colony formation in a three-dimensional cell culture system and confirmed in a mouse experimental metastasis assay. Using this approach we discovered 22 genes whose knockdown increased metastasis without affecting primary tumor growth. We focused on one of these genes, Gas1 (Growth arrest-specific 1), because we found that it was substantially down-regulated in highly metastatic B16-F10 melanoma cells, which contributed to the high metastatic potential of this mouse cell line. We further demonstrated that Gas1 has all the expected properties of a melanoma tumor suppressor including: suppression of metastasis in a spontaneous metastasis assay, promotion of apoptosis following dissemination of cells to secondary sites, and frequent down-regulation in human melanoma metastasis-derived cell lines and metastatic tumor samples. Thus, we developed a genome-wide shRNA screening strategy that enables the discovery of new metastasis suppressor genes.

[A retrospective analysis on occult neck lymphatic metastasis in early tongue cancer].

PubMed

Gong, Q L; Bian, C; Liu, H

2016-10-07

Objective: To investigate the number and level of occult neck lymphatic metastasis for squamous cell carcinoma of tongue in clinical stage Ⅰ/Ⅱ, and the relationship between cell differentiation and occult neck lymphatic metastasis. Methods: A total of 101 cases diagnosed preoperatively as having squamous cell carcinoma of tongue in clinical stage Ⅰ/Ⅱ (cT1/T2N0M0) between January 2005 and April 2015 were analysed retrospectively. Whether presence of occult neck lymphatic metastasis in these cases was studied. Results: Occult neck lymphatic metastases were found in 22 (21.78%) of 101 cases, 10 men and 12 women, with an age range of 22 to 83 years. There was not statistically significant association between tumor size or cell differentiation and occult neck lymphatic metastasis ( P >0.05). The metastasis occurred most commonly in level Ⅱ, followed by levelsⅠ, Ⅲ and Ⅳ. There was no lymph node metastasis in Level Ⅴ. There were total 20 cases with occult neck lymphatic metastasis in at least one of levelⅠ, Ⅱ, Ⅲ(90.9%), One of these case was skipping metastasis in level Ⅲ(4.6%). Conclusion: The early tongue cancer has a high rate of occult lymph metastasis, which occurs commonly in levels Ⅱ, Ⅰ and Ⅲ, but there is not significant association between the metastasis and tumor size or cell differentiation.

Advances in Decoding Breast Cancer Brain Metastasis

PubMed Central

Zhang, Chenyu; Yu, Dihua

2016-01-01

The past decade has witnessed impressive advances in cancer treatment ushered in by targeted and immunotherapies. However, with significantly prolonged survival, upon recurrence, more patients become inflicted by brain metastasis, which is mostly refractory to all currently available therapeutic regimens. Historically, brain metastasis is an understudied area in cancer research, partly due to the dearth of appropriate experimental models that closely simulate the special biological features of metastasis in the unique brain environment; and to the sophistication of techniques required to perform in-depth studies of the extremely complex and challenging brain metastasis. Yet, with increasing clinical demand for more effective treatment options, brain metastasis research has rapidly advanced in recent years. The present review spotlights the recent major progresses in basic and translational studies of brain metastasis with focuses on new animal models, novel imaging technologies, omics “big data” resources, and some new and exciting biological insights on brain metastasis. PMID:27873078

Effect of Chronic Psychological Stress on Liver Metastasis of Colon Cancer in Mice

PubMed Central

Zhao, Lu; Xu, Jianhua; Liang, Fang; Li, Ao; Zhang, Yong; Sun, Jue

2015-01-01

Metastasis to the liver is a main factor in colorectal cancer mortality. Previous studies suggest that chronic psychological stress is important in cancer progression, but its effect on liver metastasis has not been investigated. To address this, we established a liver metastasis model in BALB/c nude mice to investigate the role of chronic stress in liver metastasis. Our data suggest that chronic stress elevates catecholamine levels and promotes liver metastasis. Chronic stress was also associated with increased tumor associated macrophages infiltration into the primary tumor and increased the expression of metastatic genes. Interestingly, β-blocker treatment reversed the effects of chronic stress on liver metastasis. Our results suggest the β-adrenergic signaling pathway is involved in regulating colorectal cancer progression and liver metastasis. Additionally, we submit that adjunctive therapy with a β-blocker may complement existing colorectal cancer therapies. PMID:26444281

Lung Metastasis Mimicking Fingertip Infection

PubMed Central

Soylemez, Salih; Demiroglu, Murat; Yayla, Mehmet Ali; Ozkan, Korhan; Alpan, Bugra; Ozger, Harzem

2015-01-01

Metastasis fingers (acral metastasis) are finding a poor prognosis. Past medical history should be questioned and metastasis from primary tumor should be kept in mind in patients with pain, swelling, and hyperemia in fingers. Successful surgical treatment on acral metastasis does not extend the life expectancy; however, it reduces the patient's pain during his terminal period, saves the functions of the limb, and increases life comfort. PMID:26236517

Clinicopathologic risk factors for right paraesophageal lymph node metastasis in patients with papillary thyroid carcinoma.

PubMed

Yu, Q A; Ma, D K; Liu, K P; Wang, P; Xie, C M; Wu, Y H; Dai, W J; Jiang, H C

2018-03-17

To investigate risk factors associated with right paraesophageal lymph node (RPELN) metastasis in patients with papillary thyroid carcinoma (PTC) and to determine the indications for right lymph node dissection. Clinicopathologic data from 829 patients (104 men and 725 women) with PTC, operated on by the same thyroid surgery team at the First Affiliated Hospital of Harbin Medical University from January 2013 to May 2017, were analyzed. Overall, 309 patients underwent total thyroidectomy with bilateral lymph node dissection, 488 underwent right thyroid lobe and isthmic resection with right central compartment lymph node dissection, and 32 underwent near-total thyroidectomy (ipsilateral thyroid lobectomy with contralateral near-total lobectomy) with bilateral lymph node dissection. The overall rate of central compartment lymph node metastasis was 43.5% (361/829), with right central compartment lymph node and RPELN metastasis rates of 35.5% (294/829) and 19.1% (158/829), respectively. Tumor size, number, invasion, and location, lymph node metastasis, right central compartment lymph node metastasis, and right lateral compartment lymph node metastasis were associated with RPELN in the univariate analysis, whereas age and sex were not. Multivariate analysis identified tumors with a diameter ≥ 1 cm, multiple tumors, tumors located in the right lobe, right central compartment lymph node metastasis, and right lateral compartment lymph node metastasis as independent risk factors for RPELN metastasis. Lymph node dissection, including RPELN dissection, should be performed for patients with PTC with a tumor diameter ≥ 1 cm, multiple tumors, right-lobe tumors, right central compartment lymph node metastasis, or suspected lateral compartment lymph node metastasis.

Pattern of metastasis outside tumor-bearing segments in primary lung cancer: rationale for segmentectomy.

PubMed

Sakairi, Yuichi; Yoshino, Ichiro; Yoshida, Shigetoshi; Suzuki, Hidemi; Tagawa, Tetsuzo; Iwata, Takekazu; Mizobuchi, Teruaki

2014-05-01

Patterns of intrapulmonary metastasis, particularly metastasis outside tumor-bearing segments, were investigated in lung cancer patients to address the rationale for segmentectomy. In a consecutive series of patients who underwent resection of two or more pulmonary segments for primary lung cancer, intrapulmonary spread patterns, such as segmental/intersegmental node metastasis and pulmonary parenchymal metastasis, were pathologically examined. Eligible 244 lesions included 167 adenocarcinomas, 66 squamous cell carcinomas, and 11 large cell carcinomas. Pathologic stages included 0 to IA (n=111), IB (n=56), IIA (n=31), IIB (n=20), IIIA (n=23), and IIIB to IV (n=3); and N1 (n=26) and N2 (n=22). Intrapulmonary spread was observed in 24 cases (9.8%). Of these, metastasis outside tumor-bearing segments was only observed in 4 cases (1.6%), and such cancer spread was more frequently seen in cases with extrapulmonary (hilar to mediastinal) nodal metastasis (7.9%) than in cases without extrapulmonary metastasis (0.5%; p=0.01). Metastasis outside tumor-bearing segments was not observed in 64 tumors with pure or mixed ground glass opacity features on computed tomography. Although tumor location (peripheral or central/intermediate) was not related to the incidence of metastasis outside tumor-bearing segments, intrapulmonary spread was observed in only 1 of 52 peripheral small (≤20 mm) tumors. Metastasis outside tumor-bearing segments is rarely observed in cases with tumors (1) without extrapulmonary nodal metastasis and (2) with ground glass opacity or peripheral small (≤20 mm) features. Copyright © 2014 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

Advances in diagnosis and treatment of metastatic cervical cancer

PubMed Central

2016-01-01

Cervical cancer is one of the most common cancers in women worldwide. The outcome of patients with metastatic cervical cancer is poor. We reviewed the relevant literature concerning the treatment and diagnosis of metastatic cervical cancer. There are two types of metastasis related to different treatments and survival rates: hematogenous metastasis and lymphatic metastasis. Patients with hematogenous metastasis have a higher risk of death than those with lymphatic metastasis. In terms of diagnosis, fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) and PET-computed tomography are effective tools for the evaluation of distant metastasis. Concurrent chemoradiotherapy and subsequent chemotherapy are well-tolerated and efficient for lymphatic metastasis. As for lung metastasis, chemotherapy and/or surgery are valuable treatments for resistant, recurrent metastatic cervical cancer and chemoradiotherapy may be the optimal choice for stage IVB cervical cancer. Chemotherapy and bone irradiation are promising for bone metastasis. A better survival is achieved with multimodal therapy. Craniotomy or stereotactic radiosurgery is an optimal choice combined with radiotherapy for solitary brain metastases. Chemotherapy and palliative brain radiation may be considered for multiple brain metastases and other organ metastases. PMID:27171673

Choroidal metastasis from early rectal cancer: Case report and literature review

PubMed Central

Tei, Mitsuyoshi; Wakasugi, Masaki; Akamatsu, Hiroki

2014-01-01

INTRODUCTION Choroidal metastasis from colorectal cancer is rare, and there have been no reported cases of such metastasis from early colorectal cancer. We report a case of choroidal metastasis from early rectal cancer. PRESENTATION OF CASE A 61 year-old-man experienced myodesopsia in the left eye 2 years and 6 months after primary rectal surgery for early cancer, and was diagnosed with left choroidal metastasis and multiple lung metastases. Radiotherapy was initiated for the left eye and systemic chemotherapy is initiated for the multiple lung metastases. The patient is living 2 years and 3 months after the diagnosis of choroidal metastasis without signs of recurrence in the left eye, and continues to receive systemic chemotherapy for multiple lung metastases. DISCUSSION Current literatures have few recommendations regarding the appropriate treatment of choroidal metastasis from colorectal cancer, but an aggressive multi-disciplinary approach may be effective in local regression. CONCLUSION This is the first report of choroidal metastasis from early rectal cancer. We consider it important to enforce systemic chemotherapy in addition to radiotherapy for choroidal metastasis from colorectal cancer. PMID:25460493

Choroidal metastasis from early rectal cancer: Case report and literature review.

PubMed

Tei, Mitsuyoshi; Wakasugi, Masaki; Akamatsu, Hiroki

2014-01-01

Choroidal metastasis from colorectal cancer is rare, and there have been no reported cases of such metastasis from early colorectal cancer. We report a case of choroidal metastasis from early rectal cancer. A 61 year-old-man experienced myodesopsia in the left eye 2 years and 6 months after primary rectal surgery for early cancer, and was diagnosed with left choroidal metastasis and multiple lung metastases. Radiotherapy was initiated for the left eye and systemic chemotherapy is initiated for the multiple lung metastases. The patient is living 2 years and 3 months after the diagnosis of choroidal metastasis without signs of recurrence in the left eye, and continues to receive systemic chemotherapy for multiple lung metastases. Current literatures have few recommendations regarding the appropriate treatment of choroidal metastasis from colorectal cancer, but an aggressive multi-disciplinary approach may be effective in local regression. This is the first report of choroidal metastasis from early rectal cancer. We consider it important to enforce systemic chemotherapy in addition to radiotherapy for choroidal metastasis from colorectal cancer. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

Inhibition of breast cancer metastasis with microRNA-302a by downregulation of CXCR4 expression.

PubMed

Liang, Zhongxing; Bian, Xuehai; Shim, Hyunsuk

2014-08-01

Metastasis remains a main cause of mortality from breast cancer and an unresolved issue. The purpose of this study is to investigate the role of miR-302a in the development of breast cancer metastasis mediated by CXCR4, a critical regulator of metastasis, and to identify miR-302a as an effective therapeutic agent for therapy and prevention of breast cancer metastasis. Our studies show that miR-302a expression levels were downregulated in metastatic breast cancer cells and tumor tissues. Additionally, the expression levels of miR-302a were inversely correlated with CXCR4 levels. More promisingly, miR-302a inhibited the invasion and metastasis of breast cancer cells in vitro and in vivo and reduced the expression of CXCR4. Our findings demonstrated that the repression of miR-302a levels contributes to breast cancer metastasis and restoration of miR-302a baseline expression inhibits the invasion and metastasis of breast cancer cells. These data suggest that miR-302a mimics are potential therapeutic agents for breast cancer metastasis.

Advances in diagnosis and treatment of metastatic cervical cancer.

PubMed

Li, Haoran; Wu, Xiaohua; Cheng, Xi

2016-07-01

Cervical cancer is one of the most common cancers in women worldwide. The outcome of patients with metastatic cervical cancer is poor. We reviewed the relevant literature concerning the treatment and diagnosis of metastatic cervical cancer. There are two types of metastasis related to different treatments and survival rates: hematogenous metastasis and lymphatic metastasis. Patients with hematogenous metastasis have a higher risk of death than those with lymphatic metastasis. In terms of diagnosis, fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) and PET-computed tomography are effective tools for the evaluation of distant metastasis. Concurrent chemoradiotherapy and subsequent chemotherapy are well-tolerated and efficient for lymphatic metastasis. As for lung metastasis, chemotherapy and/or surgery are valuable treatments for resistant, recurrent metastatic cervical cancer and chemoradiotherapy may be the optimal choice for stage IVB cervical cancer. Chemotherapy and bone irradiation are promising for bone metastasis. A better survival is achieved with multimodal therapy. Craniotomy or stereotactic radiosurgery is an optimal choice combined with radiotherapy for solitary brain metastases. Chemotherapy and palliative brain radiation may be considered for multiple brain metastases and other organ metastases.

DLC1-dependent parathyroid hormone–like hormone inhibition suppresses breast cancer bone metastasis

PubMed Central

Wang, Yufeng; Lei, Rong; Zhuang, Xueqian; Zhang, Ning; Pan, Hong; Li, Gang; Hu, Jing; Pan, Xiaoqi; Tao, Qian; Fu, Da; Xiao, Jianru; Chin, Y. Eugene; Kang, Yibin; Yang, Qifeng; Hu, Guohong

2014-01-01

Bone metastasis is a frequent complication of breast cancer that is often accelerated by TGF-β signaling; however, little is known about how the TGF-β pathway is regulated during bone metastasis. Here we report that deleted in liver cancer 1 (DLC1) is an important regulator of TGF-β responses and osteolytic metastasis of breast cancer cells. In murine models, breast cancer cells lacking DLC1 expression exhibited enhanced capabilities of bone metastasis. Knockdown of DLC1 in cancer cells promoted bone metastasis, leading to manifested osteolysis and accelerated death in mice, while DLC1 overexpression suppressed bone metastasis. Activation of Rho-ROCK signaling in the absence of DLC1 mediated SMAD3 linker region phosphorylation and TGF-β–induced expression of parathyroid hormone–like hormone (PTHLH), leading to osteoclast maturation for osteolytic colonization. Furthermore, pharmacological inhibition of Rho-ROCK effectively reduced PTHLH production and breast cancer bone metastasis in vitro and in vivo. Evaluation of clinical breast tumor samples revealed that reduced DLC1 expression was linked to elevated PTHLH expression and organ-specific metastasis to bone. Overall, our findings define a stroma-dependent paradigm of Rho signaling in cancer and implicate Rho–TGF-β crosstalk in osteolytic bone metastasis. PMID:24590291

An evidence-based knowledgebase of metastasis suppressors to identify key pathways relevant to cancer metastasis

PubMed Central

Zhao, Min; Li, Zhe; Qu, Hong

2015-01-01

Metastasis suppressor genes (MS genes) are genes that play important roles in inhibiting the process of cancer metastasis without preventing growth of the primary tumor. Identification of these genes and understanding their functions are critical for investigation of cancer metastasis. Recent studies on cancer metastasis have identified many new susceptibility MS genes. However, the comprehensive illustration of diverse cellular processes regulated by metastasis suppressors during the metastasis cascade is lacking. Thus, the relationship between MS genes and cancer risk is still unclear. To unveil the cellular complexity of MS genes, we have constructed MSGene (http://MSGene.bioinfo-minzhao.org/), the first literature-based gene resource for exploring human MS genes. In total, we manually curated 194 experimentally verified MS genes and mapped to 1448 homologous genes from 17 model species. Follow-up functional analyses associated 194 human MS genes with epithelium/tissue morphogenesis and epithelia cell proliferation. In addition, pathway analysis highlights the prominent role of MS genes in activation of platelets and coagulation system in tumor metastatic cascade. Moreover, global mutation pattern of MS genes across multiple cancers may reveal common cancer metastasis mechanisms. All these results illustrate the importance of MSGene to our understanding on cell development and cancer metastasis. PMID:26486520

Efficacy of Superselective Neck Dissection in Detecting Metastasis in Patients with cN0 Papillary Thyroid Carcinoma at High Risk of Lateral Neck Metastasis

PubMed Central

An, Changming; Zhang, Xiwei; Wang, Shixu; Zhang, Zongmin; Yin, Yulin; Xu, Zhengang; Tang, Pingzhang; Li, Zhengjiang

2017-01-01

Background This study aimed to evaluate superselective neck dissection (SSND) in patients with cN0 papillary thyroid carcinoma (PTC) at high risk of lateral cervical lymph node (LN) metastasis. Material/Methods This study enrolled 138 patients with PTC who underwent SSND. These patients were at high risk for LN metastasis and the rate of cervical LN metastasis was recorded. Results In all, 146 lateral neck dissections were performed in 138 patients. Intraoperative pathological data revealed LN metastasis from 55 cases, for which Level II and V dissection were performed. Ninety SSNDs were performed in the other 83 patients without metastasis identified in frozen sections. Occult lymph node metastasis (OLNM) rates were 56.8% and 43.5% in the central compartment and lateral neck, respectively. OLNM rates of Level II–VI were 17.8%, 31.5%, 36.3%, 1.4%, and 56.8%, respectively. Level VI metastasis (p<0.001), extra thyroidal extension (p=0.003), and tumor size (p=0.011) were significant factors for lateral neck LN metastasis. Conclusions SSND might be effective for early diagnosis of lateral neck metastases of PTC. Patients with OLNM should receive level II, III, and IV dissection, but level V dissection could be omitted. PMID:28469126

Benefit of FOLFOX to unresectable liver metastases secondary from colorectal carcinoma in an oncologic emergency.

PubMed

Sugimoto, Maki; Yasuda, Hideki; Koda, Keiji; Yamazaki, Masato; Tezuka, Tohru; Takenoue, Tomohiro; Kosugi, Chihiro; Higuchi, Ryota; Yamamoto, Shiho; Watayo, Yoshihisa; Yagawa, Yohsuke; Suzuki, Masato

2007-09-01

Liver metastasis is an important prognostic factor in colorectal cancer. The efficacy of resection of metastatic lesions in liver metastasis of colorectal cancer is also widely recognized. However, studies on treatment methods of unresectable cases have not been sufficient and obtaining complete remission (CR) for liver metastasis is rare with chemotherapy. Selection of reliable chemotherapy for unresectable liver metastasis is an urgent necessity. The usefulness of oxaliplatin, 5-flurouracil and leucovorin combination therapy (FOLFOX) has recently been reported, but CR of liver metastasis is rare. The current status and new therapeutic significance of FOLFOX therapy are discussed based on the literature of colorectal cancer chemotherapy to date, and the clinical experience in which we obtained CR for liver metastasis is reported. The patient had stage IV rectal cancer, perforative peritonitis, pelvic abscess and simultaneous multiple liver metastasis. The patient underwent an emergency operation using the Hartmann's procedure. Liver metastasis is considered to be a prognostic factor and FOLFOX was selected as the postoperative chemotherapy, CR of the liver metastasis was obtained. FOLFOX was suggested to have new clinical significance in oncologic emergencies against unresectable liver metastasis in colorectal cancer and should serve as adjuvant chemotherapy that will contribute to improvement of treatment results.

MRI and hybrid PET/CT for monitoring tumour metastasis in a metastatic breast cancer model in rabbit.

PubMed

Wang, Ling; Yao, Qing; Wang, Jing; Wei, Guangquan; Li, Guoquan; Li, Dong; Ling, Rui; Chen, Jianghao

2008-02-01

To study tumour growth and metastasis in a rabbit metastatic breast cancer (MBC) model and find the most sensitive screening modality in monitoring tumour metastasis. The MBC model was established by injecting a VX2 tumour mass suspension into the mammary glands of 23 rabbits and was monitored by using physical examination, X-ray, MRI and hybrid PET/CT. Of all 23 rabbits, axillary lymph node metastasis was detected in 21 (91%) at day 33 after tumour inoculation, mediastinal node metastasis in five (22%) at day 42, abdominal node metastasis in two (9%) at day 48, lung metastasis in six (26%) at day 39, liver metastasis in three (13%) at day 48, and lumbar spine metastasis in one (4%) at day 51. Tumour invasion of pleura was found in one, stomach wall in one, and pleura and stomach concurrently in one rabbit. Sensitivity for detection of lymph node metastases was 78.6% (22/28) and 67.9% (19/28) with MRI and PET/CT, respectively; and sensitivity for detection of metastases in distant organs was 85.7% (12/14) and 71.4% (10/14), respectively. The MBC model used here exhibits fast tumour growth and extensive metastasis in a relatively short period. Its metastatic pattern is quite similar to that of human MBC and hence could be potentially used as a model for testing imaging modalities and translational research, e.g., MBC management. MRI is superior to PET/CT in monitoring tumour metastasis.

Unique activation of matrix metalloproteinase-9 within human liver metastasis from colorectal cancer.

PubMed Central

Zeng, Z. S.; Guillem, J. G.

1998-01-01

Experimental in vitro and animal data support an important role for matrix metalloproteinases (MMPs) in cancer invasion and metastasis via proteolytic degradation of the extracellular matrix (ECM). Our previous data have shown that MMP-9 mRNA is localized to the interface between liver metastasis and normal liver tissue, indicating that MMP-9 may play an important role in liver metastasis formation. In the present study, we analysed the cellular enzymatic expression of MMP-9 in 18 human colorectal cancer (CRC) liver metastasis specimens by enzyme-linked immunosorbent assay (ELISA) and zymography. ELISA analysis reveals that the latent form of MMP-9 is present in both liver metastasis and paired adjacent normal liver tissue. The mean level of the latent form of MMP-9 is 580+/-270 ng per mg total tissue protein (mean+/-s.e.) in liver metastasis vs 220+/-90 in normal liver tissue. However, this difference is not significantly different (P = 0.26). Using gelatin zymography, the 92-kDa band representative of the latent form is present in both liver metastasis and normal liver tissue. However, the 82 kDa band, representative of the active form of MMP-9, was seen only in liver metastasis. This was confirmed by Western blot analysis. Our observation of the unique presence of the active form of MMP-9 within liver metastasis suggests that proMMP-9 activation may be a pivotal event during CRC liver metastasis formation. Images Figure 3 Figure 4 PMID:9703281

Exploring factors related to metastasis free survival in breast cancer patients using Bayesian cure models.

PubMed

Jafari-Koshki, Tohid; Mansourian, Marjan; Mokarian, Fariborz

2014-01-01

Breast cancer is a fatal disease and the most frequently diagnosed cancer in women with an increasing pattern worldwide. The burden is mostly attributed to metastatic cancers that occur in one-third of patients and the treatments are palliative. It is of great interest to determine factors affecting time from cancer diagnosis to secondary metastasis. Cure rate models assume a Poisson distribution for the number of unobservable metastatic-component cells that are completely deleted from the non-metastasis patient body but some may remain and result in metastasis. Time to metastasis is defined as a function of the number of these cells and the time for each cell to develop a detectable sign of metastasis. Covariates are introduced to the model via the rate of metastatic-component cells. We used non-mixture cure rate models with Weibull and log-logistic distributions in a Bayesian setting to assess the relationship between metastasis free survival and covariates. The median of metastasis free survival was 76.9 months. Various models showed that from covariates in the study, lymph node involvement ratio and being progesterone receptor positive were significant, with an adverse and a beneficial effect on metastasis free survival, respectively. The estimated fraction of patients cured from metastasis was almost 48%. The Weibull model had a slightly better performance than log-logistic. Cure rate models are popular in survival studies and outperform other models under certain conditions. We explored the prognostic factors of metastatic breast cancer from a different viewpoint. In this study, metastasis sites were analyzed all together. Conducting similar studies in a larger sample of cancer patients as well as evaluating the prognostic value of covariates in metastasis to each site separately are recommended.

Relation between primary tumor FDG avidity and site of first distant metastasis in patients with breast cancer.

PubMed

Lim, Chae Hong; Moon, Seung Hwan; Cho, Young Seok; Im, Young-Hyuck; Choe, Yearn Seong; Kim, Byung-Tae; Lee, Kyung-Han

2016-08-01

Identification of tumor imaging features associated with metastatic pattern may allow better understanding of cancer dissemination. Here, we investigated how primary tumor F-fluorodeoxyglucose (FDG) avidity influences the first site of breast cancer metastasis.Subjects were 264 patients with advanced breast cancer who underwent positron emission tomography/computed tomography at diagnosis and had metastasis at presentation (n = 193) or metastatic relapse after surgery (n = 71). Primary tumor FDG avidity (maximum SUV [SUVmax] ≥10.1) was compared with histology and first metastatic sites.The most common site of first metastasis was the bone, occurring in 62.7% of patients with metastasis at presentation and 38.0% of those with metastatic relapse. First metastasis to lung occurred in 30.1% and 35.2%, and to liver in 25.4% and 15.2% of respective groups. In patients with metastasis at presentation, primary tumors were FDG avid in 98/193 cases, and this was associated with more frequent first metastasis to lung (37.8% vs 22.1%; P = 0.018). In patients with metastasis relapse, primary tumors were FDG avid in 31/71 cases, and this was associated with more frequent first metastasis to lung (48.4% vs 25.0%; P = 0.041) and liver (29.0% vs 5.0%; P = 0.008). In patients with metastasis relapse, primary tumors that were FDG avid but hormone receptor negative had more first metastasis to lung (57.9% vs 26.9%; P = 0.016).FDG-avid primary breast tumors have favored first spread to the lung and liver, which suggests that tumor cells with heightened glycolytic activity better colonize these organs.

An unusual case of gastric cancer presenting with breast metastasis with pleomorphic microcalcifications.

PubMed

Luk, Yiu Shiobhon; Ka, Solomon Yig Joon; Lo, Sherwin Shing Wai; Chu, Chi Yeung; Ma, Ming Wai

2012-09-01

Breast metastasis from gastric carcinoma is rare. We present a case of right breast mass with microcalcification in which the diagnosis of poorly differentiated adenocarcinoma from the stomach was made after a biopsy. Pleomorphic microcalcification was noted in the ill-defined breast mass, which is a rare feature in breast metastasis. Since breast metastasis usually signifies advanced metastatic disease, differentiating primary breast cancer from metastasis is important for appropriate treatment.

Small bowel obstruction from distant metastasis of primary breast cancer: a case report.

PubMed

Oh, Seung Jae; Park, Seon Young; Kim, Ji Young; Yim, Hyunee; Jung, Yongsik; Han, Sae Hwan

2018-02-01

Gastrointestinal (GI) tract metastasis of primary breast cancer is very rare. We present a patient with small bowel obstruction from distant metastasis of primary breast cancer. Each characteristic features of concern of GI tract distant metastasis from many pervious studies has been reported differently. We should remember that GI tract metastasis may coexist when patients with breast cancer have intermittent or recurrent abdominal pain with or without obstructive symptoms.

Metastasis of osteosarcoma to the trapezius muscle: a case report

PubMed Central

2014-01-01

Metastasis of a primary osteosarcoma to the muscles is extremely rare. As there have been few reported cases, the necessity of surgical treatment for such metastatic lesions remains controversial. We present the case of a primary osteosarcoma with development of a solitary metastasis to the trapezius muscle during chemotherapy for pulmonary metastasis. The patient was a 51-year-old man diagnosed with osteosarcoma of the right tibia. After undergoing chemotherapy and femoral amputation, he developed pulmonary metastasis. Chemotherapy was reinitiated, however, after approximately 1 year a palpable tumor was identified in the patient’s right shoulder. This tumor grew and was associated with pain in the right shoulder. It was surgically removed 3 years after the re-initiation of chemotherapy. The pathological diagnosis was osteosarcoma with metastasis to the trapezius muscle. Although the patient died of respiratory failure due to pulmonary metastasis 14 months after resection of the metastatic lesion in the trapezius muscle, no new extrapulmonary metastasis was observed after the resection. PMID:24893571

Metastasis of osteosarcoma to the trapezius muscle: a case report.

PubMed

Sakamoto, Yuichiro; Yokouchi, Masahiro; Nagano, Satoshi; Shimada, Hirofumi; Nakamura, Shunsuke; Setoguchi, Takao; Kawamura, Ichiro; Ishidou, Yasuhiro; Tanimoto, Akihide; Komiya, Setsuro

2014-06-04

Metastasis of a primary osteosarcoma to the muscles is extremely rare. As there have been few reported cases, the necessity of surgical treatment for such metastatic lesions remains controversial. We present the case of a primary osteosarcoma with development of a solitary metastasis to the trapezius muscle during chemotherapy for pulmonary metastasis. The patient was a 51-year-old man diagnosed with osteosarcoma of the right tibia. After undergoing chemotherapy and femoral amputation, he developed pulmonary metastasis. Chemotherapy was reinitiated, however, after approximately 1 year a palpable tumor was identified in the patient's right shoulder. This tumor grew and was associated with pain in the right shoulder. It was surgically removed 3 years after the re-initiation of chemotherapy. The pathological diagnosis was osteosarcoma with metastasis to the trapezius muscle. Although the patient died of respiratory failure due to pulmonary metastasis 14 months after resection of the metastatic lesion in the trapezius muscle, no new extrapulmonary metastasis was observed after the resection.

RARRES3 suppresses breast cancer lung metastasis by regulating adhesion and differentiation

PubMed Central

Morales, Mònica; Arenas, Enrique J; Urosevic, Jelena; Guiu, Marc; Fernández, Esther; Planet, Evarist; Fenwick, Robert Bryn; Fernández-Ruiz, Sonia; Salvatella, Xavier; Reverter, David; Carracedo, Arkaitz; Massagué, Joan; Gomis, Roger R

2014-01-01

In estrogen receptor-negative breast cancer patients, metastatic relapse usually occurs in the lung and is responsible for the fatal outcome of the disease. Thus, a better understanding of the biology of metastasis is needed. In particular, biomarkers to identify patients that are at risk of lung metastasis could open the avenue for new therapeutic opportunities. Here we characterize the biological activity of RARRES3, a new metastasis suppressor gene whose reduced expression in the primary breast tumors identifies a subgroup of patients more likely to develop lung metastasis. We show that RARRES3 downregulation engages metastasis-initiating capabilities by facilitating adhesion of the tumor cells to the lung parenchyma. In addition, impaired tumor cell differentiation due to the loss of RARRES3 phospholipase A1/A2 activity also contributes to lung metastasis. Our results establish RARRES3 downregulation as a potential biomarker to identify patients at high risk of lung metastasis who might benefit from a differentiation treatment in the adjuvant programme. PMID:24867881

Meeting report: Metastasis Research Society-Chinese Tumor Metastasis Society joint conference on metastasis.

PubMed

Bankaitis, Katherine; Borriello, Lucia; Cox, Thomas; Lynch, Conor; Zijlstra, Andries; Fingleton, Barbara; Gužvić, Miodrag; Anderson, Robin; Neman, Josh

2017-04-01

During September 16th-20th 2016, metastasis experts from around the world convened for the 16th Biennial Congress of the Metastasis Research Society and 12th National Congress of the Chinese Tumor Metastasis Society in Chengdu, China to share most current data covering basic, translational, and clinical metastasis research. Presentations of the more than 40 invited speakers of the main congress and presentations from the associated Young Investigator Satellite Meeting are summarized in this report by session topic. The congress program also included three concurrent short talk sessions, an advocacy forum with Chinese and American metastatic patient advocates, a 'Meet the Professors Roundtable' session for young investigators, and a 'Meet the Editors' session with editors from Cancer Cell and Nature Cell Biology. The goal of integrating expertise and exchanging the latest findings, ideas, and practices in cancer metastasis research was achieved magnificently, thanks to the excellent contributions of many leaders in the field.

Aberrant expression of CXCR4 significantly contributes to metastasis and predicts poor clinical outcome in breast cancer.

PubMed

Yang, P; Liang, S-X; Huang, W-H; Zhang, H-W; Li, X-L; Xie, L-H; Du, C-W; Zhang, G-J

2014-01-01

Triple negative breast cancer is known for its visceral metastasis. We have found that CXCR4 is overexpressed in triple negative breast cancer and is associated with visceral metastasis. We further investigated whether CXCR4 is a prognostic factor affecting survival following visceral metastasis in breast cancer patients. Our results indicate that increased CXCR4 expression among breast cancer patients with visceral metastasis was positively correlated with poor overall survival (P<0.001). Silencing of CXCR4 was associated with a decrease in the tumorigenic properties of MDA-MB-231 breast cancer cells, caused reversion of EMT and suppression of MMP-9, increased apoptosis, and caused a reduced incidence of tumor lung metastasis in mice. These results are indicative of CXCR4 having a predictive role in patients with visceral metastasis and indicate that shRNA knock down of CXCR4 might be a novel therapeutic strategy to prevent breast cancer metastasis when CXCR4 is overexpressed.

Transcriptional Network Analysis Identifies BACH1 as a Master Regulator of Breast Cancer Bone Metastasis

PubMed Central

Liang, Yajun; Wu, Heng; Lei, Rong; Chong, Robert A.; Wei, Yong; Lu, Xin; Tagkopoulos, Ilias; Kung, Sun-Yuan; Yang, Qifeng; Hu, Guohong; Kang, Yibin

2012-01-01

The application of functional genomic analysis of breast cancer metastasis has led to the identification of a growing number of organ-specific metastasis genes, which often function in concert to facilitate different steps of the metastatic cascade. However, the gene regulatory network that controls the expression of these metastasis genes remains largely unknown. Here, we demonstrate a computational approach for the deconvolution of transcriptional networks to discover master regulators of breast cancer bone metastasis. Several known regulators of breast cancer bone metastasis such as Smad4 and HIF1 were identified in our analysis. Experimental validation of the networks revealed BACH1, a basic leucine zipper transcription factor, as the common regulator of several functional metastasis genes, including MMP1 and CXCR4. Ectopic expression of BACH1 enhanced the malignance of breast cancer cells, and conversely, BACH1 knockdown significantly reduced bone metastasis. The expression of BACH1 and its target genes was linked to the higher risk of breast cancer recurrence in patients. This study established BACH1 as the master regulator of breast cancer bone metastasis and provided a paradigm to identify molecular determinants in complex pathological processes. PMID:22875853

Metastasis genetics, epigenetics, and the tumor microenvironment

USDA-ARS?s Scientific Manuscript database

KISS1 is a member of a family of genes known as metastasis suppressors, defined by their ability to block metastasis without blocking primary tumor development and growth. KISS1 re-expression in multiple metastatic cell lines of diverse cellular origin suppresses metastasis; yet, still allows comple...

P-selectin- and heparanase-dependent antimetastatic activity of non-anticoagulant heparins.

PubMed

Hostettler, Nina; Naggi, Annamaria; Torri, Giangiacomo; Ishai-Michaeli, Riva; Casu, Benito; Vlodavsky, Israel; Borsig, Lubor

2007-11-01

Vascular cell adhesion molecules, P- and L-selectins, facilitate metastasis of cancer cells in mice by mediating interactions with platelets, endothelium, and leukocytes. Heparanase is an endoglycosidase that degrades heparan sulfate of extracellular matrix, thereby promoting tumor invasion and metastasis. Heparin is known to efficiently attenuate metastasis in different tumor models. Here we identified modified, nonanticoagulant species of heparin that specifically inhibit selectin-mediated cell-cell interactions, heparanase enzymatic activity, or both. We show that selective inhibition of selectin interactions or heparanase with specific heparin derivatives in mouse models of MC-38 colon carcinoma and B16-BL6 melanoma attenuates metastasis. Selectin-specific heparin derivatives attenuated metastasis of MC-38 carcinoma, but heparanase-specific derivatives had no effect, in accordance with the virtual absence of heparanase activity in these cells. Heparin derivatives had no further effect on metastasis in mice deficient in P- and L-selectin, indicating that selectins are the primary targets of heparin antimetastatic activity. Selectin-specific and heparanase-specific derivatives attenuated metastasis of B16-BL6 melanomas to a similar extent. When mice were injected with a derivative containing both heparanase and selectin inhibitory activity, no additional attenuation of metastasis could be observed. Thus, selectin-specific heparin derivatives efficiently attenuated metastasis of both tumor cell types whereas inhibition of heparanase led to reduction of metastasis only in tumor cells producing heparanase.

[A case of lung metastasis from esophageal cancer resistant to fluorouracil and cisplatin combination therapy but responsive to radiation therapy].

PubMed

Ami, Katsunori; Seki, Ryouta; Takasaki, Jun; Amagasa, Hidetoshi; Kamikozuru, Hirotaka; Ganno, Hideaki; Kurokawa, Toshiaki; Fukuda, Akira; Nagahama, Takeshi; Ando, Masayuki; Yamada, Yosuke; Kodaka, Fumi; Arai, Kuniyoshi

2012-11-01

At present, fluorouracil and cisplatin combination therapy is the standard chemotherapy against esophageal cancer, but the choice of second-line chemotherapy is controversial. Furthermore, the effect of radiation therapy against lung metastasis from esophageal cancer is unclear. We report a case of lung metastasis from esophageal cancer resistant to fluorouracil and cisplatin combination therapy but responsive to radiation therapy. The patient was a 55-year-old woman who had undergone an operation for esophageal cancer at another hospital. A single right lung metastasis appeared 1 year after the operation. Combined fluorouracil and cisplatin therapy was administrated for 5 courses, but the lung metastasis increased in size. Afterwards, she was admitted to our hospital. We treated her with 14 courses of S-1 and docetaxel combination therapy administered over 13 months. The lung metastasis was decreased for a period. Furthermore, radiofrequency ablation under computed tomography was performed against the lung metastasis re-growth at another hospital. Although the lung metastasis increased in size, no further metastases were detected during the clinical course. The patient was treated with radiotherapy for the lung metastasis re-growth. The tumor had almost disappeared by 10 months after the completion of radiotherapy. Currently, she is receiving palliative care as an outpatient and the lung metastasis has not been evident for 2 years since the completion of radiotherapy.

Nanomolar concentration of blood-soluble drag-reducing polymer inhibits experimental metastasis of human breast cancer cells

PubMed Central

Ding, Zhijie; Joy, Marion; Kameneva, Marina V; Roy, Partha

2017-01-01

Metastasis is the leading cause of cancer mortality. Extravasation of cancer cells is a critical step of metastasis. We report a novel proof-of-concept study that investigated whether non-toxic blood-soluble chemical agents capable of rheological modification of the near-vessel-wall blood flow can reduce extravasation of tumor cells and subsequent development of metastasis. Using an experimental metastasis model, we demonstrated that systemic administration of nanomolar concentrations of so-called drag-reducing polymer dramatically impeded extravasation and development of pulmonary metastasis of breast cancer cells in mice. This is the first proof-of-principle study to directly demonstrate physical/rheological, as opposed to chemical, way to prevent cancer cells from extravasation and developing metastasis and, thus, it opens the possibility of a new direction of adjuvant interventional approach in cancer. PMID:28280386

Design and Construction of a Multi-Organ Microfluidic Chip Mimicking the in vivo Microenvironment of Lung Cancer Metastasis.

PubMed

Xu, Zhiyun; Li, Encheng; Guo, Zhe; Yu, Ruofei; Hao, Hualong; Xu, Yitong; Sun, Zhao; Li, Xiancheng; Lyu, Jianxin; Wang, Qi

2016-10-05

Metastasis is a complex pathophysiological process. As the main cause of cancer mortality in humans it represents a serious challenge to both basic researchers and clinicians. Here we report the design and construction of a multi-organ microfluidic chip that closely mimics the in vivo microenvironment of lung cancer metastasis. This multi-organs-on-a-chip includes an upstream "lung" and three downstream "distant organs", with three polydimethylsiloxane (PDMS) layers and two thin PDMS microporous membranes bonded to form three parallel microchannels. Bronchial epithelial, lung cancer, microvascular endothelial, mononuclear, and fibroblast cells were grown separated by the biomembrane in upstream "lung", while astrocytes, osteocytes, and hepatocytes were grown in distant chambers, to mimic lung cancer cell metastasis to the brain, bone, and liver. After culture in this system, lung cancer cells formed a "tumor mass", showed epithelial-mesenchymal transition (with altered expression of E-cadherin, N-cadherin, Snail1, and Snail2) and invasive capacity. A549 cells co-cultured with astrocytes overexpressed CXCR4 protein, indicating damage of astrocytes after cancer cell metastasis to the brain. Osteocytes overexpressed RANKL protein indicates damage of osteocytes after cancer cell metastasis to the bone, and hepatocytes overexpressed AFP protein indicates damage to hepatocytes after cancer cell metastasis to the liver. Finally, in vivo imaging of cancer growth and metastasis in a nude mice model validated the performance of metastasis in the organs-on-chip system. This system provides a useful tool to mimic the in vivo microenvironment of cancer metastasis and to investigate cell-cell interactions during metastasis.

[Correlation factors of lymph node metastasis in patients with clinical stage T1a non-small cell lung cancer].

PubMed

Ruochuan, Zang; Shugeng, Guo; Jie, He; Yousheng, Mao; Qi, Xue; Dali, Wang; Juwei, Mu; Jun, Zhao; Yonggang, Wang; Xiangyang, Liu; Fengwei, Tan; Gefei, Zhao; Qian, Zhang; Moyan, Zhang; Peng, Song

2015-04-01

To explore the relationship between the lymph node metastasis and clinicopathological features in patients with clinical stage T1a non-small cell lung cancer (NSCLC). Clinicopathological data of a total of 418 patients who underwent lobectomy and systematic lymph node dissection were retrospectively analyzed. Logistic regression was used to analyze the relationship between lymph node metastasis and clinicopathological features. Lymph node metastasis was observed in 25 patients. There were 122 patients who were diagnosed as ground glass opacity with no lymph node metastasis. 399 patients had subcarinal dissection, among them 7 patients were found to have lymph node metastasis. Univariate analysis showed that gender, smoking history, diameter of lymph node, ground glass opacity (GGO), differentiation of the tumor and tumor site were the factors affecting lymph node metastasis (all P < 0.05). Logistic regression analysis showed that diameter of lymph node, differentiation of the tumor and the site of lesion were independent risk factors for lymph node metastasis of NSCLC. Tumor in the left lung, poor differentiation, and diameter of lymph nodes ≥ 1 cm on the preoperative CT image are independent risk factors for lymph node metastasis of NSCLC, hence we should pay attention before surgery and systematic lymph node dissection should be done. For patients with poor differentiation and lymph nodes ≥ 1 cm, subcarinal lymph nodes dissection is recommended for the sake of higher possibility of lymph node metastasis. For patients with ground glass opacity ≤ 2 cm, the lymph node metastasis is extremely rare, therefore, selective lymph node dissection is reconmmended.

Predictive values of FAP and HGF for tumor angiogenesis and metastasis in colorectal cancer.

PubMed

Ma, T H; Gao, C C; Xie, R; Yang, X Z; Dai, W J; Zhang, J L; Yan, W; Wu, S N

2017-01-01

This study aims to explore the correlation of hepatocyte growth factor (HGF) and fibroblast activation protein (FAP) expressions with the angiogenesis and metastasis in colorectal cancer (CRC). The immunohistochemical SABC method was used to detect HGF and FAP expressions in 127 CRC tissues, 51 colorectal polyp tissues and 28 normal tissues. HGF and FAP expressions in liver metastasis were detected using western blot to analyze the correlation of their expressions with lymph node metastasis and liver metastasis. Micro-vessel density (MVD) and clinic-pathologic information of CRC patients were recorded and analyzed. In CRC group, HGF and FAP expressions were greatly higher than those in normal group and colorectal polyps group (P < 0.05). Moreover, the positive rates of HGF and FAP expressions in lymph node metastasis were evidently higher than those in non-lymph node metastasis (P < 0.05). In liver metastasis group, HGF and FAP expressions were obviously higher than non-liver metastasis group (P < 0.05). CRC group had much more MVD in comparison with normal group and colorectal polyps group (P < 0.05).When compared with negative group, MVD was significantly higher than that in CRC tissue with positive HGF and FAP (P < 0.05). Spearman rank correlation analysis showed that HGF and FAP were in positive correlation with MVD (r = 0.542, P < 0.001; r = 0.753, P < 0.001). These results indicate that FAP and HGF play an important role in CRC angiogenesis, and their expression levels are valuable to predict CRC liver metastasis and lymph node metastasis.

Cervical node metastasis in T1 squamous cell carcinoma of oral tongue- pattern and the predictive factors.

PubMed

S, Vishak; Rohan, Vinayak

2014-06-01

The squamous cell carcinoma (SCC) of the oral tongue is a common cancer in India. Elective lymphadenectomy is generally performed in all patients with T2-T4 tumors. In this study we have tried to analyze the pattern and risk factors associated with lymph node metastasis in T1 tongue cancers. A retrospective review of the records of 57 patients undergoing surgery for treatment of T1 sqamous cell carcinoma of oral tongue was carried out. The clinicopatological features of the tumor, pattern of nodal metastasis and the risk factors associated with lymph node metastasis were studied. Totally 57 patients with T1 tumor underwent excision of the primary and modified neck dissection (MND). Lymph node metastasis was found in 36.8 % of the patients. Level I to Level II was the commonest site of metastasis. Skip metastasis at level III and IV was found in 8.5 % of the patients and isolated skip metastasis at level IV in 1.5 % of the patients. The risk factors associated with the lymph node metastasis on univariete analysis were; higher grade, tumor size >1 cm and tumor thickness >3 mm. On multivariate analysis only the tumor thickness was found to be a risk factor for the lymph node metastasis (hazard ratio of 21.59). T1 sqamous cell carcinoma of tongue is associated with a high incidence of lymph node metastasis. Elective neck dissection should be considered in all patients with tumors more than 3 mm in thickness.

Cutaneous metastasis of bilateral renal cell carcinoma.

PubMed

Abbasi, Fariba; Alizadeh, Mansur; Noroozinia, Farahnaz; Moradi, Amin

2013-01-01

Renal cell carcinoma (RCC) is a malignant lethal tumour with high potential of metastasis. However, metastasis from RCC to the skin is much less common. It is virtually a sign of poor prognosis. We represent a 42 years old man with bilateral RCC of clear cell type followed by metastasis to the scalp one month later. In this case the relatively young age of the patient, bilaterality of RCC and occurance of skin metastasis in the absence of recurrent kidney tumour are interesting.

Isolated gastrointestinal metastasis of breast carcinoma: a case report.

PubMed

Titi, M A; Anabtawi, A; Newland, A D

2010-01-01

Purpose. Gastrointestinal tract is one of the rare locations for breast cancer metastasis. This paper shows such metastasis may occur even in the absence of breast metastasis in other more common locations. Case Report. A 64-year old female was admitted to the hospital with abdominal discomfort and diarrhea. She had breast carcinoma treated 7 years previously with normal follow-up since. Colonoscopy showed hepatic flexure thickening that was confirmed to be breast metastasis. Staging investigations showed upper and lower gastrointestinal tract metastasis with negative findings elsewhere. Conclusion. Although more common causes for gastrointestinal symptoms should be excluded, however, a high index of suspicion of metastatic breast cancer is needed when such patients develop gastrointestinal symptoms.

Breast cancer lung metastasis: Molecular biology and therapeutic implications.

PubMed

Jin, Liting; Han, Bingchen; Siegel, Emily; Cui, Yukun; Giuliano, Armando; Cui, Xiaojiang

2018-03-26

Distant metastasis accounts for the vast majority of deaths in patients with cancer. Breast cancer exhibits a distinct metastatic pattern commonly involving bone, liver, lung, and brain. Breast cancer can be divided into different subtypes based on gene expression profiles, and different breast cancer subtypes show preference to distinct organ sites of metastasis. Luminal breast tumors tend to metastasize to bone while basal-like breast cancer (BLBC) displays a lung tropism of metastasis. However, the mechanisms underlying this organ-specific pattern of metastasis still remain to be elucidated. In this review, we will summarize the recent advances regarding the molecular signaling pathways as well as the therapeutic strategies for treating breast cancer lung metastasis.

Characteristics and Treatments of Large Cystic Brain Metastasis: Radiosurgery and Stereotactic Aspiration

PubMed Central

Kim, Moinay; Cheok, Stephanie; Chung, Lawrance K.; Ung, Nolan; Thill, Kimberly; Voth, Brittany; Kwon, Do Hoon; Kim, Jeong Hoon; Kim, Chang Jin; Tenn, Stephen; Lee, Percy

2015-01-01

Brain metastasis represents one of the most common causes of intracranial tumors in adults, and the incidence of brain metastasis continues to rise due to the increasing survival of cancer patients. Yet, the development of cystic brain metastasis remains a relatively rare occurrence. In this review, we describe the characteristics of cystic brain metastasis and evaluate the combined use of stereotactic aspiration and radiosurgery in treating large cystic brain metastasis. The results of several studies show that stereotactic radiosurgery produces comparable local tumor control and survival rates as other surgery protocols. When the size of the tumor interferes with radiosurgery, stereotactic aspiration of the metastasis should be considered to reduce the target volume as well as decreasing the chance of radiation induced necrosis and providing symptomatic relief from mass effect. The combined use of stereotactic aspiration and radiosurgery has strong implications in improving patient outcomes. PMID:25977901

Epigenetic regulator RBP2 is critical for breast cancer progression and metastasis

PubMed Central

Cao, Jian; Liu, Zongzhi; Cheung, William K.C.; Zhao, Minghui; Chen, Sophia Y.; Chan, Siew Wee; Booth, Carmen J.; Nguyen, Don X.; Yan, Qin

2014-01-01

Summary Metastasis is a major clinical challenge for cancer treatment. Emerging evidence suggests that epigenetic aberrations contribute significantly to tumor formation and progression. However, the drivers and roles of such epigenetic changes in tumor metastasis are still poorly understood. Using bioinformatic analysis of human breast cancer gene expression datasets, we identified histone demethylase RBP2 as a putative mediator of metastatic progression. By using both human breast cancer cells and genetically engineered mice, we demonstrated that RBP2 is critical for breast cancer metastasis to the lung in multiple in vivo models. Mechanistically, RBP2 promotes metastasis as a pleiotropic positive regulator of many metastasis genes. In addition, RBP2 loss suppresses tumor formation in the MMTV-neu transgenic mice. These results suggest that therapeutically targeting RBP2 is a potential strategy to inhibit tumor progression and metastasis. PMID:24582965

Molecular Mechanisms of Metastasis Suppression in Human Breast Cancer

DTIC Science & Technology

2000-07-01

September 29 Identifying and characterizing human metastasis-suppressor genes. Novartis Pharma , May WELCH, Danny R, Ph.D...Growth and Differentiation Chemica -Biological Interactions CRC Press - Reviews European Journal of Cancer and Clinical Oncology Journal of...September 29 Identifying and characterizing human metastasis-suppressor genes. Novartis Pharma , May 27 Regulation of Metastasis in Human Cancers

An Atypical Metastasis of Follicular-Type Adenocarcinoma of the Thyroid Gland to Thumb

PubMed Central

Huri, Gazi

2011-01-01

Bone metastasis in the hand is rare. The etiology of metastatic hand cancers is different from other bones. Bronchogenic carcinoma is the most common primary tumor metastasis to hand. In this paper a rare case of thumb metastasis from “follicular-type carcinoma” of the thyroid is presented. PMID:23198224

Hematogenous Renal Cell Carcinoma Metastasis in the Postoperative Temporal Bone

PubMed Central

Konishi, Masaya; Suzuki, Kensuke; Iwai, Hiroshi

2017-01-01

Metastatic renal cell carcinoma (RCC) involving the temporal bone is a rare entity. It is usually asymptomatic and misdiagnosis as acute otitis media, mastoiditis, and Ramsay-Hunt syndrome in early onset is not uncommon. We report a case of RCC metastasis to the postoperative temporal bone in the middle of molecular targeted therapy. A 60-year-old man presented left facial palsy with severe retro-auricular pain and he also underwent left middle ear surgery for cholesteatoma more than 30 years before and had been aware of discontinuous otorrhea; therefore, initially we speculated that facial palsy was derived from recurrent cholesteatoma or Ramsay-Hunt syndrome. Exploratory tympanotomy revealed RCC metastasis and postoperative MR indicated hematogenous metastasis. To the best of our knowledge, no report was obtained on temporal bone metastasis in the middle of chemotherapy or hematogenous metastasis in the postoperative middle ear. Metastasis in the temporal bone is still a possible pathological condition despite the development of present cancer therapy. Besides, this case indicates that hematogenous metastasis can occur in the postoperative state of the temporal bone. PMID:28611633

Sexual dimorphism of liver metastasis by murine pancreatic neuroendocrine tumors is affected by expression of complement C5.

PubMed

Contractor, Tanupriya; Kobayashi, Shinta; da Silva, Edaise; Clausen, Richard; Chan, Chang; Vosburgh, Evan; Tang, Laura H; Levine, Arnold J; Harris, Chris R

2016-05-24

In a mouse model for neuroendocrine tumors of the pancreas (PanNETs), liver metastasis occurred at a higher frequency in males. Male mice also had higher serum and intratumoral levels of the innate immunity protein complement C5. In mice that lost the ability to express complement C5, there was a lower frequency of metastasis, and males no longer had a higher frequency of metastasis than females. Treatment with PMX53, a small molecule antagonist of C5aR1/CD88, the receptor for complement C5a, also reduced metastasis. Mice lacking a functional gene for complement C5 had smaller primary tumors, which were less invasive and lacked the CD68+ macrophages that have previously been associated with metastasis in this type of tumor. This is the first report of a gene that causes sexual dimorphism of metastasis in a mouse model. In the human disease, which also shows sexual dimorphism for metastasis, clinically advanced tumors expressed more complement C5 than less advanced tumors.

Inhibitory effect of magnolol on tumour metastasis in mice.

PubMed

Ikeda, Koji; Sakai, Yoshimichi; Nagase, Hisamitsu

2003-09-01

It has previously been reported that magnolol, a phenolic compound isolated from Magnolia obovata, inhibited tumour cell invasion in vitro. The purpose of this study was to investigate the antimetastatic effect of magnolol on tumour metastasis in vivo with experimental and spontaneous metastasis models and to clarify the mechanism. The antimetastatic effects of magnolol were evaluated by an experimental liver and spleen metastasis model using L5178Y-ML25 lymphoma, or an experimental and spontaneous lung metastasis model using B16-BL6 melanoma. Intraperitoneal (i.p.) administration of 2 or 10 mg/kg of magnolol significantly suppressed liver and spleen metastasis or lung metastasis. As for the spontaneous lung metastasis model using B16-BL6 melanoma, multiple i.p. administrations of 10 mg/kg of magnolol after and before tumour inoculation significantly suppressed lung metastasis and primary tumour growth. In addition, magnolol significantly inhibited B16-BL6 cell invasion of the reconstituted basement membrane (Matrigel, MG) without affecting cell growth. These data from the in vivo experiments suggest that magnolol possesses strong antimetastatic ability and that it may be a lead compound for drug development. The antimetastatic action of magnolol is considered to be due to its ability to inhibit tumour cell invasion. Copyright 2003 John Wiley & Sons, Ltd.

Clinicopathological factors associated with survival in patients with breast cancer brain metastasis.

PubMed

Li, Rong; Zhang, Kui; Siegal, Gene P; Wei, Shi

2017-06-01

Brain metastasis from breast cancer generally represents a catastrophic event yet demonstrates substantial biological heterogeneity. There have been limited studies solely focusing on the prognosis of patients with such metastasis. In this study, we carried out a comprehensive analysis in 108 consecutive patients with breast cancer brain metastases between 1997 and 2012 to further define clinicopathological factors associated with early onset of brain metastasis and survival outcomes after development of them. We found that lobular carcinoma, higher clinical stages at diagnosis, and lack of coexisting bone metastasis were significantly associated with a worse brain relapse-free survival when compared with brain-only metastasis. High histologic grade, triple-negative breast cancer, and absence of visceral involvement were unfavorable prognostic factors after brain metastasis. Furthermore, high histologic grade, advanced tumor stages, and lack of coexisting bone involvement indicated a worse overall survival. Thus, the previously established prognostic factors in early stage or advanced breast cancers may not entirely apply to patients with brain metastases. Furthermore, the prognostic significance of the clinicopathological factors differed before and after a patient develops brain metastasis. This knowledge might help in establishing an algorithm to further stratify patients with breast cancer into prognostically significant categories for optimal prevention, screening, and treatment of their brain metastasis. Copyright © 2017 Elsevier Inc. All rights reserved.

Biomechanical effects of metastasis in the osteoporotic lumbar spine: A Finite Element Analysis.

PubMed

Salvatore, Giuseppe; Berton, Alessandra; Giambini, Hugo; Ciuffreda, Mauro; Florio, Pino; Longo, Umile Giuseppe; Denaro, Vincenzo; Thoreson, Andrew; An, Kai-Nan

2018-02-05

Cancer patients are likely to undergo osteoporosis as consequence of hormone manipulation and/or chemotherapy. Little is known about possible increased risk of fracture in this population. The aim of this study was to describe the biomechanical effect of a metastatic lesion in an osteoporotic lumbar spine model. A finite element model of two spinal motion segments (L3-L5) was extracted from a previously developed L3-Sacrum model and used to analyze the effect of metastasis size and bone mineral density (BMD) on Vertebral bulge (VB) and Vertebral height (VH). VB and VH represent respectively radial and axial displacement and they have been correlated to burst fracture. A total of 6 scenarios were evaluated combining three metastasis sizes (no metastasis, 15% and 30% of the vertebral body) and two BMD conditions (normal BMD and osteoporosis). 15% metastasis increased VB and VH by 178% and 248%, respectively in normal BMD model; while VB and VH increased by 134% and 174% in osteoporotic model. 30% metastasis increased VB and VH by 88% and 109%, respectively, when compared to 15% metastasis in normal BMD model; while VB and VH increased by 59% and 74% in osteoporotic model. A metastasis in the osteoporotic lumbar spine always leads to a higher risk of vertebral fracture. This risk increases with the size of the metastasis. Unexpectedly, an increment in metastasis size in the normal BMD spine produces a greater impact on vertebral stability compared to the osteoporotic spine.

Clinical Characteristics of Patients With Renal Cell Carcinoma and Metastasis to the Thyroid Gland.

PubMed

Jackson, Gregory; Fino, Nora; Bitting, Rhonda L

2017-01-01

Renal cell carcinoma (RCC) is the most common malignancy to metastasize to the thyroid gland. The aims of this study are as follows: (1) to analyze the clinical characteristics of patients with thyroid involvement of RCC and (2) in patients with RCC thyroid metastasis, to determine whether RCC metastasis to glandular organs only portends a better prognosis compared with other patterns of RCC metastasis. Patients from Wake Forest Baptist Medical Center (WFBMC) diagnosed with thyroid metastasis from RCC were identified and medical records retrospectively examined. A systematic review of the literature for cases of RCC involving the thyroid gland was also performed. The clinical characteristics of the institutional cohort and the cases from the literature review were compared. Descriptive statistical analysis was performed, and overall survival (OS) was summarized using Kaplan-Meier methods. The median OS for the WFBMC cohort was 56.4 months. In the literature review cohort, OS of patients with RCC thyroid metastasis was 213.6 months, and there was no statistically significant survival difference based on the site of metastasis. Median survival after thyroid metastasis from RCC for the WFBMC and literature cohort was 21.6 and 45.6 months, respectively. Metastatic RCC should be included in the differential of a new thyroid mass. Treatment directed at the thyroid metastasis results in prolonged survival in some cases. Further analysis into the genomic differences and mechanisms of thyroid metastasis is warranted.

Expansion of lymph node metastasis in mixed-type submucosal invasive gastric cancer.

PubMed

Mikami, Koji; Hirano, Yukiko; Futami, Kitaro; Maekawa, Takafumi

2017-07-18

Mixed-type early gastric cancer (differentiated and undifferentiated components) incurs a higher risk of lymph node metastasis than pure-type early gastric cancer (only differentiated or only undifferentiated components). Therefore, we investigated the expansion of lymph node metastasis in mixed-type submucosal invasive gastric cancer in order to establish the most appropriate treatment for mixed-type cancer. We retrospectively analyzed 279 consecutive patients with submucosal invasive gastric cancer who underwent curative gastrectomy for gastric cancer between 1996 and 2015. We classified the patients into the mixed-type and pure-type groups according to histologic examination and evaluated the expansion of lymph node metastasis. The rate of lymph node metastasis was 23.7% (66/279) in the total patients, 36.4% (36/99) in the mixed-type group, and 16.6% (30/180) in the pure-type group. The significant independent risk factors for lymph node metastasis were tumor size ≥2.0 cm (P = 0.014), mixed-type gastric cancer (P < 0.001), and lymphatic invasion (P < 0.001). Lymphatic invasion and lymph node metastasis had a strong relationship in mixed-type group. The rates of no. 7 lymph node metastasis in the total patients and mixed-type group were 2.9% (8/279) and 5.1% (5/99), respectively; the rates of no. 8a lymph node metastasis were 1.4% (4/279) and 4.0% (4/99), respectively. Mixed histological type is an independent risk factor for lymph node metastasis. Lymph node metastasis in mixed-type gastric cancer involves expansion to the no. 7 and no. 8a lymph nodes. Therefore, lymphadenectomy for mixed-type submucosal invasive gastric cancer requires D1+ or D2 dissection. Copyright © 2017. Published by Elsevier Taiwan.

The prognostic impact of supraclavicular lymph node in N3-IIIB stage non-small cell lung cancer patients treated with definitive concurrent chemo-radiotherapy.

PubMed

Oh, Dongryul; Ahn, Yong Chan; Park, Hee Chul; Lim, Do Hoon; Noh, Jae Myoung; Cho, Won Kyung; Pyo, Hongryull

2017-05-30

This study aimed to investigate the prognostic impact of supraclavicular lymph node (SCN) metastasis in patients who were treated with definitive chemoradiotherapy for N3-IIIB stage non-small cell lung cancer (NSCLC). The 2- and 5-year overall survival (OS) rates were 57.3% and 35.7% in patients without SCN metastasis and 56.4% and 26.7% in patients with SCN metastasis, respectively. The median OS was 34 months in both groups. There was no significant difference in OS between the two groups (p = 0.679). The 2- and 5-year progression-free survival (PFS) rates were 24.1% and 12.6% in patients without SCN metastasis and 18.0% and 16.0% in patients with SCN metastasis, respectively. Patients without SCN metastasis had slightly longer median PFS (10 months vs. 8 months), but the difference was not statistically significant (p = 0.223). In multivariate analysis, SCN metastasis was not a significant factor for OS (p = 0.391) and PFS (p = 0.149). This retrospective analysis included 204 consecutive patients who were treated with chemoradiotherapy for N3-IIIB stage NSCLC between May 2003 and December 2012. A median RT dose of 66 Gy was administered over 6.5 weeks. Of these, 119 patients (58.3%) had SCN metastasis and 85 (41.7%) had another type of N3 disease: mediastinal N3 nodes in 84 patients (98.8%) and contralateral hilar node in one (1.2%). The patients were divided into two groups according to SCN metastasis. SCN metastasis does not compromise treatment outcomes compared to other mediastinal metastasis in the setting of definitive chemoradiotherapy.

Survival and clinical outcomes of patients with melanoma brain metastasis in the era of checkpoint inhibitors and targeted therapies.

PubMed

Vosoughi, Elham; Lee, Jee Min; Miller, James R; Nosrati, Mehdi; Minor, David R; Abendroth, Roy; Lee, John W; Andrews, Brian T; Leng, Lewis Z; Wu, Max; Leong, Stanley P; Kashani-Sabet, Mohammed; Kim, Kevin B

2018-04-27

Melanoma brain metastasis is associated with an extremely poor prognosis, with a median overall survival of 4-5 months. Since 2011, the overall survival of patients with stage IV melanoma has been significantly improved with the advent of new targeted therapies and checkpoint inhibitors. We analyze the survival outcomes of patients diagnosed with brain metastasis after the introduction of these novel drugs. We performed a retrospective analysis of our melanoma center database and identified 79 patients with brain metastasis between 2011 and 2015. The median time from primary melanoma diagnosis to brain metastasis was 3.2 years. The median overall survival duration from the time of initial brain metastasis was 12.8 months. Following a diagnosis of brain metastasis, 39 (49.4%), 28 (35.4%), and 24 (30.4%) patients were treated with anti-CTLA-4 antibody, anti-PD-1 antibody, or BRAF inhibitors (with or without a MEK inhibitor), with a median overall survival of 19.2 months, 37.9 months and 12.7 months, respectively. Factors associated with significantly reduced overall survival included male sex, cerebellar metastasis, higher number of brain lesions, and treatment with whole-brain radiation therapy. Factors associated with significantly longer overall survival included treatment with craniotomy, stereotactic radiosurgery, or with anti-PD-1 antibody after initial diagnosis of brain metastasis. These results show a significant improvement in the overall survival of patients with melanoma brain metastasis in the era of novel therapies. In addition, they suggest the activity of anti-PD-1 therapy specifically in the setting of brain metastasis.

Ultrasound texture analysis: Association with lymph node metastasis of papillary thyroid microcarcinoma.

PubMed

Kim, Soo-Yeon; Lee, Eunjung; Nam, Se Jin; Kim, Eun-Kyung; Moon, Hee Jung; Yoon, Jung Hyun; Han, Kyung Hwa; Kwak, Jin Young

2017-01-01

This retrospective study aimed to evaluate whether ultrasound texture analysis is useful to predict lymph node metastasis in patients with papillary thyroid microcarcinoma (PTMC). This study was approved by the Institutional Review Board, and the need to obtain informed consent was waived. Between May and July 2013, 361 patients (mean age, 43.8 ± 11.3 years; range, 16-72 years) who underwent staging ultrasound (US) and subsequent thyroidectomy for conventional PTMC ≤ 10 mm between May and July 2013 were included. Each PTMC was manually segmented and its histogram parameters (Mean, Standard deviation, Skewness, Kurtosis, and Entropy) were extracted with Matlab software. The mean values of histogram parameters and clinical and US features were compared according to lymph node metastasis using the independent t-test and Chi-square test. Multivariate logistic regression analysis was performed to identify the independent factors associated with lymph node metastasis. Tumors with lymph node metastasis (n = 117) had significantly higher entropy compared to those without lymph node metastasis (n = 244) (mean±standard deviation, 6.268±0.407 vs. 6.171±.0.405; P = .035). No additional histogram parameters showed differences in mean values according to lymph node metastasis. Entropy was not independently associated with lymph node metastasis on multivariate logistic regression analysis (Odds ratio, 0.977 [95% confidence interval (CI), 0.482-1.980]; P = .949). Younger age (Odds ratio, 0.962 [95% CI, 0.940-0.984]; P = .001) and lymph node metastasis on US (Odds ratio, 7.325 [95% CI, 3.573-15.020]; P < .001) were independently associated with lymph node metastasis. Texture analysis was not useful in predicting lymph node metastasis in patients with PTMC.

Promotion or suppression of experimental metastasis of B16 melanoma cells after oral administration of lapachol

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

Maeda, Masayo; Murakami, Manabu; Takegami, Tsutomu

Lapachol [2-hydroxy-3-(3-methyl-2-butenyl)-1,4-naphthoquinone] is a vitamin K antagonist with antitumor activity. The effect of lapachol on the experimental metastasis of murine B16BL6 melanoma cells was examined. A single oral administration of a high toxic dose of lapachol (80-100 mg/kg) 6 h before iv injection of tumor cells drastically promoted metastasis. This promotion of metastasis was also observed in T-cell-deficient mice and NK-suppressed mice. In vitro treatment of B16BL6 cells with lapachol promoted metastasis only slightly, indicating that lapachol promotes metastasis primarily by affecting host factors other than T cells and NK cells. A single oral administration of warfarin, the most commonlymore » used vitamin K antagonist, 6 h before iv injection of tumor cells also drastically promoted the metastasis of B16BL6 cells. The promotion of metastasis by lapachol and warfarin was almost completely suppressed by preadministration of vitamin K3, indicating that the promotion of metastasis by lapachol was derived from vitamin K antagonism. Six hours after oral administration of lapachol or warfarin, the protein C level was reduced maximally, without elongation of prothrombin time. These observations suggest that a high toxic dose of lapachol promotes metastasis by inducing a hypercoagulable state as a result of vitamin K-dependent pathway inhibition. On the other hand, serial oral administration of low non-toxic doses of lapachol (5-20 mg/kg) weakly but significantly suppressed metastasis by an unknown mechanism, suggesting the possible use of lapachol as an anti-metastatic agent.« less

Active Tobacco Smoking and Distant Metastasis in Patients With Oropharyngeal Cancer

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

McBride, Sean M.; Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Ali, Nawal N.

Purpose: Distant metastasis is the site of first relapse in approximately one-third of patients with locally advanced oropharyngeal carcinoma, irrespective of human papillomavirus status. Yet the risk factors associated with distant metastasis are not well characterized. We sought to characterize the relationship between smoking status and distant metastasis. Methods and Materials: We evaluated the association between tobacco smoking status and distant metastasis in a retrospective cohort study of 132 patients who underwent definitive radiation therapy and chemotherapy for Stage III-IVA/B oropharyngeal cancer. Information on tobacco smoking was prospectively collected by patient questionnaires and physician notes at the time of diagnosis.more » Thirty-three percent of the patients were nonsmokers, 51% were former smokers, 16% were active smokers. The cumulative lifetime tobacco smoking in pack-years was 20 (range, 0-150). Results: With a median follow-up time of 52 months, the overall rate of distant metastasis at 4 years was 8%. Distant metastasis was the most common first site of relapse, occurring in 56% of the patients with recurrences. Active smokers had higher rates of distant metastasis than non-active smokers (including never- and former smokers; 31% vs. 4%, p < 0.001) and former smokers (31% vs. 3%, p < 0.001). There was no statistically significant difference in the risk of distant metastasis for patients with lifetime cumulative pack-years >20 and {<=}20 (10% vs. 4%, p = 0.19). In univariate analysis, active smoking (p = 0.0004) and N category (p = 0.009) were predictive of increased risk of distant metastasis. In multivariate analysis, active smoking was the most significant predictive factor for increased risk of distant metastasis (hazard ratio, 12.7, p < 0.0001). Conclusions: This study identified a strong association between active smoking and distant metastasis in patients with oropharyngeal cancer.« less

Prognostic factors for cases with no extracranial metastasis in whom brain metastasis is detected after resection of non-small cell lung cancer.

PubMed

Bae, Mi Kyung; Yu, Woo Sik; Byun, Go Eun; Lee, Chang Young; Lee, Jin Gu; Kim, Dae Joon; Chung, Kyung Young

2015-05-01

This study aimed to determine prognostic factors associated with postrecurrence survival in cases with postoperative brain metastasis but with no extracranial metastasis in non-small cell lung cancer (NSCLC). Between 1992 and 2012, a total of 2832 patients underwent surgical resection for NSCLC. Among those, 86 patients had postoperative brain metastasis as the initial recurrence. Those patients were retrospectively reviewed. The median follow-up time after the initial lung resection was 24.0 months (range, 2.0-126.0 months). The median overall survival after initial lung cancer resection was 25.0 months and the median overall postrecurrence survival was 11 months. An initial lesion of adenocarcinoma (hazard ratio, 0.548; 95% confidence interval, 0.318 to 0.946; p=0.031), non-pneumonectomy, and a disease-free interval longer than 10.0 months (hazard ratio, 0.565; 95% confidence interval, 0.321-0.995; p=0.048) from the initial lung resection to the diagnosis of brain metastasis positively related to a good postrecurrence survival. Solitary brain metastasis and a size of less than 3 cm for the largest brain lesion were also positive factors for postrecurrence survival. Systemic chemotherapy for brain metastasis (hazard ratio, 0.356; 95% confidence interval, 0.189-0.670; p=0.001) and local treatment of surgery and/or stereotactic radiosurgery (SRS) for brain lesions (hazard ratio, 0.321; 95% confidence interval, 0.138-0.747; p=0.008) were positive factors for better postrecurrence survival. In patients with brain metastasis after resection for NSCLC with no extracranial metastasis, adenocarcinoma histologic type, longer disease-free interval, systemic chemotherapy for brain metastasis and local treatment of surgery and/or SRS for brain metastasis are independent positive prognostic factors for postrecurrence survival. Copyright © 2015. Published by Elsevier Ireland Ltd.

Panax notoginseng saponins (PNS) inhibits breast cancer metastasis.

PubMed

Wang, Peiwei; Cui, Jingang; Du, Xiaoye; Yang, Qinbo; Jia, Chenglin; Xiong, Minqi; Yu, Xintong; Li, Li; Wang, Wenjian; Chen, Yu; Zhang, Teng

2014-07-03

Panax notoginseng (Burkill) F.H. Chen (Araliaceae) has been extensively used as a therapeutic agent to treat a variety of diseases. Panax notoginseng saponins (PNS) consist of major therapeutically active components of Panax notoginseng. PNS inhibit the growth of a variety of tumor cells in vitro and in vivo. The aim of the study is to investigate the effects and underlying mechanisms of PNS on breast cancer metastasis. 4T1 cell, a highly metastatic mouse breast carcinoma cell line, was utilized for in vitro and in vivo assays. In vitro assays were first performed to examine the effects of PNS on 4T1 cell viability, migration and invasion, respectively. Real-time PCR analyses were also performed to examine the effects of PNS on the expression of genes associated with tumor metastasis. The effect of PNS on 4T1 tumor cell metastasis was further assessed in spontaneous and experimental metastasis models in vivo. PNS treatment exhibited a dose-dependent effect on impairing 4T1 cell viability in vitro. However, when examined at a lower dose that did not affect cell viability, the migration and invasion of 4T1 cell was remarkably inhibited in vitro. Meanwhile, PNS treatment led to upregulated expression of genes known to inhibit metastasis and downregulated expression of genes promoting metastasis in cultured 4T1 cells. These results suggested a selective effect of PNS on 4T1 migration and invasion. This hypothesis was further addressed in 4T1 metastasis models in vivo. The results showed that the lung metastasis was significantly inhibited by PNS treatment in both spontaneous and experimental metastasis models. Taken together, our results demonstrated an inhibitory effect of PNS on 4T1 tumor metastasis, warranting further evaluation of PNS as a therapeutic agent for treating breast cancer metastasis. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Successful Treatment with Alectinib for Choroidal Metastasis in Anaplastic Lymphoma Kinase Rearranged Non-small Cell Lung Cancer.

PubMed

Funazo, Tomoko; Morita, Kyohei; Ikegami, Naoya; Konishi, Chisato; Nakao, Satoshi; Ariyasu, Ryo; Taki, Masato; Nakagawa, Kazuhiko; Hwang, Moon Hee; Yoshimura, Chie; Wakayama, Toshiaki; Nishizaka, Yasuo

2017-09-01

Choroidal metastasis is rare in cancer patients and it may cause visual disturbances that reduce their quality of life. In non-small cell lung cancer (NSCLC), targeted therapy against actionable driver mutations has gradually replaced radiotherapy as the treatment of choice for choroidal metastasis. Recently, there have been several case reports of choroidal metastasis in patients with anaplastic lymphoma kinase (ALK)-rearranged NSCLC. We herein report the case of a 40-year-old Japanese woman diagnosed with choroidal metastasis of an ALK-rearranged NSCLC who received alectinib as the first-line chemotherapy. Alectinib may be the best treatment for choroidal metastasis in patients harboring an ALK translocation because of its favorable side effect profile involving visual disturbances.

Impact of splenic hilar lymph node metastasis on prognosis in patients with advanced gastric cancer.

PubMed

Son, Taeil; Kwon, In Gyu; Lee, Joong Ho; Choi, Youn Young; Kim, Hyoung-Il; Cheong, Jae-Ho; Noh, Sung Hoon; Hyung, Woo Jin

2017-10-13

Impact of splenic hilar LN dissection during total gastrectomy for proximal advanced gastric cancer is controversial. The objective of this study was to assess the impact on prognosis of splenic hilar lymph node(LN) metastasis compared to that of metastasis to other regional LN groups. Patients who underwent total gastrectomy with D2 LN dissection from 2000 to 2010 were reviewed retrospectively. The clinicopathologic characteristics and long-term results of patients with splenic hilar LN metastasis were compared to those of patients with only metastasis to other extraperigastric LNs (stations #8a, #9, #11, or #12a). To investigate the survival benefit of performing splenic hilar LN dissection, the estimated therapeutic index for the procedure was calculated by multiplying the incidence of metastases in the hilar region by the survival rates for individuals with nodal involvement in that region. Of 602 patients, 87(14.5%) had hilar LN metastasis. The 5-year overall and relapse-free survival rates for patients with hilar LN metastasis were 24.1% and 12.1%, respectively. These rates were similar to those for patients with metastasis to other extraperigastric LNs ( P > 0.05), with similar recurrence patterns. Overall survival in the hilar LN metastasis group was better than that for patients with distant metastasis( P < 0.05). The estimated therapeutic index of splenic hilar LN dissection was 3.5, which was similar to index values for LN dissection at other extraperigastric LNs. Dissection of splenic hilar LNs during total gastrectomy for advanced gastric cancer allows for a prognosis similar to that achieved with dissection of extraperigastric LNs.

Potential clinical value of PET/CT in predicting occult nodal metastasis in T1-T2N0M0 lung cancer patients staged by PET/CT

PubMed Central

Zhou, Xiang; Chen, Ruohua; Huang, Gang; Liu, Jianjun

2017-01-01

We assessed the clinical value of 2-fluoro-2-deoxyglucose (18F-FDG) PET/CT imaging for predicting occult nodal metastasis in non-small cell lung cancer (NSCLC) patients. This retrospective study included 54 patients with T1-2N0M0 NSCLC who had undergone 18F-FDG PET/CT before surgery. Occult nodal metastasis was detected in 25.9% (14/54) of the patients. Immunohistochemical analysis revealed that increased glucose transporter 1 expression was associated with occult nodal metastasis, but hexokinase 2 expression was not. Compared to the negative nodal metastasis group, the positive nodal metastasis group was associated with increased maximum standardized uptake value (SUVmax) and tumor size. Multivariate analysis indicated that SUVmax and tumor size were associated with nodal metastasis. Nodal metastasis could be predicted with a sensitivity of 92.9% and a specificity of 55.0% when the SUVmax cutoff was 4.35. When patients were divided into low-risk (tumor size ≤ 2.5 cm and SUVmax ≤ 4.35), moderate-risk (tumor size ≤ 2.5 cm and SUVmax > 4.35 or tumor size > 2.5 cm and SUVmax ≤ 4.35) and high-risk (tumor size > 2.5 cm and SUVmax > 4.35) groups, the lymph node metastasis rates were 4.3%, 22.7%, and 88.9%, respectively. These results indicate that the combination of SUVmax and tumor size has potential clinical value for predicting occult nodal metastasis in NSCLC patients. PMID:29137276

Integrating Structure to Protein-Protein Interaction Networks That Drive Metastasis to Brain and Lung in Breast Cancer

PubMed Central

Engin, H. Billur; Guney, Emre; Keskin, Ozlem; Oliva, Baldo; Gursoy, Attila

2013-01-01

Blocking specific protein interactions can lead to human diseases. Accordingly, protein interactions and the structural knowledge on interacting surfaces of proteins (interfaces) have an important role in predicting the genotype-phenotype relationship. We have built the phenotype specific sub-networks of protein-protein interactions (PPIs) involving the relevant genes responsible for lung and brain metastasis from primary tumor in breast cancer. First, we selected the PPIs most relevant to metastasis causing genes (seed genes), by using the “guilt-by-association” principle. Then, we modeled structures of the interactions whose complex forms are not available in Protein Databank (PDB). Finally, we mapped mutations to interface structures (real and modeled), in order to spot the interactions that might be manipulated by these mutations. Functional analyses performed on these sub-networks revealed the potential relationship between immune system-infectious diseases and lung metastasis progression, but this connection was not observed significantly in the brain metastasis. Besides, structural analyses showed that some PPI interfaces in both metastasis sub-networks are originating from microbial proteins, which in turn were mostly related with cell adhesion. Cell adhesion is a key mechanism in metastasis, therefore these PPIs may be involved in similar molecular pathways that are shared by infectious disease and metastasis. Finally, by mapping the mutations and amino acid variations on the interface regions of the proteins in the metastasis sub-networks we found evidence for some mutations to be involved in the mechanisms differentiating the type of the metastasis. PMID:24278371

Brain metastasis in gastroesophageal adenocarcinoma and HER2 status.

PubMed

Limon, Dror; Gal, Omer; Gordon, Noa; Katz, Lior; Perl, Gali; Purim, Ofer; Amit, Limor; Stemmer, Salomon M; Kundel, Yulia; Ben-Aharon, Irit; Brenner, Baruch; Siegal, Tali; Yust-Katz, Shlomit

2018-06-01

The increased survival of patients with gastroesophageal adenocarcinoma (GAD) following improvements in treatment has been accompanied by a rising incidence of secondary brain metastasis. HER2 amplification/overexpression, which has been associated with an increased risk of brain metastasis in breast cancer, is found in about 20% of patients with GAD. The aim of this study was to evaluate the effect of HER2 status on brain metastasis in GAD. The database of a tertiary cancer center was searched for patients with GAD diagnosed in 2011-2015, and data were collected on clinical characteristics, brain metastasis, HER2 status, and outcome. We identified 404 patients with a confirmed diagnosis of GAD. HER2 results were available for 298: 69 (23.2%) positive and 227 negative. Brain metastasis developed in 15 patients with GAD (3.7%); HER2 results, available in 13, were positive in 6, negative in 6, and equivocal in 1. The brain metastasis rate was significantly higher in HER2-positive than HER2-negative patients with GAD (6/69, 8.7% vs. 6/227, 2.6%; RR = 3.3, 95% CI 1.1-9.9, p = 0.034). Median overall survival from diagnosis of brain metastasis was 2.3 months, with no significant difference by HER2 status. HER2 positive GAD patients may be at increased risk to develop BM. Clinicians should maintain a lower threshold for performing brain imaging in patients with HER2-positive GAD given their increased risk of brain metastasis. The role of anti-HER2 agents in the development and treatment of brain metastasis in GAD warrants further study.

Pattern of distant extrahepatic metastases in primary liver cancer: a SEER based study.

PubMed

Wu, Wenrui; He, Xingkang; Andayani, Dewi; Yang, Liya; Ye, Jianzhong; Li, Yating; Chen, Yanfei; Li, Lanjuan

2017-01-01

Background and Aims : Primary liver cancer remains still the common cause of cancer-related deaths globally and the prognosis for patients with extrahepatic metastasis is poor. The aim of our study was to assess extrahepatic metastatic pattern of different histological subtypes and evaluate prognostic effects of extrahepatic metastasis in patients with advanced disease. Methods: Based on the Surveillance, Epidemiology and End Results (SEER) database, eligible patients diagnosed with primary liver cancer was identified between 2010 to 2012. We adopted Chi-square test to compared metastasis distribution among different histological types. We compared survival difference of patients with different extrahepatic metastasises by Kaplan-Meier analysis. Cox proportional hazard models were performed to identify other prognostic factors of overall survival. Results: We finally identified 8677 patients who were diagnosed with primary liver cancer from 2010 to 2012 and 1775 patients were in distant metastasis stages. Intrahepatic cholangiocarcinoma was more invasive and had a higher percentage of metastasis compared with hepatocellular carcinoma. Lung was the most common metastasis and brain was the least common site for both hepatocellular carcinoma and intrahepatic cholangiocarcinoma. Extrahepatic metastasis could consider as an independent prognostic factor for patients with liver cancer. Patients with brain metastasis had the worst prognosis, compared with other metastasis in overall survival (OS) and cancer-specific survival (CSS) analysis. Conclusions: Different histological subtypes of liver cancer had different metastasis patterns. There were profound differences in risk of mortality among distant extrahepatic metastatic sites. Results from our studies would provide some information for follow-up strategies and future studies.

Prognostic effect of liver metastasis in lung cancer patients with distant metastasis.

PubMed

Ren, Yijiu; Dai, Chenyang; Zheng, Hui; Zhou, Fangyu; She, Yunlang; Jiang, Gening; Fei, Ke; Yang, Ping; Xie, Dong; Chen, Chang

2016-08-16

Because the need of clinical prognostic evaluation by specific metastatic organ, we aim to analyze the prognostic factors in lung cancer patients with M1b disease with Surveillance Epidemiology and End-Results database (SEER). This retrospective study evaluated lung cancer patients of adenocarcinoma (AD), squamous cell carcinoma (SQCC), and small cell lung cancer (SCLC) selected from SEER. We provided the prognostic correlates of overall survival (OS) and lung cancer-specific survival (LCSS) in this population. 23,679 eligible patients were included. Bone was the most common metastatic site in AD (63.1%) and SQCC (61.1%), while liver was the most prevalent site (61.9%) in SCLC. Single site metastasis was significantly associated with better outcome compared to multiple sites metastases in all patients. Among patients with single site metastasis, OS and LCSS were longer for AD and SCLC if involving brain or bone, with median survival time of 5 to 7 months, comparing to 3 months if invloving liver (all p-values < 0.001). Similarly, among patients with multiple metastases, better outcomes were observed in AD patients (4 vs 3 months; OS and LCSS, p < 0.001) and SCLC patients (6 vs 4 months; OS, p = 0.017; LCSS, p = 0.023) without liver metastasis compared to those with liver metastasis. In conclusion, we estimated multiple survival outcomes by histology of primary tumor and sites of metastasis. Liver metastasis is found to be the worst prognostic factor for AD and SCLC patients with distant metastasis. More in-depth research is warranted to identify patients who are prone to develop distance metastasis, especially to liver.

Anti-metastasis effect of fucoidan from Undaria pinnatifida sporophylls in mouse hepatocarcinoma Hca-F cells.

PubMed

Wang, Peisheng; Liu, Zhichao; Liu, Xianli; Teng, Hongming; Zhang, Cuili; Hou, Lin; Zou, Xiangyang

2014-01-01

Metastasis is one of the major causes of cancer-related death. It is a complex biological process involving multiple genes, steps, and phases. It is also closely connected to many biological activities of cancer cells, such as growth, invasion, adhesion, hematogenous metastasis, and lymphatic metastasis. Fucoidan derived from Undaria pinnatifida sporophylls (Ups-fucoidan) is a sulfated polysaccharide with more biological activities than other fucoidans. However, there is no information on the effects of Ups-fucoidan on tumor invasion and metastasis. We used the mouse hepatocarcinoma Hca-F cell line, which has high invasive and lymphatic metastasis potential in vitro and in vivo, to examine the effect of Ups-fucoidan on cancer cell invasion and metastasis. Ups-fucoidan exerted a concentration- and time-dependent inhibitory effect on tumor metastasis in vivo and inhibited Hca-F cell growth, migration, invasion, and adhesion capabilities in vitro. Ups-fucoidan inhibited growth and metastasis by downregulating vascular endothelial growth factor (VEGF) C/VEGF receptor 3, hepatocyte growth factor/c-MET, cyclin D1, cyclin-dependent kinase 4, phosphorylated (p) phosphoinositide 3-kinase, p-Akt, p-extracellular signal regulated kinase (ERK) 1/2, and nuclear transcription factor-κB (NF-κB), and suppressed adhesion and invasion by downregulating L-Selectin, and upregulating protein levels of tissue inhibitor of metalloproteinases (TIMPs). The results suggest that Ups-fucoidan suppresses Hca-F cell growth, adhesion, invasion, and metastasis capabilities and that these functions are mediated through the mechanism involving inactivation of the NF-κB pathway mediated by PI3K/Akt and ERK signaling pathways.

Anti-Metastasis Effect of Fucoidan from Undaria pinnatifida Sporophylls in Mouse Hepatocarcinoma Hca-F Cells

PubMed Central

Wang, Peisheng; Liu, Zhichao; Liu, Xianli; Teng, Hongming; Zhang, Cuili; Hou, Lin; Zou, Xiangyang

2014-01-01

Metastasis is one of the major causes of cancer-related death. It is a complex biological process involving multiple genes, steps, and phases. It is also closely connected to many biological activities of cancer cells, such as growth, invasion, adhesion, hematogenous metastasis, and lymphatic metastasis. Fucoidan derived from Undaria pinnatifida sporophylls (Ups-fucoidan) is a sulfated polysaccharide with more biological activities than other fucoidans. However, there is no information on the effects of Ups-fucoidan on tumor invasion and metastasis. We used the mouse hepatocarcinoma Hca-F cell line, which has high invasive and lymphatic metastasis potential in vitro and in vivo, to examine the effect of Ups-fucoidan on cancer cell invasion and metastasis. Ups-fucoidan exerted a concentration- and time-dependent inhibitory effect on tumor metastasis in vivo and inhibited Hca-F cell growth, migration, invasion, and adhesion capabilities in vitro. Ups-fucoidan inhibited growth and metastasis by downregulating vascular endothelial growth factor (VEGF) C/VEGF receptor 3, hepatocyte growth factor/c-MET, cyclin D1, cyclin-dependent kinase 4, phosphorylated (p) phosphoinositide 3-kinase, p-Akt, p-extracellular signal regulated kinase (ERK) 1/2, and nuclear transcription factor-κB (NF-κB), and suppressed adhesion and invasion by downregulating L-Selectin, and upregulating protein levels of tissue inhibitor of metalloproteinases (TIMPs). The results suggest that Ups-fucoidan suppresses Hca-F cell growth, adhesion, invasion, and metastasis capabilities and that these functions are mediated through the mechanism involving inactivation of the NF-κB pathway mediated by PI3K/Akt and ERK signaling pathways. PMID:25162296

Overexpression of neuromedin U is correlated with regional metastasis of head and neck squamous cell carcinoma

PubMed Central

Wang, Lei; Chen, Chen; Li, Fen; Hua, Qing-Quan; Chen, Shiming; Xiao, Bokui; Dai, Mengyuan; Li, Man; Zheng, Anyuan; Yu, Di; Hu, Zhang Wei; Tao, Zezhang

2016-01-01

Regional metastasis is an important prognostic factor for patients with head and neck squamous cell carcinoma (HNSCC). Neuromedin U (Nmu) is a secreted neuropeptide, named due to its potent uterine contraction-inducing activity. The aim of the present study was to analyze the significance of Nmu in the regional metastasis of HNSCC. The characteristics of 240 patients recruited from the Department of Otolaryngology Head and Neck Surgery, Renmin Hospital of Wuhan University (Wuhan, China) were summarized retrospectively. The positive rate of neck dissection was analyzed according to the material. The expression levels of Nmu in human tumor samples were analyzed using immunohistochemistry. Subsequently, the expression of Nmu was investigated using a tissue microassay to analyze the association between Nmu protein expression and Tumor Node Metastasis (TNM) status. The positive rate of neck dissection was 51.4% in the study sample. The expression levels of Nmu in primary tumors with regional metastasis were higher, compared with those without metastasis. There was increased protein expression of Nmu in the advanced tumor tissues. The data obtained in the present study demonstrated that the expression of Nmu was correlated with regional metastasis and TNM status. Overexpression of Nmu may be involved in the process of regional metastasis of HNSCC, and may serve as a novel and valuable biomarker for predicting regional metastasis in patients with HNSCC. PMID:27279246

Individualized optimal surgical extent of the lateral neck in papillary thyroid cancer with lateral cervical metastasis.

PubMed

Park, Jae-Yong; Koo, Bon Seok

2014-06-01

Despite an excellent prognosis, cervical lymph node (LN) metastases are common in patients with papillary thyroid cancer (PTC). The presence of metastasis is associated with an increased risk of locoregional recurrence, which significantly impairs quality of life and may decrease survival. Therefore, it has been an important determinant of the extent of lateral LN dissection in the initial treatment of PTC patients with lateral cervical metastasis. However, the optimal extent of therapeutic lateral neck dissection (ND) remains controversial. Optimizing the surgical extent of LN dissection is fundamental for balancing the surgical morbidity and oncological benefits of ND in PTC patients with lateral neck metastasis. We reviewed the currently available literature regarding the optimal extent of lateral LN dissection in PTC patients with lateral neck metastasis. Even in cases with suspicion of metastatic LN at the single lateral level or isolated metastatic lateral LN, the application of ND including all sublevels from IIa and IIb to Va and Vb may be overtreatment, due to the surgical morbidity. When there is no suspicion of LN metastasis at levels II and V, or when multilevel aggressive neck metastasis is not found, sublevel IIb and Va dissection may not be necessary in PTC patients with lateral neck metastasis. Thus consideration of the individualized optimal surgical extent of lateral ND is important when treating PTC patients with lateral cervical metastasis.

Up-regulation of Rho-associated kinase 1/2 by glucocorticoids promotes migration, invasion and metastasis of melanoma.

PubMed

Huang, Gao-Xiang; Wang, Yan; Su, Jie; Zhou, Peng; Li, Bo; Yin, Li-Juan; Lu, Jian

2017-12-01

Although glucocorticoids (GCs) regulate proliferation, differentiation and apoptosis of tumor cells, their influence on metastasis of tumor cells is poorly understood. Melanoma is a type of skin cancers with high metastasis. We investigated the effect of GCs on metastasis of melanoma cells and its mechanism. We found that GCs significantly promoted the adhesion, migration, invasion of melanoma cells in vitro and lung metastasis in experimental melanoma metastasis mice. Dexamethasone (Dex), a synthetic GC, did not change the RhoA, RhoB and RhoC signalings, but significantly increased the expression and activity of Rho-associated kinase 1/2 (ROCK1/2). The effect of Dex was to increase ROCK1/2 stability mediated by glucocorticoid receptor. Inhibiting ROCK1/2 activity with Y-27632, a ROCK1/2 inhibitor abrogated the pro-migration and pro-metastasis effects of GCs in vitro and in vivo, indicating that ROCK1/2 mediated the pro-metastasis effects of GCs. Activation of PI3K/AKT also contributed to the pro-migration and pro-invasion effects of Dex partially through up-regulating ROCK1/2 expression. Additionally, Dex also down-regulated the expression of tissue inhibitors of matrix metalloproteinase-2. Taken together, our findings provide new data to understand the possible promoting roles and mechanisms of GCs in melanoma metastasis. Copyright © 2017. Published by Elsevier B.V.

Clinicopathological features of gastric metastasis from breast cancer in three cases.

PubMed

Koike, Kenta; Kitahara, Kenji; Higaki, Mayumi; Urata, Masako; Yamazaki, Fumio; Noshiro, Hirokazu

2014-09-01

The common sites for metastases from breast cancer are lymph nodes, bone, lung, liver, and brain. Gastrointestinal (GI) metastasis is rarely found or diagnosed in patients with breast cancer. This report presents three cases of gastric metastasis from breast cancer. Case 1 was a 42-year-old female diagnosed with gastric metastasis after mastectomy with axillary lymph node dissection for invasive lobular carcinoma of the left breast. Case 2 was a 54-year-old female who was diagnosed to have invasive lobular carcinoma of the left breast with systemic bone and gastric metastasis. Case 3 was a 54-year-old female who was diagnosed to have bilateral invasive ductal carcinoma of the breast with simultaneous bone and gastric metastasis. The immunohistochemical statuses for estrogen receptor, progesterone receptor, mammaglobin, and gross cystic disease fluid protein-15 (GCDFP-15) between the primary and gastric metastatic lesions were all well matched. All three cases were treated with systemic chemotherapy, hormone therapy or both, without surgical intervention for gastric lesions. Two patients with disseminated disease died 27 and 58 months after diagnosis of gastric metastasis, while one patient without organ metastasis is still alive at 56 months after diagnosis. It is important to make a correct diagnosis by distinguishing gastric metastasis from breast cancer in order to select the optimal initial treatment for systemic disease of breast cancer.

Metastasis Suppressor Gene Inactivates Actin-Based Mechanism of Tumor Cell Motility | Center for Cancer Research

Cancer.gov

Metastasis is responsible for up to 90 percent of all cancer-related deaths. Though proteins derived from nearly a dozen metastasis suppressor genes have been discovered over the past 15 years, strategies for exploiting the proteins in metastasis-prevention therapies has been hampered by the lack of knowledge regarding the mechanisms underlying the proteins’ interactions with

Competition and niche construction in a model of cancer metastasis.

PubMed

Qian, Jimmy J; Akçay, Erol

2018-01-01

Niche construction theory states that not only does the environment act on populations to generate Darwinian selection, but organisms reciprocally modify the environment and the sources of natural selection. Cancer cells participate in niche construction as they alter their microenvironments and create pre-metastatic niches; in fact, metastasis is a product of niche construction. Here, we present a mathematical model of niche construction and metastasis. Our model contains producers, which pay a cost to contribute to niche construction that benefits all tumor cells, and cheaters, which reap the benefits without paying the cost. We derive expressions for the conditions necessary for metastasis, showing that the establishment of a mutant lineage that promotes metastasis depends on niche construction specificity and strength of interclonal competition. We identify a tension between the arrival and invasion of metastasis-promoting mutants, where tumors composed only of cheaters remain small but are susceptible to invasion whereas larger tumors containing producers may be unable to facilitate metastasis depending on the level of niche construction specificity. Our results indicate that even if metastatic subclones arise through mutation, metastasis may be hindered by interclonal competition, providing a potential explanation for recent surprising findings that most metastases are derived from early mutants in primary tumors.

OB glue paste technique for establishing nude mouse human gastric cancer orthotopic transplantation models

PubMed Central

Shi, Jun; Wei, Pin-Kang; Zhang, Shen; Qin, Zhi-Feng; Li, Jun; Sun, Da-Zhi; Xiao, Yan; Yu, Zhi-Hong; Lin, Hui-Ming; Zheng, Guo-Jing; Su, Xiao-Mei; Chen, Ya-Lin; Liu, Yan-Fang; Xu, Ling

2008-01-01

AIM: To establish nude mouse human gastric cancer orthotopic transplantation models using OB glue paste technique. METHODS: Using OB glue paste technique, orthotopic transplantation models were established by implanting SGC-7901 and MKN-45 human gastric cancer cell strains into the gastric wall of nude mice. Biological features, growth of the implanted tumors, the success rate of transplantation and the rate of auto-metastasis of the two models were observed. RESULTS: The success rates of orthotopic transplan-tation of the two models were 94.20% and 96%. The rates of hepatic metastasis, pulmonary metastasis, peritoneal metastasis, lymphocytic metastasis and splenic metastasis were 42.13% and 94.20%, 48.43% and 57.97%, 30.83% and 36.96%, 67.30% and 84.06%, and 59.75% and 10.53%, respectively. The occurrence of ascites was 47.80% and 36.96%. CONCLUSION: OB glue paste technique is easy to follow. The biological behaviors of the nude mouse human gastric cancer orthotopic transplantation models established with this technique are similar to the natural processes of growth and metastasis of human gastric cancer, and, therefore, can be used as an ideal model for experimental research of proliferative metastasis of tumors. PMID:18720543

[Evaluation and classification of drug therapy for breast cancer with bone-only metastasis].

PubMed

Meng, X Y; Song, S T

2017-03-23

Skeleton is one of the most common metastatic organs for breast cancer, which has a better prognosis than visceral metastases. Bone-only metastasis was defined"non-measurable" in the RECIST (Response Evaluation Criteria in Solid Tumors) criteria, and was excluded by clinical trials. However, patients with bone-only metastasis are also in need of effective treatment to prolong survival. Endocrine therapy is the most important treatment for bone metastatic patients. Tumor response of bone metastases can be determined objectively by bone-window CT. Effective treatment should be continued if the symptoms are relieved or osteogenesis is observed. Osteoblastic change in bone-window CT is a sign of improvement after treatment. Endocrine therapy is proper for ER-positive patients. The patients with initial osteoblastic metastasis should not be treated with salvage chemotherapy or anti-HER2 treatment, only if osteolytic metastasis or visceral metastasis is observed. Bishosphonates are just auxiliary drugs in bone metastasis, which should not be abused.

Bcl-3 regulates TGFβ signaling by stabilizing Smad3 during breast cancer pulmonary metastasis

PubMed Central

Chen, Xi; Cao, Xinwei; Sun, Xiaohua; Lei, Rong; Chen, Pengfei; Zhao, Yongxu; Jiang, Yuhang; Yin, Jie; Chen, Ran; Ye, Deji; Wang, Qi; Liu, Zhanjie; Liu, Sanhong; Cheng, Chunyan; Mao, Jie; Hou, Yingyong; Wang, Mingliang; Siebenlist, Ulrich; Eugene Chin, Y; Wang, Ying; Cao, Liu; Hu, Guohong; Zhang, Xiaoren

2016-01-01

Transforming growth factor beta (TGFβ) signaling in breast cancer is selectively associated with pulmonary metastasis. However, the underlying mechanisms remain unclear. Here we show that Bcl-3, a member of the IκB family, serves as a critical regulator in TGFβ signaling to modulate breast cancer pulmonary metastasis. Bcl-3 expression was significantly associated with metastasis-free survival in breast cancer patients. Bcl-3 deletion inhibited the migration and invasion of breast cancer cells in vitro, as well as breast cancer lung metastasis in vivo. Bcl-3 was required for the expression of downstream TGFβ signaling genes that are involved in breast cancer lung metastasis. Bcl-3 knockdown enhanced the degradation of Smad3 but not Smad2 following TGFβ treatment. Bcl-3 could bind to Smad3 and prevent the ubiquitination and degradation of Smad3 protein. These results indicate that Bcl-3 serves as a promising target to prevent breast tumor lung metastasis. PMID:27906182

A genome-wide scan identifies variants in NFIB associated with metastasis in patients with osteosarcoma

PubMed Central

Mirabello, Lisa; Koster, Roelof; Moriarity, Branden S.; Spector, Logan G.; Meltzer, Paul S.; Gary, Joy; Machiela, Mitchell J.; Pankratz, Nathan; Panagiotou, Orestis A.; Largaespada, David; Wang, Zhaoming; Gastier-Foster, Julie M.; Gorlick, Richard; Khanna, Chand; de Toledo, Silvia Regina Caminada; Petrilli, Antonio S.; Patiño-Garcia, Ana; Sierrasesúmaga, Luis; Lecanda, Fernando; Andrulis, Irene L.; Wunder, Jay S.; Gokgoz, Nalan; Serra, Massimo; Hattinger, Claudia; Picci, Piero; Scotlandi, Katia; Flanagan, Adrienne M.; Tirabosco, Roberto; Amary, Maria Fernanda; Halai, Dina; Ballinger, Mandy L.; Thomas, David M.; Davis, Sean; Barkauskas, Donald A.; Marina, Neyssa; Helman, Lee; Otto, George M.; Becklin, Kelsie L.; Wolf, Natalie K.; Weg, Madison T.; Tucker, Margaret; Wacholder, Sholom; Fraumeni, Joseph F.; Caporaso, Neil E.; Boland, Joseph F.; Hicks, Belynda D.; Vogt, Aurelie; Burdett, Laurie; Yeager, Meredith; Hoover, Robert N.; Chanock, Stephen J.; Savage, Sharon A.

2015-01-01

Metastasis is the leading cause of death in osteosarcoma patients, the most common pediatric bone malignancy. We conducted a multi-stage genome-wide association study of osteosarcoma metastasis at diagnosis in 935 osteosarcoma patients to determine whether germline genetic variation contributes to risk of metastasis. We identified a SNP, rs7034162, in NFIB significantly associated with metastasis in European osteosarcoma cases, as well as in cases of African and Brazilian ancestry (meta-analysis of all cases: P=1.2×10−9, OR 2.43, 95% CI 1.83–3.24). The risk allele was significantly associated with lowered NFIB expression, which led to increased osteosarcoma cell migration, proliferation, and colony formation. Additionally, a transposon screen in mice identified a significant proportion of osteosarcomas harboring inactivating insertions in Nfib, and had lowered Nfib expression. These data suggest that germline genetic variation at rs7034162 is important in osteosarcoma metastasis, and that NFIB is an osteosarcoma metastasis susceptibility gene. PMID:26084801

Ethanol inhibits B16-BL6 melanoma metastasis and cell phenotypes associated with metastasis.

PubMed

Kushiro, Kyoko; Núñez, Nomelí P

2012-01-01

Every year, approximately 68,000 new cases of malignant melanoma are diagnosed in the US. Ethanol consumption inhibits metastasis of melanoma in mice, but the mechanism is not well understood. C57BL/6J ob/+ mice, given either water or 20% ethanol, were injected intravenously with B16-BL6 melanoma cells to determine pulmonary metastasis. The effects of ethanol on cell phenotypes and markers of the epithelial-to-mesenchymal transition were determined in cell culture. In mice, ethanol consumption inhibited experimental pulmonary metastasis. This inhibition was associated with decreased body weight, and levels of systemic leptin, and insulin. In cell culture, ethanol inhibited B16-BL6 cell motility, invasion, and anchorage-independent growth. Additionally, ethanol reduced Snai1 expression and increased E-cadherin expression. Lastly, ethanol increased the expression of Kiss1 metastasis-suppressor and the metastasis suppressor Nm23/nucleoside diphosphate kinase. In both animal and in cell culture conditions, ethanol inhibited the metastatic ability of B16-BL6 melanoma cells.

Transient SNAIL1 expression is necessary for metastatic competence in breast cancer.

PubMed

Tran, Hung D; Luitel, Krishna; Kim, Michael; Zhang, Kun; Longmore, Gregory D; Tran, David D

2014-11-01

SNAIL1 has been suggested to regulate breast cancer metastasis based on analyses of human breast tumor transcriptomes and experiments using cancer cell lines and xenografts. However, in vivo genetic experimental support for a role for SNAIL1 in breast cancer metastasis that develops in an immunocompetent tumor microenvironment has not been determined. To address this question, we created a genetic SNAIL1 model by coupling an endogenous SNAIL1 reporter with an inducible SNAIL1 transgene. Using multiple genetic models of breast cancer, we demonstrated that endogenous SNAIL1 expression was restricted to primary tumors that ultimately disseminate. SNAIL1 gene deletion either during the premalignant phase or after primary tumors have reached a palpable size blunted metastasis, indicating that late metastasis was the main driver of metastasis and that this was dependent on SNAIL1. Importantly, SNAIL1 expression during breast cancer metastasis was transient and forced transient, but not continuous. SNAIL1 expression in breast tumors was sufficient to increase metastasis. ©2014 American Association for Cancer Research.

[Encounter of cancer cells with bone. Histological examination of bone metastasis].

PubMed

Kanda, Hiroaki

2011-03-01

Management of the cancer bone metastasis is important clinical problem. The mechanism (s) of bone metastasis has been studied mainly by animal models and in vitro system. There might be discrepancy between model systems and in vivo human clinical materials. But there is surprisingly rare study of histological examination of human skeletal metastasis, since it is hard to obtain human materials without modification by chemotherapy or irradiation. There are many surgical materials suitable for this examination in our hospital and we have been examined histological features of them. Stromal cells between metastatic cancer cells and OCs (osteoclasts) and÷or OBs (osteoblasts) might play a role in bone metastasis, since these cells are frequently accompanied with OCs÷OBs. We called these stromal cells as "fibroblast-like cells" and examined their nature and roles in bone metastasis. We hope these fibroblast-like cells might become the target of anti bone metastasis therapy, same as osteoclasts targeted by bisphosphonates.

Cutaneous metastasis of signet-ring gastric adenocarcinoma to the breast with unusual clinicopathological features.

PubMed

Avgerinou, Georgia; Flessas, Ioannis; Hatziolou, Eftychia; Zografos, Georgios; Nitsios, Ilias; Zagouri, Flora; Katsambas, Andreas; Kanitakis, Jean

2011-06-01

Cutaneous metastasis of gastric adenocarcinoma is rare and usually presents in men, as nodules over the abdomen. We present the case of a woman with cutaneous metastasis of gastric adenocarcinoma showing unusual clinicopathological features. A 37-year-old woman developed florid cutaneous metastasis over the skin of the left breast two years after total gastrectomy for a signet-ring adenocarcinoma of the diffuse type. The metastasis presented as a multinodular growth developing over erythematous skin of the left hemithorax. Microscopically, the skin tumor was predominantly made up of spindle-shaped cells, mimicking a mesenchymal/fibrohistiocytic neoplasm. A comparative immunohistochemical study of the gastric primary and the skin tumor showed an almost identical profile (keratin 7/20+; epithelial membrane antigen+, MUC-5AC+), highlighting the gastric adenocarcinoma as the origin of the skin metastasis. Although rare, cutaneous metastases of gastric adenocarcinomas can develop in women and may mimic inflammatory metastasis of breast adenocarcinoma. Immunohistochemistry is invaluable in establishing the correct diagnosis.

Perigastric lymph node metastasis from papillary thyroid carcinoma in a patient with early gastric cancer: the first case report.

PubMed

Jeong, Gui-Ae; Kim, Hyung-Chul; Kim, Hee-Kyung; Cho, Gyu-Seok

2014-09-01

Distant metastasis from papillary thyroid carcinoma (PTC), particularly from papillary thyroid microcarcinoma, is rare. We present a case of perigastric lymph node metastasis from PTC in a patient with early gastric cancer and breast cancer. During post-surgical follow-up for breast cancer, a 56-year-old woman was diagnosed incidentally with early gastric cancer and synchronous left thyroid cancer. Therefore, laparoscopic distal gastrectomy with lymph node dissection and left thyroidectomy were performed. On the basis of the pathologic findings of the surgical specimens, the patient was diagnosed to have papillary thyroid microcarcinoma with perigastric lymph node metastasis and early gastric cancer with mucosal invasion. Finally, on the basis of immunohistochemical staining with galectin-3, the diagnosis of perigastric lymph node metastasis from PTC was made. When a patient has multiple primary malignancies with lymph node metastasis, careful pathologic examination of the surgical specimen is necessary; immunohistochemical staining may be helpful in determining the primary origin of lymph node metastasis.

The RON Receptor Tyrosine Kinase Promotes Metastasis by Triggering MBD4-Dependent DNA Methylation Reprogramming

PubMed Central

Cunha, Stéphanie; Lin, Yi-Chun; Goossen, Elizabeth A.; DeVette, Christa I.; Albertella, Mark R.; Thomson, Stuart; Mulvihill, Mark J.; Welm, Alana L.

2017-01-01

SUMMARY Metastasis is the major cause of death in cancer patients, yet the genetic and epigenetic programs that drive metastasis are poorly understood. Here, we report an epigenetic reprogramming pathway that is required for breast cancer metastasis. Concerted differential DNA methylation is initiated by the activation of the RON receptor tyrosine kinase by its ligand, macrophage stimulating protein (MSP). Through PI3K signaling, RON/MSP promotes expression of the G:T mismatch-specific thymine glycosylase MBD4. RON/MSP and MBD4-dependent aberrant DNA methylation results in the misregulation of a specific set of genes. Knockdown of MBD4 reverses methylation at these specific loci and blocks metastasis. We also show that the MBD4 glycosylase catalytic residue is required for RON/MSP-driven metastasis. Analysis of human breast cancers revealed that this epigenetic program is significantly associated with poor clinical outcome. Furthermore, inhibition of Ron kinase activity with a pharmacological agent blocks metastasis of patient-derived breast tumor grafts in vivo. PMID:24388747

The rodent liver undergoes weaning-induced involution and supports breast cancer metastasis

PubMed Central

Goddard, Erica T.; Hill, Ryan C.; Nemkov, Travis; D’Alessandro, Angelo; Hansen, Kirk C.; Maller, Ori; Mongoue-Tchokote, Solange; Mori, Motomi; Partridge, Ann H.; Borges, Virginia F.; Schedin, Pepper

2017-01-01

Postpartum breast cancer patients are at increased risk for metastasis compared to age-matched nulliparous or pregnant patients. Here, we address whether circulating tumor cells have a metastatic advantage in the postpartum host and find the post-lactation rodent liver preferentially supports metastasis. Upon weaning, we observed liver weight loss, hepatocyte apoptosis, ECM remodeling including deposition of collagen and tenascin-C, and myeloid cell influx, data consistent with weaning-induced liver involution and establishment of a pro-metastatic microenvironment. Using intracardiac and intraportal metastasis models, we observed increased liver metastasis in post-weaning Balb/c mice compared to nulliparous controls. Human relevance is suggested by a ~3-fold increase in liver metastasis in postpartum breast cancer patients (n=564) and by liver-specific tropism (n=117). In sum, our data reveal a previously unknown biology of the rodent liver, weaning-induced liver involution, which may provide insight into the increased liver metastasis and poor prognosis of women diagnosed with postpartum breast cancer. PMID:27974414

MiR-218 Inhibits Invasion and Metastasis of Gastric Cancer by Targeting the Robo1 Receptor

PubMed Central

Wu, Kaichun; Liu, Jie; Sun, Shiren; Guo, Xuegang; Wang, Biaoluo; Gang, Yi; Zhang, Yongguo; Li, Quanjiang; Qiao, Taidong; Zhao, Qingchuan; Nie, Yongzhan; Fan, Daiming

2010-01-01

MicroRNAs play key roles in tumor metastasis. Here, we describe the regulation and function of miR-218 in gastric cancer (GC) metastasis. miR-218 expression is decreased along with the expression of one of its host genes, Slit3 in metastatic GC. However, Robo1, one of several Slit receptors, is negatively regulated by miR-218, thus establishing a negative feedback loop. Decreased miR-218 levels eliminate Robo1 repression, which activates the Slit-Robo1 pathway through the interaction between Robo1 and Slit2, thus triggering tumor metastasis. The restoration of miR-218 suppresses Robo1 expression and inhibits tumor cell invasion and metastasis in vitro and in vivo. Taken together, our results describe a Slit-miR-218-Robo1 regulatory circuit whose disruption may contribute to GC metastasis. Targeting miR-218 may provide a strategy for blocking tumor metastasis. PMID:20300657

NSG Mice Provide a Better Spontaneous Model of Breast Cancer Metastasis than Athymic (Nude) Mice

PubMed Central

Puchalapalli, Madhavi; Zeng, Xianke; Mu, Liang; Anderson, Aubree; Hix Glickman, Laura; Zhang, Ming; Sayyad, Megan R.; Mosticone Wangensteen, Sierra; Clevenger, Charles V.; Koblinski, Jennifer E.

2016-01-01

Metastasis is the most common cause of mortality in breast cancer patients worldwide. To identify improved mouse models for breast cancer growth and spontaneous metastasis, we examined growth and metastasis of both estrogen receptor positive (T47D) and negative (MDA-MB-231, SUM1315, and CN34BrM) human breast cancer cells in nude and NSG mice. Both primary tumor growth and spontaneous metastases were increased in NSG mice compared to nude mice. In addition, a pattern of metastasis similar to that observed in human breast cancer patients (metastases to the lungs, liver, bones, brain, and lymph nodes) was found in NSG mice. Furthermore, there was an increase in the metastatic burden in NSG compared to nude mice that were injected with MDA-MB-231 breast cancer cells in an intracardiac experimental metastasis model. This data demonstrates that NSG mice provide a better model for studying human breast cancer metastasis compared to the current nude mouse model. PMID:27662655

Successful Treatment with Alectinib for Choroidal Metastasis in Anaplastic Lymphoma Kinase Rearranged Non-small Cell Lung Cancer

PubMed Central

Funazo, Tomoko; Morita, Kyohei; Ikegami, Naoya; Konishi, Chisato; Nakao, Satoshi; Ariyasu, Ryo; Taki, Masato; Nakagawa, Kazuhiko; Hwang, Moon Hee; Yoshimura, Chie; Wakayama, Toshiaki; Nishizaka, Yasuo

2017-01-01

Choroidal metastasis is rare in cancer patients and it may cause visual disturbances that reduce their quality of life. In non-small cell lung cancer (NSCLC), targeted therapy against actionable driver mutations has gradually replaced radiotherapy as the treatment of choice for choroidal metastasis. Recently, there have been several case reports of choroidal metastasis in patients with anaplastic lymphoma kinase (ALK)-rearranged NSCLC. We herein report the case of a 40-year-old Japanese woman diagnosed with choroidal metastasis of an ALK-rearranged NSCLC who received alectinib as the first-line chemotherapy. Alectinib may be the best treatment for choroidal metastasis in patients harboring an ALK translocation because of its favorable side effect profile involving visual disturbances. PMID:28794371

Long non-coding RNA-CTD-2108O9.1 represses breast cancer metastasis by influencing leukemia inhibitory factor receptor.

PubMed

Wang, Mozhi; Wang, Mengshen; Wang, Zhenning; Yu, Xueting; Song, Yongxi; Wang, Chong; Xu, Yujie; Wei, Fengheng; Zhao, Yi; Xu, Yingying

2018-06-01

Breast cancer (BC) is an aggressive malignant disease in women worldwide with a high tendency to metastasize. However, important biomarkers for BC metastasis remain largely undefined. In the present study, we identified that long non-coding RNA-CTD-2108O9.1 is downregulated in BC tissues and cells and acts as a metastatic inhibitor of BC. Mechanistic investigation determined that lncRNA-CTD-2108O9.1 represses metastasis by targeting leukemia inhibitory factor receptor (LIFR), which is designated as a metastasis suppressor in BC. Our study characterizes a significant tumor suppressor active in BC metastasis repression through the known metastasis inhibitor LIFR. © 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Sudden loss of vision due to breast cancer metastasis to the eyeball.

PubMed

Antosz, Zbigniew S; Walocha, Jerzy; Poręba, Ryszard; Sioma-Markowska, Urszula

2014-01-01

Intraocular choroidal metastasis is a very rare cause of blindness. Carcinoma of breast is the most common primary malignancy the accounts for choroidal metastasis in females. Other primary neoplasms which can uncommonly metastasize to the choroid are gastrointestinal tract, thyroid, pancreas, prostate and testis. Metastatic neoplasm to the eye outnumbers the primary tumors such as retinoblastoma and malignant melanoma. We present a case of sudden loss of vision due to breast cancer metastasis to the eyeball. The interval between the diagnosis of the primary tumor and the choroidal metastasis was 4 years.

Solitary fibular metastasis from nonsmall cell lung carcinoma

PubMed Central

Akram, Mohammad; Zaheer, Samreen; Hussain, Asif; Siddiqui, Shahid A; Afrose, Ruquiya; Khalid, Saifullah

2017-01-01

Solitary bone metastasis to fibula in patients of lung carcinoma is a rare entity, with only four cases reported in literature. We, hereby, present a case of a 50 year-old-male who was given three cycles of chemotherapy for lung carcinoma with no distant metastasis but presented 2 months later with a fusiform, painful swelling around the knee that was clinically suspected to be inflammatory in nature but proved to be fibular metastasis on cytology. There was no evidence of skeletal metastasis on initial bone scan. He was given palliative radiotherapy for this with symptomatic relief. PMID:28469322

Solitary fibular metastasis from nonsmall cell lung carcinoma.

PubMed

Akram, Mohammad; Zaheer, Samreen; Hussain, Asif; Siddiqui, Shahid A; Afrose, Ruquiya; Khalid, Saifullah

2017-01-01

Solitary bone metastasis to fibula in patients of lung carcinoma is a rare entity, with only four cases reported in literature. We, hereby, present a case of a 50 year-old-male who was given three cycles of chemotherapy for lung carcinoma with no distant metastasis but presented 2 months later with a fusiform, painful swelling around the knee that was clinically suspected to be inflammatory in nature but proved to be fibular metastasis on cytology. There was no evidence of skeletal metastasis on initial bone scan. He was given palliative radiotherapy for this with symptomatic relief.

Dissecting and Targeting Latent Metastasis

DTIC Science & Technology

2014-09-01

metastasis of breast cancer (LMBC). These cells retain the potential to form overt metastasis for years. Targeting LMBC with new drugs offers an...cancer cell extravasation through the BBB in experimental models and predict brain metastasis in the clinic (16). Once inside the brain parenchyma... drugs that perturb gap junction activity (Chen et al submitted for publication). In our experiments, both drugs as single agents were effective

Regenerative Stem Cell Therapy for Breast Cancer Bone Metastasis

DTIC Science & Technology

2014-09-01

13. SUPPLEMENTARY NOTES 14. ABSTRACT Bone is the most common site of metastasis for human breast cancer (BCa), which results in significant...to all major bones as in human patients. 15. SUBJECT TERMS Bone metastasis; osteolysis; osteoprotegerin 16. SECURITY CLASSIFICATION OF: 17...metastasis for human breast cancer (BCa), which results in significant morbidity and mortality in patients with advanced disease. A vicious cycle

Metastasis Suppressor Gene Inactivates Actin-Based Mechanism of Tumor Cell Motility | Center for Cancer Research

Cancer.gov

Metastasis is responsible for up to 90 percent of all cancer-related deaths. Though proteins derived from nearly a dozen metastasis suppressor genes have been discovered over the past 15 years, strategies for exploiting the proteins in metastasis-prevention therapies has been hampered by the lack of knowledge regarding the mechanisms underlying the proteins’ interactions with other proteins.

Genomic Copy Number Imbalances Associated with Bone and Non-bone Metastasis of Early-Stage Breast Cancer

PubMed Central

Liu, Yanhong; Zhou, Renke; Baumbusch, Lars O.; Tsavachidis, Spyros; Brewster, Abenaa M.; Do, Kim-Anh; Sahin, Aysegul; Hortobagyi, Gabriel N.; Taube, Joseph H.; Mani, Sendurai A.; Aarøe, Jørgen; Wärnberg, Fredrik; Børresen-Dale, Anne-Lise; Mills, Gordon B.; Thompson, Patricia A.; Bondy, Melissa L.

2014-01-01

Purpose To identify and validate copy number aberrations in early-stage primary breast tumors associated with bone or non-bone metastasis. Patients and Methods Whole-genome molecular inversion probe arrays were used to evaluate copy number imbalances (CNIs) in breast tumors from 960 early-stage patients with information about site of metastasis. The CoxBoost algorithm was used to select metastasis site-related CNIs and to fit a Cox proportional hazards model. Results Gains at 1q41 and 1q42.12 and losses at 1p13.3, 8p22, and Xp11.3 were significantly associated with bone metastasis. Gains at 2p11.2, 3q21.3–22.2, 3q27.1, 10q23.1, and 14q13.2–3 and loss at 7q21.11 were associated with non-bone metastasis. To examine the joint effect of CNIs and clinical predictors, patients were stratified into three risk groups (low, intermediate, and high) based on the sum of predicted linear hazard ratios (HRs). For bone metastasis, the hazard (95% confidence interval) for the low-risk group was 0.32 (0.11–0.92) compared to the intermediate-risk group and 2.99 (1.74–5.11) for the high-risk group. For non-bone metastasis, the hazard for the low-risk group was 0.34 (0.17–0.66) and 2.33 (1.59–3.43) for the high-risk group. The prognostic value of loss at 8p22 for bone metastasis and gains at 10q23.1 for non-bone metastasis, and gain at 11q13.5 for both bone and non-bone metastases were externally validated in 335 breast tumors pooled from four independent cohorts. Conclusions Distinct CNIs are independently associated with bone and non-bone metastasis for early-stage breast cancer patients across cohorts. These data warrant consideration for tailoring surveillance and management of metastasis risk. PMID:24305980

A nomogram to predict brain metastasis as the first relapse in curatively resected non-small cell lung cancer patients.

PubMed

Won, Young-Woong; Joo, Jungnam; Yun, Tak; Lee, Geon-Kook; Han, Ji-Youn; Kim, Heung Tae; Lee, Jin Soo; Kim, Moon Soo; Lee, Jong Mog; Lee, Hyun-Sung; Zo, Jae Ill; Kim, Sohee

2015-05-01

Development of brain metastasis results in a significant reduction in overall survival. However, there is no an effective tool to predict brain metastasis in non-small cell lung cancer (NSCLC) patients. We conducted this study to develop a feasible nomogram that can predict metastasis to the brain as the first relapse site in patients with curatively resected NSCLC. A retrospective review of NSCLC patients who had received curative surgery at National Cancer Center (Goyang, South Korea) between 2001 and 2008 was performed. We chose metastasis to the brain as the first relapse site after curative surgery as the primary endpoint of the study. A nomogram was modeled using logistic regression. Among 1218 patients, brain metastasis as the first relapse developed in 87 patients (7.14%) during the median follow-up of 43.6 months. Occurrence rates of brain metastasis were higher in patients with adenocarcinoma or those with a high pT and pN stage. Younger age appeared to be associated with brain metastasis, but this result was not statistically significant. The final prediction model included histology, smoking status, pT stage, and the interaction between adenocarcinoma and pN stage. The model showed fairly good discriminatory ability with a C-statistic of 69.3% and 69.8% for predicting brain metastasis within 2 years and 5 years, respectively. Internal validation using 2000 bootstrap samples resulted in C-statistics of 67.0% and 67.4% which still indicated good discriminatory performances. The nomogram presented here provides the individual risk estimate of developing metastasis to the brain as the first relapse site in patients with NSCLC who have undergone curative surgery. Surveillance programs or preventive treatment strategies for brain metastasis could be established based on this nomogram. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

[Study on the relationship between ultrasonographic features of papillary thyroid carcinoma and central cervical lymph node metastasis].

PubMed

Wang, X Q; Wei, W; Wei, X; Xu, Y; Wang, H L; Xing, X J; Zhang, S

2018-03-23

Objective: To investigate the correlation between ultrasonographic features of papillary thyroid carcinoma and central cervical lymph node metastasis. Methods: We retrospectively analyzed 486 patients with papillary thyroid carcinoma(PTC), pathologically confirmed after surgery in Tianjin Medical University Cancer Institute & Hospital. All patients were divided into central cervical lymph node metastasis group and non-metastasis group. No lateral cervical lymph node metastasis was found in preoperative ultrasonography and postoperative pathology. The characteristics of the ultrasound was observed and analyzed. Results: 297 out of 486 patients with papillary thyroid carcinomahad central metastasis, and the other 189 cases did not. Take pathology results as a standard, the sensitivity, specificity, positive predictive value, negative predictive value and accuracy rate of preoperative ultrasound diagnosis in PTC patients with central cervical lymph node metastasis were 35.3%, 88.6%, 83.2%, 47.4%, 56.6%, respectively. Univariate analysis showed that multi-focus, taller-than-wide, diameter>1 cm, located in the lower pole, ill-defined margin, hypoechogenicity, micro-calcification, capsule invasion more than 1/4 perimeter of papillary thyroid carcinoma were significantly associated with central cervical lymph node metastasis (all P <0.05). Multivariate analysis showed that diameter>1 cm, micro-calcification, capsule invasion more than 1/4 perimeter of papillary thyroid carcinoma became independent risk factors of central cervical neck lymph node metastasis (all P <0.05). Conclusions: Preoperative description of ultrasonographical features has important value to assess central cervical lymph node metastasis in patients with papillary thyroid carcinoma. More information could be provided for clinical treatment. When the papillary thyroid carcinoma presented as diameter>1 cm, micro-calcification, and capsule invasion more than 1/4 perimeter of, there will be a greater risk of central cervical lymph node metastasis, and we shall suggest prophylactic central lymph cervical node dissection.

Successful Total En Bloc Spondylectomy of T7 Vertebra for Hepatocellular Carcinoma Metastasis After Living Donor Liver Transplantation.

PubMed

Kimura, Hiroaki; Fujibayashi, Shunsuke; Shimizu, Takayoshi; Otsuki, Bungo; Murakami, Hideki; Kaido, Toshimi; Uemoto, Shinji; Matsuda, Shuichi

2015-08-15

Case report. We report a patient who was successfully treated with total en bloc spondylectomy (TES) for T7 metastasis after living donor liver transplantation for hepatocellular carcinoma (HCC). Spinal metastasis from HCC has a poor prognosis. There are only a few studies on surgical outcomes of spinal metastasis from HCC. Because of the high surgical morbidity and short life expectancy in patients with HCC with spinal metastasis, TES is not considered in these patients, although several studies have reported satisfactory results for TES for some types of metastatic spinal tumors. Liver transplantation (LT) is the curative treatment option for early HCC. However, the recurrence of HCC is a possible problem after LT, although no reports on surgery for spinal metastasis following LT for HCC have been published. We report on the first case of a patient who was successfully treated with TES for T7 metastasis after living donor LT for HCC. The patient was a 65-year-old man, who had undergone living donor LT for HCC 2 years before. His main symptom was progressive gait disturbance because of the spinal cord compression by the tumor at T7. Radiology and pathology examinations revealed a solitary metastasis at T7 with neither recurrence in the liver nor metastasis in the other organs. We performed TES using a pedicle screw system and a mesh cage filled with frozen autografts. After surgery, the patient showed clear improvement in neurological symptoms. At 3 months after surgery, a T4 metastasis was detected with magnetic resonance imaging, and the patient was treated with heavy ion radiotherapy. He could walk without a cane and there was no evidence of recurrence at 1.5 years after surgery. Solitary spinal metastasis of HCC may become an indication for TES if liver function improves after LT. 5.

Identifying the potential long-term survivors among breast cancer patients with distant metastasis.

PubMed

Lee, E S; Jung, S Y; Kim, J Y; Kim, J J; Yoo, T K; Kim, Y G; Lee, K S; Lee, E S; Kim, E K; Min, J W; Han, W; Noh, D Y; Moon, H G

2016-05-01

We aimed to develop a prediction model to identify long-term survivors after developing distant metastasis from breast cancer. From the institution's database, we collected data of 547 patients who developed distant metastasis during their follow-ups. We developed a model that predicts the post-metastasis overall survival (PMOS) based on the clinicopathologic factors of the primary tumors and the characteristics of the distant metastasis. For validation, the survival data of 254 patients from four independent institutions were used. The median duration of the PMOS was 31.0 months. The characteristics of the initial primary tumor, such as tumor stage, hormone receptor status, and Ki-67 expression level, and the characteristics of the distant metastasis presentation including the duration of disease-free interval, the site of metastasis, and the presence of metastasis-related symptoms were independent prognostic factors determining the PMOS. The association between tumor stage and the PMOS was only seen in tumors with early relapses. The PMOS score, which was developed based on the above six factors, successfully identified patients with superior survival after metastasis. The median PMOS for patients with a PMOS score of <2 and for patients with a PMOS score of >5 were 71.0 and 12 months, respectively. The clinical significance of the PMOS score was further validated using independent multicenter datasets. We have developed a novel prediction model that can classify breast cancer patients with distant metastasis according to their survival after metastasis. Our model can be a valuable tool to identify long-term survivors who can be potential candidates for more intensive multidisciplinary approaches. Furthermore, our model can provide a more reliable survival information for both physicians and patients during their informed decision-making process. © The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Cigarette Smoking and Risk of Lung Metastasis from Esophageal Cancer

PubMed Central

Abrams, Julian A.; Lee, Paul C.; Port, Jeffrey L.; Altorki, Nasser K.; Neugut, Alfred I.

2008-01-01

Background While extensive research has explored the impact of environmental factors on the etiology of specific cancers, the influence of exposures such as smoking on risk of site-specific metastasis is unknown. We investigated the association of cigarette smoking with lung metastasis in esophageal cancer. Methods We performed a case-control study of esophageal cancer patients from two centers, comparing cases with lung metastases to controls without lung metastases. Information was gathered from medical records on smoking history, imaging results, site(s) of metastasis, and other patient and tumor characteristics. We used logistic regression to assess association. Results We identified 354 esophageal cancer cases; smoking status was known in 289 (82%). Among patients with lung metastases, 73.6% (39/53) were ever smokers, versus 47.8% (144/301) of patients without lung metastases (p=0.001) (summary OR 2.52, 95%CI 1.17-5.45; stratified by histology). Smoking was associated with a nonsignificant increased adjusted odds of lung metastasis (OR 1.89, 95%CI 0.80-4.46). Upper esophageal subsite (OR 4.71, 95%CI 1.20-18.5) but not histology (squamous OR 0.65,95%CI 0.27-1.60) was associated with lung metastasis. Compared to the combined never/unknown smoking status group, smoking was associated with a significantly increased odds of lung metastasis (OR 2.35, 95%CI 1.11-4.97). There was no association between liver metastasis and smoking (OR 0.88, 95%CI 0.42-1.83) Conclusions Smoking is associated with increased odds of lung metastasis from esophageal cancer, and this relationship appears to be site-specific. Future studies are needed to determine whether smoking affects the tumor cell or the site of metastasis, and whether this changes the survival outcome. PMID:18843013

Cigarette smoking and risk of lung metastasis from esophageal cancer.

PubMed

Abrams, Julian A; Lee, Paul C; Port, Jeffrey L; Altorki, Nasser K; Neugut, Alfred I

2008-10-01

Whereas extensive research has explored the effect of environmental factors on the etiology of specific cancers, the influence of exposures such as smoking on risk of site-specific metastasis is unknown. We investigated the association of cigarette smoking with lung metastasis in esophageal cancer. We conducted a case-control study of esophageal cancer patients from two centers, comparing cases with lung metastases to controls without lung metastases. Information was gathered from medical records on smoking history, imaging results, site(s) of metastasis, and other patient and tumor characteristics. We used logistic regression to assess association. We identified 354 esophageal cancer cases; smoking status was known in 289 (82%). Among patients with lung metastases, 73.6% (39 of 53) were ever smokers, versus 47.8% (144 of 301) of patients without lung metastases [P=0.001; summary odds ratio (OR), 2.52; 95% confidence interval (95% CI), 1.17-5.45; stratified by histology]. Smoking was associated with a nonsignificant increased adjusted odds of lung metastasis (OR, 1.89; 95% CI, 0.80-4.46). Upper esophageal subsite (OR, 4.71; 95% CI, 1.20-18.5), but not histology (squamous OR 0.65,95% CI 0.27-1.60), was associated with lung metastasis. Compared with the combined never/unknown smoking status group, smoking was associated with a significantly increased odds of lung metastasis (OR, 2.35; 95% CI, 1.11-4.97). There was no association between liver metastasis and smoking (OR, 0.88; 95% CI, 0.42-1.83). Smoking is associated with increased odds of lung metastasis from esophageal cancer, and this relationship seems to be site specific. Future studies are needed to determine whether smoking affects the tumor cell or the site of metastasis, and whether this changes the survival outcome.

Impact of splenic hilar lymph node metastasis on prognosis in patients with advanced gastric cancer

PubMed Central

Son, Taeil; Kwon, In Gyu; Lee, Joong Ho; Choi, Youn Young; Kim, Hyoung-Il; Cheong, Jae-Ho; Noh, Sung Hoon; Hyung, Woo Jin

2017-01-01

Background: Impact of splenic hilar LN dissection during total gastrectomy for proximal advanced gastric cancer is controversial. The objective of this study was to assess the impact on prognosis of splenic hilar lymph node(LN) metastasis compared to that of metastasis to other regional LN groups. Study Design Patients who underwent total gastrectomy with D2 LN dissection from 2000 to 2010 were reviewed retrospectively. The clinicopathologic characteristics and long-term results of patients with splenic hilar LN metastasis were compared to those of patients with only metastasis to other extraperigastric LNs (stations #8a, #9, #11, or #12a). To investigate the survival benefit of performing splenic hilar LN dissection, the estimated therapeutic index for the procedure was calculated by multiplying the incidence of metastases in the hilar region by the survival rates for individuals with nodal involvement in that region. Results Of 602 patients, 87(14.5%) had hilar LN metastasis. The 5-year overall and relapse-free survival rates for patients with hilar LN metastasis were 24.1% and 12.1%, respectively. These rates were similar to those for patients with metastasis to other extraperigastric LNs (P > 0.05), with similar recurrence patterns. Overall survival in the hilar LN metastasis group was better than that for patients with distant metastasis(P < 0.05). The estimated therapeutic index of splenic hilar LN dissection was 3.5, which was similar to index values for LN dissection at other extraperigastric LNs. Conclusions Dissection of splenic hilar LNs during total gastrectomy for advanced gastric cancer allows for a prognosis similar to that achieved with dissection of extraperigastric LNs. PMID:29137444

Methylation-associated silencing of microRNA-129-3p promotes epithelial-mesenchymal transition, invasion and metastasis of hepatocelluar cancer by targeting Aurora-A.

PubMed

Cui, Shiyun; Zhang, Kai; Li, Chen; Chen, Jing; Pan, Yan; Feng, Bing; Lu, Lei; Zhu, Ziman; Wang, Rui; Chen, Longbang

2016-11-22

Metastasis and recurrence has become one major obstacle for further improving the survival of hepatocelluar cancer (HCC) patients. Therefore, it is critical to elucidate the mechanisms involved in HCC metastasis. This study aimed to investigate the roles of microRNA (miR)-129-3p in HCC metastasis and its possible molecular mechanisms. By using microarray analysis to compare levels of different miRNAs in HCC tissues with or without lymph node metastasis (LNM), we showed that HCC tissues with LNM had reduced levels of miR-129-3p, which was related to its promoter hypermethylation and correlated with tumor metastasis, recurrence and poor prognosis. Gain - and loss - of - function assays indicated that re-expression of miR-129-3p could reverse epithelial-mesenchymal transition (EMT), and reduce in vitro invasion and in vivo metastasis of HCC cells. Aurora-A, a serine/threonine protein kinase, was identified as a direct target of miR-129-3p. Knockdown of Aurora-A phenocopied the effect of miR-129-3p overexpression on HCC metastasis. In addition, Aurora-A upregulation could partially rescue the effect of miR-129-3p. We further demonstrated that activation of PI3K/Akt and p38-MAPK signalings were involved in miR-129-3p-mediated HCC metastasis. These findings suggest that methylation-mediated miR-129-3p downregulation promotes EMT, in vitro invasion and in vivo metastasis of HCC cells via activation of PI3K/Akt and p38-MAPK signalings partially by targeting Aurora-A. Therefore, miR-129-3p may be a novel prognostic biomarker and potential therapeutic target for HCC.

Alveolar Macrophages Drive Hepatocellular Carcinoma Lung Metastasis by Generating Leukotriene B4.

PubMed

Nosaka, Takuto; Baba, Tomohisa; Tanabe, Yamato; Sasaki, Soichiro; Nishimura, Tatsunori; Imamura, Yoshiaki; Yurino, Hideaki; Hashimoto, Shinichi; Arita, Makoto; Nakamoto, Yasunari; Mukaida, Naofumi

2018-03-01

Macrophages in lungs can be classified into two subpopulations, alveolar macrophages (AMs) and interstitial macrophages (IMs), which reside in the alveolar and interstitial spaces, respectively. Accumulating evidence indicates the involvement of IMs in lung metastasis, but the roles of AMs in lung metastasis still remain elusive. An i.v. injection of a mouse hepatocellular carcinoma (HCC) cell line, BNL, caused lung metastasis foci with infiltration of AMs and IMs. Comprehensive determination of arachidonic acid metabolite levels revealed increases in leukotrienes and PGs in lungs in this metastasis model. A 5-lipoxygenase (LOX) inhibitor but not a cyclooxygenase inhibitor reduced the numbers of metastatic foci, particularly those of a larger size. A major 5-LOX metabolite, LTB 4 , augmented in vitro cell proliferation of human HCC cell lines as well as BNL cells. Moreover, in this lung metastasis course, AMs exhibited higher expression levels of the 5-LOX and LTB 4 than IMs. Consistently, 5-LOX-expressing AMs increased in the lungs of human HCC patients with lung metastasis, compared with those without lung metastasis. Furthermore, intratracheal clodronate liposome injection selectively depleted AMs but not IMs, together with reduced LTB 4 content and metastatic foci numbers in this lung metastasis process. Finally, IMs in mouse metastatic foci produced CCL2, thereby recruiting blood-borne, CCR2-expressing AMs into lungs. Thus, AMs can be recruited under the guidance of IM-derived CCL2 into metastatic lungs and can eventually contribute to the progression of lung metastasis by providing a potent arachidonic acid-derived tumor growth promoting mediator, LTB 4 . Copyright © 2018 by The American Association of Immunologists, Inc.

An integrated systems genetics screen reveals the transcriptional structure of inherited predisposition to metastatic disease

PubMed Central

Faraji, Farhoud; Hu, Ying; Wu, Gang; Goldberger, Natalie E.; Walker, Renard C.; Zhang, Jinghui; Hunter, Kent W.

2014-01-01

Metastasis is the result of stochastic genomic and epigenetic events leading to gene expression profiles that drive tumor dissemination. Here we exploit the principle that metastatic propensity is modified by the genetic background to generate prognostic gene expression signatures that illuminate regulators of metastasis. We also identify multiple microRNAs whose germline variation is causally linked to tumor progression and metastasis. We employ network analysis of global gene expression profiles in tumors derived from a panel of recombinant inbred mice to identify a network of co-expressed genes centered on Cnot2 that predicts metastasis-free survival. Modulating Cnot2 expression changes tumor cell metastatic potential in vivo, supporting a functional role for Cnot2 in metastasis. Small RNA sequencing of the same tumor set revealed a negative correlation between expression of the Mir216/217 cluster and tumor progression. Expression quantitative trait locus analysis (eQTL) identified cis-eQTLs at the Mir216/217 locus, indicating that differences in expression may be inherited. Ectopic expression of Mir216/217 in tumor cells suppressed metastasis in vivo. Finally, small RNA sequencing and mRNA expression profiling data were integrated to reveal that miR-3470a/b target a high proportion of network transcripts. In vivo analysis of Mir3470a/b demonstrated that both promote metastasis. Moreover, Mir3470b is a likely regulator of the Cnot2 network as its overexpression down-regulated expression of network hub genes and enhanced metastasis in vivo, phenocopying Cnot2 knockdown. The resulting data from this strategy identify Cnot2 as a novel regulator of metastasis and demonstrate the power of our systems-level approach in identifying modifiers of metastasis. PMID:24322557

Site of metastasis and breast cancer mortality: a Danish nationwide registry-based cohort study.

PubMed

Ording, Anne Gulbech; Heide-Jørgensen, Uffe; Christiansen, Christian Fynbo; Nørgaard, Mette; Acquavella, John; Sørensen, Henrik Toft

2017-01-01

Survival among patients with metastatic breast cancer may vary according to the site of metastasis and receptor status. We used Danish nationwide medical registries to establish a cohort of patients with metastatic breast cancer (870 with de novo metastatic disease and 3518 with recurrent disease with distant metastasis) diagnosed during 1997-2011. We examined 1-year and >1 to 5-year mortality associated with first site of metastasis and receptor expression status of the primary tumor. Cox proportional regression was used to compute confounder-adjusted mortality rate ratios (MRRs) associated with site of metastasis, stratified by receptor status. Overall 1-year and >1 to 5-year mortality risks were 36 and 69 %, respectively. Risk of death within 1 year was highest for brain-only (62 %) and liver-only (43 %) involvement and nearly the same for patients with lung-only (32 %), bone-only (32 %) involvement, and other/combination of sites (34 %). Using bone-only metastasis as reference, women with brain-only metastasis had more than two-fold increased risk of dying. The adjusted MRR for women with liver-only metastasis also was increased, though less pronounced. Patients with lung-only [adjusted MRR 0.9 (95 % confidence interval (CI) 0.8, 1.1)] or other metastases [adjusted MRR 1.0 (95 % CI 0.9, 1.2)] had similar mortality as patients with bone-only metastasis. Positive hormonal receptor status was a favorable prognostic factor. Metastatic breast cancer has a serious prognosis. Patients with brain-only metastasis had the highest mortality. Positive hormonal receptor status on the primary tumor was a favorable prognostic factor for all metastatic sites.

Expression of anaesthetic and analgesic drug target genes in excised breast tumour tissue: Association with clinical disease recurrence or metastasis.

PubMed

Connolly, C; Madden, S F; Buggy, D J; Gallagher, H C

2017-01-01

Retrospective analyses suggest anaesthetic-analgesics technique during cancer surgery may affect recurrence/metastasis. This could involve direct effects of anaesthetic-analgesic drugs on cancer cells. While μ-opioid receptor over-expression in lung tumours is associated with greater metastasis, other anaesthetic-analgesic receptor targets in cancer recurrence/metastasis remain unexplored. Therefore, we evaluated the association between genetic expression of anaesthetic-analgesic receptor targets and recurrence/metastasis, using a repository of breast cancer gene expression and matching clinical data. A list of 23 genes encoding for the most prominent anaesthetic-analgesic receptor targets was compiled. This was processed through BreastMark- an algorithm integrating gene expression data from ~17,000 samples and clinical data from >4,500 breast cancer samples. Gene expression data was dichotomized using disease-free survival (survival without recurrence) and distant disease-free survival (survival without metastasis) as end points. Hazard ratios were calculated by Cox-regression analysis. Enrichment for prognostic markers was determined by randomly choosing 23-member gene lists from all available genes, calculating how often >5 significant markers were observed and adjusting p-values for multiple testing. This was repeated 10,000 times and an empirical p-value calculated. Of 23 selected genes, 9 were significantly associated with altered rates of metastasis and 4 with recurrence on univariate analysis. Adjusting for multiple testing, 5 of these 9 genes remained significantly associated with metastasis, non with recurrence. This ratio of genes (5/23) was not significantly enriched for markers of metastasis (p = 0.07). Several anaesthetic-analgesic receptor genes were associated with metastatic spread in breast cancer. Overall there was no significant enrichment in prognostic markers of metastasis, although a trend was observed.

ADAM-12 as a Diagnostic Marker for the Proliferation, Migration and Invasion in Patients with Small Cell Lung Cancer

PubMed Central

Shao, Shuhong; Li, Zunling; Gao, Wei; Yu, Guohua; Liu, Dexiang; Pan, Fang

2014-01-01

Small cell lung cancer (SCLC) is highly aggressive and is characterized by malignant metastasis. Approximately 90% of patients die due to extensive metastasis. The extracellular matrix (ECM) is a natural barrier that can prevent cellular invasion and metastasis. Therefore, degradation of the ECM must take place in order for extensive metastasis to occur. A disintegrin and metalloprotease (ADAM) is a multi-domain protease that plays an important role in tumorigenesis, as well as tumor development, invasion and metastasis. However, there have been few reports on the expression and role of ADAMs in SCLC. In the current study, the expression and role of ADAMs in SCLC proliferation, invasion and metastasis was investigated. A total of 150 SCLC tissue samples were examined by immunohistochemistry for ADAMs expression. ADAM-12 was found to be abundantly expressed in 72.67% samples and other ADAMs were found to be expressed in 10% to 40% of samples. ADAM-12 levels in serum and urine, from 70 SCLC patients and 40 normal controls, were also measured using ELISA. ADAM-12 expression was significantly higher in SCLC patients than in healthy controls and in patients with extensive disease compared to those with more limited disease. Silencing the expression of ADAM-12 in H1688 cells through the use of specific siRNA significantly reduced cellular proliferation, invasion and metastasis. Supplementing the expression of ADAM-12-L or -S in H345 cells, significantly enhanced cellular proliferation, invasion and metastasis. Animal models with metastatic SCLC also exhibited increased expression of ADAM-12 along with enhanced invasion and metastasis. In brief, ADAM-12 is an independent prognostic factor and diagnostic marker, and is involved in the proliferation, invasion and metastasis of SCLC. PMID:24465799

DCB - Tumor Metastasis Research

Cancer.gov

Tumor metastasis research examines the mechanisms that allow cancer cells to leave the primary tumor and spread to another part of the body. Learn about recent tumor metastasis research studies supported by the Division of Cancer Biology.

Lung microenvironment promotes the metastasis of human hepatocellular carcinoma cells to the lungs.

PubMed

Jin, Yun; Ai, Junhua; Shi, Jun

2015-01-01

Cancer metastasis is a highly tissue-specific and organ-selective process. It has been shown that the affected tissues and/or organs play a major role in this complex process. The lung is the most common target organ of extrahepatic hepatocellular carcinoma (HCC) metastasis, but the precise molecular mechanism underlying this organ-specific metastasis remains unclear. We hypothesized that lung microenvironment was able to promote the metastasis of HCC cells to the lungs leading to distant metastases. In support of our hypothesis, we provided evidence from targeted metastasis in various types of cancer and contributing factors in the microenvironment of targeted tissues/organs. A better understanding of the steps involved in the interplay between HCC cells and lung microenvironment may offer new perspectives for the medical management of lung metastases of HCC.

Polycomb complex protein BMI-1 promotes invasion and metastasis of pancreatic cancer stem cells by activating PI3K/AKT signaling, an ex vivo, in vitro, and in vivo study

PubMed Central

Wang, Min-Cong; Jiao, Min; Wu, Tao; Jing, Li; Cui, Jie; Guo, Hui; Tian, Tao; Ruan, Zhi-ping; Wei, Yong-Chang; Jiang, Li-Li; Sun, Hai-Feng; Huang, Lan-Xuan; Nan, Ke-Jun; Li, Chun-Li

2016-01-01

Cancer stem cell theory indicates cancer stem cells are the key to promote tumor invasion and metastasis. Studies showed that BMI-1 could promote self-renew, differentiation and tumor formation of CSCs and invasion/metastasis of human cancer. However, whether BMI-1 could regulate invasion and metastasis ability of CSCs is still unclear. In our study, we found that up-regulated expression of BMI-1 was associated with tumor invasion, metastasis and poor survival of pancreatic cancer patients. CD133+ cells were obtained by using magnetic cell sorting and identified of CSCs properties such as self-renew, multi-differentiation and tumor formation ability. Then, we found that BMI-1 expression was up-regulated in pancreatic cancer stem cells. Knockdown of BMI-1 expression attenuated invasion ability of pancreatic cancer stem cells in Transwell system and liver metastasis capacity in nude mice which were injected CSCs through the caudal vein. We are the first to reveal that BMI-1 could promote invasion and metastasis ability of pancreatic cancer stem cells. Finally, we identified that BMI-1 expression activating PI3K/AKT singing pathway by negative regulating PTEN was the main mechanism of promoting invasion and metastasis ability of pancreatic CSCs. In summary, our findings indicate that BMI-1 could be used as the therapeutic target to inhibiting CSCs-mediated pancreatic cancer metastasis. PMID:26840020

MicroRNA-143 Regulates Human Osteosarcoma Metastasis by Regulating Matrix Metalloprotease-13 Expression

PubMed Central

Osaki, Mitsuhiko; Takeshita, Fumitaka; Sugimoto, Yui; Kosaka, Nobuyoshi; Yamamoto, Yusuke; Yoshioka, Yusuke; Kobayashi, Eisuke; Yamada, Tesshi; Kawai, Akira; Inoue, Toshiaki; Ito, Hisao; Oshimura, Mitsuo; Ochiya, Takahiro

2011-01-01

Pulmonary metastases are the main cause of death in patients with osteosarcoma, however, the molecular mechanisms of metastasis are not well understood. To detect lung metastasis-related microRNA (miRNA) in human osteosarcoma, we compared parental (HOS) and its subclone (143B) human osteosarcoma cell lines showing lung metastasis in a mouse model. miR-143 was the most downregulated miRNA (P < 0.01), and transfection of miR-143 into 143B significantly decreased its invasiveness, but not cell proliferation. Noninvasive optical imaging technologies revealed that intravenous injection of miR-143, but not negative control miRNA, significantly suppressed lung metastasis of 143B (P < 0.01). To search for miR-143 target mRNA in 143B, microarray analyses were performed using an independent RNA pool extracted by two different comprehensive miR-143-target mRNA collecting systems. Western blot analyses revealed that MMP-13 was mostly protein downregulated by miR-143. Immunohistochemistry using clinical samples clearly revealed MMP-13-positive cells in lung metastasis-positive cases, but not in at least three cases showing higher miR-143 expression in the no metastasis group. Taken together, these data indicated that the downregulation of miR-143 correlates with the lung metastasis of human osteosarcoma cells by promoting cellular invasion, probably via MMP-13 upregulation, suggesting that miRNA could be used to develop new molecular targets for osteosarcoma metastasis. PMID:21427707

Downregulation of NEDD9 by apigenin suppresses migration, invasion, and metastasis of colorectal cancer cells

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

Dai, Jin; Van Wie, Peter G.; Fai, Leonard Yenwong

Apigenin is a natural flavonoid which possesses multiple anti-cancer properties such as anti-proliferation, anti-inflammation, and anti-metastasis in many types of cancers including colorectal cancer. Neural precursor cell expressed developmentally downregulated 9 (NEDD9) is a multi-domain scaffolding protein of the Cas family which has been shown to correlate with cancer metastasis and progression. The present study investigates the role of NEDD9 in apigenin-inhibited cell migration, invasion, and metastasis of colorectal adenocarcinoma DLD1 and SW480 cells. The results show that knockdown of NEDD9 inhibited cell migration, invasion, and metastasis and that overexpression of NEDD9 promoted cell migration and invasion of DLD1 cellsmore » and SW4890 cells. Apigenin treatment attenuated NEDD9 expression at protein level, resulting in reduced phosphorylations of FAK, Src, and Akt, leading to inhibition on cell migration, invasion, and metastasis of both DLD1 and SW480 cells. The present study has demonstrated that apigenin inhibits cell migration, invasion, and metastasis through NEDD9/Src/Akt cascade in colorectal cancer cells. NEDD9 may function as a biomarker for evaluation of cancer aggressiveness and for selection of therapeutic drugs against cancer progression. - Highlights: • Apigenin inhibits migration, invasion, and metastasis of colorectal cancer cells. • Apigenin downregulates NEDD9. • Apigenin decreases phosphorylations of FAK, Src, and Akt. • Apigenin inhibits cell migration, invasion, and metastasis through NEDD9/Src/Akt.« less

The expression of MACC1 and its role in the proliferation and apoptosis of salivary adenoid cystic carcinoma.

PubMed

Li, Haifeng; Liao, Xiaoying; Liu, Yeqing; Shen, Zhuojian; Gan, Xiangfeng; Li, Haigang; Huang, Zhiquan

2015-11-01

The objective of this study was to investigate the relationship between metastasis-associated in colon cancer-1 and patient clinical characteristics. We also examined the role of metastasis-associated in colon cancer-1 in the proliferation and apoptosis in adenoid cystic carcinoma. Metastasis-associated in colon cancer-1 expression was analysed in 65 paraffin-embedded tissue specimens of salivary adenoid cystic carcinoma and 25 adjacent non-cancerous tissues by immunohistochemistry (IHC). We used RNA interference technology to silence metastasis-associated in colon cancer-1 expression in ACCM cells. Cell Counting Kit-8 tests, transwell experiments and flow cytometry were used to test the proliferation, cisplatin resistance, migration, invasion and apoptosis of ACCM cells. Metastasis-associated in colon cancer-1 nuclear and cytoplasmic expression in salivary adenoid cystic carcinoma tissue was higher than in the adjacent normal salivary tissue. The expression level was closely associated with tumour histological grading, perineural invasion and surrounding tumour invasion. The downregulation of metastasis-associated in colon cancer-1 expression inhibited proliferation and induced apoptosis in ACCM cells. The knock-down of metastasis-associated in colon cancer-1 expression had no effect on migration, invasion and chemoresistance. Metastasis-associated in colon cancer-1 may have an important role in tumour development in adenoid cystic carcinoma. Metastasis-associated in colon cancer-1 is a potential biomarker for adenoid cystic carcinoma. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

The prognosis analysis of different metastasis pattern in patients with different breast cancer subtypes: a SEER based study.

PubMed

Wang, Haiyong; Zhang, Chenyue; Zhang, Jingze; Kong, Li; Zhu, Hui; Yu, Jinming

2017-04-18

Studies on prognosis of different metastasis patterns in patients with different breast cancer subtypes (BCS) are limited. Therefore, we identified 7862 breast cancer patients with distant metastasis from 2010 to 2013 using Surveillance, Epidemiology, wand End Results (SEER) population-based data. The results showed that bone was the most common metastatic site and brain was the least common metastatic site, and the patients with HR+/HER2- occupied the highest metastasis proportion, the lowest metastasis proportion were found in HR-/HER2+ patients. Univariate and multivariate logistic regression analysis were used to analyze the association, and it was found that there were significant differences of distant metastasis patterns in patients with different BCS(different P value). Importantly, univariate and multivariate Cox regression analysis were used to analyze the prognosis. It was proven that only bone metastasis was not a prognostic factor in the HR+/HER2-, HR+/HER2+ and HR-/HER2+ subgroup (all, P > 0.05), and patients with brain metastasis had the worst cancer specific survival (CSS) in all the subgroups of BCS (all, P<0.01). Interestingly, for patients with two metastatic sites, those with bone and lung metastasis had best CSS in the HR+/HER2- (P<0.001) and HR+/HER2+ subgroups (P=0.009) However, for patients with three and four metastatic sites, there was no statistical difference in their CSS (all, P>0.05).

The prognosis analysis of different metastasis pattern in patients with different breast cancer subtypes: a SEER based study

PubMed Central

Wang, Haiyong; Zhang, Chenyue; Zhang, Jingze; Kong, Li; Zhu, Hui; Yu, Jinming

2017-01-01

Studies on prognosis of different metastasis patterns in patients with different breast cancer subtypes (BCS) are limited. Therefore, we identified 7862 breast cancer patients with distant metastasis from 2010 to 2013 using Surveillance, Epidemiology, wand End Results (SEER) population-based data. The results showed that bone was the most common metastatic site and brain was the least common metastatic site, and the patients with HR+/HER2− occupied the highest metastasis proportion, the lowest metastasis proportion were found in HR-/HER2+ patients. Univariate and multivariate logistic regression analysis were used to analyze the association, and it was found that there were significant differences of distant metastasis patterns in patients with different BCS(different P value). Importantly, univariate and multivariate Cox regression analysis were used to analyze the prognosis. It was proven that only bone metastasis was not a prognostic factor in the HR+/HER2-, HR+/HER2+ and HR-/HER2+ subgroup (all, P > 0.05), and patients with brain metastasis had the worst cancer specific survival (CSS) in all the subgroups of BCS (all, P<0.01). Interestingly, for patients with two metastatic sites, those with bone and lung metastasis had best CSS in the HR+/HER2- (P<0.001) and HR+/HER2+ subgroups (P=0.009) However, for patients with three and four metastatic sites, there was no statistical difference in their CSS (all, P>0.05). PMID:28038448

Defining Tumor Cell and Immune Cell Behavior in Vivo during Pulmonary Metastasis of Breast Cancer

DTIC Science & Technology

2014-09-01

outcome of which is still to be determined. 15. SUBJECT TERMS Lung Metastasis, Intravital Imaging , Tumor Immunology, Tumor Microparticles 16. SECURITY...metastatic fitness in the lung. 2) KEYWORDS: Metastasis, Intravital Imaging , Lung, Breast Cancer, 3) ACCOMPLISHMENTS: What were the major goals of the... intravital imaging of Lung Metastasis b) Characterization of Tumor Cell Behavior During Pulmonary Seeding via 2-photon microscopy c) Characterization of

The innate immune receptor Dectin-2 mediates the phagocytosis of cancer cells by Kupffer cells for the suppression of liver metastasis.

PubMed

Kimura, Yoshitaka; Inoue, Asuka; Hangai, Sho; Saijo, Shinobu; Negishi, Hideo; Nishio, Junko; Yamasaki, Sho; Iwakura, Yoichiro; Yanai, Hideyuki; Taniguchi, Tadatsugu

2016-12-06

Tumor metastasis is the cause of most cancer deaths. Although metastases can form in multiple end organs, the liver is recognized as a highly permissive organ. Nevertheless, there is evidence for immune cell-mediated mechanisms that function to suppress liver metastasis by certain tumors, although the underlying mechanisms for the suppression of metastasis remain elusive. Here, we show that Dectin-2, a C-type lectin receptor (CLR) family of innate receptors, is critical for the suppression of liver metastasis of cancer cells. We provide evidence that Dectin-2 functions in resident macrophages in the liver, known as Kupffer cells, to mediate the uptake and clearance of cancer cells. Interestingly, Kupffer cells are selectively endowed with Dectin-2-dependent phagocytotic activity, with neither bone marrow-derived macrophages nor alveolar macrophages showing this potential. Concordantly, subcutaneous primary tumor growth and lung metastasis are not affected by the absence of Dectin-2. In addition, macrophage C-type lectin, a CLR known to be complex with Dectin-2, also contributes to the suppression of liver metastasis. Collectively, these results highlight the hitherto poorly understood mechanism of Kupffer cell-mediated control of metastasis that is mediated by the CLR innate receptor family, with implications for the development of anticancer therapy targeting CLRs.

A novel long non-coding RNA linc-ZNF469-3 promotes lung metastasis through miR-574-5p-ZEB1 axis in triple negative breast cancer.

PubMed

Wang, Po-Shun; Chou, Cheng-Han; Lin, Cheng-Han; Yao, Yun-Chin; Cheng, Hui-Chuan; Li, Hao-Yi; Chuang, Yu-Chung; Yang, Chia-Ning; Ger, Luo-Ping; Chen, Yu-Chia; Lin, Forn-Chia; Shen, Tang-Long; Hsiao, Michael; Lu, Pei-Jung

2018-05-14

Triple-negative breast cancer (TNBC) patients usually lead to poor prognosis and survival because of metastasis. The major sites for TNBC metastasis include the lungs, brain, liver, and bone. Long non-coding RNAs (lncRNAs) are non-protein-coding transcripts longer than 200 nucleotides and have been reported as important regulators in BC metastasis. However, the underlying mechanisms for lncRNAs regulating TNBC metastasis are not fully understood. Here we found that linc-ZNF469-3 was highly expressed in lung-metastatic LM2-4175 TNBC cells and overexpression of linc-ZNF469-3 enhanced invasion ability and stemness properties in vitro and lung metastasis in vivo. Furthermore, we found linc-ZNF469-3 physically interacted with miR-574-5p and overexpression of miR-574-5p attenuated ZEB1 expression. Importantly, endogenous high expressions of linc-ZNF469-3 and ZEB1 were correlated with tumor recurrence in TNBC patients with lung metastasis. Taken together, our findings suggested that linc-ZNF469-3 promotes lung metastasis of TNBC through miR-574-5p-ZEB1 signaling axis and may be used as potential prognostic marker for TNBC patients.

Competition and niche construction in a model of cancer metastasis

PubMed Central

Akçay, Erol

2018-01-01

Niche construction theory states that not only does the environment act on populations to generate Darwinian selection, but organisms reciprocally modify the environment and the sources of natural selection. Cancer cells participate in niche construction as they alter their microenvironments and create pre-metastatic niches; in fact, metastasis is a product of niche construction. Here, we present a mathematical model of niche construction and metastasis. Our model contains producers, which pay a cost to contribute to niche construction that benefits all tumor cells, and cheaters, which reap the benefits without paying the cost. We derive expressions for the conditions necessary for metastasis, showing that the establishment of a mutant lineage that promotes metastasis depends on niche construction specificity and strength of interclonal competition. We identify a tension between the arrival and invasion of metastasis-promoting mutants, where tumors composed only of cheaters remain small but are susceptible to invasion whereas larger tumors containing producers may be unable to facilitate metastasis depending on the level of niche construction specificity. Our results indicate that even if metastatic subclones arise through mutation, metastasis may be hindered by interclonal competition, providing a potential explanation for recent surprising findings that most metastases are derived from early mutants in primary tumors. PMID:29813117

Rrp1b, a New Candidate Susceptibility Gene for Breast Cancer Progression and Metastasis

PubMed Central

Crawford, Nigel P. S; Qian, Xiaolan; Ziogas, Argyrios; Papageorge, Alex G; Boersma, Brenda J; Walker, Renard C; Lukes, Luanne; Rowe, William L; Zhang, Jinghui; Ambs, Stefan; Lowy, Douglas R; Anton-Culver, Hoda; Hunter, Kent W

2007-01-01

A novel candidate metastasis modifier, ribosomal RNA processing 1 homolog B (Rrp1b), was identified through two independent approaches. First, yeast two-hybrid, immunoprecipitation, and functional assays demonstrated a physical and functional interaction between Rrp1b and the previous identified metastasis modifier Sipa1. In parallel, using mouse and human metastasis gene expression data it was observed that extracellular matrix (ECM) genes are common components of metastasis predictive signatures, suggesting that ECM genes are either important markers or causal factors in metastasis. To investigate the relationship between ECM genes and poor prognosis in breast cancer, expression quantitative trait locus analysis of polyoma middle-T transgene-induced mammary tumor was performed. ECM gene expression was found to be consistently associated with Rrp1b expression. In vitro expression of Rrp1b significantly altered ECM gene expression, tumor growth, and dissemination in metastasis assays. Furthermore, a gene signature induced by ectopic expression of Rrp1b in tumor cells predicted survival in a human breast cancer gene expression dataset. Finally, constitutional polymorphism within RRP1B was found to be significantly associated with tumor progression in two independent breast cancer cohorts. These data suggest that RRP1B may be a novel susceptibility gene for breast cancer progression and metastasis. PMID:18081427

Rare metastasis of nasopharyngeal carcinoma to the thyroid gland with subsequent metastatic abdominal lymph nodes: A case report and literature review.

PubMed

Cai, Changjing; Shen, Hong; Liu, Wenqiang; Ma, Junli; Zhang, Yan; Yin, Ling; Li, Jindong; Shen, Liangfang; Zeng, Shan

2017-11-01

Thyroid metastasis from nasopharyngeal carcinoma is rare. Metastasis of nasopharyngeal carcinoma to the thyroid gland with subsequent metastatic abdominal lymph nodes hasn't been reported before. We want to share our experience about the treatment choice. A 27-year-old man was diagnosed with nasopharyngeal nonkeratinizing carcinoma in August 2004. In March 2013 he underwent a thyroid carcinoma radical operation, and histological examination revealed metastasis to the thyroid gland from nasopharyngeal carcinoma. An 18F-FDG-PET/CT scan and biopsy showed metastatic abdominal lymph nodes of nasopharyngeal carcinoma in April 2015. A 27-year-old man was diagnosed with metastasis of nasopharyngeal carcinoma to the thyroid gland with subsequent metastatic abdominal lymph nodes. The patient was treated with concurrent chemotherapy and radiotherapy for nasopharyngeal carcinoma and metastasis to the thyroid gland. The metastases to the abdominal lymph nodes received chemotherapy. After 6 cycles of chemotherapy with gemcitabine, cisplatin, and 5-fluorouracil for metastasis to the abdominal lymph nodes, the patient is currently asymptomatic with stable disease and improved quality of life. The treatment choice for metastasis of nasopharyngeal carcinoma depends on the clinical disease extent, and surgery and/or chemo-radiation therapy must be drafted to the individual patient in order to improve the prognosis and quality of life.

Gastric metastasis of breast cancer: a single centre retrospective study.

PubMed

Almubarak, Maher M; Laé, Marick; Cacheux, Wulfran; de Cremoux, Patricia; Pierga, Jean-Yves; Reyal, Fabien; Bennett, Simon P; Falcou, Marie-Christine; Salmon, Remy J; Baranger, Bernard; Mariani, Pascale

2011-10-01

Digestive metastasis of breast cancer are rare but when they do occur the stomach is one of the commoner sites. To describe the clinical, endoscopic, pathological features and treatment. 35 cases of gastric metastasis were identified retrospectively between 1980 and 2008. The location of the gastric metastasis was fundus (n=15, 43%), antrum (n=15, 43%) or both (n=5, 14%). The histological subtype of primary breast cancer was invasive lobular carcinoma in 34 patients (97%). Hormonal receptors were positive in 19 out of 24 cases (79%), two out of 22 analysed were HER2 positive (9%). There were 16 (46%) patients with peritoneal carcinosis. The treatment was chemotherapy (n=13, 37%), hormonotherapy (n=2, 6%) or both (n=13, 37%). The 2-year survival rate after gastric metastasis diagnosis was 53% with a median follow up of 31 months [7-84 months]. Ninety-seven percent of gastric metastasis from breast cancers are derived from invasive lobular carcinoma. Seventy-nine percent of these are HER+ and comparison with the original histopathological slides of primary breast carcinoma should be performed to differentiate gastric metastasis from primary gastric carcinoma. Peritoneal carcinomatosis accompanied gastric metastasis in almost half the cases in this series and treatment was generally chemotherapy. Copyright © 2011 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

Investigation of the roles of exosomes in colorectal cancer liver metastasis.

PubMed

Wang, Xia; Ding, Xiaoling; Nan, Lijuan; Wang, Yiting; Wang, Jing; Yan, Zhiqiang; Zhang, Wei; Sun, Jihong; Zhu, Wei; Ni, Bing; Dong, Suzhen; Yu, Lei

2015-05-01

The leading cause of death among cancer patients is tumor metastasis. Tumor-derived exosomes are emerging as mediators of metastasis. In the present study, we demonstrated that exosomes play a pivotal role in the metastatic progression of colorectal cancer. First, a nude mouse model of colorectal cancer liver metastasis was established and characterized. Then, we demonstrated that exosomes from a highly liver metastatic colorectal cancer cell line (HT-29) could significantly increase the metastatic tumor burden and distribution in the mouse liver of Caco-2 colorectal cancer cells, which ordinarily exhibit poor liver metastatic potential. We further investigated the mechanisms by which HT-29-derived-exosomes influence the liver metastasis of colorectal cancer and found that mice treated with HT-29-derived exosomes had a relatively higher level of CXCR4 in the metastatic microenvironment, indicating that exosomes may promote colorectal cancer metastasis by recruiting CXCR4-expressing stromal cells to develop a permissive metastatic microenvironment. Finally, the migration of Caco-2 cells was significantly increased following treatment with HT-29-derived exosomes in vitro, further supporting a role for exosomes in modulating colorectal tumor-derived liver metastasis. The data from the present study may facilitate further translational medicine research into the prevention and treatment of colorectal cancer liver metastasis.

Reduced ING1 levels in breast cancer promotes metastasis.

PubMed

Thakur, Satbir; Singla, Arvind K; Chen, Jie; Tran, Uyen; Yang, Yang; Salazar, Carolina; Magliocco, Anthony; Klimowicz, Alexander; Jirik, Frank; Riabowol, Karl

2014-06-30

INhibitor of Growth 1 (ING1) expression is repressed in breast carcinomas, but its role in breast cancer development and metastasis is unknown. ING1 levels were quantified in >500 patient samples using automated quantitative fluorescence immunohistochemistry, and data were analysed for correlations to patient outcome. Effects of altering ING levels were examined in microarrays and metastasis assays in vitro, and in a mouse metastasis model in vivo. ING1 levels were lower in tumors compared to adjacent normal breast tissue and correlated with tumor size (p=0.019) and distant recurrence (p=0.001) in ER- or Her2+ patients. In these patients ING1 predicted disease-specific and distant metastasis-free survival. Transcriptome analysis showed that the pathway most affected by ING1 was breast cancer (p = 0.0008). Decreasing levels of ING1 increased, and increasing levels decreased, migration and invasion of MDA-MB231 cells in vitro. ING1 overexpression also blocked cancer cell metastasis in vivo and eliminated tumor-induced mortality in mouse models. Our data show that ING1 protein levels are downregulated in breast cancer and for the first time, we show that altering their levels regulates metastasis in vitro and in vivo, which indicates that ING1 may have a therapeutic role for inhibiting metastasis of breast cancer.

[A case of fulminant hepatic failure secondary to hepatic metastasis of small cell lung carcinoma].

PubMed

Hwang, Young Tae; Shin, Jung Woo; Lee, Jun Ho; Hwang, Dae Sung; Eum, Jun Bum; Choi, Hye Jeong; Park, Neung Hwa

2007-12-01

Although liver metastasis is commonly found in cancer patients, fulminant hepatic failure secondary to diffuse cancer infiltration into the liver is rare. Liver metastasis-induced fulminant hepatic failure has been reported in patients with primary cancer of the gastrointestinal tract, breast and uroepithelium, and in patients with melanoma and hematologic malignancy. Small cell lung cancer is so highly invasive that hepatic metastasis is common, but rapid progression to fulminant hepatic failure is extremely rare. We report here on a case of a patient who died because of rapid progression to fulminant hepatic failure as a result of hepatic metastasis of small cell lung carcinoma.

Skeletal metastasis: treatments, mouse models, and the Wnt signaling

PubMed Central

Valkenburg, Kenneth C.; Steensma, Matthew R.; Williams, Bart O.; Zhong, Zhendong

2013-01-01

Skeletal metastases result in significant morbidity and mortality. This is particularly true of cancers with a strong predilection for the bone, such as breast, prostate, and lung cancers. There is currently no reliable cure for skeletal metastasis, and palliative therapy options are limited. The Wnt signaling pathway has been found to play an integral role in the process of skeletal metastasis and may be an important clinical target. Several experimental models of skeletal metastasis have been used to find new biomarkers and test new treatments. In this review, we discuss pathologic process of bone metastasis, the roles of the Wnt signaling, and the available experimental models and treatments. PMID:23327798

[Hyperthyroidism by autonomous metastasis of thyroid carcinoma (author's transl)].

PubMed

Mornex, R; Pousset, G; Briere, J; Daumont, M; Paffoy, J C

1976-01-01

Nine years after surgical ablation of a trabeculo-vesicular carcinoma of the tyroid, a patient developped bone and liver metastasis. She had clinical signs of thyrotoxicosis, clear increase of blood T3 and sligh increase of T4. The TSH secretion was blocked. Exogenous TSH increased iodine uptake in the thyroid and not in the metastasis. After 2 doses of 120 mCi of 131I, she became hypothyroid, the liver was normal and the scan revealed the disappearance of uptake in thyroid and in metastasis. Such a clinical course was previously found in only 10 cases despite the frequent funcitonal differenciation of the metastasis of thyroid carcinomas.

Palatine tonsillar metastasis of a small pulmonary adenocarcinoma showing an invasive micropapillary carcinoma pattern and Pagetoid spread at the tonsil: a case suggesting retrograde lymphatic metastasis from bulky lymph node metastases of the neck.

PubMed

Tajima, Shogo; Koda, Kenji

2015-01-01

Metastasis rarely occurs in the palatine tonsils. Among primary pulmonary carcinoma subtypes, small cell carcinoma more frequently metastasizes to this site. Herein, we present an exceedingly rare case of a small pulmonary adenocarcinoma that metastasized to the cervical lymph nodes and the right palatine tonsil in a 62-year-old man. In spite of the small size of the primary site, such extensive metastasis may have occurred because of the invasive micropapillary carcinoma pattern seen in the metastatic sites. The manner of metastasis to the palatine tonsil was considered retrograde lymphatic metastasis originating from carcinoma cells in the cervical lymph nodes. Furthermore, Pagetoid spread was observed at the palatine tonsil. Although there have been only a few cases showing retrograde lymphatic metastasis and Pagetoid spread at the metastatic site, we should be careful when speculating about the primary site based on such metastatic sites, especially when dealing with a biopsy sample exhibiting Pagetoid spread.

Metastasis Risk of Cutaneous Squamous Cell Carcinoma in Organ Transplant Recipients and Immunocompetent Patients.

PubMed

Genders, Roel E; Osinga, Joris A J; Tromp, Elise E; O'Rourke, Peter; Bouwes Bavinck, Jan N; Plasmeijer, Elsemieke I

2018-06-08

Organ transplant recipients (OTRs) have a high incidence of cutaneous squamous cell carcinoma (cSCC), and immunosuppression has been reported to be an important risk factor for metastasis. The aim of this study was to identify the metastasis risk over a 10-year period for 593 patients with cSCC, of whom 134 were OTR and 459 were immunocompetent. Metastasis incidence rate was 1,046 (95% confidence interval (95% CI) 524-2,096) per 100,000 person years in OTR and 656 (95% CI; 388-1,107) in immunocompetent patients, yielding an incidence rate ratio of 1.6 (95% CI 0.67-3.81). In OTRs head/neck location, older age at transplantation and older age at diagnosis of first cSCC were associated with metastatic risk, and 7 out of 8 metastasized tumours were smaller than 2 cm. In immunocompetent patients tumour size and tumour depth were associated with metastasis. In conclusion, we were not able to demonstrate an increased incidence rate of metastasis in OTRs compared with immunocompetent patients. However, OTRs and immunocompetent patients differed with regard to risk factors for metastasis.

[A Long-Term Disease-Free Survival Case of Synchronous Pulmonary and Liver Metastasis of Rectal Cancer with Systemic Chemotherapy and Radiofrequency Ablation Therapy for Liver Metastasis].

PubMed

Enomoto, Masaya; Katsumata, Kenji; Kasahara, Kenta; Kuwabara, Hiroshi; Matsudo, Takaaki; Shigoka, Masatoshi; Enomoto, Masanobu; Ishizaki, Tetsuo; Tsuchida, Akihiko

2017-11-01

A 55-year-old woman underwent laparoscopic anterior resection and D2 lymph node dissection for recto-sigmoid colon cancer in November 2014, which was diagnosed as T3N1M1(H3, PUL2), stage IV , for the purpose of preserving the ileus. FOLFOX therapy with panitumumab(Pmab)was started in January 2015.A t the end of 11 courses, pulmonary metastasis changed to CR, and liver metastasis was down-graded to H2 on the CT.Because of the risk of hepatic dysfunction with advanced fatty liver due to chemotherapy and extrahepatic lesions, we chose radiofrequency ablation(RFA)therapy for liver metastasis.Pmab combined FOLFIRI therapy was administered, and maintenance therapy was initiated.This patient is alive 2 years and 7 months after surgery and 10 months after RFA without relapse.It is suggested that RFA therapy for liver metastasis of colon cancer with pulmonary metastasis combined with chemotherapy could be an effective treatment strategy.

A20 promotes metastasis of aggressive basal-like breast cancers through multi-monoubiquitylation of Snail1.

PubMed

Lee, Ji-Hyung; Jung, Su Myung; Yang, Kyung-Min; Bae, Eunjin; Ahn, Sung Gwe; Park, Jin Seok; Seo, Dongyeob; Kim, Minbeom; Ha, Jihoon; Lee, Jaewon; Kim, Jun-Hyeong; Kim, Jun Hwan; Ooshima, Akira; Park, Jinah; Shin, Donghyuk; Lee, Youn Sook; Lee, Sangho; van Loo, Geert; Jeong, Joon; Kim, Seong-Jin; Park, Seok Hee

2017-10-01

Although the ubiquitin-editing enzyme A20 is a key player in inflammation and autoimmunity, its role in cancer metastasis remains unknown. Here we show that A20 monoubiquitylates Snail1 at three lysine residues and thereby promotes metastasis of aggressive basal-like breast cancers. A20 is significantly upregulated in human basal-like breast cancers and its expression level is inversely correlated with metastasis-free patient survival. A20 facilitates TGF-β1-induced epithelial-mesenchymal transition (EMT) of breast cancer cells through multi-monoubiquitylation of Snail1. Monoubiquitylated Snail1 has reduced affinity for glycogen synthase kinase 3β (GSK3β), and is thus stabilized in the nucleus through decreased phosphorylation. Knockdown of A20 or overexpression of Snail1 with mutation of the monoubiquitylated lysine residues into arginine abolishes lung metastasis in mouse xenograft and orthotopic breast cancer models, indicating that A20 and monoubiquitylated Snail1 are required for metastasis. Our findings uncover an essential role of the A20-Snail1 axis in TGF-β1-induced EMT and metastasis of basal-like breast cancers.

Bone morphogenetic protein and bone metastasis, implication and therapeutic potential.

PubMed

Ye, Lin; Mason, Malcolm D; Jiang, Wen G

2011-01-01

Bone metastasis is one of the most common and severe complications in advanced malignancies, particularly in the three leading cancers; breast cancer, prostate cancer and lung cancer. It is currently incurable and causes severe morbidities, including bone pain, hypercalcemia, pathological fracture, spinal cord compression and consequent paralysis. However, the mechanisms underlying the development of bone metastasis remain largely unknown. Bone morphogenetic proteins (BMPs) belong to the TGF-beta superfamily and are pluripotent factors involved in the regulation of embryonic development and postnatal homeostasis of various organs and tissues, by controlling cellular differentiation, proliferation and apoptosis. Since they are potent regulators for bone formation, there is an increasing interest to investigate BMPs and their roles in bone metastasis. BMPs have been implicated in various neoplasms, at both primary and secondary tumors, particularly skeletal metastasis. Recently studies have also suggested that BMP signaling and their antagonists play pivotal roles in bone metastasis. In this review, we discuss the current knowledge of aberrations of BMPs which have been indicated in tumor progression, and particularly in the development of bone metastasis.

Roles of long non-coding RNAs in gastric cancer metastasis

PubMed Central

Yang, Zi-Guo; Gao, Ling; Guo, Xiao-Bo; Shi, Yu-Long

2015-01-01

Gastric cancer is the second leading cause of cancer-related deaths. Metastasis, which is an important element of gastric cancer, leads to a high mortality rate and to a poor prognosis. Gastric cancer metastasis has a complex progression that involves multiple biological processes. The comprehensive mechanisms of metastasis remain unclear, though traditional regulation modulates the molecular functions associated with metastasis. Long non-coding RNAs (lncRNAs) have a role in different gene regulatory pathways by epigenetic modification and by transcriptional and post-transcription regulation. lncRNAs participate in various diseases, including Alzheimer’s disease, cardiovascular disease, and cancer. The altered expressions of certain lncRNAs are linked to gastric cancer metastasis and invasion, as with tumor suppressor genes or oncogenes. Studies have partly elucidated the roles of lncRNAs as biomarkers and in therapies, as well as their gene regulatory mechanisms. However, comprehensive knowledge regarding the functional mechanisms of gene regulation in metastatic gastric cancer remains scarce. To provide a theoretical basis for therapeutic intervention in metastatic gastric cancer, we reviewed the functions of lncRNAs and their regulatory roles in gastric cancer metastasis. PMID:25954095

Identification of Staphylococcal Nuclease Domain-containing 1 (SND1) as a Metadherin-interacting Protein with Metastasis-promoting Functions*

PubMed Central

Blanco, Mario Andres; Alečković, Maša; Hua, Yuling; Li, Tuo; Wei, Yong; Xu, Zhen; Cristea, Ileana M.; Kang, Yibin

2011-01-01

Metastasis is the deadliest and most poorly understood feature of malignant diseases. Recent work has shown that Metadherin (MTDH) is overexpressed in over 40% of breast cancer patients and promotes metastasis and chemoresistance in experimental models of breast cancer progression. Here we applied mass spectrometry-based screen to identify staphylococcal nuclease domain-containing 1 (SND1) as a candidate MTDH-interacting protein. After confirming the interaction between SND1 and MTDH, we tested the role of SND1 in breast cancer and found that it strongly promotes lung metastasis. SND1 was further shown to promote resistance to apoptosis and to regulate the expression of genes associated with metastasis and chemoresistance. Analyses of breast cancer clinical microarray data indicated that high expression of SND1 in primary tumors is strongly associated with reduced metastasis-free survival in multiple large scale data sets. Thus, we have uncovered SND1 as a novel MTDH-interacting protein and shown that it is a functionally and clinically significant mediator of metastasis. PMID:21478147

Biomechanical forces in the skeleton and their relevance to bone metastasis: biology and engineering considerations

PubMed Central

Lynch, Maureen; Fischbach, Claudia

2014-01-01

Bone metastasis represents the leading cause of breast cancer related-deaths. However, the effect of skeleton-associated biomechanical signals on the initiation, progression, and therapy response of breast cancer bone metastasis is largely unknown. This review seeks to highlight possible functional connections between skeletal mechanical signals and breast cancer bone metastasis and their contribution to clinical outcome. It provides an introduction to the physical and biological signals underlying bone functional adaptation and discusses the modulatory roles of mechanical loading and breast cancer metastasis in this process. Following a definition of biophysical design criteria, in vitro and in vivo approaches from the fields of bone biomechanics and tissue engineering will be reviewed that may be suitable to investigate breast cancer bone metastasis as a function of varied mechano-signaling. Finally, an outlook of future opportunities and challenges associated with this newly emerging field will be provided. PMID:25174311

Discontinuation of anti-VEGF cancer therapy promotes metastasis through a liver revascularization mechanism

PubMed Central

Yang, Yunlong; Zhang, Yin; Iwamoto, Hideki; Hosaka, Kayoko; Seki, Takahiro; Andersson, Patrik; Lim, Sharon; Fischer, Carina; Nakamura, Masaki; Abe, Mitsuhiko; Cao, Renhai; Skov, Peter Vilhelm; Chen, Fang; Chen, Xiaoyun; Lu, Yongtian; Nie, Guohui; Cao, Yihai

2016-01-01

The impact of discontinuation of anti-VEGF cancer therapy in promoting cancer metastasis is unknown. Here we show discontinuation of anti-VEGF treatment creates a time-window of profound structural changes of liver sinusoidal vasculatures, exhibiting hyper-permeability and enlarged open-pore sizes of the fenestrated endothelium and loss of VE-cadherin. The drug cessation caused highly leaky hepatic vasculatures permit tumour cell intravasation and extravasation. Discontinuation of an anti-VEGF antibody-based drug and sunitinib markedly promotes liver metastasis. Mechanistically, host hepatocyte, but not tumour cell-derived vascular endothelial growth factor (VEGF), is responsible for cancer metastasis. Deletion of hepatocyte VEGF markedly ablates the ‘off-drug'-induced metastasis. These findings provide mechanistic insights on anti-VEGF cessation-induced metastasis and raise a new challenge for uninterrupted and sustained antiangiogenic therapy for treatment of human cancers. PMID:27580750

Endometrial metastasis of colorectal cancer with coincident endometrial adenocarcinoma.

PubMed

Colling, Richard; Lopes, Tito; Das, Nagiindra; Mathew, Joe

2010-11-05

Metastasis to the uterine corpus is uncommon and secondary colorectal tumours of the endometrium are rare. We describe a uterine tumour with components of both primary endometrial and metastatic colorectal carcinomata. In this case, a 72-year-old obese woman presented with a 2-week history of postmenopausal bleeding per vaginum and weight loss. She had an abdominoperineal resection 3 years previously for a Dukes stage B rectal carcinoma. A transvaginal ultrasonography showed a thickened endometrium. Histology immunophenotyping showed a CK7+, CK20+, CA125- and CEA+ colorectal metastasis (a profile consistent with her previous cancer) associated with a primary CK7+, CK20-, CA125+ and CEA- endometroid endometrial adenocarcinoma. We conclude this represents endometrial metastasis of colorectal carcinoma with coincident primary endometrial adenocarcinoma. We speculate as to whether the endometrial carcinoma arose de novo or was induced by the colorectal metastasis, or whether the primary endometrial tumour provided a fertile site for the colorectal metastasis.

Iris metastasis of gastric adenocarcinoma.

PubMed

Celebi, Ali Riza Cenk; Kilavuzoglu, Ayse Ebru; Altiparmak, U Emrah; Cosar, C Banu; Ozkiris, Abdullah

2016-03-08

Iris metastasis in patients with gastric cancer is extremely rare. Herein, it is aimed to report on a patient with gastric adenocarcinoma and iris metastasis. A 65-year-old patient with the history of gastric cancer was admitted for eye pain and eye redness on his left eye. There was ciliary injection, severe +4 cells with hypopyon in the anterior chamber and a solitary, friable, yellow-white, fleshy-creamy vascularized 2 mm × 4 mm mass on the upper nasal part of the iris within the left eye. The presented patient's mass lesion in the iris fulfilled the criteria of the metastatic iris lesion's appearance. The ocular metastasis occurred during chemotherapy. Iris metastasis can masquerade as iridocyclitis with pseudohypopyon or glaucoma. In patients with a history of gastric cancer that present with an iris mass, uveitis, and high intraocular pressure, ocular metastasis of gastric cancer should be a consideration.

Overexpression of MTA1 and loss of KAI-1 and KiSS-1 expressions are associated with invasion, metastasis, and poor-prognosis of gallbladder adenocarcinoma.

PubMed

Wang, Wenjun; Yang, Zhu-lin; Liu, Jie-qiong; Yang, Le-ping; Yang, Xiao-jing; Fu, Xi

2014-01-01

Over 90% of patients with gallbladder cancer have invasion and/or metastasis when they are diagnosed at the clinic. Such patients usually have an extremely poor prognosis. The molecular mechanism responsible for the high prevalence of invasion and metastasis remains unknown. We investigated the expression of two metastasis-suppression genes--KAI-1 and KiSS-1--and a metastasis-associated gene--MTA1--in 108 adenocarcinomas, 15 gallbladder polyps, 35 chronic cholecystitis tissues, and 46 peritumoral tissues using in situ hybridization or immunohistochemistry. We demonstrated that positive MTA1 expression was significantly higher whereas positive expressions of KAI-1 and KiSS-1 genes were significantly lower in gallbladder adenocarcinoma than in peritumoral tissues, polyps, and chronic cholecystitis. Positive MTA1 expression was significantly lower, but positive KAI-1 and KiSS-1 expressions were significantly higher in cases with well-differentiated adenocarcinoma, smaller tumor mass, no metastasis of lymph node, and no invasion of regional tissues than in cases having poorly differentiated adenocarcinoma, larger tumor mass, metastasis and invasion. Univariate Kaplan-Meier analysis showed that increased expression of MTA1 and lowered expression of KAI-1 and KiSS-1 were significantly associated with decreased overall survival. Cox regression analysis showed that tumor mass, lymph node metastasis, invasion, and MTA1 expression levels negatively correlated with survival. Our study suggested that KAI-1, KiSS-1, and MTA1 might be important biological markers involved in the carcinogenesis, metastasis, and invasion of gallbladder adenocarcinoma, but MTA1 is an independent factor of prognosis.

Natural killer (NK) cells inhibit systemic metastasis of glioblastoma cells and have therapeutic effects against glioblastomas in the brain.

PubMed

Lee, Se Jeong; Kang, Won Young; Yoon, Yeup; Jin, Ju Youn; Song, Hye Jin; Her, Jung Hyun; Kang, Sang Mi; Hwang, Yu Kyeong; Kang, Kyeong Jin; Joo, Kyeung Min; Nam, Do-Hyun

2015-12-24

Glioblastoma multiforme (GBM) is characterized by extensive local invasion, which is in contrast with extremely rare systemic metastasis of GBM. Molecular mechanisms inhibiting systemic metastasis of GBM would be a novel therapeutic candidate for GBM in the brain. Patient-derived GBM cells were primarily cultured from surgical samples of GBM patients and were inoculated into the brains of immune deficient BALB/c-nude or NOD-SCID IL2Rgamma(null) (NSG) mice. Human NK cells were isolated from peripheral blood mononucleated cells and expanded in vitro. Patient-derived GBM cells in the brains of NSG mice unexpectedly induced spontaneous lung metastasis although no metastasis was detected in BALB/c-nude mice. Based on the difference of the innate immunity between two mouse strains, NK cell activities of orthotopic GBM xenograft models based on BALB/c-nude mice were inhibited. NK cell inactivation induced spontaneous lung metastasis of GBM cells, which indicated that NK cells inhibit the systemic metastasis. In vitro cytotoxic activities of human NK cells against GBM cells indicated that cytotoxic activity of NK cells against GBM cells prevents systemic metastasis of GBM and that NK cells could be effective cell therapeutics against GBM. Accordingly, NK cells transplanted into orthotopic GBM xenograft models intravenously or intratumorally induced apoptosis of GBM cells in the brain and showed significant therapeutic effects. Our results suggest that innate NK immunity is responsible for rare systemic metastasis of GBM and that sufficient supplementation of NK cells could be a promising immunotherapeutic strategy for GBM in the brain.

Characteristics of breast cancer patients with central nervous system metastases: a single-center experience.

PubMed

Harputluoglu, Hakan; Dizdar, Omer; Aksoy, Sercan; Kilickap, Saadettin; Dede, Didem S; Ozisik, Yavuz; Guler, Nilufer; Barista, Ibrahim; Gullu, Ibrahim; Hayran, Mutlu; Selek, Ugur; Cengiz, Mustafa; Zorlu, Faruk; Tekuzman, Gulten; Altundag, Kadri

2008-05-01

The aim of this study was to assess the characteristics of breast cancer patients with central nervous system (CNS) metastases and factors associated with survival after development of CNS metastasis. One-hundred-forty-four patients with brain metastases were retrospectively analyzed. Median age at the time of brain metastasis diagnosis was 48.9. Median time between initial diagnosis and development of brain metastasis was 36 months. Fourteen cases had leptomeningeal involvement. Twenty-two patients (15.3%) had single metastasis. Ten percent of the patients had surgery, 94% had radiotherapy and 63% had chemotherapy. Median survival after development of brain metastasis was 7.4 months. Survival of patients with single metastasis was significantly longer than those with multiple metastases (33.5 vs. 6.5 months, p = 0.0006). Survival of patients who received chemotherapy was significantly longer than those who received radiotherapy alone (9.9 vs. 2 months, p < 0.0001). In multivariate Cox regression analyses, presence of single metastasis and application of chemotherapy were the only significant factors associated with better survival (p = 0.047 and p < 0.0001, respectively). Age at initial diagnosis or at the time of brain metastasis, time from initial diagnosis to development of brain metastasis, menopausal status, tumor stage, grade, hormone receptor or HER2 status individually were not associated with survival. In this study, survival after the diagnosis of CNS metastases appeared to be affected by patient characteristics rather than biologic characteristics of the tumor. This is probably secondary to the lack of effective treatment options in these patients and overall poor prognosis.

[Clinical analysis of 23 gynecologic carcinoma patients with brain metastasis].

PubMed

Zhang, J X; Wang, S Z; Li, B; Zhang, Z Y

2016-06-21

To explore the clinicopathological characteristics and treatments of brain metastasis (BM) in patients with gynecologic carcinoma. Twenty-three pathologically confirmed patients with gynecologic carcinoma who had brain metastasis between February 2008 and October 2012 were analyzed retrospectively. The primary carcinoma was cervical cancer in 5 patients, endometrial carcinoma in 8 patients and ovarian cancer in 10 patients, which accounted for 1.81% (5/276), 2.10% (8/380) and 2.67% (10/374) of patient with the same diagnosis of the same period, respectively.Among them, 91.3% (21/23) patients had heterochronous BM.Single BM was documented in 52.2% (12/23) patients.Besides, 78.2% (18/23) BM located in cerebrum.At the time of BM, 91.3% (21/23) patients had symptoms of central nervous system, in which headache ranked the top (90.4%). Altogether, thirteen patients had extracranial metastasis, in which 9 of them had metastasis of the lung.The median post-brain-metastasis survival (mPBMS) for the recursive partitioning analysis (RPA) classes Ⅰ-Ⅲ was 54 months, 9 months and 1 month, respectively (P<0.01). None of surgery, radiotherapy or chemotherapy treatment was proven to have prognosis-improving ability either in single variant or multivariate analysis.However, in patients with extracranial metastasis, chemotherapy could significantly improve their mPBMS (P<0.05). The incidence of brain metastasis in patients with cervical cancer, endometrial carcinoma, and ovarian cancer increased gradually.RPA was valuable for a prognostic assessment in gynecologic carcinoma patients with BM.Chemotherapy could significantly improve prognosis of gynecologic carcinoma patients with BM if extracranial metastasis was presented.

Novel immunohistochemistry-based signatures to predict metastatic site of triple-negative breast cancers.

PubMed

Klimov, Sergey; Rida, Padmashree Cg; Aleskandarany, Mohammed A; Green, Andrew R; Ellis, Ian O; Janssen, Emiel Am; Rakha, Emad A; Aneja, Ritu

2017-09-05

Although distant metastasis (DM) in breast cancer (BC) is the most lethal form of recurrence and the most common underlying cause of cancer related deaths, the outcome following the development of DM is related to the site of metastasis. Triple negative BC (TNBC) is an aggressive form of BC characterised by early recurrences and high mortality. Athough multiple variables can be used to predict the risk of metastasis, few markers can predict the specific site of metastasis. This study aimed at identifying a biomarker signature to predict particular sites of DM in TNBC. A clinically annotated series of 322 TNBC were immunohistochemically stained with 133 biomarkers relevant to BC, to develop multibiomarker models for predicting metastasis to the bone, liver, lung and brain. Patients who experienced metastasis to each site were compared with those who did not, by gradually filtering the biomarker set via a two-tailed t-test and Cox univariate analyses. Biomarker combinations were finally ranked based on statistical significance, and evaluated in multivariable analyses. Our final models were able to stratify TNBC patients into high risk groups that showed over 5, 6, 7 and 8 times higher risk of developing metastasis to the bone, liver, lung and brain, respectively, than low-risk subgroups. These models for predicting site-specific metastasis retained significance following adjustment for tumour size, patient age and chemotherapy status. Our novel IHC-based biomarkers signatures, when assessed in primary TNBC tumours, enable prediction of specific sites of metastasis, and potentially unravel biomarkers previously unknown in site tropism.

[The related factors of head and neck mocosal melanoma with lymph node metastasis].

PubMed

Yin, G F; Guo, W; Chen, X H; Huang, Z G

2017-12-05

Objective: To investigate the related factors of mucosal melanoma of head and neck with lymph node metastasis for early diagnosis and further treatments. Method: A retrospective analysis of 117 cases of head and neck mucosal malignant melanoma patients which received surgical treatment was performed. Eleven cases of patients with pathologically confirmed lymph node metastasis and 33 cases without lymph node metastasis (1∶3) were randomly selected to analyze. The related factors of lymph node metastasis of head and neck mucosal melanoma patients including age, gender, whether the existence of recurrence, bone invasion, lesion location were analyzed. The single factor and logistic regression analysis were performed, P <0.05 difference was statistically significant. Result: The lymph node metastasis rate of head and neck mucosal melanoma was 9.40%(11/117), the single factor analysis showed that there were 3 factors to be associated with lymph node metastasis, which was recurrence ( P =0.0000), bone invasion ( P =0.001), primary position ( P =0.007). Recurrence ( P =0.021) was a risk factor for lymph node metastasis according to the Logistic regression analysis, and the impact of bone invasion ( P =0.487) and primary location ( P =0.367) remained to be further explored. Conclusion: The patients of head and neck mucosal melanoma with the presence of recurrent usually accompanied by a further progression of the disease, such as lymph node metastasis, so for recurrent patients should pay special attention to the situation of lymph node and choose the reasonable treatment. Copyright© by the Editorial Department of Journal of Clinical Otorhinolaryngology Head and Neck Surgery.

From Breast to Bone: Tracking Gene Expression Changes Responsible for Breast Cancer Metastasis in a Humanized Mouse Model with Molecular Imaging

DTIC Science & Technology

2015-11-01

strategies to predict and prevent metastasis. 15. SUBJECT TERMS triple-negative breast cancer, metastasis, p53, BTG2, PDX Models 16. SECURITY CLASSIFICATION...membrane and into the circulation, survival in the circulation, extravasation into distant organs, tumor dormancy, and finally tumor growth in the...sequencing analysis are novel targets for metastasis prevention or are more effective at destroying metastatic cells while minimizing the risk of

Tongue metastasis mimicking an abscess.

PubMed

Mavili, Ertuğrul; Oztürk, Mustafa; Yücel, Tuba; Yüce, Imdat; Cağli, Sedat

2010-03-01

Primary tumors metastasizing to the oral cavity are extremely rare. Lung is one of the most common primary sources of metastases to the tongue. Although the incidence of lung cancer is increasing, tongue metastasis as the initial presentation of the tumor remains uncommon. Due to the rarity of tongue metastasis, little is known about its imaging findings. Herein we report the magnetic resonance imaging and clinical findings of a lingual metastasis, mimicking an abscess, from a primary lung cancer.

Suppression of MIM by microRNA-182 activates RhoA and promotes breast cancer metastasis.

PubMed

Lei, R; Tang, J; Zhuang, X; Deng, R; Li, G; Yu, J; Liang, Y; Xiao, J; Wang, H-Y; Yang, Q; Hu, G

2014-03-06

Breast cancer is the most common type of cancer among women worldwide, and metastasis represents the most devastating stage of the disease. Recent studies have revealed that microRNAs (miRNA) have critical roles to regulate cancer cell invasion and metastasis. Here we present evidence to show the role of miR-182 in breast cancer metastasis. miR-182 is upregulated in the malignant cell line variants of both human MCF10 and mouse 4T1 series. Ectopic expression of miR-182 enhanced breast cancer cell motility and invasiveness, whereas miR-182 inhibition resulted in opposite changes. In nude mice, miR-182 led to increased pulmonary colonization of cancer cells. We further demonstrated that miR-182 directly targets MIM (Missing in Metastasis), which suppresses metastasis by inhibiting ras homolog family member A (RhoA) activity and stress fiber formation in breast cancer cells. Restoring MIM expression completely blocked the pro-metastasis function of miR-182, while RhoA inhibition reversed the phenotypes of both miR-182 overexpression and MIM knockdown. In breast tumor samples, miR-182 induction is linked to downregulation of MIM, RhoA activation and poor prognosis. Hence, our data delineates the molecular pathway by which miR-182 promotes breast cancer invasion and metastasis, and may have important implication for the treatment of metastatic cancers.

Effect of expressions of tumor necrosis factor α and interleukin 1B on peritoneal metastasis of gastric cancer.

PubMed

Guo, Lin; Ou, Jin-Lei; Zhang, Tong; Ma, Liang; Qu, Long-Fei

2015-11-01

Our study aimed to investigate effect of expressions of tumor necrosis factor α (TNF-α) and interleukin 1B (IL-1B) on peritoneal metastasis of gastric cancer (GC). From June 2012 to June 2014, a total of 60 patients with advanced peritoneal metastasis from GC were collected from Department of Gastrointestinal and Nutriology Surgery at Shengjing Hospital of China Medical University. Furthermore, 60 GC patients without peritoneal metastasis were enrolled as controls. Immunohistochemistry was performed to test TNF-α and IL-1B expression, and logistic regression analysis was employed for evaluating risk factors for peritoneal metastasis of GC. Our results showed that TNF-α expression in metastatic group and non-metastatic group was significantly different (P = 0.043), but no significant difference was found in IL-1B expression between two groups (P = 0.261). In addition, TNF-α expression in metastatic group and non-metastatic group was associated with tumor size, depth of invasion, the degree of differentiation (all P < 0.05). Logistic regression analysis indicated that tumor size, depth of invasion, the degree of differentiation and TNF-α expression were risk factors for peritoneal metastasis of GC (all P < 0.05). Our study found that TNF-α expression may play a vital role in peritoneal metastasis of GC, while IL-1B expression might not be correlated with peritoneal metastasis.

The effect of down regulation of calcineurin Aα by lentiviral vector-mediated RNAi on the biological behavior of small-cell lung cancer and its bone metastasis.

PubMed

Ma, Ning-Qiang; Liu, Li-Li; Min, Jie; Wang, Jun-Wei; Jiang, Wei-Feng; Liu, Yan; Feng, Yan-Guo; Su, Hai-Chuan; Feng, Ying-Ming; Zhang, He-Long

2011-12-01

Bone is the third most common site of cancer metastasis. Over 30 to 40% of lung cancers can develop skeletal metastasis and no effective curative therapy exists in clinic cases. Previously we screened the different expression of proteins between SBC-5 cells and SBC-3 cells by proteomic study methods (MALDI-TOF/TOF-MS) and found that calcineurin (hereafter referred as Cn) overexpresses in SBC-5 which has special priority in metastasis to bone in a multiple-organ metastasis mice model. However the roles of Cn in osteotropism of SCLC remain to be elucidated. At present study, we decrease CnAα expression in SBC-5 by lentiviral vector-mediated RNAi and found that down regulation of CnAα gene expression can decrease the proliferation and colony formation rate, impede the cell cycle progression, reduce the cell migration and invasion, and inhibit cells adhering to bone matrix, but not change the apoptosis rate of SBC-5 in vitro. In vivo down or up regulation of CnAα gene expression can only decrease or increase the bone metastasis rate, but not affect the metastasis rate to the visceral organs. Our research reveals that CnAα is closely related to the osteotropism metastasis of SCLC and a candidate tumor promotor gene for developing bone metastases.

Induction of experimental bone metastasis in mice by transfection of integrin alpha 4 beta 1 into tumor cells.

PubMed Central

Matsuura, N.; Puzon-McLaughlin, W.; Irie, A.; Morikawa, Y.; Kakudo, K.; Takada, Y.

1996-01-01

Cell adhesion receptors (eg, integrins and CD44) play an important role in invasion and metastasis during tumor progression. The increase in integrin alpha 4 beta 1 expression on primary melanomas has been reported to significantly correlate with the development of metastases. alpha 4 beta 1 is a cell surface heterodimer that mediates cell-cell and cell-extracellular matrix interactions through adhesion to vascular cell adhesion molecule (VCAM)-1 and to the IIICS region of fibronectin. To test the effects of alpha 4 beta 1 expression on tumor cell metastasis, Chinese hamster ovary cells were transfected with human alpha 4 cDNA. Whereas alpha 4-negative Chinese hamster ovary cells developed only pulmonary metastasis, alpha 4-positive Chinese hamster ovary cells developed bone and pulmonary metastasis in 3 to 4 weeks when injected intravenously into nude mice. Bone metastasis was inhibited by antibody against alpha 4 or VCAM-1. Expression of alpha 3 beta 1, alpha 6 beta 1, or alpha V beta 1 did not induce bone metastasis. Expression of alpha 4 beta 1 also induced bone metastasis in K562 human erythroleukemia cells injected into SCID mice. These results demonstrate that alpha 4 beta 1 can induce tumor cell trafficking to bone, probably via interaction with VCAM-1 that is constitutively expressed on bone marrow stromal cells. Images Figure 1 Figure 3 PMID:8546226

Role of periostin and its antagonist PNDA-3 in gastric cancer metastasis.

PubMed

Liu, Guo-Xiao; Xi, Hong-Qing; Sun, Xiao-Yan; Wei, Bo

2015-03-07

The extracellular matrix component periostin is a secreted protein that functions as both a cell attachment protein and an autocrine or paracrine factor that signals through the cell adhesion molecule integrins αvβ3 and αvβ5. Periostin participates in normal physiological activities such as cardiac development, but is also involved in pathophysiological processes in vascular diseases, wound repair, bone formation, and tumor development. It is of increasing interest in tumor biology because it is frequently overexpressed in a variety of epithelial carcinomas and is functionally involved in multiple steps of metastasis progression. These include the maintenance of stemness, niche formation, EMT, the survival of tumor cells, and angiogenesis, all of which are indispensable for gastric cancer metastasis. Periostin has been reported to activate the PI-3K/AKT, Wnt, and FAK-mediated signaling pathways to promote metastasis. Therefore, periostin represents a potentially promising candidate for the inhibition of metastasis. In this review article, we summarize recent advances in knowledge concerning periostin, its antagonist PNDA-3, and their influence on such key processes in cancer metastasis as maintenance of stemness, niche formation, epithelial-to-mesenchymal transition, tumor cell survival, and angiogenesis. In particular, we focus our attention on the role of periostin in gastric cancer metastasis, speculate as to the usefulness of periostin as a therapeutic and diagnostic target for gastric cancer metastasis, and consider potential avenues for future research.

RKIP and HMGA2 regulate breast tumor survival and metastasis through lysyl oxidase and syndecan-2.

PubMed

Sun, M; Gomes, S; Chen, P; Frankenberger, C A; Sankarasharma, D; Chung, C H; Chada, K K; Rosner, M R

2014-07-03

Elucidating targets of physiological tumor metastasis suppressors can highlight key signaling pathways leading to invasion and metastasis. To identify downstream targets of the metastasis suppressor Raf-1 kinase inhibitory protein (RKIP/PEBP1), we utilized an integrated approach based upon statistical analysis of tumor gene expression data combined with experimental validation. Previous studies from our laboratory identified the architectural transcription factor and oncogene, high mobility group AT-hook 2 (HMGA2), as a target of inhibition by RKIP. Here we identify two signaling pathways that promote HMGA2-driven metastasis. Using both human breast tumor cells and an MMTV-Wnt mouse breast tumor model, we show that RKIP induces and HMGA2 inhibits expression of miR-200b; miR-200b directly inhibits expression of lysyl oxidase (LOX), leading to decreased invasion. RKIP also inhibits syndecan-2 (SDC2), which is aberrantly expressed in breast cancer, via downregulation of HMGA2; but this mechanism is independent of miR-200. Depletion of SDC2 induces apoptosis and suppresses breast tumor growth and metastasis in mouse xenografts. RKIP, LOX and SDC2 are coordinately regulated and collectively encompass a prognostic signature for metastasis-free survival in ER-negative breast cancer patients. Taken together, our findings reveal two novel signaling pathways targeted by the metastasis suppressor RKIP that regulate remodeling of the extracellular matrix and tumor survival.

A novel gammaretroviral shuttle vector insertional mutagenesis screen identifies SHARPIN as a breast cancer metastasis gene and prognostic biomarker.

PubMed

Bii, Victor M; Rae, Dustin T; Trobridge, Grant D

2015-11-24

Breast cancer (BC) is the second leading cause of malignancy among U.S. women. Metastasis results in a poor prognosis and increased mortality, but the molecular mechanisms by which metastatic tumors occur are not well understood. Identifying the genes that drive the metastatic process could provide targets for improved therapy and biomarkers to improve BC patient outcomes. Using a forward mutagenesis screen, BC cells mutagenized with a replication-incompetent gammaretroviral vector (γRV) were xenotransplanted into the mammary fat pad of immunodeficient mice. In this approach the vector provirus dysregulates nearby genes, providing a selective advantage to transduced cells to form metastases. Metastatic tumors were analyzed for proviral integration sites to identify nearby candidate metastasis genes. The γRV has a transgene cassette that allows for rescue in bacteria and rapid identification of vector integration sites. Using this approach, we identified the previously described metastasis gene WWTR1 (TAZ), and three other novel candidate metastasis genes including SHARPIN. SHARPIN was independently validated in vivo as a BC metastasis gene. Analysis of patient data showed that SHARPIN expression predicts metastasis-free survival after adjuvant therapy. Our approach has broad potential to identify genes involved in oncogenic processes for BC and other cancers. We show here it can identify both known (WWTR1) and novel (SHARPIN) BC metastasis genes.

Risk factors and the preoperative assessment of right para-oesophageal lymph node metastasis in right lobe papillary thyroid carcinoma: A case series.

PubMed

Qu, You; Zhang, Hao; Zhang, Ping; Dong, Wenwu; He, Liang; Sun, Wei; Liu, Jinhao

2017-06-01

Right para-oesophageal lymph nodes (RPELN) are included among the right central compartment lymph nodes (rCLN) and located behind right recurrent laryngeal nerve (rRLN). However, due to the likelihood of increasing postoperative complications, and the extremely difficulties of RPELN dissection, the decision to perform RPELN dissection remains controversial. The aim of this study was to explore the risk factors of RPELN metastasis and evaluate RPELN metastasis by preoperative examination. We reviewed the medical records of 163 consecutive papillary thyroid carcinoma (PTC) patients (125 females and 38 males) who underwent right lobe plus isthmic resection (91 patients) or total thyroidectomy (72 patients) with right or bilateral central compartment lymph node dissection. The RPELN dissections were performed in all patients and were individually dissected and recorded intraoperatively. All patients underwent thyroid ultrasound and enhanced neck computed tomography (CT) routinely during preoperative examination. RPELN metastasis was detected in 20 patients (12.3%), among whom 6 (3.7%) had RPELN metastasis without rCLN metastasis. Total rCLN metastasis and lateral compartment lymph node metastasis were confirmed in 57 (35.0%) and 24 (14.7%) patients, respectively. The tumour diameter, number of metastatic rCLN and lateral compartment lymph nodes, RPELN visible on CT, and enhanced CT value of RPELN were confirmed significantly associated with RPELN metastasis by univariate analysis (P < 0.05). The area under the ROC curve of CT values was 0.77 (95% CI, 0.59-0.95; P = 0.003). The CT value of 132.0 was used as the cut-off point, and the specificity and sensitivity were 84.1% and 71.4%, respectively. PTC patients with a large tumour (>1 cm) in the right lobe or suspected rCLN metastasis were recommended to undergo prophylactic RPELN dissection, particularly in those with a high enhanced CT value (>132) of RPELN or those with the copresence of lateral compartment lymph node metastasis. Copyright © 2017 IJS Publishing Group Ltd. Published by Elsevier Ltd. All rights reserved.

[Incidence and influencing factors of distal external iliac lymph node metastasis in early cervical cancer].

PubMed

Yin, Yueju; Sheng, Xiugui; Li, Xinglan; Li, Dapeng; Han, Xiaoyun; Zhang, Xiaoling; Zhang, Tingting

2014-06-01

The distal external iliac lymph nodes are located along the external iliac artery between the deep circumflex iliac vein and the inguinal canal. Our study aimed to investigate the incidence of metastasis in distal external iliac lymph nodes and its association with clinicopathological factors in patients with early stage cervical cancer, and to determine the role of distal external iliac lymph nodes dissection in the surgery. Five hundred and twenty-four patients with early stage cervical cancer underwent radical hysterectomy and bilateral pelvic lymphadenectomy in the Shandong Province Cancer Hospital between June 1995 and December 2011, and their clinicopathological features were analyzed retrospectively. Of the 524 patients, 124 (23.7%) had pelvic lymph node metastasis. The metastasis rates were 16.2% (85 of 524 patients) in the obturator lymph nodes, 12.2% (64 of 524 patients) in the internal and external iliac lymph nodes, 2.9% (15 of 524 patients) in the common iliac lymph nodes, 2.1% (11 of 524 patients) in the distal external iliac lymph nodes, and 1.7% (9 of 524 patients) in the para-aortic nodes. The incidence of isolated positive distal external iliac lymph nodes was 0.2%. Univariate analysis showed that lymphovascular space invasion, pelvic lymph node metastases (excluding distal external iliac lymph nodes) were significantly associated with distal external iliac lymph node metastasis (P < 0.05). Logistic regression analysis showed that pelvic lymph node metastasis (excluding distal external iliac lymph nodes) was the independent risk factor for metastasis to distal external iliac lymph nodes. In early stage cervical cancer, distal external iliac lymph node metastasis is rare, especially in cases with stage IA or without pelvic lymph node metastasis. Less extensive pelvic lymphadenectomy may be considered in these patients in order to reduce operative complications and improve patients' quality of life. The deep circumflex iliac vein may be an appropriate landmark for the caudal limit of external iliac lymphadenectomy. However, if pelvic lymph node metastasis (excluding distal external iliac lymph nodes) is found by intraoperative rapid pathological diagnosis, systematic pelvic lymphadenectomy including removal of the distal external iliac lymph nodes should be performed in order to reduce the risk of distant metastasis.

[Breast tumor revealed by a gastric metastasis discovered incidentally].

PubMed

Moussaoui, Aziz El; Assi, Fadi; Bental, Abdeslam

2016-01-01

The gastric metastasis of breast cancer are rare, and their discovery is difficult, because the symptoms is often unspecific or even absent. We report an original case of ductal carcinoma of the breast revealed by a gastric metastasis discovered incidentally.

Severe pulmonary metastasis in obese and diabetic mice.

PubMed

Mori, Akinori; Sakurai, Hiroaki; Choo, Min-Kyung; Obi, Ryosuke; Koizumi, Keiichi; Yoshida, Chiho; Shimada, Yutaka; Saiki, Ikuo

2006-12-15

Although obesity is known as a risk factor for several human cancers, the association of obesity with cancer recurrence and metastasis remains to be characterized. Here, B16-BL6 melanoma and Lewis lung carcinoma cells were intravenously injected into diabetic (db/db) and obese (ob/ob) mice. The number of experimental lung colonies was markedly promoted in these mice when compared with C57BL/6 mice. In contrast, tumor growth at the implanted site was comparable when cells were inoculated orthotopically. The use of B16-BL6 cells stably transfected with the luciferase gene revealed that the increased metastasis reflected a difference mainly within 6 hr after the intravenous inoculation of tumor cells. Administration of recombinant leptin in ob/ob mice abolished the increase in metastasis early on as well as the decrease in the splenic NK cell number. In addition, depletion of NK cells by an anti-asialo-GM1 antibody abrogated the enhanced metastasis in db/db mice. These results demonstrate that metastasis is markedly promoted in diabetic and obese mice mainly because of decreased NK cell function during the early phase of metastasis. Copyright 2006 Wiley-Liss, Inc.

Pituitary metastasis of hepatocellular carcinoma presenting with panhypopituitarism: a case report.

PubMed

Tanaka, Tomoko; Hiramatsu, Katsushi; Nosaka, Takuto; Saito, Yasushi; Naito, Tatsushi; Takahashi, Kazuto; Ofuji, Kazuya; Matsuda, Hidetaka; Ohtani, Masahiro; Nemoto, Tomoyuki; Suto, Hiroyuki; Yamamoto, Tatsuya; Kimura, Hirohiko; Nakamoto, Yasunari

2015-11-06

Metastasis to the pituitary gland is extremely rare and is often detected incidentally by symptoms associated with endocrine dysfunction. Breast and lung cancer are the most common primary metastasizing to pituitary gland. Metastasis from hepatocellular carcinoma to the pituitary gland is extremely rare, with only 10 cases having been previously reported. We present here the first case of pituitary metastasis of hepatocellular carcinoma presenting with panhypopituitarism diagnosed by magnetic resonance imaging. We report the case of an 80-year-old Japanese woman who presented with the sudden onset of hypotension and bradycardia after having previously been diagnosed with hepatocellular carcinoma. Based on low levels of pituitary hormones, she was diagnosed with panhypopituitarism caused by metastasis of the hepatocellular carcinoma to the pituitary gland. Magnetic resonance imaging with arterial spin-labeling was effective in the differential diagnosis of the intrasellar tumor. The patient died despite hormone replacement therapy because of hypovolemic shock. Metastasis to the pituitary gland causes various non-specific symptoms, so it is difficult to diagnose. The present case emphasizes the importance of diagnostic imaging in identifying these metastases. Clinicians should consider the possibility of pituitary metastasis in patients with malignant tumors who demonstrate hypopituitarism.

ABCB5 promotes melanoma metastasis through enhancing NF-κB p65 protein stability.

PubMed

Wang, Shenghao; Tang, Li; Lin, Junyu; Shen, Zhongliang; Yao, Yikun; Wang, Wei; Tao, Shuai; Gu, Chenjian; Ma, Jie; Xie, Youhua; Liu, Yanfeng

2017-10-07

Melanoma is the most aggressive type of skin cancer. Melanoma has an extremely poor prognosis because of its high potential for vascular invasion, metastasis and recurrence. The mechanism of melanoma metastasis is not well understood. ATP-binding cassette sub-family B member 5 (ABCB5) plays a key role in melanoma growth. However, it is uncertain what function ABCB5 may exert in melanoma metastasis. In this report, we for the first time demonstrate ABCB5 as a crucial factor that promotes melanoma metastasis. ABCB5 positive (ABCB5 + ) malignant melanoma initiating cells (MMICs) display a higher metastatic potential compared with ABCB5 negative (ABCB5 - ) melanoma subpopulation. Knockdown of ABCB5 expression reduces melanoma cell migration and invasion in vitro and melanoma pulmonary metastasis in tumor xenograft mice. ABCB5 and NF-κB p65 expression levels are positively correlated in both melanoma tissues and cell lines. Consequently, ABCB5 activates the NF-κB pathway by inhibiting p65 ubiquitination to enhance p65 protein stability. Our finding highlights ABCB5 as a novel pro-metastasis factor and provides a potential therapeutic target for melanoma. Copyright © 2017 Elsevier Inc. All rights reserved.

Downregulation of NEDD9 by apigenin suppresses migration, invasion, and metastasis of colorectal cancer cells

PubMed Central

Dai, Jin; Van Wie, Peter G.; Fai, Leonard Yenwong; Kim, Donghern; Wang, Lei; Poyil, Pratheeshkumar; Luo, Jia; Zhang, Zhuo

2018-01-01

Apigenin is a natural flavonoid which possesses multiple anti-cancer properties such as anti-proliferation, anti-inflammation, and anti-metastasis in many types of cancers including colorectal cancer. Neural precursor cell expressed developmentally downregulated 9 (NEDD9) is a multi-domain scaffolding protein of the Cas family which has been shown to correlate with cancer metastasis and progression. The present study investigates the role of NEDD9 in apigenin-inhibited cell migration, invasion, and metastasis of colorectal adenocarcinoma DLD1 and SW480 cells. The results show that knockdown of NEDD9 inhibited cell migration, invasion, and metastasis and that overexpression of NEDD9 promoted cell migration and invasion of DLD1 cells and SW4890 cells. Apigenin treatment attenuated NEDD9 expression at protein level, resulting in reduced phosphorylations of FAK, Src, and Akt, leading to inhibition on cell migration, invasion, and metastasis of both DLD1 and SW480 cells. The present study has demonstrated that apigenin inhibits cell migration, invasion, and metastasis through NEDD9/Src/Akt cascade in colorectal cancer cells. NEDD9 may function as a biomarker for evaluation of cancer aggressiveness and for selection of therapeutic drugs against cancer progression. PMID:27664007

Can Platelet and Leukocyte Indicators Give Us an Idea about Distant Metastasis in Nasopharyngeal Cancer?

PubMed

Arıcıgil, Mitat; Dündar, Mehmet Akif; Yücel, Abitter; Arbağ, Hamdi; Aziz, Suhayb Kuria

This study aimes to evaluate platelet and leucocyte indicators, such as the mean platelet volume, platelet distribution width, plateletcrit, white blood cell count, neutrophil to lymphocyte ratio in nasopharyngeal cancer patients and also to evaluate the relationship between these indicators and nasopharyngeal cancer with distant metastasis. The medical records of 118 patients diagnosed with nasopharyngeal cancer in our hospital between January 2006 and August 2015 were reviewed. The nasopharyngeal cancer group was further sub grouped according to the presence or absence of distant metastasis and TNM (tumour - T, node - N, metastasis - M) classification. A control group consisted of 120 healthy patients. The platelet and leucocyte values at the time of the initial diagnosis were recorded. Neutrophil to lymphocyte ratio and platelet distribution width values were significantly higher in the nasopharyngeal cancer group. But only platelet distribution width values were significantly higher in the nasopharyngeal cancer group with distant metastasis compared to the nasopharyngeal cancer group without distant metastasis. Neutrophil to lymphocyte ratio and platelet distribution width values may increase in nasopharyngeal cancer. But only the platelet distribution width values may give us an idea about the distant metastasis in nasopharyngeal cancer.

[Adenocarcinoma of lung cancer with solitary metastasis to the stomach].

PubMed

Koh, Sung Ae; Lee, Kyung Hee

2014-09-25

Although hematogenous metastasis of cancer to the gastrointestinal track is rare, it sometime has been reported in patients with malignant melanoma and breast cancer. However, it is extremely rare for lung cancer to metastasize to the stomach, not to mention solitary gastric metastasis. Herein, the authors report a case of a 69-year-old man who was initially diagnosed with lung cancer with synchronous primary gastric cancer which proved to be lung cancer with solitary gastric metastasis after the operation.

Breast cancer metastasis to the pituitary gland.

PubMed

Magalhães, Julia Fragoso; Bacchin, Renata Prota; Costa, Priscila Scatena; Alves, Gisele Malavazi; Fraige Filho, Fadlo; Stella, Lenira Cristina

2014-11-01

Metastatic tumors to the pituitary gland are an unusual complication typically seen in elderly patients with diffuse malignant disease. Breast and lung are the commonest sites of the primary tumor. Prognosis of patients with breast cancer metastasis is poor and depends on the primary neoplastic extension. We report a 54 year-old woman with breast cancer metastasis to the pituitary stalk first diagnosed because of visual disturbance with no other symptoms. Pituitary gland stalk metastasis is a very uncommon find and this case report includes a literature review.

An open cohort study of bone metastasis incidence following surgery in breast cancer patients.

PubMed

Koizumi, Mitsuru; Yoshimoto, Masataka; Kasumi, Fujio; Iwase, Takuji

2010-07-21

To help design clinical trials of adjuvant bisphosphonate therapy for breast cancer, the temporal incidence of bone metastasis was investigated in a cohort of patients. We have tried to draw the criteria to use adjuvant bisphosphonate. Consecutive breast cancer patients undergoing surgery between 1988 and 1998 (5459 patients) were followed up regarding bone metastasis until December 2006. Patients' characteristics at the time of surgery were analyzed by Cox's method, with bone metastasis as events. Patient groups were assigned according to Cox's analysis, and were judged either to require the adjuvant bisphosphonate or not, using the tentative criteria: high risk (>3% person-year), medium risk (1-3%), and low risk (<1%). Bone metastasis incidence was constant between 1.0 and 2.8% per person-year more than 10 years. Non-invasive cancer was associated with a very low incidence of bone metastasis (1/436). Multivariate Cox's analysis indicated important factors for bone metastasis were tumor grade (T), nodal grade (pN), and histology. Because T and pN were important factors for bone metastasis prediction, subgroups were made by pTNM stage. Patients at stages IIIA, IIIB and IV had an incidence of >3% per person-year, patients with stage I <1% per person-year, and those with stages II were between 1 and 3%. Further analysis with histology in stage II patients showed that stage IIB with high risk histology also had a high incidence (3% person year), whereas stage IIA with medium risk histology were <1%. Bone metastasis incidence remained constant for many years. Using pN, T, and histopathology, patients could be classified into high, medium, and low risk groups.

Liver recurrence in endometrial cancer: a multi-institutional analysis of factors predictive of postrecurrence survival.

PubMed

Toptas, Tayfun; Karalok, Alper; Ureyen, Isin; Tasci, Tolga; Erol, Onur; Bozkurt, Selen; Tulunay, Gokhan; Simsek, Tayup; Turan, Taner

2016-10-01

Predictive factors for survival following liver metastasis in endometrial cancer (EC) have not been studied to date. It is expected that patients who initially presented with liver metastasis or developed liver metastasis as the subsequent metastatic site of progressive disease are likely to have poor outcomes. However, patients developing liver metastasis as the first site of recurrence may have a chance of benefiting from the salvage therapies. Therefore, we aimed to determine factors influencing postrecurrence survival in EC patients who developed liver metastasis as the first site of recurrence. Patients with EC who underwent primary surgery at three centers between 1993 and 2013 were reviewed. Liver recurrence was defined as documentation of parenchymal liver metastasis either by radiologically or biopsy, after a disease-free interval of ≥3 months. Patients with liver metastasis at presentation, or liver metastasis as the subsequent metastatic site of progressive disease were excluded. Forty-six patients were identified. Median time to liver recurrence was 12 months, with 91.3 % of recurrences detected within 3 years. Most patients (73.9 %) had liver recurrence concomitant with extra-hepatic disease. Median survival after the diagnosis of liver recurrence was 9 months. While in univariate analysis, time to liver recurrence (p < 0.001) and presence of concomitant extra-hepatic metastasis (p = 0.048) were potential predictors of survival, multivariate analysis revealed that time to liver recurrence (p < 0.001) was the only independent predictor. This criterion may be used as a marker for stratifying patients into different prognostic risk groups and for selection of patients for salvage therapies.

Brain metastasis from ovarian cancer: a systematic review.

PubMed

Pakneshan, Shabnam; Safarpour, Damoun; Tavassoli, Fattaneh; Jabbari, Bahman

2014-08-01

To review the existing literature on brain metastasis (BM) from ovarian cancer and to assess the frequency, anatomical, clinical and paraclinical information and factors associated with prognosis. Ovarian cancer is a rare cause of brain metastasis with a recently reported increasing prevalence. Progressive neurologic disability and poor prognosis is common. A comprehensive review on this subject has not been published previously. This systematic literature search used the Pubmed and Yale library. A total of 66 publications were found, 57 of which were used representing 591 patients with BM from ovarian cancer. The median age of the patients was 54.3 years (range 20-81). A majority of patients (57.3 %) had multiple brain lesions. The location of the lesion was cerebellar (30 %), frontal (20 %), parietal (18 %) and occipital (11 %). Extracranial metastasis was present in 49.8 % of cases involving liver (20.7 %), lung (20.4 %), lymph nodes (12.6 %), bones (6.6 %) and pelvic organs (4.3 %). The most common symptoms were weakness (16 %), seizures (11 %), altered mentality (11 %) visual disturbances (9 %) and dizziness (8 %). The interval from diagnosis of breast cancer to BM ranged from 0 to 133 months (median 24 months) and median survival was 8.2 months. Local radiation, surgical resection, stereotactic radiosurgery and medical therapy were used. Factors that significantly increased the survival were younger age at the time of ovarian cancer diagnosis and brain metastasis diagnosis, lower grade of the primary tumor, higher KPS score and multimodality treatment for the brain metastases. Ovarian cancer is a rare cause of brain metastasis. Development of brain metastasis among older patients and lower KPS score correlate with less favorable prognosis. The more prolonged survival after using multimodality treatment for brain metastasis is important due to potential impact on management of brain metastasis in future.

Roles of the cyclooxygenase 2 matrix metalloproteinase 1 pathway in brain metastasis of breast cancer.

PubMed

Wu, Kerui; Fukuda, Koji; Xing, Fei; Zhang, Yingyu; Sharma, Sambad; Liu, Yin; Chan, Michael D; Zhou, Xiaobo; Qasem, Shadi A; Pochampally, Radhika; Mo, Yin-Yuan; Watabe, Kounosuke

2015-04-10

Brain is one of the major sites of metastasis in breast cancer; however, the pathological mechanism of brain metastasis is poorly understood. One of the critical rate-limiting steps of brain metastasis is the breaching of blood-brain barrier, which acts as a selective interface between the circulation and the central nervous system, and this process is considered to involve tumor-secreted proteinases. We analyzed clinical significance of 21 matrix metalloproteinases on brain metastasis-free survival of breast cancer followed by verification in brain metastatic cell lines and found that only matrix metalloproteinase 1 (MMP1) is significantly correlated with brain metastasis. We have shown that MMP1 is highly expressed in brain metastatic cells and is capable of degrading Claudin and Occludin but not Zo-1, which are key components of blood-brain barrier. Knockdown of MMP1 in brain metastatic cells significantly suppressed their ability of brain metastasis in vivo, whereas ectopic expression of MMP1 significantly increased the brain metastatic ability of the cells that are not brain metastatic. We also found that COX2 was highly up-regulated in brain metastatic cells and that COX2-induced prostaglandins were directly able to promote the expression of MMP1 followed by augmenting brain metastasis. Furthermore, we found that COX2 and prostaglandin were able to activate astrocytes to release chemokine (C-C motif) ligand 7 (CCL7), which in turn promoted self-renewal of tumor-initiating cells in the brain and that knockdown of COX2 significantly reduced the brain metastatic ability of tumor cells. Our results suggest the COX2-MMP1/CCL7 axis as a novel therapeutic target for brain metastasis. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Roles of the Cyclooxygenase 2 Matrix Metalloproteinase 1 Pathway in Brain Metastasis of Breast Cancer*

PubMed Central

Wu, Kerui; Fukuda, Koji; Xing, Fei; Zhang, Yingyu; Sharma, Sambad; Liu, Yin; Chan, Michael D.; Zhou, Xiaobo; Qasem, Shadi A.; Pochampally, Radhika; Mo, Yin-Yuan; Watabe, Kounosuke

2015-01-01

Brain is one of the major sites of metastasis in breast cancer; however, the pathological mechanism of brain metastasis is poorly understood. One of the critical rate-limiting steps of brain metastasis is the breaching of blood-brain barrier, which acts as a selective interface between the circulation and the central nervous system, and this process is considered to involve tumor-secreted proteinases. We analyzed clinical significance of 21 matrix metalloproteinases on brain metastasis-free survival of breast cancer followed by verification in brain metastatic cell lines and found that only matrix metalloproteinase 1 (MMP1) is significantly correlated with brain metastasis. We have shown that MMP1 is highly expressed in brain metastatic cells and is capable of degrading Claudin and Occludin but not Zo-1, which are key components of blood-brain barrier. Knockdown of MMP1 in brain metastatic cells significantly suppressed their ability of brain metastasis in vivo, whereas ectopic expression of MMP1 significantly increased the brain metastatic ability of the cells that are not brain metastatic. We also found that COX2 was highly up-regulated in brain metastatic cells and that COX2-induced prostaglandins were directly able to promote the expression of MMP1 followed by augmenting brain metastasis. Furthermore, we found that COX2 and prostaglandin were able to activate astrocytes to release chemokine (C-C motif) ligand 7 (CCL7), which in turn promoted self-renewal of tumor-initiating cells in the brain and that knockdown of COX2 significantly reduced the brain metastatic ability of tumor cells. Our results suggest the COX2-MMP1/CCL7 axis as a novel therapeutic target for brain metastasis. PMID:25691572

Gene Regulation and Targeted Therapy in Gastric Cancer Peritoneal Metastasis: Radiological Findings from Dual Energy CT and PET/CT.

PubMed

Shi, Bowen; Lin, Huimin; Zhang, Miao; Lu, Wei; Qu, Ying; Zhang, Huan

2018-01-22

Gastric cancer remains fourth in cancer incidence worldwide with a five-year survival of only 20%-30%. Peritoneal metastasis is the most frequent type of metastasis that accompanies unresectable gastric cancer and is a definitive determinant of prognosis. Preventing and controlling the development of peritoneal metastasis could play a role in helping to prolong the survival of gastric cancer patients. A non-invasive and efficient imaging technique will help us to identify the invasion and metastasis process of peritoneal metastasis and to monitor the changes in tumor nodules in response to treatments. This will enable us to obtain an accurate description of the development process and molecular mechanisms of gastric cancer. We have recently described experiment using dual energy CT (DECT) and positron emission tomography/computed tomography (PET/CT) platforms for the detection and monitoring of gastric tumor metastasis in nude mice models. We have shown that weekly continuous monitoring with DECT and PET/CT can identify dynamic changes in peritoneal metastasis. The sFRP1-overexpression in gastric cancer mice models showed positive radiological performance, a higher FDG uptake and increasing enhancement, and the SUVmax (standardized uptake value) of nodules demonstrated an obvious alteration trend in response to targeted therapy of TGF-β1 inhibitor. In this article, we described the detailed non-invasive imaging procedures to conduct more complex research on gastric cancer peritoneal metastasis using animal models and provided representative imaging results. The use of non-invasive imaging techniques should enable us to better understand the mechanisms of tumorigenesis, monitor tumor growth, and evaluate the effect of therapeutic interventions for gastric cancer.

Ubiquitin-conjugating enzyme complex Uev1A-Ubc13 promotes breast cancer metastasis through nuclear factor-кB mediated matrix metalloproteinase-1 gene regulation

PubMed Central

2014-01-01

Introduction UEV1A encodes a ubiquitin-conjugating enzyme variant (Ubc13), which is required for Ubc13-catalyzed Lys63-linked polyubiquitination of target proteins and nuclear factor κB (NF-кB) activation. Previous reports have correlated the level of UEV1A expression with tumorigenesis; however, the detailed molecular events leading to tumors particularly breast cancer and metastasis are unclear. This study is to investigate roles of different UEV1 splicing variants, and its close homolog MMS2, in promoting tumorigenesis and metastasis in breast cancer cells. Methods We experimentally manipulated the UEV1 and MMS2 levels in MDA-MB-231 breast cancer cells and monitored their effects on cell invasion and migration, as well as tumor formation and metastasis in xenograft mice. The underlying molecular mechanisms leading to metastasis were also examined. Results It was found that overexpression of UEV1A alone, but not UEV1C or MMS2, is sufficient to induce cell invasion in vitro and metastasis in vivo. This process is mediated by NF-κB activation and requires functional Ubc13. Our experimental data establish that among NF-κB target genes, UEV1A-regulated matrix metalloproteinase-1 (MMP1) expression plays a critical role in cell invasion and metastasis. Interestingly, experimental depletion of UEV1 in MDA-MB-231 cells reduces MMP1 expression and prevents tumor formation and metastasis in a xenograft mouse model, while overexpression of MMP1 overrides the metastasis effects in UEV1-depleted cells. Conclusions These results identify UEV1A as a potential therapeutic target in the treatment of metastasic breast cancers. PMID:25022892

Enhanced tumor metastasis in response to blockade of the chemokine receptor CXCR6 is overcome by NKT cell activation.

PubMed

Cullen, Robyn; Germanov, Elitza; Shimaoka, Takeshi; Johnston, Brent

2009-11-01

Invariant NKT (iNKT) cells can induce potent antitumor responses in vivo. However, the mechanisms that regulate the effects of iNKT cells are unclear. The chemokine receptor CXCR6, and its ligand CXCL16, have been shown to play critical roles in iNKT cell homeostasis and activation. Thus we investigated the role of CXCR6 in protection against experimental metastasis of B16-F10 melanoma (B16) and Lewis lung carcinoma (LLC) cells to the liver and lungs. Wild-type and CXCR6(-/-) mice exhibited no differences in tumor cell metastasis to the lungs. However, metastasis of LLC and B16 tumor cells to the liver was enhanced in CXCR6(-/-) mice. Liver metastasis was also increased in wild-type mice treated with a CXCL16 neutralizing Ab. As Ab treatments did not alter iNKT cell numbers, this implicates a direct role for CXCR6/CXCL16 in regulating antitumor immunity. Cytokine induction was significantly attenuated in CXCR6(-/-) mice upon systemic iNKT cell activation with the glycolipid Ags alpha-galactosylceramide (alpha-GalCer), alpha-C-GalCer (a Th1 polarizing derivative), or OCH (a Th2 polarizing derivative). Despite differences in the levels of cytokine production, liver and lung metastasis were inhibited significantly in both wild-type and CXCR6(-/-) mice treated with glycolipids. Single doses of alpha-GalCer, alpha-C-GalCer, or OCH were sufficient to prevent liver metastasis and subsequent doses failed to elicit optimal cytokine responses. Our findings implicate a role for CXCR6 in natural immunosurveillance against liver metastasis. However, CXCR6 deficiency could be overcome by systemic iNKT cell activation, demonstrating that even suboptimal iNKT cell activation can protect against metastasis.

Hypoxia-Inducible Factor-1α Polymorphisms and Risk of Cancer Metastasis: A Meta-Analysis

PubMed Central

Shi, Bin; Weng, Wenjun; Chen, Zhipeng; Guo, Nannan; Hua, Yibing; Zhu, Lingjun

2013-01-01

Background HIF-1α is a major regulator in tumor progression and metastasis which responds to hypoxia. Many studies have demonstrated that hypoxia-inducible factor1-α (HIF-1α) polymorphisms are significantly associated with cancer metastasis, but the results are inconsistent. We conducted a comprehensive meta-analysis to estimate the associations between HIF-1α C1772 T polymorphism and cancer metastasis. Methods Comprehensive searches were conducted on PubMed and EMBASE database. Fifteen studies were included in the meta-analysis. We used the OR and 95%CI to assess the associations between HIF-1α C1772T polymorphism and cancer metastasis. Heterogeneity and publication bias were also assessed by Q test, I 2, and funnel plot. Results Totally, fifteen studies including 1239 cases with metastasis-positive (M+) and 2711 cases with metastasis-negative (M−) were performed in this meta-analysis. The results showed that HIF-1a C1772T polymorphism was associated with the increased risk of cancer metastasis (T allele vs. C allele, OR  = 1.36, 95% CI  = 1.12–1.64; TT+ TC vs. CC, OR  = 1.39, 95% CI  = 1.13–1.71; TT vs. TC+ CC, OR  = 1.93, 95% CI  = 0.86–4.36). In the subgroup analyses, the significant associations remained significant among Asians, Caucasians and other cancers in the dominant model. Publication bias was not observed in the analysis. Conclusions Our results indicate that the HIF-1αC1772T polymorphism T allele may increase the risk of cancer metastasis, which might be a potential risk factor of cancer progress. PMID:24015181

CD133+CD54+CD44+ circulating tumor cells as a biomarker of treatment selection and liver metastasis in patients with colorectal cancer

PubMed Central

Wang, Cun; Huang, Qiaorong; Meng, Wentong; Yu, Yongyang; Yang, Lie; Peng, Zhihai; Hu, Jiankun; Li, Yuan; Mo, Xianming; Zhou, Zongguang

2016-01-01

Introduction Liver is the most common site of distant metastasis in colorectal cancer (CRC). Early diagnosis and appropriate treatment selection decides overall prognosis of patients. However, current diagnostic measures were basically imaging but not functional. Circulating tumor cells (CTCs) known as hold the key to understand the biology of metastatic mechanism provide a novel and auxiliary diagnostic strategy for CRC with liver metastasis (CRC-LM). Results The expression of CD133+ and CD133+CD54+CD44+ cellular subpopulations were higher in the peripheral blood of CRC-LM patients when compared with those without metastasis (P<0.001). Multivariate analysis proved the association between the expression of CD133+CD44+CD54+ cellular subpopulation and the existence of CRC-LM (P<0.001). The combination of abdominal CT/MRI, CEA and the CD133+CD44+CD54+ cellular subpopulation showed increased detection and discrimination rate for liver metastasis, with a sensitivity of 88.2% and a specificity of 92.4%. Meanwhile, it also show accurate predictive value for liver metastasis (OR=2.898, 95% C.I.1.374–6.110). Materials and Method Flow cytometry and multivariate analysis was performed to detect the expression of cancer initiating cells the correlation between cellular subpopulations and liver metastasis in patients with CRC. The receiver operating characteristic curves combined with the area under the curve were generated to compare the predictive ability of the cellular subpopulation for liver metastasis with current CT and MRI images. Conclusions The identification, expression and application of CTC subpopulations will provide an ideal cellular predictive marker for CRC liver metastasis and a potential marker for further investigation. PMID:27764803

Factors predictive of pelvic lymph node involvement and outcomes in melanoma patients with metastatic sentinel lymph node of the groin: A multicentre study.

PubMed

Mozzillo, N; Pasquali, S; Santinami, M; Testori, A; Di Marzo, M; Crispo, A; Patuzzo, R; Verrecchia, F; Botti, G; Montella, M; Rossi, C R; Caracò, C

2015-07-01

The optimal extent of the groin lymph node (LN) dissection for melanoma patients with positive sentinel LN biopsy is still debated and no agreement exist on dissection of pelvic LN. This study aimed at investigating predictors of pelvic LN metastasis and prognostic significance of having metastasis in the pelvic LNs. Clinicopathologic data of 740 patients with positive groin sentinel LN who underwent ilioinguinal completion LN dissection at four Italian centre were analysed. Multivariable logistic and Cox regression analysis was used to identify independent predictors of pelvic LN metastasis and to adjust prognostic significance of pelvic LN metastasis. More than a quarter (26%) of patients had positive non-SLNs after inguinal and pelvic lymphadenectomy, which were located in their pelvis in the 12% of cases. Older patients [(OR) 1.69; 95% confidence interval (CI) 1.02-2.78] having thick primary (OR 1.6; 95% CI, 1.01-2.53) and ≥ 2 positive SLNs (OR 2.5; 95% CI, 1.4-4.47) were more likely to harbour pelvic LN metastasis. Interestingly, 4% of all patients (34% of patients with positive pelvic LNs) had pelvic LN metastasis with negative inguinal LNs. Pelvic LN metastasis was independently associated with higher risk of recurrence and lower survival. 5-year disease free and overall survival was 30% and 50%, respectively, for patients with pelvic LN metastasis. Pelvic LNs are frequently positive after ilioinguinal lymphadenectomy and it should be considered for all patients, especially those who are older, have thick primary and ≥ 2 positive SLN. Patients with pelvic LN metastasis have worse prognosis. Copyright © 2015 Elsevier Ltd. All rights reserved.

An Orthotopic Mouse Model of Spontaneous Breast Cancer Metastasis.

PubMed

Paschall, Amy V; Liu, Kebin

2016-08-14

Metastasis is the primary cause of mortality of breast cancer patients. The mechanism underlying cancer cell metastasis, including breast cancer metastasis, is largely unknown and is a focus in cancer research. Various breast cancer spontaneous metastasis mouse models have been established. Here, we report a simplified procedure to establish orthotopic transplanted breast cancer primary tumor and resultant spontaneous metastasis that mimic human breast cancer metastasis. Combined with the bioluminescence live tumor imaging, this mouse model allows tumor growth and progression kinetics to be monitored and quantified. In this model, a low dose (1 x 10(4) cells) of 4T1-Luc breast cancer cells was injected into BALB/c mouse mammary fat pad using a tuberculin syringe. Mice were injected with luciferin and imaged at various time points using a bioluminescent imaging system. When the primary tumors grew to the size limit as in the IACUC-approved protocol (approximately 30 days), mice were anesthetized under constant flow of 2% isoflurane and oxygen. The tumor area was sterilized with 70% ethanol. The mouse skin around the tumor was excised to expose the tumor which was removed with a pair of sterile scissors. Removal of the primary tumor extends the survival of the 4T-1 tumor-bearing mice for one month. The mice were then repeatedly imaged for metastatic tumor spreading to distant organs. Therapeutic agents can be administered to suppress tumor metastasis at this point. This model is simple and yet sensitive in quantifying breast cancer cell growth in the primary site and progression kinetics to distant organs, and thus is an excellent model for studying breast cancer growth and progression, and for testing anti-metastasis therapeutic and immunotherapeutic agents in vivo.

The Clinicopathological Factors Associated with Disease Progression in Luminal A Breast Cancer and Characteristics of Metastasis: A Retrospective Study from A Single Center in China.

PubMed

Ye, Jingming; Wang, Wenjun; Xin, Ling; Owen, Sioned; Xu, Ling; Duan, Xuening; Cheng, Yuanjia; Zhang, Hong; Zhang, Shuang; Li, Ting; Liu, Yinhua

2017-08-01

This study investigated the clinicopathological factors associated with outcomes in patients with Luminal A breast cancer. Retrospective analysis of the association of clinicopathological factors and breast cancer outcome in 421 patients with newly-diagnosed Luminal-A breast cancer that were enrolled from January 2008 to December 2014. Clinicopathological data were analyzed to validate the relationship with disease-free survival (DFS) and overall survival (OS). Kaplan-Meier curves and log-rank tests were used to analyze the value of clinicopathological factors (tumor size, node status and lymphovascular invasion), and subsequent Cox regression analysis revealed significant prognostic factors. With a median of 61 months follow-up, the 5-year DFS and 5-year OS rate were 98.3% and 99.3%. Cox multivariate regression analysis showed that clinical anatomic stage, tumor size, status of lymph nodes, lymphovascular invasion and systemic treatment are strong prognostic factors for clinical outcome in patients with Luminal-A breast cancer. Of all 413 patients with stage I-III breast cancer, 14 presented with metastasis (3.4%) during the follow up. Bone (6/14, 42.9%) was the most common site of metastasis followed by liver (5/14, 35.7%) and lung (4/14, 28.6%). The median survival time after metastasis was 20.4 months. Of all the sites of distant metastasis, liver metastasis was the only factor that affected survival time after metastasis (χ 2 =6.263, p=0.012). Patients with Luminal A breast cancer have excellent outcomes. Liver metastasis is an important factor compressing the survival time after distant metastasis presents. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Rapamycin Promotes Mouse 4T1 Tumor Metastasis that Can Be Reversed by a Dendritic Cell-Based Vaccine

PubMed Central

Lin, Tien-Jen; Liang, Wen-Miin; Hsiao, Pei-Wen; M. S, Pradeep; Wei, Wen-Chi; Lin, Hsin-Ting; Yin, Shu-Yi; Yang, Ning-Sun

2015-01-01

Suppression of tumor metastasis is a key strategy for successful cancer interventions. Previous studies indicated that rapamycin (sirolimus) may promote tumor regression activity or enhance immune response against tumor targets. However, rapamycin also exhibits immunosuppressant effects and is hence used clinically as an organ transplantation drug. We hypothesized that the immunosuppressive activities of rapamycin might also negatively mediate host immunity, resulting in promotion of tumor metastasis. In this study, the effects of rapamycin and phytochemical shikonin were investigated in vitro and in vivo in a 4T1 mouse mammary tumor model through quantitative assessment of immunogenic cell death (ICD), autophagy, tumor growth and metastasis. Tumor-bearing mice were immunized with test vaccines to monitor their effect on tumor metastasis. We found that intraperitoneal (ip) administration of rapamycin after a tumor-resection surgery drastically increased the metastatic activity of 4T1 tumors. Possible correlation of this finding to human cancers was suggested by epidemiological analysis of data from Taiwan’s National Health Insurance Research Database (NHIRD). Since our previous studies showed that modified tumor cell lysate (TCL)-pulsed, dendritic cell (DC)-based cancer vaccines can effectively suppress metastasis in mouse tumor models, we assessed whether such vaccines may help offset this rapamycin-promoted metastasis. We observed that shikonin efficiently induced ICD of 4T1 cells in culture, and DC vaccines pulsed with shikonin-treated TCL (SK-TCL-DC) significantly suppressed rapamycin-enhanced metastasis and Treg cell expansion in test mice. In conclusion, rapamycin treatment in mice (and perhaps in humans) promotes metastasis and the effect may be offset by treatment with a DC-based cancer vaccine. PMID:26426423

Brain metastasis in lung cancer: Building a molecular and systems-level understanding to improve outcomes.

PubMed

Ebben, Johnathan D; You, Ming

2016-09-01

Lung cancer is a clinically difficult disease with rising disease burden around the world. Unfortunately, most lung cancers present at a clinically advanced stage. Of these cancers, many also present with brain metastasis which complicates the clinical picture. This review summarizes current knowledge on the molecular basis of lung cancer brain metastases. We start from the clinical perspective, aiming to provide a clinical context for a significant problem that requires much deeper scientific investigation. We review new research governing the metastatic process, including tumor cell signaling, establishment of a receptive tumor niches in the brain and evaluate potential new therapeutic options that take advantage of these new scientific advances. Lung cancer remains the largest single cause of cancer mortality in the United States (Siegel et al., 2015). This continues to be the clinical picture despite significant advances in therapy, including the advent of targeted molecular therapies and newly adopted immunotherapies for certain subtypes of lung cancer. In the vast majority of cases, lung cancer presents as advanced disease; in many instances, this advanced disease state is intimately associated with micro and macrometastatic disease (Goldberg et al., 2015). For both non-small cell lung cancer and small cell lung cancer patients, the predominant metastatic site is the brain, with up to 68% of patients with mediastinal lymph node metastasis eventually demonstrating brain metastasis (Wang et al., 2009).The frequency (incidence) of brain metastasis is highest in lung cancers, relative to other common epithelial malignancies (Schouten et al., 2002). Other studies have attempted to predict the risk of brain metastasis in the setting of previously non-metastatic disease. One of the largest studies to do this, analyzing historical data from 1973 to 2011 using the SEER database revealed a 9% risk of patients with previously non-metastatic NSCLC developing brain metastasis over the course of their disease, while 18% of small cell lung cancer patients without previous metastasis went on to develop brain metastasis as their disease progressed (Goncalves et al., 2016).The reasons underlying this predilection for the central nervous system, as well as the recent increase in the frequency of brain metastasis identified in patients remain important questions for both clinicians and basic scientists. More than ever, the question of how brain metastasis develop and how they can be treated and managed requires the involvement of interdisciplinary teams-and more importantly-scientists who are capable of thinking like clinicians and clinicians who are capable of thinking like scientists. This review aims to present a translational perspective on brain metastasis. We will investigate the scope of the problem of brain metastasis and the current management of the metastatic disease process in lung cancer. From this clinical starting point, we will investigate the literature surrounding the molecular underpinnings of lung tumor metastasis and seek to understand the process from a biological perspective to generate new hypotheses. Copyright © 2016 Elsevier Ltd. All rights reserved.

False-Positive Cases of Fluorodeoxyglucose-Positron Emission Tomography/Computed Tomographic Scans in Metastasis of Esophageal Cancer

PubMed Central

Yamatsuji, Tomoki; Ishida, Naomasa; Takaoka, Munenori; Hayashi, Jiro; Yoshida, Kazuhiro; Shigemitsu, Kaori; Urakami, Atsushi; Haisa, Minoru; Naomoto, Yoshio

2017-01-01

Of 129 esophagectomies at our institute from June 2010 to March 2015, we experienced three preoperative positron emission tomography-computed tomographic (PET/CT) false positives. Bone metastasis was originally suspected in 2 cases, but they were later found to be bone metastasis negative after a preoperative bone biopsy and clinical course observation. The other cases suspected of mediastinal lymph node metastasis were diagnosed as inflammatory lymphadenopathy by a pathological examination of the removed lymph nodes. Conducting a PET/CT is useful when diagnosing esophageal cancer metastasis, but we need to be aware of the possibility of false positives. Therapeutic decisions should be made based on appropriate and accurate diagnoses, with pathological diagnosis actively introduced if necessary. PMID:28469502

Searching early bone metastasis on plain radiography by using digital imaging processing

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

Jaramillo-Nunez, A.; Perez-Meza, M.; Universidad de la Sierra Sur, C. P. 70800, Miahuatlan, Oax.

2012-10-23

Some authors mention that it is not possible to detect early bone metastasis on plain radiography. In this work we use digital imaging processing to analyze three radiographs taken from a patient with bone metastasis discomfort on the right shoulder. The time period among the first and second radiography was approximately one month and between the first and the third one year. This procedure is a first approach in order to know if in this particular case it was possible to detect an early bone metastasis. The obtained results suggest that by carrying out a digital processing is possible tomore » detect the metastasis since the radiography contains the information although visually it is not possible to observe it.« less

Anal metastasis as the sentinel and isolated presentation of invasive ductal breast carcinoma.

PubMed

Rengifo, C; Titi, S; Walls, J

2016-05-01

Breast cancer currently affects 1 in 8 women in the UK during their lifetime. Common sites for breast cancer metastasis include the axillary lymph nodes, bones, lung, liver, brain, soft tissue and adrenal glands. There is well documented evidence detailing breast metastasis to the gastrointestinal tract but anal metastasis is exceptionally rare. We present the case of a 78-year-old woman with an anal metastasis as the sentinel and isolated presentation of an invasive ductal breast carcinoma. As advances in the treatment of breast cancer improve, and with an ageing and expanding population, there will be an increasing number of cancer survivors, and more of these unusual presentations may be encountered in the future.

Choroidal metastasis of a minor salivary gland adenoid cystic carcinoma: A case report.

PubMed

Portilla Blanco, R R; Roberts Martínez-Aguirre, I; Pontón Méndez, P; Zarzosa Martín, M E; Pérez-Salvador García, E

2018-03-21

A 61-year-old man with a lower lip minor salivary gland adenoid cystic carcinoma, suffered from a unilateral progressive visual acuity loss due to choroidal metastasis. Adenoid cystic carcinoma is a rare primary tumour with significant metastatic potential. Our patient presented with a unilateral choroidal metastasis. According to the current literature, 8 cases of choroidal metastasis of salivary gland adenoid cystic carcinoma have been reported. This is the second case reported of choroidal metastasis with origin in a minor salivary gland, and the first one with origin in the minor salivary glands of the lower lip. Copyright © 2018 Sociedad Española de Oftalmología. Publicado por Elsevier España, S.L.U. All rights reserved.

On the Origin of Cancer Metastasis

PubMed Central

Seyfried, Thomas N.; Huysentruyt, Leanne C.

2013-01-01

Metastasis involves the spread of cancer cells from the primary tumor to surrounding tissues and to distant organs and is the primary cause of cancer morbidity and mortality. In order to complete the metastatic cascade, cancer cells must detach from the primary tumor, intravasate into the circulatory and lymphatic systems, evade immune attack, extravasate at distant capillary beds, and invade and proliferate in distant organs. Currently, several hypotheses have been advanced to explain the origin of cancer metastasis. These involve an epithelial mesenchymal transition, an accumulation of mutations in stem cells, a macrophage facilitation process, and a macrophage origin involving either transformation or fusion hybridization with neoplastic cells. Many of the properties of metastatic cancer cells are also seen in normal macrophages. A macrophage origin of metastasis can also explain the long-standing “seed and soil” hypothesis and the absence of metastasis in plant cancers. The view of metastasis as a macrophage metabolic disease can provide novel insight for therapeutic management. PMID:23237552

Systematic analysis of molecular mechanisms for HCC metastasis via text mining approach.

PubMed

Zhen, Cheng; Zhu, Caizhong; Chen, Haoyang; Xiong, Yiru; Tan, Junyuan; Chen, Dong; Li, Jin

2017-02-21

To systematically explore the molecular mechanism for hepatocellular carcinoma (HCC) metastasis and identify regulatory genes with text mining methods. Genes with highest frequencies and significant pathways related to HCC metastasis were listed. A handful of proteins such as EGFR, MDM2, TP53 and APP, were identified as hub nodes in PPI (protein-protein interaction) network. Compared with unique genes for HBV-HCCs, genes particular to HCV-HCCs were less, but may participate in more extensive signaling processes. VEGFA, PI3KCA, MAPK1, MMP9 and other genes may play important roles in multiple phenotypes of metastasis. Genes in abstracts of HCC-metastasis literatures were identified. Word frequency analysis, KEGG pathway and PPI network analysis were performed. Then co-occurrence analysis between genes and metastasis-related phenotypes were carried out. Text mining is effective for revealing potential regulators or pathways, but the purpose of it should be specific, and the combination of various methods will be more useful.

Effective Treatment of Solitary Pituitary Metastasis with Panhypopituitarism in HER2-Positive Breast Cancer by Lapatinib.

PubMed

Park, Youngmok; Kim, Hyemin; Kim, Eui-Hyun; Suh, Chang-Ok; Lee, Soohyeon

2016-01-01

Brain metastasis affects one third of patients with HER2-positive breast cancer after treatment with trastuzumab. Surgical resection and radiation therapy are often unsuccessful at accomplishing complete control of metastasis. Lapatinib is presumed to cross the blood-brain barrier, and exhibits clinical activities for treatment of HER2-positive breast cancer. A 43-year-old woman was treated for early breast carcinoma with total mastectomy, axillary lymph-node dissection, and adjuvant chemotherapy with cyclophosphamide plus doxorubicin. After the end of adjuvant trastuzumab therapy, she was diagnosed with panhypopituitarism due to pituitary metastasis. Surgical removal and whole brain radiation therapy were performed, but a portion of viable tumor remained. Only taking lapatinib, the size of the metastatic lesion began to shrink. Trastuzumab may have controlled the micro-metastasis of breast cancer, but it was unable to control its progression to the central nervous system. Lapatinib is a possible option for HER2-positive metastatic breast cancer patients with brain metastasis.

High-risk squamous cell carcinoma of the ear - A potential role for sentinel node biopsy.

PubMed

Beecher, Suzanne; Wrafter, Paula F; Joyce, Cormac W; Regan, Padraic J; Kelly, Jack L

2017-09-01

Squamous cell carcinomas (SCCs) of the external ear have a significant rate of metastasis. The purpose of this study was to present analyzed factors associated with auricular SCC metastasis in order to identify a group that may benefit from sentinel lymph node biopsy (SLNB). We performed a retrospective review of all operable SCCs between 2009 and 2014. The association between high-risk features and metastasis were analyzed. One hundred eighty-nine auricular SCCs were excised. Local recurrence was noted in 11% and 9.5% developed metastases. Cartilage, perineural, and lymphovascular invasion were significantly associated with metastasis, as were increased tumor depth and diameter (P < .001). All patients with metastasis developed nodal disease. Factors, including poor differentiation, perineural, cartilage, and lymphovascular invasion, are associated with auricular SCC metastasis. Patients with 2 or more high-risk features may benefit from SLNB in order to identify and treat early nodal disease and possibly reduce the risk of further spread. © 2017 Wiley Periodicals, Inc.

Invasion and Metastasis of SY86B Human Gastric Carcinoma Cells in Nude Mice

PubMed Central

Zhang, Yin‐Chang

1988-01-01

A moderately differentiated tubular adenocarcinoma of human stomach, named SY86B, was successfully transplanted subcutaneously to nude mice of different genetic backgrounds (BALB/CA/PBI‐nu, C57BL/6J.615/PBI‐nu and ICR‐BALB/CA/PBI‐nu). The tumor has been passaged for 13 generations and the transplantability was 100%. The SY86B cells retained the capacity of invasive and metastatic growth in the nude mice and showed a high rate of metastasis to the regional lymph nodes and to such distant organs as the lungs, liver and pancreas. The overall rate of metastasis was 77.7%. The species of the nude mice, their age and sex apparently did not significantly affect the occurrence of metastasis. Tumor‐bearing time and the aggressive character of the tumor cells themselves appeared important for the genesis of metastasis. This experimental model can provide a new approach to basic and clinical studies of cancer metastasis. PMID:3137202

Gpr132 sensing of lactate mediates tumor–macrophage interplay to promote breast cancer metastasis

PubMed Central

Chen, Peiwen; Zuo, Hao; Xiong, Hu; Kolar, Matthew J.; Chu, Qian; Saghatelian, Alan; Siegwart, Daniel J.; Wan, Yihong

2017-01-01

Macrophages are prominent immune cells in the tumor microenvironment that exert potent effects on cancer metastasis. However, the signals and receivers for the tumor–macrophage communication remain enigmatic. Here, we show that G protein-coupled receptor 132 (Gpr132) functions as a key macrophage sensor of the rising lactate in the acidic tumor milieu to mediate the reciprocal interaction between cancer cells and macrophages during breast cancer metastasis. Lactate activates macrophage Gpr132 to promote the alternatively activated macrophage (M2)-like phenotype, which, in turn, facilitates cancer cell adhesion, migration, and invasion. Consequently, Gpr132 deletion reduces M2 macrophages and impedes breast cancer lung metastasis in mice. Clinically, Gpr132 expression positively correlates with M2 macrophages, metastasis, and poor prognosis in patients with breast cancer. These findings uncover the lactate-Gpr132 axis as a driver of breast cancer metastasis by stimulating tumor–macrophage interplay, and reveal potential new therapeutic targets for breast cancer treatment. PMID:28049847

Brain Metastasis: Unique Challenges and Open Opportunities

PubMed Central

Lowery, Frank J.; Yu, Dihua

2016-01-01

The metastasis of cancer to the central nervous system (CNS) remains a devastating clinical reality, carrying an estimated survival time of less than one year in spite of recent therapeutic breakthroughs for other disease contexts. Advances in brain metastasis research are hindered by a number of reasons, including its complicated nature and the difficulty of modeling metastatic cancer growth in the unique brain microenvironment. In this review, we will discuss the clinical challenge, and compare the values and limitations of the available models for brain metastasis research. Additionally, we will specifically address current knowledge on how brain metastases take advantage of the unique brain environment to benefit their own growth. Finally, we will explore the distinctive metabolic and nutrient characteristics of the brain; how these paradoxically represent barriers to establishment of brain metastasis, but also provide ample supplies for metastatic cells’ growth in the brain. We envision that multi-disciplinary innovative approaches will open opportunities for the field to make breakthroughs in tackling unique challenges of brain metastasis. PMID:27939792

Biomechanical forces in the skeleton and their relevance to bone metastasis: biology and engineering considerations.

PubMed

Lynch, Maureen E; Fischbach, Claudia

2014-12-15

Bone metastasis represents the leading cause of breast cancer related-deaths. However, the effect of skeleton-associated biomechanical signals on the initiation, progression, and therapy response of breast cancer bone metastasis is largely unknown. This review seeks to highlight possible functional connections between skeletal mechanical signals and breast cancer bone metastasis and their contribution to clinical outcome. It provides an introduction to the physical and biological signals underlying bone functional adaptation and discusses the modulatory roles of mechanical loading and breast cancer metastasis in this process. Following a definition of biophysical design criteria, in vitro and in vivo approaches from the fields of bone biomechanics and tissue engineering that may be suitable to investigate breast cancer bone metastasis as a function of varied mechano-signaling will be reviewed. Finally, an outlook of future opportunities and challenges associated with this newly emerging field will be provided. Copyright © 2014 Elsevier B.V. All rights reserved.

Massive trapezial metastasis from gastric adenocarcinoma resected and reconstructed with a vascularized scapular bone graft

PubMed Central

Okamoto, Masanori; Yamazaki, Hiroshi; Yoshimura, Yasuo; Aoki, Kaoru; Tanaka, Atsushi; Kato, Hiroyuki

2017-01-01

Abstract Rationale: Isolated metastasis to the hand bones is very rare. Only seven cases of metastasis to the trapezium have been reported. To the best of our knowledge, this is the first report of a single metastasis to the trapezium from a gastric adenocarcinoma. Patient concerns: A 62-year-old man presented with pain and massive swelling in the right carpometacarpal joint of the thumb. Diagnoses: The patient was diagnosed with trapezial metastasis of advanced gastric adenocarcinoma. Interventions: The patient underwent systemic chemotherapy with cisplatin and S-1, radiotherapy to the metastatic bone, and treatment with denosumab. One year later, the huge metastatic tumor was resected, and the hand was reconstructed using vascularized scapular bone. Outcomes: Eighteen months postoperatively, the patient was satisfied with the appearance of the reconstructed hand and was able to use his right thumb in activities of daily living. Lessons: Although rare, metastasis to the trapezium should be considered in patients with persistent and progressive thumb CMC joint pain. PMID:29390390

[Therapy of malignant melanoma at the stage of distant metastasis].

PubMed

Garbe, C; Eigentler, T K

2004-02-01

Treatment of melanoma in the stage of distant metastasis aims on palliation and achievement of durable tumor remission with prolongation of survival. As long as metastasis is confined to one organ system and is removable, surgery remains the treatment of first choice. In limited metastasis radiotherapy may likewise be indicated, particularly in bone and brain metastasis. More extensive metastasis should be treated by chemotherapy or chemoimmunotherapy. Monochemotherapy with dacarbazine, temozolomide, fotemustine and vindesine or its combinations with interferon-alpha are currently preferred. Polychemotherapy or its combinations with interferon-alpha and interleukin-2 are suitable to produce higher response rates but failed to prolong survival. As these treatments are associated with substantially higher toxicity they have been widely abandoned. Combined treatment with dacarbazine and interferon-alpha obtain tumor responses or stable disease in 40-50% and objective tumor remissions in 15-20% of patients. Effective cancer vaccination strategies and blockade of melanoma specific target molecules are currently developed as new treatment options.

Inhibiting platelet-derived growth factor beta reduces Ewing's sarcoma growth and metastasis in a novel orthotopic human xenograft model.

PubMed

Wang, Yong Xin; Mandal, Deendayal; Wang, Suizhau; Hughes, Dennis; Pollock, Raphael E; Lev, Dina; Kleinerman, Eugenie; Hayes-Jordan, Andrea

2009-01-01

Despite aggressive therapy, Ewing's sarcoma (ES) patients have a poor five-year overall survival of only 20-40%. Pulmonary metastasis is the most common form of demise in these patients. The pathogenesis of pulmonary metastasis is poorly understood and few orthotopic models exist that allow study of spontaneous pulmonary metastasis in ES. We have developed a novel orthotopic xenograft model in which spontaneous pulmonary metastases develop. While the underlying biology of ES is incompletely understood, in addition to the EWS-FLI-1 mutation, it is known that platelet-derived growth factor receptor beta (PDGFR-beta) is highly expressed in ES. Hypothesizing that PDGFR-beta expression is indicative of a specific role for this receptor protein in ES progression, the effect of PDGFR-beta inhibition on ES growth and metastasis was assessed in this novel orthotopic ES model. Silencing PDGFR-beta reduced spontaneous growth and metastasis in ES. Preclinical therapeutically relevant findings such as these may ultimately lead to new treatment initiatives in ES.

Sudden Onset of Brain Metastasis despite the Use of Vemurafenib for Another Metastatic Lesion in Malignant Melanoma Patients.

PubMed

Imafuku, Keisuke; Yoshino, Koji; Yamaguchi, Kei; Tsuboi, Satoshi; Ohara, Kuniaki; Hata, Hiroo

2017-01-01

Vemurafenib is an inhibitor of the BRAF mutation and has been approved by the Food and Drug Administration as a treatment option for patients with unresectable melanoma without brain metastasis. In the literature, vemurafenib has been reported to be also effective against brain metastasis. We encountered 3 cases with brain metastasis on vemurafenib therapy. In these cases, vemurafenib was clinically effective against metastatic lesions other than those in the brain. The brain lesions developed after the metastatic lesion had occurred. Therefore, we assume that the melanomas of the patients acquired resistance against vemurafenib. The brain metastases were treated with the cyberknife. Patients 1 and 2 without LDH elevation are still alive, but patient 3 with abnormal LDH elevation died despite the treatment. We need to carefully follow patients on vemurafenib therapy because brain metastasis can suddenly occur even if the metastatic lesion has decreased clinically. The therapeutic effect of vemurafenib against brain metastasis is poor in cases with LDH elevation.

Trends in port-site metastasis after laparoscopic resection of incidental gallbladder cancer: A systematic review.

PubMed

Berger-Richardson, David; Chesney, Tyler R; Englesakis, Marina; Govindarajan, Anand; Cleary, Sean P; Swallow, Carol J

2017-03-01

The risk of port-site metastasis after laparoscopic removal of incidental gallbladder cancer was previously estimated to be 14-30%. The present study was designed to determine the incidence of port-site metastasis in incidental gallbladder cancer in the modern era (2000-2014) versus the historic era (1991-1999). We also investigated the site of port-site metastasis. Using PRISMA, a systematic review was conducted to identify papers that addressed the development of port-site metastasis after laparoscopic resection of incidental gallbladder cancer. Studies that described cancer-specific outcomes in ≥5 patients were included. A validated quality appraisal tool was used, and a weighted estimate of the incidence of port-site metastasis was calculated. Based on data extracted from 27 papers that met inclusion criteria, the incidence of port-site metastasis in incidental gallbladder cancer has decreased from 18.6% prior to 2000 (95% confidence interval 15.3-21.9%, n = 7) to 10.3% since then (95% confidence interval 7.9-12.7%, n = 20) (P < .001). The extraction site is at significantly higher risk than nonextraction sites. The incidence of port-site metastasis in incidental gallbladder cancer has decreased but remains high relative to other primary tumors. Any preoperative finding that raises the suspicion of gallbladder cancer should prompt further investigation and referral to a hepato-pancreato-biliary specialist. Copyright © 2016 Elsevier Inc. All rights reserved.

MicroRNA targeting microtubule cross-linked protein (MACF1) would suppress the invasion and metastasis of malignant tumor.

PubMed

Zhao, Wenpeng; Qian, Huiming; Zhang, Ruisan; Gao, Xingchun; Gou, Xingchun

2017-07-01

Cancer is one of the most serious diseases that endanger human health in the world today, and the incidence and mortality of cancer increases year by year. Invasion and metastasis is the most prominent feature of malignant tumors, but also becomes the primary factor of threatening patient's health. Tumor cell invasion and metastasis which closely related to the dynamic changes of the cytoskeleton is an important factor influencing the survival of patients. Therefore, inhibition of tumor cell invasion and metastasis is a key strategy for the treatment of cancer. MACF1 is a microtubule microfilament cross-linking factor that plays an important role in cell polarization, cell migration, and maintenance of tissue integrity. A lot of studies have shown that microRNAs play an important role in tumorigenesis, invasion and metastasis. Therefore, we propose the following scientific assumptions: MACF1, an important molecule in adjusting the invasion and metastasis of tumor cells, regulates microfilaments, microtubules participating in cytoskeleton dynamics to promote malignant tumor cell migration and invasion; MicroRNA targeting MACF1 can decrease the expression of MACF1 and thus disrupt the dynamic balance of microtubule or microfilaments as an effective way to inhibit the invasion and metastasis of tumor cells. So we can use it as a new target for clinical early diagnosis and treatment of malignant tumor invasion and metastasis. Copyright © 2017 Elsevier Ltd. All rights reserved.

Tumor-targeting Salmonella typhimurium A1-R inhibits human prostate cancer experimental bone metastasis in mouse models.

PubMed

Toneri, Makoto; Miwa, Shinji; Zhang, Yong; Hu, Cameron; Yano, Shuya; Matsumoto, Yasunori; Bouvet, Michael; Nakanishi, Hayao; Hoffman, Robert M; Zhao, Ming

2015-10-13

Bone metastasis is a frequent occurrence in prostate cancer patients and often is lethal. Zoledronic acid (ZOL) is often used for bone metastasis with limited efficacy. More effective models and treatment methods are required to improve the outcome of prostate cancer patients. In the present study, the effects of tumor-targeting Salmonella typhimurium A1-R were analyzed in vitro and in vivo on prostate cancer cells and experimental bone metastasis. Both ZOL and S. typhimurium A1-R inhibited the growth of PC-3 cells expressing red fluorescent protien in vitro. To investigate the efficacy of S. typhimurium A1-R on prostate cancer experimental bone metastasis, we established models of both early and advanced stage bone metastasis. The mice were treated with ZOL, S. typhimurium A1-R, and combination therapy of both ZOL and S. typhimurium A1-R. ZOL and S. typhimurium A1-R inhibited the growth of solitary bone metastases. S. typhimurium A1-R treatment significantly decreased bone metastasis and delayed the appearance of PC-3 bone metastases of multiple mouse models. Additionally, S. typhimurium A1-R treatment significantly improved the overall survival of the mice with multiple bone metastases. The results of the present study indicate that S. typhimurium A1-R is useful to prevent and inhibit prostate cancer bone metastasis and has potential for future clinical use in the adjuvant setting.

AMD3100 inhibits brain-specific metastasis in lung cancer via suppressing the SDF-1/CXCR4 axis and protecting blood-brain barrier

PubMed Central

Li, Hongru; Chen, Yusheng; Xu, Nengluan; Yu, Meie; Tu, Xunwei; Chen, Zhengwei; Lin, Ming; Xie, Baosong; Fu, Jianjun; Han, Lili

2017-01-01

Lung cancer represents the foremost cause of cancer-related mortality in both men and women throughout the world. Metastasis to the brain constitutes a major problem in the management of patients with lung cancer. However, the mechanism of brain-specific metastasis in lung cancer has not been fully elucidated. Chemokines and their receptors have emerged as attractive targets regulating the cancer metastasis. It has been discovered that the stromal cell-derived factor 1 (SDF-1)/CXCR4 axis plays a critical role in determining the metastatic destination of tumor cells. In this study, strong expression of SDF-1 was observed in highly metastatic brain tissues, and CXCR4 overexpressed in PC-9 lung cancer cells and tumor foci. Therefore, we chose to block SDF-1/CXCR4 axis with AMD3100, which led to the increased tight junction protein level, less damage, and decreased permeability of blood-brain barrier (BBB). Consequently, the process of lung cancer metastasis to the brain was significantly slowed down. These findings were further validated by in vivo experiments, which showed that AMD3100 can effectively inhibit lung cancer brain metastasis and extend the survival of nude mice model, suggesting that it is a potential drug candidate for inhibiting the lung cancer metastasis to brain. These findings provided valuable information for designing new therapeutic strategies for the treatment of lung cancer brain metastasis. PMID:29312481

Organ Preference of Cancer Metastasis and Metastasis-Related Cell Adhesion Molecules Including Carbohydrates.

PubMed

Kawaguchi, Takanori

2016-01-01

This review starts on one of our special interests, the organ preference of metastasis. We examined data on 1,117 autopsy cases and found that the organ distribution of metastasis of cancers of the lung, pancreas, stomach, colon, rectum, uterine cervix, liver, bile duct, and esophagus involved the lung, liver, adrenal gland, bone/bone marrow, lymph node, and pleura/peritoneum. Cancers of the kidney, thyroid, ovary, choriocarcinoma, and breast, however, manifested different metastatic patterns. The distribution of leukemia and lymphoma metastases was quite different from that of epithelial cancers. On the basis of experimental studies, we believe that the anatomical-mechanical hypothesis should be replaced by the microinjury hypothesis, which suggests that tissue microinjury induced by temporal tumor cell embolization is crucial for successful metastasis. This hypothesis may actually reflect the so-called inflammatory oncotaxis concept. To clarify the mechanisms underlying metastasis, we developed an experimental model system of a rat hepatoma AH7974 that embraced substrate adhesiveness. This model did not prove a relationship between substrate-adhesion potential and metastatic lung-colonizing potential of tumor cells, but metastatic potential was correlated with the expression of the laminin carbohydrate that was recognized by Griffonia (Bandeiraea) simplicifolia isolectin G4. Therefore, we investigated the relationship between carbohydrate expression profiles and metastasis and prognosis. We indeed found an intimate relationship between the carbohydrate expression of cancer cells and the progression of malignant tumors, organ preference of metastasis, metastatic potential of tumor cells, and prognosis of patients.

Development and external validation of nomograms to predict the risk of skeletal metastasis at the time of diagnosis and skeletal metastasis-free survival in nasopharyngeal carcinoma.

PubMed

Yang, Lin; Xia, Liangping; Wang, Yan; He, Shasha; Chen, Haiyang; Liang, Shaobo; Peng, Peijian; Hong, Shaodong; Chen, Yong

2017-09-06

The skeletal system is the most common site of distant metastasis in nasopharyngeal carcinoma (NPC); various prognostic factors have been reported for skeletal metastasis, though most studies have focused on a single factor. We aimed to establish nomograms to effectively predict skeletal metastasis at initial diagnosis (SMAD) and skeletal metastasis-free survival (SMFS) in NPC. A total of 2685 patients with NPC who received bone scintigraphy (BS) and/or 18F-deoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) and 2496 patients without skeletal metastasis were retrospectively assessed to develop individual nomograms for SMAD and SMFS. The models were validated externally using separate cohorts of 1329 and 1231 patients treated at two other institutions. Five independent prognostic factors were included in each nomogram. The SMAD nomogram had a significantly higher c-index than the TNM staging system (training cohort, P = 0.005; validation cohort, P < 0.001). The SMFS nomogram had significantly higher c-index values in the training and validation sets than the TNM staging system (P < 0.001 and P = 0.005, respectively). Three proposed risk stratification groups were created using the nomograms, and enabled significant discrimination of SMFS for each risk group. The prognostic nomograms established in this study enable accurate stratification of distinct risk groups for skeletal metastasis, which may improve counseling and facilitate individualized management of patients with NPC.

Inhibition of c-Met reduces lymphatic metastasis in RIP-Tag2 transgenic mice

PubMed Central

Sennino, Barbara; Ishiguro-Oonuma, Toshina; Schriver, Brian J.; Christensen, James G.; McDonald, Donald M.

2013-01-01

Inhibition of vascular endothelial growth factor (VEGF) signaling can promote lymph node metastasis in preclinical models, but the mechanism is not fully understood, and successful methods of prevention have not been found. Signaling of hepatocyte growth factor (HGF) and its receptor c-Met can promote the growth of lymphatics and metastasis of some tumors. We sought to explore the contributions of c-Met signaling to lymph node metastasis after inhibition of VEGF signaling. In particular, we examined whether c-Met is upregulated in lymphatics in or near pancreatic neuroendocrine tumors in RIP-Tag2 transgenic mice and whether lymph node metastasis can be reduced by concurrent inhibition of VEGF and c-Met signaling. Inhibition of VEGF signaling by anti-VEGF antibody or sunitinib in mice from age 14 to 17 weeks was accompanied by more intratumoral lymphatics, more tumor cells inside lymphatics, and more lymph node metastases. Under these conditions, lymphatic endothelial cells - like tumor cells - had strong immunoreactivity for c-Met and phospho-c-Met. c-Met blockade by the selective inhibitor PF-04217903 significantly reduced metastasis to local lymph nodes. Together, these results indicate that inhibition of VEGF signaling in RIP-Tag2 mice upregulates c-Met expression in lymphatic endothelial cells, increases the number of intratumoral lymphatics and number of tumor cells within lymphatics, and promotes metastasis to local lymph nodes. Prevention of lymph node metastasis by PF-04217903 in this setting implicates c-Met signaling in tumor cell spread to lymph nodes. PMID:23576559

KISS1 over-expression suppresses metastasis of pancreatic adenocarcinoma in a xenograft mouse model

USDA-ARS?s Scientific Manuscript database

Identifying molecular targets for treatment of pancreatic cancer metastasis is critical due to the high frequency of dissemination prior to diagnosis of this lethal disease. Because the KISS1 metastasis suppressor is expressed at reduced levels in advanced pancreatic cancer, we hypothesized that re-...

A New In Vitro Model of Breast Cancer Metastasis to Bone

DTIC Science & Technology

2009-04-01

videomicroscopy [11, 12] have revealed that early stage, pre-angiogenic interactions between the cancer cells and the bone environment are crucial regulators of...1995) Steps in tumor metastasis: new concepts from intravital videomicroscopy . Cancer Metastasis Rev 14:279–301. doi:10.1007/BF00690599 12. Chambers AF

Metastasis suppressor KISS1 seems to reverse the Warburg effect by enhancing mitochondrial biogenesis

USDA-ARS?s Scientific Manuscript database

Cancer cells tend to utilize aerobic glycolysis even under normoxic conditions, commonly called the "Warburg Effect." Aerobic glycolysis often directly correlates with malignancy, but its purpose, if any, in metastasis remains unclear. When wild-type KISS1 metastasis suppressor is expressed, aerob...

EMERGING BIOLOGICAL PRINCIPLES OF METASTASIS

PubMed Central

Lambert, Arthur W.; Pattabiraman, Diwakar R.; Weinberg, Robert A.

2016-01-01

Metastases account for the great majority of cancer-associated deaths, yet this complex process remains the least understood aspect of cancer biology. As the body of research concerning metastasis continues to grow at a rapid rate, the biological programs that underlie the dissemination and metastatic outgrowth of cancer cells are beginning to come into view. In this review we summarize the cellular and molecular mechanisms involved in metastasis, with a focus on carcinomas where the most is known, and highlight the general principles of metastasis that have begun to emerge. PMID:28187288

[Breast carcinoma metastasis to the gastrointestinal tract and tumour-to-tumour metastasis to renal cell carcinoma].

PubMed

Mosholt, Karina Sif Søndergaard; Pilt, Anette Pedersen; Wittendorff, Hans-Erik

2015-04-06

Breast carcinoma metastasis to the gastrointestinal tract and tumour-to-tumour metastasis is rare. We describe a case of a 71-year-old woman with previous breast cancer presenting with dyspepsia, nausea and weight-loss. Biopsies from the pylorus revealed what appeared to be a gastric carcinoma. A CT scan showed large kidney mass and biopsies revealed clear cell renal cell carcinoma with areas of poorly differentiated adenocarcinoma. Subsequent immunohistochemical analysis revealed the presence of breast carcinoma in both locations.

Isolated splenic metastasis in a patient with two distinct genitourinary malignancies.

PubMed

Zhang, Lulu; Pasquale, Donald; Le, Maithao; Patel, Raina; Mehdi, Syed

2015-06-01

Splenic metastasis is rare, occurring in 2.3%- 7.1% of cases, of which 95% are carcinomas.1 The lung is the most common primary tumor site (21% of cases), followed by the gastrointestinal system, breast, ovaries, and skin. In a retrospective study evaluating the clinical and pathological impact of splenic metastases during a 25-year period in China, it was found that about 5.3% of metastases were isolated splenic metastasis.2 Isolated splenic metastasis from kidney cancer is very rare and is often an incidental finding. Here we report a case with isolated splenic metastasis in a patient with both primary renal cell carcinoma and prostate cancer, which turned out to be metastatic renal cell carcinoma in the spleen. ©2015 Frontline Medical Communications.

Cerebral peritumoral oedema study: does a single dynamic MR sequence assessing perfusion and permeability can help to differentiate glioblastoma from metastasis?

PubMed

Lehmann, Pierre; Saliou, Guillaume; de Marco, Giovanni; Monet, Pauline; Souraya, Stoquart-Elsankari; Bruniau, Alexis; Vallée, Jean Noel; Ducreux, Denis

2012-03-01

Our purpose was to differentiate glioblastoma from metastasis using a single dynamic MR sequence to assess perfusion and permeability parameters. 24 patients with glioblastoma or cerebral metastasis with peritumoral oedema were recruited and explored with a 3T MR unit. Post processing used DPTools software. Regions of interest were drawn around contrast enhancement to assess relative cerebral blood volume and permeability parameters. Around the contrast enhancement Glioblastoma present high rCBV with modification of the permeability, metastasis present slight modified rCBV without modification of permeability. In conclusion, peritumoral T2 hypersignal exploration associating morphological MR and functional MR parameters can help to differentiate cerebral metastasis from glioblastoma. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Gastric cancer presenting with solitary gigantic pelvic metastasis.

PubMed

Zheng, Qi; Nan, Kejun; Yao, Yu

2012-07-01

Bone metastasis of gastric cancer is relatively uncommon in clinical practice. Moreover, it is all the more unusual for the primary presentation of gastric malignancy to be bone metastasis. Here, we describe a male patient who complained of pain and edema in his right lower extremity. Further assessment by computed tomography and positron emission tomography revealed an abnormally thickened gastric cardia and a giant neoplasm in the right pelvis with bone damage. Consequently, the finding of adenocarcinoma cells in pelvic and cardia biopsy specimens contributed to the diagnosis of pelvic metastasis from gastric cancer. This case report illustrates that stomach cancer has the potential, although far less than breast, prostate and lung cancers, to metastasize to bone. In addition, it highlights the peculiarity of this bone metastasis which is pelvic, solitary and huge.

EHMT2 is a metastasis regulator in breast cancer.

PubMed

Kim, Kwangho; Son, Mi-Young; Jung, Cho-Rok; Kim, Dae-Soo; Cho, Hyun-Soo

2018-02-05

Various modes of epigenetic regulation of breast cancer proliferation and metastasis have been investigated, but epigenetic mechanisms involved in breast cancer metastasis remain elusive. Thus, in this study, EHMT2 (a histone methyltransferase) was determined to be significantly overexpressed in breast cancer tissues and in Oncomine data. In addition, knockdown of EHMT2 reduced cell migration/invasion and regulated the expression of EMT-related markers (E-cadherin, Claudin 1, and Vimentin). Furthermore, treatment with BIX-01294, a specific inhibitor of EHMT2, affected migration/invasion in MDA-MB-231 cells. Therefore, our findings demonstrate functions of EHMT2 in breast cancer metastasis and suggest that targeting EHMT2 may be an effective therapeutic strategy for preventing breast cancer metastasis. Copyright © 2018 Elsevier Inc. All rights reserved.

The distance between breast cancer and the skin is associated with axillary nodal metastasis.

PubMed

Eom, Yong Hwa; Kim, Eun Jin; Chae, Byung Joo; Song, Byung Joo; Jung, Sang Seol

2015-06-01

More superficially located tumors may be more likely than deeper tumors to metastasize to the axillary nodes via the lymphatics. The aim of this study was to determine whether breast cancer distance from the skin affects axillary node metastasis, ipsilateral breast cancer recurrence, or recurrence-free survival. A total of 1,005 consecutive patients with breast cancer who underwent surgery between January 2003 and December 2009 were selected. The distance of the tumor from the skin was measured from the skin to the most anterior hypoechoic leading edge of the lesion. In total, 603 (68%) patients had no axillary nodal metastasis, and 288 (32%) had axillary nodal metastasis. A breast cancer distance from the skin <3 mm induced more axillary nodal metastasis (P = 0.039). However, no significant correlation was observed between breast cancer distance from the skin <3 mm and ipsilateral breast cancer recurrence (P = 0.788) or recurrence-free survival (P = 0.353). Breast cancers located closer to the skin had a higher incidence of axillary nodal metastasis. Therefore, tumor distance from the skin should be considered when evaluating a patient with breast cancer and considering the risk of nodal metastasis. © 2015 Wiley Periodicals, Inc.

A novel microfluidic model can mimic organ-specific metastasis of circulating tumor cells.

PubMed

Kong, Jing; Luo, Yong; Jin, Dong; An, Fan; Zhang, Wenyuan; Liu, Lilu; Li, Jiao; Fang, Shimeng; Li, Xiaojie; Yang, Xuesong; Lin, Bingcheng; Liu, Tingjiao

2016-11-29

A biomimetic microsystem might compensate costly and time-consuming animal metastatic models. Herein we developed a biomimetic microfluidic model to study cancer metastasis. Primary cells isolated from different organs were cultured on the microlfuidic model to represent individual organs. Breast and salivary gland cancer cells were driven to flow over primary cell culture chambers, mimicking dynamic adhesion of circulating tumor cells (CTCs) to endothelium in vivo. These flowing artificial CTCs showed different metastatic potentials to lung on the microfluidic model. The traditional nude mouse model of lung metastasis was performed to investigate the physiological similarity of the microfluidic model to animal models. It was found that the metastatic potential of different cancer cells assessed by the microfluidic model was in agreement with that assessed by the nude mouse model. Furthermore, it was demonstrated that the metastatic inhibitor AMD3100 inhibited lung metastasis effectively in both the microfluidic model and the nude mouse model. Then the microfluidic model was used to mimick liver and bone metastasis of CTCs and confirm the potential for research of multiple-organ metastasis. Thus, the metastasis of CTCs to different organs was reconstituted on the microfluidic model. It may expand the capabilities of traditional cell culture models, providing a low-cost, time-saving, and rapid alternative to animal models.

Comparison of five systems for staging lymph node metastasis in gastric cancer.

PubMed

Yu, W; Choi, G S; Whang, I; Suh, I S

1997-09-01

There are several systems for staging lymph node metastasis in gastric cancer. Their relative merits are not clear. In this retrospective analysis, the nodal status was classified according to the Union Internacional Contra la Cancrum (UICC) and Japanese staging systems, the number and frequency of lymph node metastasis, and the level of involved nodes. Each staging system was scored as good (+1), fair (0) or poor (-1) with respect to prognostic value, theoretical value, convenience, reproducibility and surgical applicability. There were no differences between the five staging systems in predicting survival. The Japanese staging system was most arbitrary owing to the complexity of the system, although it had an advantage in surgical application. The same disadvantage was found in the UICC system and the level system. Determination of the number and frequency of involved nodes was convenient and reproducible, but the number of lymph nodes dissected must be considered when the number of positive nodes is used for staging. The classification of metastasis to the regional lymph nodes as N0 (no nodal metastasis), N1 (metastasis in 1-25 per cent of dissected nodes) and N2 (metastasis in more than 25 per cent of dissected nodes) would be a simple, convenient, reproducible staging system with an ability to predict surgical results.

AACR Centennial Series: The Biology of Cancer Metastasis: Historical Perspective

PubMed Central

Talmadge, James E; Fidler, Isaiah J

2014-01-01

Metastases resistant to therapy is the major cause of death from cancer. Despite almost 200 years of study, the process of tumor metastasis remains controversial. Stephen Paget initially identified the role of host-tumor interactions on the basis of a review of autopsy records. His “seed and soil” hypothesis was substantiated a century later with experimental studies and numerous reports have confirmed these seminal observations. Inarguably, an improved understanding of the metastatic process and the attributes of the cells selected by this process are critical to the treatment of patients with systemic disease. In many patients, metastasis has occurred by the time of diagnosis, such that metastasis prevention may not be relevant, and treatment of systemic disease, as well as the identity of patients with early disease, should be our goal. During the last three decades, revitalized research has focused on new discoveries in the biology of metastasis. While our understanding of the molecular events that regulate metastasis has improved; nonetheless, the relevant contributions and timing of molecular lesion(s) potentially involved in its pathogenesis remain unclear. The history of pioneering observations and discussion of current controversies should help investigators understand the complex and multifactorial interactions between the host and selected tumor cells that contribute to fatal metastasis and allow for the design of successful therapy. PMID:20610625

Downregulation of NEDD9 by apigenin suppresses migration, invasion, and metastasis of colorectal cancer cells.

PubMed

Dai, Jin; Van Wie, Peter G; Fai, Leonard Yenwong; Kim, Donghern; Wang, Lei; Poyil, Pratheeshkumar; Luo, Jia; Zhang, Zhuo

2016-11-15

Apigenin is a natural flavonoid which possesses multiple anti-cancer properties such as anti-proliferation, anti-inflammation, and anti-metastasis in many types of cancers including colorectal cancer. Neural precursor cell expressed developmentally downregulated 9 (NEDD9) is a multi-domain scaffolding protein of the Cas family which has been shown to correlate with cancer metastasis and progression. The present study investigates the role of NEDD9 in apigenin-inhibited cell migration, invasion, and metastasis of colorectal adenocarcinoma DLD1 and SW480 cells. The results show that knockdown of NEDD9 inhibited cell migration, invasion, and metastasis and that overexpression of NEDD9 promoted cell migration and invasion of DLD1 cells and SW4890 cells. Apigenin treatment attenuated NEDD9 expression at protein level, resulting in reduced phosphorylations of FAK, Src, and Akt, leading to inhibition on cell migration, invasion, and metastasis of both DLD1 and SW480 cells. The present study has demonstrated that apigenin inhibits cell migration, invasion, and metastasis through NEDD9/Src/Akt cascade in colorectal cancer cells. NEDD9 may function as a biomarker for evaluation of cancer aggressiveness and for selection of therapeutic drugs against cancer progression. Copyright © 2016 Elsevier Inc. All rights reserved.

Blocking the Adhesion Cascade at the Premetastatic Niche for Prevention of Breast Cancer Metastasis

PubMed Central

Kang, Shin-Ae; Hasan, Nafis; Mann, Aman P; Zheng, Wei; Zhao, Lichao; Morris, Lynsie; Zhu, Weizhu; Zhao, Yan D; Suh, K Stephen; Dooley, William C; Volk, David; Gorenstein, David G; Cristofanilli, Massimo; Rui, Hallgeir; Tanaka, Takemi

2015-01-01

Shear-resistant adhesion and extravasation of disseminated cancer cells at the target organ is a crucial step in hematogenous metastasis. We found that the vascular adhesion molecule E-selectin preferentially promoted the shear-resistant adhesion and transendothelial migration of the estrogen receptor (ER)–/CD44+ hormone-independent breast cancer cells, but not of the ER+/CD44-/low hormone-dependent breast cancer cells. Coincidentally, CD44+ breast cancer cells were abundant in metastatic lung and brain lesions in ER– breast cancer, suggesting that E-selectin supports hematogenous metastasis of ER–/CD44+ breast cancer. In an attempt to prevent hematogenous metastasis through the inhibition of a shear-resistant adhesion of CD44+ cancer cells to E-selectin-expressing blood vessels on the premetastatic niche, an E-selectin targeted aptamer (ESTA) was developed. We demonstrated that a single intravenous injection of ESTA reduced metastases to a baseline level in both syngeneic and xenogeneic forced breast cancer metastasis models without relocating the site of metastasis. The effect of ESTA was absent in E-selectin knockout mice, suggesting that E-selectin is a molecular target of ESTA. Our data highlight the potential application of an E-selectin antagonist for the prevention of hematogenous metastasis of ER–/CD44+ breast cancer. PMID:25815697

Blocking the adhesion cascade at the premetastatic niche for prevention of breast cancer metastasis.

PubMed

Kang, Shin-Ae; Hasan, Nafis; Mann, Aman P; Zheng, Wei; Zhao, Lichao; Morris, Lynsie; Zhu, Weizhu; Zhao, Yan D; Suh, K Stephen; Dooley, William C; Volk, David; Gorenstein, David G; Cristofanilli, Massimo; Rui, Hallgeir; Tanaka, Takemi

2015-06-01

Shear-resistant adhesion and extravasation of disseminated cancer cells at the target organ is a crucial step in hematogenous metastasis. We found that the vascular adhesion molecule E-selectin preferentially promoted the shear-resistant adhesion and transendothelial migration of the estrogen receptor (ER)(-)/CD44(+) hormone-independent breast cancer cells, but not of the ER(+)/CD44(-/low) hormone-dependent breast cancer cells. Coincidentally, CD44(+) breast cancer cells were abundant in metastatic lung and brain lesions in ER(-) breast cancer, suggesting that E-selectin supports hematogenous metastasis of ER(-)/CD44(+) breast cancer. In an attempt to prevent hematogenous metastasis through the inhibition of a shear-resistant adhesion of CD44(+) cancer cells to E-selectin-expressing blood vessels on the premetastatic niche, an E-selectin targeted aptamer (ESTA) was developed. We demonstrated that a single intravenous injection of ESTA reduced metastases to a baseline level in both syngeneic and xenogeneic forced breast cancer metastasis models without relocating the site of metastasis. The effect of ESTA was absent in E-selectin knockout mice, suggesting that E-selectin is a molecular target of ESTA. Our data highlight the potential application of an E-selectin antagonist for the prevention of hematogenous metastasis of ER(-)/CD44(+) breast cancer.

Intracarotid Cancer Cell Injection to Produce Mouse Models of Brain Metastasis.

PubMed

Zhang, Chenyu; Lowery, Frank J; Yu, Dihua

2017-02-08

Metastasis, the spread and growth of malignant cells at secondary sites within a patient's body, accounts for > 90% of cancer-related mortality. Recently, impressive advances in novel therapies have dramatically prolonged survival and improved quality of life for many cancer patients. Sadly, incidence of brain metastatic recurrences is fast rising, and all current therapies are merely palliative. Hence, good experimental animal models are urgently needed to facilitate in-depth studies of the disease biology and to assess novel therapeutic regimens for preclinical evaluation. However, the standard in vivo metastasis assay via tail vein injection of cancer cells produces predominantly lung metastatic lesions; animals usually succumb to the lung tumor burden before any meaningful outgrowth of brain metastasis. Intracardiac injection of tumor cells produces metastatic lesions to multiple organ sites including the brain; however, the variability of tumor growth produced with this model is large, dampening its utility in evaluating therapeutic efficacy. To generate reliable and consistent animal models for brain metastasis study, here we describe a procedure for producing experimental brain metastasis in the house mouse (Mus musculus) via intracarotid injection of tumor cells. This approach allows one to produce large number of brain metastasis-bearing mice with similar growth and mortality characteristics, thus facilitating research efforts to study basic biological mechanisms and to assess novel therapeutic agents.

Magnetic Resonance Imaging of Liver Metastasis.

PubMed

Karaosmanoglu, Ali Devrim; Onur, Mehmet Ruhi; Ozmen, Mustafa Nasuh; Akata, Deniz; Karcaaltincaba, Musturay

2016-12-01

Liver magnetic resonance imaging (MRI) is becoming the gold standard in liver metastasis detection and treatment response assessment. The most sensitive magnetic resonance sequences are diffusion-weighted images and hepatobiliary phase images after Gd-EOB-DTPA. Peripheral ring enhancement, diffusion restriction, and hypointensity on hepatobiliary phase images are hallmarks of liver metastases. In patients with normal ultrasonography, computed tomography (CT), and positron emission tomography (PET)-CT findings and high clinical suspicion of metastasis, MRI should be performed for diagnosis of unseen metastasis. In melanoma, colon cancer, and neuroendocrine tumor metastases, MRI allows confident diagnosis of treatment-related changes in liver and enables differential diagnosis from primary liver tumors. Focal nodular hyperplasia-like nodules in patients who received platinum-based chemotherapy, hypersteatosis, and focal fat can mimic metastasis. In cancer patients with fatty liver, MRI should be preferred to CT. Although the first-line imaging for metastases is CT, MRI can be used as a problem-solving method. MRI may be used as the first-line method in patients who would undergo curative surgery or metastatectomy. Current limitation of MRI is low sensitivity for metastasis smaller than 3mm. MRI fingerprinting, glucoCEST MRI, and PET-MRI may allow simpler and more sensitive diagnosis of liver metastasis. Copyright © 2016 Elsevier Inc. All rights reserved.

Efficacy of icotinib versus traditional chemotherapy as first-line treatment for preventing brain metastasis from advanced lung adenocarcinoma in patients with epidermal growth factor receptor-sensitive mutation.

PubMed

Zhao, Xiao; Zhu, Guangqin; Chen, Huoming; Yang, Ping; Li, Fang; Du, Nan

2016-01-01

This study aimed to investigate the potential use of icotinib as first-line treatment to prevent brain metastasis from advanced lung adenocarcinoma. This investigation was designed as a retrospective nonrandomized controlled study. Enrolled patients received either icotinib or traditional chemotherapy as their first-line treatment. The therapeutic efficacy was compared among patients with advanced. (stages IIIB and IV) lung adenocarcinoma with epidermal growth factor receptor (EGFR)-sensitive mutation. The primary endpoint was the cumulative incidence of brain metastasis, whereas, the secondary endpoint was overall survival(OS). Death without brain metastasis was considered a competitive risk to calculate the cumulative risk of brain metastasis. Survival analysis was conducted using the Kaplan-Meier method and statistical significance was determined using the log-rank test. The present study included 396 patients with 131 in the icotinib group and 265 in the chemotherapy group. Among those with EGFR-sensitive mutation, the cumulative risk of brain metastasis was lower in the icotinib group than in the chemotherapy group. However, no significant difference in OS was observed between the two groups. Icotinib can effectively reduce the incidence of brain metastasis and therefore improve prognosis in advanced lung adenocarcinoma patients with EGFR.sensitive mutation.

Efficacy of icotinib versus traditional chemotherapy as first-line treatment for preventing brain metastasis from advanced lung adenocarcinoma in patients with epidermal growth factor receptor-sensitive mutation.

PubMed

Zhao, Xiao; Zhu, Guangqin; Chen, Huoming; Yang, Ping; Li, Fang; Du, Nan

2014-11-01

This study aimed to investigate the potential use of icotinib as first-line treatment to prevent brain metastasis from advanced lung adenocarcinoma. This investigation was designed as a retrospective nonrandomized controlled study. Enrolled patients received either icotinib or traditional chemotherapy as their first-line treatment. The therapeutic efficacy was compared among patients with advanced (stages IIIB and IV) lung adenocarcinoma with epidermal growth factor receptor (EGFR)-sensitive mutation. The primary endpoint was the cumulative incidence of brain metastasis, whereas the secondary endpoint was overall survival (OS). Death without brain metastasis was considered a competitive risk to calculate the cumulative risk of brain metastasis. Survival analysis was conducted using the Kaplan-Meier method and statistical significance were determined using the log-rank test. The present study included 396 patients with 131 in the icotinib group and 265 in the chemotherapy group. Among those with EGFR-sensitive mutation, the cumulative risk of brain metastasis was lower in the icotinib group than in the chemotherapy group. However, no significant difference in OS was observed between the two groups. Icotinib can effectively reduce the incidence of brain metastasis and therefore improve prognosis in advanced lung adenocarcinoma patients with EGFR-sensitive mutation.

Identification of Ras suppressor-1 (RSU-1) as a potential breast cancer metastasis biomarker using a three-dimensional in vitro approach.

PubMed

Gkretsi, Vasiliki; Stylianou, Andreas; Louca, Maria; Stylianopoulos, Triantafyllos

2017-04-18

Breast cancer (BC) is the most common malignant disease in women, with most patients dying from metastasis to distant organs, making discovery of novel metastasis biomarkers and therapeutic targets imperative. Extracellular matrix (ECM)-related adhesion proteins as well as tumor matrix stiffness are important determinants for metastasis. As traditional two-dimensional culture does not take into account ECM stiffness, we employed 3-dimensional collagen I gels of increasing concentration and stiffness to embed BC cells of different invasiveness (MCF-7, MDA-MB-231 and MDA-MB-231-LM2) or tumor spheroids. We tested the expression of cell-ECM adhesion proteins and found that Ras Suppressor-1 (RSU-1) is significantly upregulated in increased stiffness conditions. Interestingly, RSU-1 siRNA-mediated silencing inhibited Urokinase Plasminogen Activator, and metalloproteinase-13, whereas tumor spheroids formed from RSU-1-depleted cells lost their invasive capacity in all cell lines and stiffness conditions. Kaplan-Meier survival plot analysis corroborated our findings showing that high RSU-1 expression is associated with poor prognosis for distant metastasis-free and remission-free survival in BC patients. Taken together, our results indicate the important role of RSU-1 in BC metastasis and set the foundations for its validation as potential BC metastasis marker.

Bovine Lactoferrin and Lactoferricin, a Peptide Derived from Bovine Lactoferrin, Inhibit Tumor Metastasis in Mice

PubMed Central

Watanabe, Shikiko; Watanabe, Ryosuke; Hata, Katsusuke; Shimazaki, Kei–ichi; Azuma, Ichiro

1997-01-01

We investigated the effect of a bovine milk protein, lactoferrin (LF–B), and a pepsin–generated peptide of LF–B, lactoferricin (Lfcin–B), on inhibition of tumor metastasis produced by highly metastatic murine tumor cells, B16–BL6 melanoma and L5178Y–ML25 lymphoma cells, using experimental and spontaneous metastasis models in syngeneic mice. The subcutaneous (s.c.) administration of bovine apo–lactoferrin (apo–LF–B, 1 mg/mouse) and Lfcin–B (0.5 mg/monse) 1 day after tumor inoculation significantly inhibited liver and lung metastasis of L5178Y–ML25 cells. However, human apo–lactoferrin (apo–LF–H) and bovine holo–lactoferrin (holo–LF–B) at the dose of 1 mg/mouse failed to inhibit tumor metastasis of L5178Y–ML25 cells. Similarly, the s.c. administration of apo–LF–B as well as Lfcin–B, but not apo–LF–H and holo–LF–B, 1 day after tumor inoculation resulted in significant inhibition of lung metastasis of B16–BL6 cells in an experimental metastasis model. Furthermore, in in vivo analysis for tumor–induced angiogenesis, both apo–LF–B and Lfcin–B inhibited the number of tumor–induced blood vessels and suppressed tumor growth on day 8 after tumor inoculation. However, in a long–term analysis of tumor growth for up to 21 days after tumor inoculation, single administration of apo–LF–B significantly suppressed the growth of B16–BL6 cells throughout the examination period, whereas Lfcin–B showed inhibitory activity only during the early period (8 days). In spontaneous metastasis of B16–BL6 melanoma cells, multiple administration of both apo–LF–B and Lfcin–B into tumor–bearing mice significantly inhibited lung metastasis produced by B16–BL6 cells, though only apo–LF–B exhibited an inhibitory effect on tumor growth at the time of primary tumor amputation (on day 21) after tumor inoculation. These results suggest that apo–LF–B and Lfcin–B inhibit tumor metastasis through different mechanisms, and that the inhibitory activity of LF–B on tumor metastasis may he related to iron (Fe3+)–saturation. PMID:9119747

A mathematical prediction model incorporating molecular subtype for risk of non-sentinel lymph node metastasis in sentinel lymph node-positive breast cancer patients: a retrospective analysis and nomogram development.

PubMed

Wang, Na-Na; Yang, Zheng-Jun; Wang, Xue; Chen, Li-Xuan; Zhao, Hong-Meng; Cao, Wen-Feng; Zhang, Bin

2018-04-25

Molecular subtype of breast cancer is associated with sentinel lymph node status. We sought to establish a mathematical prediction model that included breast cancer molecular subtype for risk of positive non-sentinel lymph nodes in breast cancer patients with sentinel lymph node metastasis and further validate the model in a separate validation cohort. We reviewed the clinicopathologic data of breast cancer patients with sentinel lymph node metastasis who underwent axillary lymph node dissection between June 16, 2014 and November 16, 2017 at our hospital. Sentinel lymph node biopsy was performed and patients with pathologically proven sentinel lymph node metastasis underwent axillary lymph node dissection. Independent risks for non-sentinel lymph node metastasis were assessed in a training cohort by multivariate analysis and incorporated into a mathematical prediction model. The model was further validated in a separate validation cohort, and a nomogram was developed and evaluated for diagnostic performance in predicting the risk of non-sentinel lymph node metastasis. Moreover, we assessed the performance of five different models in predicting non-sentinel lymph node metastasis in training cohort. Totally, 495 cases were eligible for the study, including 291 patients in the training cohort and 204 in the validation cohort. Non-sentinel lymph node metastasis was observed in 33.3% (97/291) patients in the training cohort. The AUC of MSKCC, Tenon, MDA, Ljubljana, and Louisville models in training cohort were 0.7613, 0.7142, 0.7076, 0.7483, and 0.671, respectively. Multivariate regression analysis indicated that tumor size (OR = 1.439; 95% CI 1.025-2.021; P = 0.036), sentinel lymph node macro-metastasis versus micro-metastasis (OR = 5.063; 95% CI 1.111-23.074; P = 0.036), the number of positive sentinel lymph nodes (OR = 2.583, 95% CI 1.714-3.892; P < 0.001), and the number of negative sentinel lymph nodes (OR = 0.686, 95% CI 0.575-0.817; P < 0.001) were independent statistically significant predictors of non-sentinel lymph node metastasis. Furthermore, luminal B (OR = 3.311, 95% CI 1.593-6.884; P = 0.001) and HER2 overexpression (OR = 4.308, 95% CI 1.097-16.912; P = 0.036) were independent and statistically significant predictor of non-sentinel lymph node metastasis versus luminal A. A regression model based on the results of multivariate analysis was established to predict the risk of non-sentinel lymph node metastasis, which had an AUC of 0.8188. The model was validated in the validation cohort and showed excellent diagnostic performance. The mathematical prediction model that incorporates five variables including breast cancer molecular subtype demonstrates excellent diagnostic performance in assessing the risk of non-sentinel lymph node metastasis in sentinel lymph node-positive patients. The prediction model could be of help surgeons in evaluating the risk of non-sentinel lymph node involvement for breast cancer patients; however, the model requires further validation in prospective studies.

Trends in the surgical treatment for spinal metastasis and the in-hospital patient outcomes in the United States from 2000 to 2009.

PubMed

Yoshihara, Hiroyuki; Yoneoka, Daisuke

2014-09-01

Surgical treatment for spinal metastasis is still controversial. However, with the improvements in treatment for primary tumors, the survival rate of patients with spinal metastasis is enhanced. At the same time, surgical technique for spinal metastasis has also improved. The purpose of this study was to examine trends in the surgical treatment for spinal metastasis and in-hospital patient outcomes on a national level. This was an epidemiologic study using national administrative data from the Nationwide Inpatient Sample (NIS) database. All discharges in the NIS with a diagnosis code of secondary malignant neoplasm of the spinal cord/brain, meninges, or bone who also underwent spinal surgery from 2000 to 2009 were included. Trends in the surgical treatment for spinal metastasis, in-hospital complications and mortality, and resource use were analyzed. The NIS was used to identify patients who underwent surgical treatment for spinal metastasis from 2000 to 2009, using the International Classification of Diseases, Ninth revision, Clinical Modification codes. Trends in the surgical treatment for spinal metastasis and in-hospital patient outcomes were analyzed. From 2000 to 2009, there was an increasing trend in the population growth-adjusted rate of surgical treatment for spinal metastasis (1.15-1.77 per 100,000; p<.001). Average Elixhauser comorbidity score increased over time (2.6-3.8; p<.001), and the overall in-hospital complication rate increased over time (14.8%-27.7%; p<.001), whereas in-hospital mortality rate and length of hospital stay remained stable over time (5.2%-4.6%, p=.413; 10.6-10.8 days, p=.626). Inflation-adjusted mean hospital charges increased more than two-fold over time ($50,390-$110,173; p<.001). During the last decade, surgical treatment for spinal metastasis has increased in the United States. The overall in-hospital complication rate and hospital charges increased, whereas the in-hospital mortality rate and length of hospital stay remained stable. Copyright © 2014 Elsevier Inc. All rights reserved.

Association of Nodal Metastasis and Mortality With Vermilion vs Cutaneous Lip Location in Cutaneous Squamous Cell Carcinoma of the Lip.

PubMed

Wang, David M; Kraft, Stefan; Rohani, Pooyan; Murphy, George F; Besaw, Robert J; Karia, Pritesh S; Morgan, Frederick C; Schmults, Chrysalyne D

2018-06-01

Although the lip is considered a high-risk location in cutaneous squamous cell carcinoma (cSCC), it has not been established whether this risk stems from vermilion or cutaneous locations or both. To compare differences in risks of recurrence, metastasis, and death from cSCCs on the vermilion vs cutaneous lip. Retrospective cohort study of 303 patients with 310 primary cSCCs of the lip (138 cutaneous, 172 vermilion) diagnosed between 2000 and 2015 at 2 academic tertiary care centers in Boston, Massachusetts. Development of local recurrence, nodal metastasis, distant metastasis, disease-specific death, and all-cause death. Of the 303 study participants with 310 SCCs of the lip, 153 (50.5%) were men, and 150 (49.5%) were women; median age at diagnosis, 68 years (range, 27-93 years). Outcomes were as follows for vermilion vs cutaneous locations: local recurrence, 6.4% (11 of 172) vs 2.9% (4 of 138); nodal metastasis, 7.6% (13 of 172) vs 1.5% (2 of 138); distant metastasis, 0.6% (1 of 172) vs 0.7% (1 of 138); disease-specific death, 3.5% (6 of 172) vs 2.9% (4 of 138); and all-cause death, 26.7% (46 of 172) vs 29.0% (40 of 138). The difference was statistically significant for nodal metastasis (P = .01). In multivariable analysis, nodal metastasis was associated with vermilion lip location (subhazard ratio, 5.0; 95% CI, 1.1-23.8) and invasion beyond fat (fascia or beyond for vermilion lip) (subhazard ratio, 4.4; 95% CI, 1.3-14.9). The risk of nodal metastasis is 5-fold greater for cSCCs on the vermilion lip compared with those on the cutaneous lip. Squamous cell carcinomas of the cutaneous lip have a nodal metastasis risk similar to cSCCs in general (1.5%). Thus, vermilion involvement appears responsible for the increased risk associated with cSCC of lip. Vermilion involvement may merit radiologic nodal staging and inclusion in future tumor staging, since it was independently associated with higher-risk cSCC of the lip region.

Association between expression of MMP-7 and MMP-9 and pelvic lymph node and para-aortic lymph node metastasis in early cervical cancer.

PubMed

Guo, Hui; Dai, Yifei; Wang, Anna; Wang, Chunyan; Sun, Lili; Wang, Zheng

2018-05-16

To investigate the association of matrix metalloproteinase (MMP)-7 and MMP-9 with pelvic lymph node and para-aortic lymph node metastasis in early cervical cancer. A total of 137 patients with early cervical cancer (Stage Ia2-IIa2) were recruited from the Department of Gynecology and Obstetrics, Tumor Hospital of Liaoning Province from January 2009 to May 2014. We evaluated the expression of MMP-7 and MMP-9 by immunohistochemistry and their association with the clinicopathological parameters such as pelvic, common iliac and para-aortic lymph node metastasis. Spearman correlation was performed to analyze the correlation between MMP-7 and MMP-9 in cervical cancer. Finally, the areas under the receiver operating characteristic curve (ROC) of MMP-7 and MMP-9 in pelvic lymph node metastasis were assessed. MMP-7 expression was significantly higher in patients with adenocarcinomas and adenosquamous carcinomas (P = 0.014), vascular cancer embolus (P = 0.041), pelvic lymph node metastasis (P = 0.000) and a higher level of Ki-67 (P = 0.000). MMP-9 expression was significantly associated with vascular cancer embolus (P = 0.003), depth of stromal invasion (P = 0.001), pelvic lymph node metastasis (P = 0.003), common iliac lymph node metastasis (P = 0.001) and para-aortic lymph nodes metastasis (P = 0.004). Coexpression of MMP-7 and MMP-9 was significantly associated with vascular cancer embolus (P < 0.001), higher expression of Ki-67 (P < 0.001) and pelvic lymph node metastasis (P < 0.001). Spearman correlation analysis indicated a positive correlation between MMP-7 and MMP-9 (r = 0.263, P = 0.002). Areas under the ROC of MMP-7 and MMP-9 were 0.707 and 0.646, respectively. MMP-7 and MMP-9 expressions were associated with lymph node metastasis in patients with early cervical cancers, suggesting a positive correlation of MMP-7 and MMP-9 with invasive potential in early cervical cancers. © 2018 Japan Society of Obstetrics and Gynecology.

Cellular and molecular processes in ovarian cancer metastasis. A Review in the Theme: Cell and Molecular Processes in Cancer Metastasis

PubMed Central

Yeung, Tsz-Lun; Leung, Cecilia S.; Yip, Kay-Pong; Au Yeung, Chi Lam; Wong, Stephen T. C.

2015-01-01

Ovarian cancer is the most lethal gynecological malignancy. It is usually diagnosed at a late stage, with a 5-yr survival rate of <30%. The majority of ovarian cancer cases are diagnosed after tumors have widely spread within the peritoneal cavity, limiting the effectiveness of debulking surgery and chemotherapy. Owing to a substantially lower survival rate at late stages of disease than at earlier stages, the major cause of ovarian cancer deaths is believed to be therapy-resistant metastasis. Although metastasis plays a crucial role in promoting ovarian tumor progression and decreasing patient survival rates, the underlying mechanisms of ovarian cancer spread have yet to be thoroughly explored. For many years, researchers have believed that ovarian cancer metastasizes via a passive mechanism by which ovarian cancer cells are shed from the primary tumor and carried by the physiological movement of peritoneal fluid to the peritoneum and omentum. However, the recent discovery of hematogenous metastasis of ovarian cancer to the omentum via circulating tumor cells instigated rethinking of the mode of ovarian cancer metastasis and the importance of the “seed-and-soil” hypothesis for ovarian cancer metastasis. In this review we discuss the possible mechanisms by which ovarian cancer cells metastasize from the primary tumor to the omentum, the cross-talk signaling events between ovarian cancer cells and various stromal cells that play crucial roles in ovarian cancer metastasis, and the possible clinical implications of these findings in the management of this deadly, highly metastatic disease. PMID:26224579

Low-molecular-weight hyaluronan (LMW-HA) accelerates lymph node metastasis of melanoma cells by inducing disruption of lymphatic intercellular adhesion.

PubMed

Du, Yan; Cao, Manlin; Liu, Yiwen; He, Yiqing; Yang, Cuixia; Wu, Man; Zhang, Guoliang; Gao, Feng

2016-01-01

Endothelial integrity defects initiate lymphatic metastasis of tumor cells. Low-molecular-weight hyaluronan (LMW-HA) derived from plasma and interstitial fluid was reported to be associated with tumor lymphatic metastasis. In addition, LMW-HA was proved to disrupt lymphatic vessel endothelium integrity, thus promoting lymphatic metastasis of tumor cells. Until now, there are few reports on how LMW-HA modulates lymphatic endothelial cells adhesion junctions and affects cancer cells metastasizing into lymph vessels. The aim of our study is to unravel the novel mechanism of LMW-HA in mediating tumor lymphatic metastasis. Here, we employed a melanoma metastasis model to investigate whether LMW-HA facilitates tumor cells transferring from foci to remote lymph nodes by disrupting the lymphatic endothelial integrity. Our data indicate that LMW-HA significantly induces metastasis of melanoma cells to lymph nodes and accelerates interstitial-lymphatic flow in vivo . Further experiments show that increased migration of melanoma cells across human dermal lymphatic endothelial cell (HDLEC) monolayers is accompanied by impaired lymphatic endothelial barrier function and increased permeability. The mechanism study reveals that VE-cadherin-β-catenin pathway and relevant signals are involved in modulating the interactions between endothelial cells and that a significant inhibition of lymphatic endothelium disruption is observed when antibodies to the LMW-HA receptor (LYVE-1) are present. Thus, our findings demonstrate a disruptive effect of LMW-HA on lymphatic endothelium continuity which leads to a promotion on melanoma lymphatic metastasis and also suggest a cellular signaling mechanism associated with VE-cadherin-mediated lymphatic intercellular junctions.

POU2F2-oriented network promotes human gastric cancer metastasis

PubMed Central

Wang, Si-Meng; Tie, Jun; Wang, Wen-Lan; Hu, Si-Jun; Yin, Ji-Peng; Yi, Xiao-Fang; Tian, Zu-Hong; Zhang, Xiang-Yuan; Li, Meng-Bin; Li, Zeng-Shan; Nie, Yong-Zhan; Wu, Kai-Chun; Fan, Dai-Ming

2016-01-01

Background and aims Aberrant upregulation of POU2F2 expression has been discovered in metastatic gastric cancer (GC). However, the mechanisms underlying the aberrant upregulation and the potential functions of POU2F2 remain uncertain. Design The role and mechanism of POU2F2 in GC metastasis were investigated in gastric epithelial cells, GC cell lines and an experimental metastasis animal model by gain of function and loss of function. Upstream and downstream targets of POU2F2 were selected by bioinformatics and identified by luciferase reporter assay, electrophoretic mobility shift assay and chromatin immunoprecipitation PCR. The influence of miR-218 on its putative target genes (POU2F2, ROBO1 and IKK-β) and GC metastasis was further explored via in vitro and in vivo approaches. Results Increased POU2F2 expression was detected in metastatic GC cell lines and patient samples. POU2F2 was induced by the activation of nuclear factor (NF)-κB and, in turn, regulated ROBO1 transcription, thus functionally contributing to GC metastasis. Finally, miR-218 was found to suppress GC metastasis by simultaneously mediating multiple molecules in the POU2F2-oriented network. Conclusions This study demonstrated that NF-κB and the SLIT2/ROBO1 interaction network with POU2F2 as the central part may exert critical effects on tumour metastasis. Blocking the activation of the POU2F2-oriented metastasis network using miR-218 precursors exemplified a promising approach that sheds light on new strategies for GC treatment. PMID:26019213

SERPINE2 is a possible candidate promotor for lymph node metastasis in testicular cancer

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

Nagahara, Akira; Nakayama, Masashi; Oka, Daizo

2010-01-22

Testicular germ cell tumors (TGCTs) commonly metastasize to the lymph node or lung. However, it remains unclear which genes are associated with TGCT metastasis. The aim of this study was to identify gene(s) that promoted human TGCT metastasis. We intraperitoneally administered conditioned medium (CM) from JKT-1, a cell-line from a human testicular seminoma, or JKT-HM, a JKT-1 cell sub-line with high metastatic potential, into mice with JKT-1 xenografts. Administration of CM from JKT-HM significantly promoted lymph node metastasis. A cDNA microarray analysis showed that JKT-HM cells highly expressed the Serpine peptidase inhibitor, clade E, member 2 (SERPINE2), which encodes amore » secreted protein. Administration of CM from SERPINE2-silenced JKT-HM cells inhibited lymph node metastasis in the xenograft model, compared with administration of CM from JKT-HM cells. There was no significant difference in xenograft volume. Moreover, administration of CM from SERPINE2-over-expressing JKT-1 was likely to promote lymph node metastasis in the xenograft model. There was no difference in the in vitro proliferation or migration of JKT-1 cells cultured with CM from JKT-HM cells, compared to that with CM from JKT-1. There was no promotion of proliferation or lymphangiogenesis in the xenografts, as measured by Ki-67 and LYVE-1 immunohistochemistry, respectively. Although we could not clarify how SERPINE2 promoted lymph node metastasis, it may be a promoter in the development of lymph node metastasis in the human seminoma cells in a mouse xenograft model.« less

Analysis of prognostic factors after resection of solitary liver metastasis in colorectal cancer: a 22-year bicentre study.

PubMed

Acciuffi, Sara; Meyer, Frank; Bauschke, Astrid; Settmacher, Utz; Lippert, Hans; Croner, Roland; Altendorf-Hofmann, Annelore

2018-03-01

The investigation of the predictors of outcome after hepatic resection for solitary colorectal liver metastasis. We recruited 350 patients with solitary colorectal liver metastasis at the University Hospitals of Jena and Magdeburg, who underwent curative liver resection between 1993 and 2014. All patients had follow-up until death or till summer 2016. The follow-up data concern 96.6% of observed patients. The 5- and 10-year overall survival rates were 47 and 28%, respectively. The 5- and 10-year disease-free survival rates were 30 and 20%, respectively. The analysis of the prognostic factors revealed that the pT category of primary tumour, size and grade of the metastasis and extension of the liver resection had no statistically significant impact on survival and recurrence rates. In multivariate analysis, age, status of lymph node metastasis at the primary tumour, location of primary tumour, time of appearance of the metastasis, the use of preoperative chemotherapy and the presence of extrahepatic tumour proved to be independent statistically significant predictors for the prognosis. Moreover, patients with rectal cancer had a lower intrahepatic recurrence rate, but a higher extrahepatic recurrence rate. The long-term follow-up of patients with R0-resected liver metastasis is multifactorially influenced. Age and comorbidity have a role only in the overall survival. More than three lymph node metastasis reduced both the overall and disease-free survival. Extrahepatic tumour had a negative influence on the extrahepatic recurrence and on the overall survival. Neither overall survival nor recurrence rates was improved using neoadjuvant chemotherapy.

Synchronous isolated splenic metastasis from colon carcinoma and concomitant splenic abscess: A case report and review of the literature

PubMed Central

Pisanu, Adolfo; Ravarino, Alberto; Nieddu, Riccardo; Uccheddu, Alessandro

2007-01-01

This study aimed to describe a case in which an isolated splenic metastasis was synchronous with the colonic primary and a concomitant splenic abscess was associated. A wide review of the literature was also performed. A 54-year-old woman with abdominal pain and fever was admitted to our department. Abdominal CT revealed two low-density areas in the spleen and wall-thickening of the left colonic flexure, which was indistinguishable from the spleen parenchyma. The patient underwent emergency celiotomy, with the presumptive diagnosis of obstructing colon carcinoma of the splenic flexure, and concomitant splenic abscess. Subtotal colectomy and splenectomy were performed. Pathological findings were consistent with mucinous colonic carcinoma, synchronous isolated splenic metastasis and concomitant splenic abscess. This paper is also a review of the existing literature on the association between colorectal cancer and splenic metastasis. Only 41 cases of isolated splenic metastasis from colon carcinoma have been reported in the literature. This report is the third described case of synchronous isolated splenic metastasis from colon carcinoma. Only one case with concomitant splenic abscess has been previously reported. When obstructing left-sided colorectal cancer is suspected, careful CT examination can allow early diagnosis of splenic involvement by the tumor. The literature review suggests that there might be a significant improvement in survival following splenectomy for a metachronous isolated splenic metastasis from colon carcinoma. Prognosis for synchronous splenic metastasis seems to be related to the advanced stage of the disease. Nevertheless, no definitive conclusions can be drawn because of the small number of cases. PMID:17907299

A novel co-drug of aspirin and ursolic acid interrupts adhesion, invasion and migration of cancer cells to vascular endothelium via regulating EMT and EGFR-mediated signaling pathways: multiple targets for cancer metastasis prevention and treatment

PubMed Central

Tang, Qiao; Liu, Yajun; Li, Tao; Yang, Xiang; Zheng, Guirong; Chen, Hongning; Jia, Lee; Shao, Jingwei

2016-01-01

Metastasis currently remains the predominant cause of breast carcinoma treatment failure. The effective targeting of metastasis-related-pathways in cancer holds promise for a new generation of therapeutics. In this study, we developed an novel Asp-UA conjugate, which was composed of classical “old drug” aspirin and low toxicity natural product ursolic acid for targeting breast cancer metastasis. Our results showed that Asp-UA could attenuate the adhesion, migration and invasion of breast cancer MCF-7 and MDA-MB-231 cells in a more safe and effective manner in vitro. Molecular and cellular study demonstrated that Asp-UA significantly down-regulated the expression of cell adhesion and invasion molecules including integrin α6β1, CD44, MMP-2, MMP-9, COX-2, EGFR and ERK proteins, and up-regulated the epithelial markers “E-cadherin” and “β-catenin”, and PTEN proteins. Furthermore, Asp-UA (80 mg/kg) reduced lung metastasis in a 4T1 murine breast cancer metastasis model more efficiently, which was associated with a decrease in the expression of CD44. More importantly, we did not detect side effects with Asp-UA in mice such as weight loss and main viscera tissues toxicity. Overall, our research suggested that co-drug Asp-UA possessed potential metastasis chemoprevention abilities via influencing EMT and EGFR-mediated pathways and could be a more promising drug candidate for the prevention and/or treatment of breast cancer metastasis. PMID:27683033

Histologic and immunohistochemical predictors of clinical behavior for feline diffuse iris melanoma.

PubMed

Wiggans, K Tomo; Reilly, Christopher M; Kass, Philip H; Maggs, David J

2016-07-01

To determine histologic and immunohistochemical predictors of metastasis of feline diffuse iris melanoma (FDIM). Globes from 47 client-owned cats enucleated for FDIM between January 1985 and December 2013. Hematoxylin and eosin-stained sections were evaluated for neoplastic invasiveness and cell morphology, necrosis within the neoplasm, inflammation, and glaucoma. Sections were immunolabeled with antibodies against melan-A, PNL2, E-cadherin, or B-Raf, and label intensity, percentage of labeled cells, and label homogeneity were semi-quantitatively graded. Medical records were evaluated, and referring veterinarians and clients were contacted to determine whether cats developed metastasis following enucleation. The log-rank test or Cox proportional hazards model was used to determine associations between histologic or immunohistochemical parameters and metastasis. Metastasis was suspected or confirmed in 9/47 (19%) cats. Extrascleral extension, necrosis within the neoplasm, a mitotic index of >7 mitoses in 10 high-power (×400) fields, choroidal invasion, and increased E-cadherin and melan-A label intensity were each associated with increased rate of metastasis. PNL2 label homogeneity was associated with decreased rate of metastasis. Decreased PNL2 label intensity and an increasing percentage of neoplastic cells labeled for melan-A each approached significance for increased rate of metastasis. We report four histologic and three immunohistochemical parameters helpful in determining cats at risk of metastasis of FDIM. Further studies should determine if B-Raf mutations identified in human malignant melanomas are found in cats with FDIM and assess benefits of adjunctive therapy following enucleation of eyes with FDIM bearing poor prognostic indicators. © 2016 American College of Veterinary Ophthalmologists.

A novel co-drug of aspirin and ursolic acid interrupts adhesion, invasion and migration of cancer cells to vascular endothelium via regulating EMT and EGFR-mediated signaling pathways: multiple targets for cancer metastasis prevention and treatment.

PubMed

Tang, Qiao; Liu, Yajun; Li, Tao; Yang, Xiang; Zheng, Guirong; Chen, Hongning; Jia, Lee; Shao, Jingwei

2016-11-08

Metastasis currently remains the predominant cause of breast carcinoma treatment failure. The effective targeting of metastasis-related-pathways in cancer holds promise for a new generation of therapeutics. In this study, we developed an novel Asp-UA conjugate, which was composed of classical "old drug" aspirin and low toxicity natural product ursolic acid for targeting breast cancer metastasis. Our results showed that Asp-UA could attenuate the adhesion, migration and invasion of breast cancer MCF-7 and MDA-MB-231 cells in a more safe and effective manner in vitro. Molecular and cellular study demonstrated that Asp-UA significantly down-regulated the expression of cell adhesion and invasion molecules including integrin α6β1, CD44 ,MMP-2, MMP-9, COX-2, EGFR and ERK proteins, and up-regulated the epithelial markers "E-cadherin" and "β-catenin", and PTEN proteins. Furthermore, Asp-UA (80 mg/kg) reduced lung metastasis in a 4T1 murine breast cancer metastasis model more efficiently, which was associated with a decrease in the expression of CD44. More importantly, we did not detect side effects with Asp-UA in mice such as weight loss and main viscera tissues toxicity. Overall, our research suggested that co-drug Asp-UA possessed potential metastasis chemoprevention abilities via influencing EMT and EGFR-mediated pathways and could be a more promising drug candidate for the prevention and/or treatment of breast cancer metastasis.

Brain metastases in patients diagnosed with a solid primary cancer during childhood: experience from a single referral cancer center.

PubMed

Suki, Dima; Khoury Abdulla, Rami; Ding, Minming; Khatua, Soumen; Sawaya, Raymond

2014-10-01

Metastasis to the brain is frequent in adult cancer patients but rare among children. Advances in primary tumor treatment and the associated prolonged survival are said to have increased the frequency of brain metastasis in children. The authors present a series of cases of brain metastases in children diagnosed with a solid primary cancer, evaluate brain metastasis trends, and describe tumor type, patterns of occurrence, and prognosis. Patients with brain metastases whose primary cancer was diagnosed during childhood were identified in the 1990-2012 Tumor Registry at The University of Texas M.D. Anderson Cancer Center. A review of their hospital records provided demographic data, history, and clinical data, including primary cancer sites, number and location of brain metastases, sites of extracranial metastases, treatments, and outcomes. Fifty-four pediatric patients (1.4%) had a brain metastasis from a solid primary tumor. Sarcomas were the most common (54%), followed by melanoma (15%). The patients' median ages at diagnosis of the primary cancer and the brain metastasis were 11.37 years and 15.03 years, respectively. The primary cancer was localized at diagnosis in 48% of patients and disseminated regionally in only 14%. The primary tumor and brain metastasis presented synchronously in 15% of patients, and other extracranial metastases were present when the primary cancer was diagnosed. The remaining patients were diagnosed with brain metastasis after initiation of primary cancer treatment, with a median presentation interval of 17 months after primary cancer diagnosis (range 2-77 months). At the time of diagnosis, the brain metastasis was the first site of systemic metastasis in only 4 (8%) of the 51 patients for whom data were available. Up to 70% of patients had lung metastases when brain metastases were found. Symptoms led to the brain metastasis diagnosis in 65% of cases. Brain metastases were single in 60% of cases and multiple in 35%; 6% had only leptomeningeal disease. The median Kaplan-Meier estimates of survival after diagnoses of primary cancer and brain metastasis were 29 months (95% CI 24-34 months) and 9 months (95% CI 6-11 months), respectively. Untreated patients survived for a median of 0.9 months after brain metastasis diagnosis (95% CI 0.3-1.5 months). Those receiving treatment survived for a median of 8 months after initiation of therapy (95% CI 6-11 months). The results of this study challenge the current notion of an increased incidence of brain metastases among children with a solid primary cancer. The earlier diagnosis of the primary cancer, prior to its dissemination to distant sites (especially the brain), and initiation of presumably more effective treatments may support such an observation. However, although the actual number of cases may not be increasing, the prognosis after the diagnosis of a brain metastasis remains poor regardless of the management strategy.

Appendiceal metastasis 10 years following ‘curative’ resection for low-grade primary endometrial carcinoma

PubMed Central

Addison, Alfred Bentsi; Miller, Katy; Hammouch, Dalia; Waraich, Naseem; Kaye, Phillip; Kapur, Rakesh; Tennant, William

2012-01-01

Metastasis of primary endometrial adenocarcinoma to unusual sites has been occasionally reported. However, the authors believe this to be the first case report of metastasis to the appendix. This occurred more than 10 years after curative resection, and presented as sepsis with an intra-abdominal focus. PMID:22605700

Prediction of Metastasis Using Second Harmonic Generation

DTIC Science & Technology

2016-07-01

extracellular matrix through which metastasizing cells must travel. We and others have demonstrated that tumor collagen structure, as measured with the...algorithm using separate training and validation sets, etc. Keywords: metastasis, overtreatment, extracellular matrix , collagen , second harmonic...optical process called second harmonic generation (SHG), influences tumor metastasis. This suggests that collagen structure may provide prognostic

Evaluate the Mechanism of Enhanced Metastasis Induced by Arthritis

DTIC Science & Technology

2012-09-01

Genes that mediate breast ca ncer metastasis to lung . Nature 2005, 436(7050):518-524. 6. Das Roy L, Pathangey L, Tinder T, Schettini J, Gruber H...7. Das Roy L, Ghosh S, Pathangey LB, Tinder TL, Gruber HE, Mukherjee P: Collagen induced arthritis increases s econdary metastasis in MMTV-PyV

Tumour exosome integrins determine organotropic metastasis

PubMed Central

Hoshino, Ayuko; Costa-Silva, Bruno; Shen, Tang-Long; Rodrigues, Goncalo; Hashimoto, Ayako; Mark, Milica Tesic; Molina, Henrik; Kohsaka, Shinji; Di Giannatale, Angela; Ceder, Sophia; Singh, Swarnima; Williams, Caitlin; Soplop, Nadine; Uryu, Kunihiro; Pharmer, Lindsay; King, Tari; Bojmar, Linda; Davies, Alexander E.; Ararso, Yonathan; Zhang, Tuo; Zhang, Haiying; Hernandez, Jonathan; Weiss, Joshua M.; Dumont-Cole, Vanessa D.; Kramer, Kimberly; Wexler, Leonard H.; Narendran, Aru; Schwartz, Gary K.; Healey, John H.; Sandstrom, Per; Labori, Knut Jørgen; Kure, Elin H.; Grandgenett, Paul M.; Hollingsworth, Michael A.; de Sousa, Maria; Kaur, Sukhwinder; Jain, Maneesh; Mallya, Kavita; Batra, Surinder K.; Jarnagin, William R.; Brady, Mary S.; Fodstad, Oystein; Muller, Volkmar; Pantel, Klaus; Minn, Andy J.; Bissell, Mina J.; Garcia, Benjamin A.; Kang, Yibin; Rajasekhar, Vinagolu K.; Ghajar, Cyrus M.; Matei, Irina; Peinado, Hector; Bromberg, Jacqueline; Lyden, David

2015-01-01

Ever since Stephen Paget’s 1889 hypothesis, metastatic organotropism has remained one of cancer’s greatest mysteries. Here we demonstrate that exosomes from mouse and human lung-, liver- and brain-tropic tumour cells fuse preferentially with resident cells at their predicted destination, namely lung fibroblasts and epithelial cells, liver Kupffer cells and brain endothelial cells. We show that tumour-derived exosomes uptaken by organ-specific cells prepare the pre-metastatic niche. Treatment with exosomes from lung-tropic models redirected the metastasis of bone-tropic tumour cells. Exosome proteomics revealed distinct integrin expression patterns, in which the exosomal integrins α6β4 and α6β1 were associated with lung metastasis, while exosomal integrin αvβ5 was linked to liver metastasis. Targeting the integrins α6β4 and αvβ5 decreased exosome uptake, as well as lung and liver metastasis, respectively. We demonstrate that exosome integrin uptake by resident cells activates Src phosphorylation and pro-inflammatory S100 gene expression. Finally, our clinical data indicate that exosomal integrins could be used to predict organ-specific metastasis. PMID:26524530

Bone marrow-derived Gr1+ cells can generate a metastasis-resistant microenvironment via induced secretion of thrombospondin-1

PubMed Central

Catena, Raúl; Bhattacharya, Nandita; Rayes, Tina El; Wang, Suming; Choi, Hyejin; Gao, Dingcheng; Ryu, Seongho; Joshi, Natasha; Bielenberg, Diane; Lee, Sharrell B.; Haukaas, Svein A.; Gravdal, Karsten; Halvorsen, Ole J.; Akslen, Lars A.; Watnick, Randolph S.; Mittal, Vivek

2013-01-01

Metastatic tumors have been shown to establish permissive microenvironments for metastases via recruitment of bone marrow (BM)- derived cells. Here, we show that metastasis-incompetent tumors are also capable of generating such microenvironments. However, in these situations the otherwise pro-metastatic Gr1+ myeloid cells create a metastasis-refractory microenvironment via the induction of thrombospondin-1 (Tsp-1) by tumor-secreted prosaposin. (BM)-specific genetic deletion of Tsp-1 abolished the inhibition of metastasis, which was restored by BM transplant from Tsp-1+ donors. We also developed a 5-amino acid peptide from prosaposin as a pharmacological inducer of Tsp-1 in Gr1+ BM cells, which dramatically suppresses metastasis. These results provide mechanistic insights into why certain tumors are deficient in metastatic potential and implicate recruited Gr1+ myeloid cells as the main source of Tsp-1. The results underscore the plasticity of Gr1+ cells, which, depending on the context, promote or inhibit metastasis, and suggest that the peptide could be a potential therapeutic agent against metastatic cancer. PMID:23633432

Tumour exosome integrins determine organotropic metastasis

DOE PAGES

Hoshino, Ayuko; Costa-Silva, Bruno; Shen, Tang-Long; ...

2015-10-28

Ever since Stephen Paget’s 1889 hypothesis, metastatic organotropism has remained one of cancer’s greatest mysteries. In this paper, we demonstrate that exosomes from mouse and human lung-, liver- and brain-tropic tumour cells fuse preferentially with resident cells at their predicted destination, namely lung fibroblasts and epithelial cells, liver Kupffer cells and brain endothelial cells. We show that tumour-derived exosomes uptaken by organ-specific cells prepare the pre-metastatic niche. Treatment with exosomes from lung-tropic models redirected the metastasis of bone-tropic tumour cells. Exosome proteomics revealed distinct integrin expression patterns, in which the exosomal integrins α 6β 4 and α 6β 1 weremore » associated with lung metastasis, while exosomal integrin α vβ 5 was linked to liver metastasis. Targeting the integrins α 6β 4 and α vβ 5 decreased exosome uptake, as well as lung and liver metastasis, respectively. We demonstrate that exosome integrin uptake by resident cells activates Src phosphorylation and pro-inflammatory S100 gene expression. In conclusion, our clinical data indicate that exosomal integrins could be used to predict organ-specific metastasis.« less

Tumour exosome integrins determine organotropic metastasis

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

Hoshino, Ayuko; Costa-Silva, Bruno; Shen, Tang-Long

Ever since Stephen Paget’s 1889 hypothesis, metastatic organotropism has remained one of cancer’s greatest mysteries. In this paper, we demonstrate that exosomes from mouse and human lung-, liver- and brain-tropic tumour cells fuse preferentially with resident cells at their predicted destination, namely lung fibroblasts and epithelial cells, liver Kupffer cells and brain endothelial cells. We show that tumour-derived exosomes uptaken by organ-specific cells prepare the pre-metastatic niche. Treatment with exosomes from lung-tropic models redirected the metastasis of bone-tropic tumour cells. Exosome proteomics revealed distinct integrin expression patterns, in which the exosomal integrins α 6β 4 and α 6β 1 weremore » associated with lung metastasis, while exosomal integrin α vβ 5 was linked to liver metastasis. Targeting the integrins α 6β 4 and α vβ 5 decreased exosome uptake, as well as lung and liver metastasis, respectively. We demonstrate that exosome integrin uptake by resident cells activates Src phosphorylation and pro-inflammatory S100 gene expression. In conclusion, our clinical data indicate that exosomal integrins could be used to predict organ-specific metastasis.« less

Histologic assessment of tumor budding in preoperative biopsies to predict nodal metastasis in squamous cell carcinoma of the tongue and floor of the mouth.

PubMed

Seki, Mai; Sano, Takaaki; Yokoo, Satoshi; Oyama, Tetsunari

2016-04-01

In squamous cell carcinoma (SCC) of the tongue and the floor of the mouth (FOM), it is important to predict lymph node metastasis, including occult metastasis, before operating. The purpose of this study was for us to determine practical histopathologic parameters as predictive factors for lymph node metastasis in preoperative SCC biopsy specimens. We examined 91 cases of SCC for conventional histopathologic assessment and a new factor, tumor budding, and their relationship with lymph node metastasis. Significant factors via univariate analysis (p < .01) were budding (score ≥3) and tumor depth (≥3 mm) and these were associated with lymph node metastasis. Moreover, both budding and tumor depth significantly correlated with relapse-free survival; however, evaluating biopsy specimens often proved inaccurate for predicting true tumor depth of cancer invasion. Tumor budding using immunohistochemistry for cytokeratin should be added to routine histologic assessments as a new criterion factoring into the decision as to whether neck dissection is indicated. © 2015 Wiley Periodicals, Inc. Head Neck 38: E1582-E1590, 2016. © 2015 Wiley Periodicals, Inc.

[Assessment of lymph node metastasis in gastric cancer: status quo, recent advances and new perspectives].

PubMed

Tu, Min; Zhu, Zhen-shu; Shi, Lin-sen; Jiang, Xi-qun; Wang, Hao; Guan, Wen-xian

2012-02-01

The precondition of accurate gastric cancer surgery is precise assessment of lymph node metastasis. To date, no imaging modality achieves both high sensitivity and high specificity in detecting lymph node metastasis in gastric cancer. Intraoperative sentinel node tracing and biopsy are the most popular method to identify the localization of tumor cell, but is limited to early gastric cancer. Nano-composite materials, designed for tumor imaging and tracing, show us a newly emerging domain for tumor detection in gastric cancer. The function of these nano-composite materials to detect lymph node metastasis in gastric cancer relies on the effective backflow of lymph system. However, the lymph vessels can be obstructed by tumor cells in advanced gastric cancer, which may restrain the application of these nanoparticles. Therefore, more methods to detect lymph node metastasis in gastric cancer should be explored. This review summarizes the characteristic of the targeted nanosphere. Based on the reported studies, a novel idea is conceived that targeted multifunctional nanosphere may be a potential method to achieve precise assessment of lymph node metastasis in gastric cancer.

Value of CT added to ultrasonography for the diagnosis of lymph node metastasis in patients with thyroid cancer.

PubMed

Lee, Younghen; Kim, Ji-Hoon; Baek, Jung Hwan; Jung, So Lyung; Park, Sun-Won; Kim, Jinna; Yun, Tae Jin; Ha, Eun Ju; Lee, Kyu Eun; Kwon, Soon Young; Yang, Kyung-Sook; Na, Dong Gyu

2018-05-13

The benefit of CT for the diagnosis of lymph node metastasis in patients with thyroid cancer is still unclear. Three hundred fifty-one patients with thyroid cancers from 7 hospitals were prospectively enrolled in order to compare diagnostic performance between a combination of ultrasound and CT (ultrasound/CT) and ultrasound alone for prediction of lymph node metastasis and to calculate patient-based benefits of CT added to ultrasound. Of 801 pathologically proven neck levels, ultrasound/CT showed higher sensitivities in both central and lateral compartments and improved accuracy in the lateral compartment compared to ultrasound alone. In the retropharyngeal/superior mediastinal compartment, although CT could detect lymph node metastasis an ultrasound could not. Patient-based benefit was demonstrated in 13.1% of patients (46/351), and was higher in patients with cancers >1 cm than cancers ≤1 cm. In patients with thyroid cancer, CT improved surgical planning by enhancing the sensitivity for lymph node metastasis and by detecting lymph node metastasis that was overlooked with ultrasound alone. © 2018 Wiley Periodicals, Inc.

EMT and induction of miR-21 mediate metastasis development in Trp53-deficient tumours

PubMed Central

Bornachea, Olga; Santos, Mirentxu; Martínez-Cruz, Ana Belén; García-Escudero, Ramón; Dueñas, Marta; Costa, Clotilde; Segrelles, Carmen; Lorz, Corina; Buitrago, Agueda; Saiz-Ladera, Cristina; Agirre, Xabier; Grande, Teresa; Paradela, Beatriz; Maraver, Antonio; Ariza, José M.; Prosper, Felipe; Serrano, Manuel; Sánchez-Céspedes, Montse; Paramio, Jesús M.

2012-01-01

Missense mutations in TP53 gene promote metastasis in human tumours. However, little is known about the complete loss of function of p53 in tumour metastasis. Here we show that squamous cell carcinomas generated by the specific ablation of Trp53 gene in mouse epidermis are highly metastatic. Biochemical and genome-wide mRNA and miRNA analyses demonstrated that metastases are associated with the early induction of epithelial-mesenchymal transition (EMT) and deregulated miRNA expression in primary tumours. Increased expression of miR-21 was observed in undifferentiated, prometastatic mouse tumours and in human tumours characterized by p53 mutations and distant metastasis. The augmented expression of miR-21, mediated by active mTOR and Stat3 signalling, conferred increased invasive properties to mouse keratinocytes in vitro and in vivo, whereas blockade of miR-21 in a metastatic spindle cell line inhibits metastasis development. Collectively these data identify novel molecular mechanisms leading to metastasis in vivo originated by p53 loss in epithelia. PMID:22666537

Lithium inhibits tumor lymphangiogenesis and metastasis through the inhibition of TGFBIp expression in cancer cells

PubMed Central

Maeng, Yong-Sun; Lee, Rina; Lee, Boram; Choi, Seung-il; Kim, Eung Kweon

2016-01-01

Metastasis is the main cause of mortality in cancer patients. Although there are many anti-cancer drugs targeting tumor growth, anti-metastatic agents are rarely developed. Angiogenesis and lymphangiogenesis are crucial for cancer progression; in particular, lymphangiogenesis is pivotal for metastasis in cancer. Here we report that lithium inhibits colon cancer metastasis by blocking lymphangiogenesis. Lithium reduces the expression of transforming growth factor-β-induced protein (TGFBIp) in colon cancer cells by inhibiting Smad3 phosphorylation via GSK3β inactivation. Moreover, lithium inhibits lymphatic endothelial cell migration, which is increased upon TGFBIp expression in tumor cells. Lithium had no significant effect on SW620 tumor growth in vitro and in vivo; however, it inhibited lymphangiogenesis in tumors. In tumor xenografts model, lithium was found to prevent metastasis to the lungs, liver, and lymph nodes by inhibiting TGFBIp-induced tumor lymphangiogenesis. Collectively, our findings demonstrate a novel role of lithium in the inhibition of colon cancer metastasis by blocking TGFBIp expression, and thereby TGFBIp-induced lymphangiogenesis, in primary tumors. PMID:26857144

Griffipavixanthone, a dimeric xanthone extracted from edible plants, inhibits tumor metastasis and proliferation via downregulation of the RAF pathway in esophageal cancer.

PubMed

Ding, Zhijie; Lao, Yuanzhi; Zhang, Hong; Fu, Wenwei; Zhu, Lunlun; Tan, Hongsheng; Xu, Hongxi

2016-01-12

Metastasis causes a large number of deaths among esophageal cancer patients. The activation of RAF family proteins elevates tumor metastasis and proliferation. In screen targeting the RAF protein, we identified that Griffipavixanthone (GPX), a dimeric xanthone isolated from Garcinia esculenta, is a B-RAF and C-RAF inhibitor against esophageal cancer cells. Using wound healing, transwell migration and matrigel invasion assays, we confirmed that GPX significantly inhibited cell migration and invasion. Furthermore, exposure to GPX rendered cell proliferation and induced G2/M cell cycle arrest. Our mechanistic study showed that GPX suppressed cancer metastasis and proliferation through downregulation of RAF-MEK-ERK cascades proteins as well as RAF mRNA levels. In a pulmonary metastasis model, the intraperitoneal injection of GPX significantly suppressed esophageal tumor metastasis and ERK protein level in vivo. In conclusion, our present study suggested that GPX could inhibit tumor migration, invasion and proliferation in vitro and in vivo, which indicated the potential of GPX for preventing and treating esophageal cancer.

A Targetable Molecular Chaperone Hsp27 Confers Aggressiveness in Hepatocellular Carcinoma.

PubMed

Zhang, Yurong; Tao, Xuemei; Jin, Guangzhi; Jin, Haojie; Wang, Ning; Hu, Fangyuan; Luo, Qin; Shu, Huiqun; Zhao, Fangyu; Yao, Ming; Fang, Jingyuan; Cong, Wenming; Qin, Wenxin; Wang, Cun

2016-01-01

Heat shock protein 27 (Hsp27) is an ATP-independent molecular chaperone and confers survival advantages and resistance to cancer cells under stress conditions. The effects and molecular mechanisms of Hsp27 in HCC invasion and metastasis are still unclear. In this study, hepatocellular carcinoma (HCC) tissue array (n = 167) was used to investigate the expression and prognostic relevance of Hsp27 in HCC patients. HCC patients with high expression of Hsp27 exhibited poor prognosis. Overexpression of Hsp27 led to the forced invasion of HCC cells, whereas silencing Hsp27 attenuated invasion and metastasis of HCC cells in vitro and in vivo. We revealed that Hsp27 activated Akt signaling, which in turn promoted MMP2 and ITGA7 expression and HCC metastasis. We further observed that targeting Hsp27 using OGX-427 obviously suppressed HCC metastasis in two metastatic models. These findings indicate that Hsp27 is a useful predictive factor for prognosis of HCC and it facilitates HCC metastasis through Akt signaling. Targeting Hsp27 with OGX-427 may represent an attractive therapeutic option for suppressing HCC metastasis.

A Targetable Molecular Chaperone Hsp27 Confers Aggressiveness in Hepatocellular Carcinoma

PubMed Central

Zhang, Yurong; Tao, Xuemei; Jin, Guangzhi; Jin, Haojie; Wang, Ning; Hu, Fangyuan; Luo, Qin; Shu, Huiqun; Zhao, Fangyu; Yao, Ming; Fang, Jingyuan; Cong, Wenming; Qin, Wenxin; Wang, Cun

2016-01-01

Heat shock protein 27 (Hsp27) is an ATP-independent molecular chaperone and confers survival advantages and resistance to cancer cells under stress conditions. The effects and molecular mechanisms of Hsp27 in HCC invasion and metastasis are still unclear. In this study, hepatocellular carcinoma (HCC) tissue array (n = 167) was used to investigate the expression and prognostic relevance of Hsp27 in HCC patients. HCC patients with high expression of Hsp27 exhibited poor prognosis. Overexpression of Hsp27 led to the forced invasion of HCC cells, whereas silencing Hsp27 attenuated invasion and metastasis of HCC cells in vitro and in vivo. We revealed that Hsp27 activated Akt signaling, which in turn promoted MMP2 and ITGA7 expression and HCC metastasis. We further observed that targeting Hsp27 using OGX-427 obviously suppressed HCC metastasis in two metastatic models. These findings indicate that Hsp27 is a useful predictive factor for prognosis of HCC and it facilitates HCC metastasis through Akt signaling. Targeting Hsp27 with OGX-427 may represent an attractive therapeutic option for suppressing HCC metastasis. PMID:26941848

[Gastric Cancer Diagnosed with Metastasis of the Navel(Sister Mary Joseph's Nodule) - A Case Report].

PubMed

Katayama, Tomohiro; Ishii, Takaaki; Tono, Takeshi; Okubo, Yusuke; Shinozaki, Koji; Kawasaki, Yasuhito; Senba, Shuho; Yasuda, Seiji; Otsuru, Minoru

2016-11-01

A woman in her 60s was admitted to our hospital with pain and induration of the navel. She was diagnosed with gastric cancer with metastasis to the navel and underwent total gastrectomy and navel extraction. Because disseminated nodules were detected in the Douglas pouch and sigmoid colon, sigmoidectomy was performed to prevent bowel obstruction. The navel tumor was histologically diagnosed as a metastasis of the gastric cancer. One month after surgery, a chest skin tumor, which was also a skin metastasis of the gastric cancer[T4aN3M1(SKI, OTH)H0P1, fStage IV ], was detected, and tumor enucleation was performed. Enucleation was followed by 47 courses of systemic chemotherapy consisting of capecitabine, cisplatin, and trastuzumab. No recurrence or metastasis has been observed via FDG-PET/CT as of 5 years after surgery. Gastric cancer with peritoneal dissemination in addition to navel metastasis has been reported to have an extremely poor prognosis. However, long-term, recurrence-free survival was obtained in this case owing to aggressive surgical resection, followed by persistent systemic chemotherapy.

Lymphatic endothelium stimulates melanoma metastasis and invasion via MMP14-dependent Notch3 and β1-integrin activation

PubMed Central

Balistreri, Giuseppe; Gramolelli, Silvia; Tatti-Bugaeva, Olga; Paatero, Ilkka; Niiranen, Otso; Tuohinto, Krista; Perälä, Nina; Taiwo, Adewale; Zinovkina, Nadezhda; Repo, Pauliina; Icay, Katherine; Ivaska, Johanna; Saharinen, Pipsa; Hautaniemi, Sampsa; Lehti, Kaisa

2018-01-01

Lymphatic invasion and lymph node metastasis correlate with poor clinical outcome in melanoma. However, the mechanisms of lymphatic dissemination in distant metastasis remain incompletely understood. We show here that exposure of expansively growing human WM852 melanoma cells, but not singly invasive Bowes cells, to lymphatic endothelial cells (LEC) in 3D co-culture facilitates melanoma distant organ metastasis in mice. To dissect the underlying molecular mechanisms, we established LEC co-cultures with different melanoma cells originating from primary tumors or metastases. Notably, the expansively growing metastatic melanoma cells adopted an invasively sprouting phenotype in 3D matrix that was dependent on MMP14, Notch3 and β1-integrin. Unexpectedly, MMP14 was necessary for LEC-induced Notch3 induction and coincident β1-integrin activation. Moreover, MMP14 and Notch3 were required for LEC-mediated metastasis of zebrafish xenografts. This study uncovers a unique mechanism whereby LEC contact promotes melanoma metastasis by inducing a reversible switch from 3D growth to invasively sprouting cell phenotype. PMID:29712618

Massive trapezial metastasis from gastric adenocarcinoma resected and reconstructed with a vascularized scapular bone graft: A case report.

PubMed

Okamoto, Masanori; Yamazaki, Hiroshi; Yoshimura, Yasuo; Aoki, Kaoru; Tanaka, Atsushi; Kato, Hiroyuki

2017-12-01

Isolated metastasis to the hand bones is very rare. Only seven cases of metastasis to the trapezium have been reported. To the best of our knowledge, this is the first report of a single metastasis to the trapezium from a gastric adenocarcinoma. A 62-year-old man presented with pain and massive swelling in the right carpometacarpal joint of the thumb. The patient was diagnosed with trapezial metastasis of advanced gastric adenocarcinoma. The patient underwent systemic chemotherapy with cisplatin and S-1, radiotherapy to the metastatic bone, and treatment with denosumab. One year later, the huge metastatic tumor was resected, and the hand was reconstructed using vascularized scapular bone. Eighteen months postoperatively, the patient was satisfied with the appearance of the reconstructed hand and was able to use his right thumb in activities of daily living. Although rare, metastasis to the trapezium should be considered in patients with persistent and progressive thumb CMC joint pain. Copyright © 2017 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.

Tumour exosome integrins determine organotropic metastasis.

PubMed

Hoshino, Ayuko; Costa-Silva, Bruno; Shen, Tang-Long; Rodrigues, Goncalo; Hashimoto, Ayako; Tesic Mark, Milica; Molina, Henrik; Kohsaka, Shinji; Di Giannatale, Angela; Ceder, Sophia; Singh, Swarnima; Williams, Caitlin; Soplop, Nadine; Uryu, Kunihiro; Pharmer, Lindsay; King, Tari; Bojmar, Linda; Davies, Alexander E; Ararso, Yonathan; Zhang, Tuo; Zhang, Haiying; Hernandez, Jonathan; Weiss, Joshua M; Dumont-Cole, Vanessa D; Kramer, Kimberly; Wexler, Leonard H; Narendran, Aru; Schwartz, Gary K; Healey, John H; Sandstrom, Per; Labori, Knut Jørgen; Kure, Elin H; Grandgenett, Paul M; Hollingsworth, Michael A; de Sousa, Maria; Kaur, Sukhwinder; Jain, Maneesh; Mallya, Kavita; Batra, Surinder K; Jarnagin, William R; Brady, Mary S; Fodstad, Oystein; Muller, Volkmar; Pantel, Klaus; Minn, Andy J; Bissell, Mina J; Garcia, Benjamin A; Kang, Yibin; Rajasekhar, Vinagolu K; Ghajar, Cyrus M; Matei, Irina; Peinado, Hector; Bromberg, Jacqueline; Lyden, David

2015-11-19

Ever since Stephen Paget's 1889 hypothesis, metastatic organotropism has remained one of cancer's greatest mysteries. Here we demonstrate that exosomes from mouse and human lung-, liver- and brain-tropic tumour cells fuse preferentially with resident cells at their predicted destination, namely lung fibroblasts and epithelial cells, liver Kupffer cells and brain endothelial cells. We show that tumour-derived exosomes uptaken by organ-specific cells prepare the pre-metastatic niche. Treatment with exosomes from lung-tropic models redirected the metastasis of bone-tropic tumour cells. Exosome proteomics revealed distinct integrin expression patterns, in which the exosomal integrins α6β4 and α6β1 were associated with lung metastasis, while exosomal integrin αvβ5 was linked to liver metastasis. Targeting the integrins α6β4 and αvβ5 decreased exosome uptake, as well as lung and liver metastasis, respectively. We demonstrate that exosome integrin uptake by resident cells activates Src phosphorylation and pro-inflammatory S100 gene expression. Finally, our clinical data indicate that exosomal integrins could be used to predict organ-specific metastasis.

Lymphatic vessel invasion and lymph node metastasis in patients with clinical stage I non-small cell lung cancer.

PubMed

Kang, Du-Young; Lee, Sungsoo

2014-09-01

The aim of this study was to investigate the association between the presence of lymphatic vessel invasion (LVI) in primary tumors and lymph node (LN) metastasis in clinical stage I non-small cell lung cancer (NSCLC) patients. A total of 76 patients who underwent complete resection for clinical stage I adenocarcinoma and squamous cell carcinoma were retrospectively examined. Tumors consisted of 51 cases of adenocarcinoma and 25 cases of squamous cell carcinoma as determined by histology. LN metastasis was detected in 24.4% (19/76) of patients. Factors associated with LN metastasis on univariate analysis included LVI (p < 0.001) and increased tumor dimensions (p < 0.05). Binary logistic regression analysis showed that the presence of LVI (p < 0.001) was the only predictor of LN metastasis. LVI is significantly associated with LN metastasis in patients with clinical stage I NSCLC. These findings may be helpful in determining the most appropriate operative strategy for patients if preoperative detection of LVI becomes feasible. Georg Thieme Verlag KG Stuttgart · New York.

Comparison between wait-and-see policy and elective neck dissection in clinically N0 cutaneous squamous cell carcinoma of head and neck.

PubMed

Xiao, Yan; Yuan, Shuai; Liu, Fei; Liu, Bing; Zhu, Juanfang; He, Wei; Li, Wenlu; Kan, Quancheng

2018-06-01

To analyze the superiority of wait-and-see policy and elective neck dissection in treating cN0 patients with facial cutaneous cell carcinoma (cSCC).Patients with clinically negative parotid and neck metastasis disease were prospectively enrolled. Three groups were divided based on whether the patient received an operation of superficial parotidectomy or/and elective dissection, and regional control and disease-specific survival rates were compared.The occult parotid and neck metastasis rate was 20% and 16%, respectively. There was neck node metastasis without parotid metastasis in only 1 patient. All the node metastasis occurred in level II. Regional recurrence was noted in 16 (16%) patients, and 6 patients died of the disease. In the group undergoing superficial parotidectomy and elective neck dissection, 2 patients had neck node metastasis, and there was no disease-related death, further survival analysis indicated it had better regional control and disease-specific survival rates compared with the other 2 groups.Superficial parotidectomy and elective neck dissection are suggested for patients with T3-4 facial cutaneous squamous cell carcinoma.

Steps in Prostate Cancer Progression that lead to Bone Metastasis

PubMed Central

Jin, Jung-Kang; Dayyani, Farshid; Gallick, Gary E.

2011-01-01

Prostate cancer is a complex disease in which metastasis to the bone is the main cause of death. Initial stages of metastasis are generally similar to those for most solid tumors; however, the mechanisms that underlie the homing of prostate tumor cells to the bone remain incompletely understood. Prostate cancer bone metastasis is also a microenvironment-driven disease, involving bi-directional interactions between the tumor and the bone microenvironment. In this review, we discuss the current understanding of the biologic processes and regulatory factors involved in the metastasis of prostate cancer cells, and their specific properties that promote growth in bone. Although many of these processes still need to be fully elucidated, a better understanding of the complex tumor/microenvironment interplay is slowly leading to more effective therapies for patients with prostate cancer bone metastases. PMID:21365645

A case of synchronous metastasis of breast cancer to stomach and colon.

PubMed

Takeuchi, Hideya; Hiroshige, Shozi; Yoshikawa, Yasuji; Kusumoto, Tetusya; Muto, Yoichi

2012-09-01

A case of synchronous metastasis of breast cancer to the stomach and colon is reported. A 38-year-old woman with a history of bilateral breast cancer was admitted for endoscopic examination because of occult blood. Endoscopic examination showed elevated lesions on the mucosal surface of the stomach and cecum. Histopathological examination of the biopsy specimens obtained from both sites showed adenocarcinoma, comprised of tumor cells with structural and nuclear atypia, which were similar to those of the primary breast cancer cells. In immunohistochemical analysis, these tumor cells stained positive for ER. Therefore, we diagnosed a synchronous metastasis of breast cancer to the stomach and colon. Synchronous metastasis of breast cancer to the stomach and colon without liver metastasis or peritoneal dissemination is extremely rare, with only 4 reported cases existing in literature.

Complex pattern of colon cancer recurrence including a kidney metastasis: A case report

PubMed Central

Waleczek, Helfried; Wente, Moritz N; Kozianka, Jürgen

2005-01-01

We report a case of a 77-year-old female with a local recurrence of cancer after right hemicolectomy which infiltrated the pancreatic head affording pancrea-toduodenectomy, who developed 3 years later recurrent tumor masses localized in the mesentery of the jejunum and in the lower pole of the left kidney. Partial nephrectomy and a segment resection of the small bowel were performed. Histological examination of both specimens revealed a necrotic metastasis of the primary carcinoma of the colon. Although intraluminal implantation of colon cancer cells in the renal pelvic mucosa from ureteric metastasis has been described, metastasis of a colorectal cancer in the kidney parenchyma is extremely rare and can be treated in an organ preserving manner. A complex pattern of colon cancer recurrence with unusual and rare sites of metastasis is reported. PMID:16222759

Umbilical metastasis derived from early stage rectal cancer: a case report

PubMed Central

2014-01-01

Background Umbilical metastasis, also called Sister Mary Joseph’s nodule (SMJN), is defined as the umbilical nodule associated with advanced metastatic intra-abdominal and pelvic malignancies. A patient with umbilical metastasis has been deemed to have a poor prognosis. Rectal cancer presenting with a SMJN is a rare phenomenon, especially in the early stage and in middle-low rectal cancer. Case presentation We report a case of a 70-year-old male presenting with umbilical metastasis derived from rectal cancer (10 cm from the anal verge, T2N0). Discussion and conclusion For rectal cancer with umbilical metastasis, the exact metastatic routes as well as the criterion of diagnosis and treatments are not very clear. Here we review the literature on rectal cancer and SMJN to deepen the understanding of this disease. PMID:24708697

Partial resection and reconstruction of the sternum for treatment of metachronous sternal metastasis of thyroid carcinoma: A case report.

PubMed

Lan, Hong-Jing; Wu, Zhi-Qiang; Gong, Dong-Ge; Zheng, Wang-Yong; Jin, Yun

2017-11-01

Metachronous sternal metastasis of thyroid carcinoma was a rare disease. There was no consensus in the treatment for bone metastasis after the initial thyroid carcinoma surgery. A 53-year-old female patient was hospitalized due to recurrent dull chest pains, with a history of radical right side thyroid carcinoma 4 years ago. On examination, there was an irregular mass on the lower left half of the sternum. Computerized tomography scan showed sternal bone destruction with a soft tissue mass. Metachronous sternal metastasis of thyroid carcinoma. Partial resection of the sternum and reconstruction with a titanium alloy mesh were performed. After a 3-year follow-up, the patient had no recurrence. Surgical resection may be a sufficient treatment for metachronous sternal metastasis of thyroid carcinoma. Biosynthesis material mesh is preferred to be used.

Splenic hilar lymph node metastasis independently predicts poor survival for patients with gastric cancers in the upper and/or the middle third of the stomach.

PubMed

Zhu, Guo-Lian; Sun, Zhe; Wang, Zhen-Ning; Xu, Ying-Ying; Huang, Bao-Jun; Xu, Yan; Zhu, Zhi; Xu, Hui-Mian

2012-06-15

Effectiveness of splenectomy for advanced gastric cancers occupying the upper and/or the middle third of the stomach is still in debate. The aim of the present study is to elucidate the impact of splenectomy on patient survival by investigating the pathological characteristics and prognostic significance of splenic hilar lymph node metastasis. Clinicopathologic and prognostic data of 265 patients with gastric cancer in the upper and/or the middle third of the stomach who underwent the operation of en bloc resection of primary cancer and D2/D3 lymphadenectomy combined with splenectomy were retrospectively reviewed. Multivariate analysis revealed pT category, pN category, and distant lymph node metastasis independently correlated with the presence of splenic hilar lymph node metastasis. Prognoses of patients with positive splenic hilar lymph nodes were significantly poorer than that of patients with negative splenic hilar lymph nodes for the entire study population and for those who underwent R0 resection, but not for those who underwent R1-2 resection. There was no significant difference in survival between patients who underwent R0 resection with positive splenic hilar lymph nodes and those who underwent R1-2 resection. Splenic hilar lymph node metastasis was one of independent indicators predicting worse prognosis and the presence of distant metastasis after surgery. Subset analysis according to the TNM stage revealed there were significant differences in survival between patients with and without splenic hilar lymph node metastasis. Splenic hilar lymph node metastasis should be considered as one of incurable factors. Consequently, the efficiency of splenectomy aiming at prolonging survival for patients with high risk of splenic hilar lymph nodes metastasis should be questioned, although resection of invasive organs form gastric cancers has been recommended if R0 surgery could be achieved. Copyright © 2011 Wiley Periodicals, Inc.

[Correlations between cellular immunity and invasiveness in differentiated thyroid cancer].

PubMed

Han, Ting; Liang, Jun; Meng, Chao; Yang, Ke; Li, Xiao-yi; Lin, Yan-song

2014-02-01

To investigate the relationship between the immunity and invasiveness in differentiated thyroid cancer (DTC). Totally 74 DTC who were treated in Peking Union Medical College Hospital from September 2012 to December 2012 were enrolled in this study. These 74 patients were divided into membrane invasion group (n=36) and without membrane invasion group (n=38); also, they were divided into distant metastasis group (n=18) and without distant metastasis group (n=56). Natural killer (NK) cells and T-cell subsets were chosen as indicators for cellular immunity to investigate the correlation between cellular immunity and invasiveness in DTC. Univariate analysis showed that the membrane invasion (Χ(2)=12.175, P=0.000) and distant metastasis (Χ(2)=8.139, P=0.006) correlated with cell immunity, whereas distant metastasis correlated with lymphocytic thyroiditis (Χ(2)=7.094, P=0.008). Further investigation shows that distant metastasis was associated with the percentage of CD8+T cell subgroup (Χ(2)=5.429, P=0.020), and membrane invasion was significantly associated with NK cells (Χ(2)=2.445, P=0.018) and CD4/CD8 disorder subgroup (Χ(2)=8.079, P=0.002). Multivariate analysis showed that cell immunity disorder was a risk factor for membrane invasion [OR=5.701,95%CI(2.075~15.666), P=0.001] and distant metastasis [OR=5.063,95%CI (1.571~16.320), P=0.008]. Further analysis showed that CD8+T cell was a risk factor for metastasis [OR=2.236,95%CI( 1.084~4.613), P=0.029], and CD4/CD8 disorders were the risk factors for membrane invasion [OR=2.802,95%CI(1.257~6.244), P=0.012]. Cell immunity in thyroid cancer has close relationship with membrane invasion and distant metastasis, especially when the percentage of CD8+T cells decreases and when the NK cells and CD4/CD8 are abnormal, which may lead to membrane invasion and distant metastasis.

Prognostic factors of early metastasis and mortality in dogs with appendicular osteosarcoma after receiving surgery: an individual patient data meta-analysis.

PubMed

Schmidt, A F; Nielen, M; Klungel, O H; Hoes, A W; de Boer, A; Groenwold, R H H; Kirpensteijn, J

2013-11-01

Recently an aggregated data meta-analysis showed that serum alkaline phosphatase (SALP) and proximal humerus location are predictors for shorter survival in canine osteosarcoma. To identify additional prognostic factors of mortality and metastasis an individual patient data meta-analysis (IPDMA) was conducted. Individual patient data from 20 studies, identified via the VSSO society, were pooled. Univariable and multivariable hazard ratios (HR) for metastasis and mortality were assessed, using stratified Cox models. The study included 1405 dogs who received surgical treatment, of which the metastasis status was measured in 1155 dogs and mortality status in 1336 dogs; median survival was 256 days. High versus normal SALP and weight (kg) were associated with an increase in hazard of metastasis [HR 1.34 (95%CI 1.07; 1.68) and HR 1.02 (per kg increase) (95%CI 1.01; 1.03)] and for mortality [HR 1.43 (95%CI 1.16; 1.77) and HR 1.02 (95%CI 1.01; 1.02)]. Distal radius tumor was associated with a lower hazard of metastasis compared to other locations: HR 0.75 (95%CI 0.58; 0.96). Proximal humerus and distal femur or proximal tibia location were related with an increased mortality: HR 1.53 (95%CI 1.26; 1.84) and HR 1.23 (95%CI 1.01; 1.49) compared to other locations. Older age (years) was associated with a higher hazard for mortality [HR 1.06 per year (95%CI 1.03; 1.09)] but not for metastasis: HR 1.03 (95%CI 0.99; 1.06). These results confirm findings from a recent aggregated data meta-analysis and (in addition) showed that tumor location, SALP, weight were prognostic factors for both mortality and metastasis. Age was a prognostic factor for mortality but not for metastasis. Copyright © 2013 Elsevier B.V. All rights reserved.

[Breast cancer metastasis in distal phalanx of the big toe. Case report].

PubMed

Carlesimo, B; Tempesta, M; Fioramonti, P; Bistoni, G; Ruggiero, M; Marchetti, F

2009-01-01

Breast cancer represents the most prevalent malignancies in women and bone is the first site of metastasis in 26-50% of cases. Usually metastasis involve limbs in 16%. We present a rare case of 47-year-old woman, who underwent to monolateral mastectomy for lobular cancer. After 8 years from surgery, she presented pain, swelling and functional limitations, gradually increasing, to the left big toe. X-rays and MRI showed a lucent area of bone destruction on the shaft of the distal phalanx of the left big toe. Surgical biopsy on the excised bone assessed for breast cancer metastasis.

Cutaneous metastasis revealing a relapse of gastric linitis: Another case.

PubMed

Kairouani, Mouna; Perrin, Julie; Dietemann-Barabinot, Anne; Diab, Rafiq; Ruck, Stephane

2013-01-01

Cutaneous metastasis from gastric cancer is a rare occurrence. The linitis gastric carcinoma accounts only 8.7% of all gastric cancers. We report a case of female patient who was followed for linits cancer with peritoneal metastasis treated by six cycles of chemotherapy. After seventeen months of control, the relapse of the disease revealed by occurrence of cutaneous metastatsis. Cutaneous metastasis from linit gastric is rare and the prognostic remains poor. The treatment is palliative. This rare presentation should encourage the practitioners to biopsy any suspicion skin lesion. Copyright © 2012 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved.

Cutaneous metastasis revealing a relapse of gastric linitis: Another case

PubMed Central

Kairouani, Mouna; Perrin, Julie; Dietemann-Barabinot, Anne; Diab, Rafiq; Ruck, Stephane

2012-01-01

INTRODUCTION Cutaneous metastasis from gastric cancer is a rare occurrence. The linitis gastric carcinoma accounts only 8.7% of all gastric cancers. PRESENTATION OF CASE We report a case of female patient who was followed for linits cancer with peritoneal metastasis treated by six cycles of chemotherapy. After seventeen months of control, the relapse of the disease revealed by occurrence of cutaneous metastatsis. DISCUSSION Cutaneous metastasis from linit gastric is rare and the prognostic remains poor. The treatment is palliative. CONCLUSION This rare presentation should encourage the practitioners to biopsy any suspicion skin lesion. PMID:23276763

Integrins in bone metastasis formation and potential therapeutic implications.

PubMed

Clëzardin, P

2009-11-01

Integrins constitute a family of cell surface receptors that are heterodimers composed of noncovalently associated alpha and beta subunits. Integrins bind to extracellular matrix proteins and immunogobulin superfamily molecules. They exert a stringent control on cell migration, survival and proliferation. However, their expression and functions are often deregulated in cancer, and many lines of evidence implicate them as key regulators during progression from primary tumor growth to metastasis. Here, we review the role of integrins in bone metastasis formation and present evidence that the use of integrin-targeted therapeutic agents may be an efficient strategy to block tumor metastasis.

Isolated Hepatic Metastasis from Prostate Carcinoma.

PubMed

Wang, Stephani C; McCarthy, Lezah P; Mehdi, Syed

2017-01-01

Worldwide, prostate cancer is considered the second most common cancer in men. Most common sites for metastatic disease are lymph nodes and bones. However, isolated liver metastasis from prostate cancer is rare. We present a 75 year-old male with prostate adenocarcinoma diagnosed 7 years ago. With rising PSA, he underwent imaging and found to have isolated hepatic metastasis. After left hepatic lobectomy, his PSA dramatically decreased to < 0.01. Physicians should be aware of isolated hepatic metastasis in patients with prostate cancer. Metastasectomy should be considered in such case, and combined medical and surgical approach may prolong the overall survival.

A Patient with Four-Year Survival after Nonsmall Cell Lung Carcinoma with a Solitary Metachronous Small Bowel Metastasis

PubMed Central

Kant, Klaas M.; Noordhoek Hegt, Vincent; Aerts, Joachim G. J. V.

2010-01-01

Solitary small bowel metastasis secondary to lung cancer is very uncommon. In this report, we present a patient with NSCLC and a metachronous solitary metastasis of the jejunum. She is alive without evidence of disease and doing well four years after palliative surgery, radiotherapy, and chemotherapy. To the best of our knowledge, this is the first case report describing a prolonged survival in a patient with a symptomatic solitary small bowel metastasis treated with palliative surgery, chemo- and radiotherapy instead of complete surgical resection. PMID:20224647

Asymptomatic solitary cerebral metastasis from papillary carcinoma thyroid: 131I SPECT/CT for accurate staging.

PubMed

Jain, Tarun Kumar; Karunanithi, Sellam; Sharma, Punit; Vijay, Maneesh Kumar; Ballal, Sanjana; Bal, Chandrasekhar

2014-11-01

Isolated asymptomatic brain metastasis in papillary carcinoma thyroid (PCT) is extremely rare. We here present such a case of a 48-year-old woman with PCT. SPECT/CT localized the 131I radiotracer concentration seen on whole-body scan in this patient to the right posterior parietal cortex, suggesting brain metastasis. Contrast-enhanced MRI and 18F-FDG PET/CT confirmed the diagnosis and the patient was taken for gamma-knife radiosurgery. 131I SPECT/CT in this case accurately restaged the patient by detecting asymptomatic isolated brain metastasis and correctly directed the management strategy.

A derivative of oleamide potently inhibits the spontaneous metastasis of mouse melanoma BL6 cells.

PubMed

Ito, Akihiko; Morita, Nobuyoshi; Miura, Daisaku; Koma, Yu-Ichiro; Kataoka, Tatsuki R; Yamasaki, Hiroshi; Kitamura, Yukihiko; Kita, Yasuyuki; Nojima, Hiroshi

2004-10-01

We reported previously that the abnormally augmented expression of connexin 26 (Cx26) is responsible for the enhanced spontaneous metastasis of mouse BL6 melanoma cells, and that the exogenous expression of a dominant negative form of Cx26 inhibits the spontaneous metastasis of BL6. Here we show that daily intraperitoneal (i.p.) injections of oleamide, a sleep-inducing lipid hormone, weakly inhibited the spontaneous metastasis of BL6 cells. To obtain a more effective reagent, 19 oleamide derivatives were chemically synthesized and tested for their ability to inhibit the gap junction-mediated intercellular communications (GJIC) that are formed between HeLa cells by the ectopic expression of Cx26 or Cx43. One of these, denoted metastasis inhibitor-18 (MI-18), inhibited the GJIC formed by Cx26 as well as oleamide but unlike oleamide, which is a non-selective inhibitor of connexin, it did not inhibit the GJIC formed by Cx43. Daily i.p. injections of MI-18 potently blocked the spontaneous metastasis of BL6 cells down to 15% of that in the untreated control mice. MI-18 was safe because even after >7 weeks of daily injections, the survival rate of the mice was 93%. We propose that MI-18 may serve as a novel and clinically important prototype of a potent inhibitor of spontaneous metastasis.

Lipoxygenase mediates invasion of intrametastatic lymphatic vessels and propagates lymph node metastasis of human mammary carcinoma xenografts in mouse

PubMed Central

Kerjaschki, Dontscho; Bago-Horvath, Zsuzsanna; Rudas, Margaretha; Sexl, Veronika; Schneckenleithner, Christine; Wolbank, Susanne; Bartel, Gregor; Krieger, Sigurd; Kalt, Romana; Hantusch, Brigitte; Keller, Thomas; Nagy-Bojarszky, Katalin; Huttary, Nicole; Raab, Ingrid; Lackner, Karin; Krautgasser, Katharina; Schachner, Helga; Kaserer, Klaus; Rezar, Sandra; Madlener, Sybille; Vonach, Caroline; Davidovits, Agnes; Nosaka, Hitonari; Hämmerle, Monika; Viola, Katharina; Dolznig, Helmut; Schreiber, Martin; Nader, Alexander; Mikulits, Wolfgang; Gnant, Michael; Hirakawa, Satoshi; Detmar, Michael; Alitalo, Kari; Nijman, Sebastian; Offner, Felix; Maier, Thorsten J.; Steinhilber, Dieter; Krupitza, Georg

2011-01-01

In individuals with mammary carcinoma, the most relevant prognostic predictor of distant organ metastasis and clinical outcome is the status of axillary lymph node metastasis. Metastases form initially in axillary sentinel lymph nodes and progress via connecting lymphatic vessels into postsentinel lymph nodes. However, the mechanisms of consecutive lymph node colonization are unknown. Through the analysis of human mammary carcinomas and their matching axillary lymph nodes, we show here that intrametastatic lymphatic vessels and bulk tumor cell invasion into these vessels highly correlate with formation of postsentinel metastasis. In an in vitro model of tumor bulk invasion, human mammary carcinoma cells caused circular defects in lymphatic endothelial monolayers. These circular defects were highly reminiscent of defects of the lymphovascular walls at sites of tumor invasion in vivo and were primarily generated by the tumor-derived arachidonic acid metabolite 12S-HETE following 15-lipoxygenase-1 (ALOX15) catalysis. Accordingly, pharmacological inhibition and shRNA knockdown of ALOX15 each repressed formation of circular defects in vitro. Importantly, ALOX15 knockdown antagonized formation of lymph node metastasis in xenografted tumors. Furthermore, expression of lipoxygenase in human sentinel lymph node metastases correlated inversely with metastasis-free survival. These results provide evidence that lipoxygenase serves as a mediator of tumor cell invasion into lymphatic vessels and formation of lymph node metastasis in ductal mammary carcinomas. PMID:21540548

Platelet GPIIb supports initial pulmonary retention but inhibits subsequent proliferation of melanoma cells during hematogenic metastasis

PubMed Central

Echtler, Katrin; Konrad, Ildiko; Lorenz, Michael; Schneider, Simon; Hofmaier, Sebastian; Plenagl, Florian; Stark, Konstantin; Czermak, Thomas; Tirniceriu, Anca; Eichhorn, Martin; Walch, Axel; Enders, Georg; Massberg, Steffen; Schulz, Christian

2017-01-01

Platelets modulate the process of cancer metastasis. However, current knowledge on the direct interaction of platelets and tumor cells is mostly based on findings obtained in vitro. We addressed the role of the platelet fibrinogen receptor glycoprotein IIb (integrin αIIb) for experimental melanoma metastasis in vivo. Highly metastatic B16-D5 melanoma cells were injected intravenously into GPIIb-deficient (GPIIb-/-) or wildtype (WT) mice. Acute accumulation of tumor cells in the pulmonary vasculature was assessed in real-time by confocal videofluorescence microscopy. Arrest of tumor cells was dramatically reduced in GPIIb-/- mice as compared to WT. Importantly, we found that mainly multicellular aggregates accumulated in the pulmonary circulation of WT, instead B16-D5 aggregates were significantly smaller in GPIIb-/- mice. While pulmonary arrest of melanoma was clearly dependent on GPIIb in this early phase of metastasis, we also addressed tumor progression 10 days after injection. Inversely, and unexpectedly, we found that melanoma metastasis was now increased in GPIIb-/- mice. In contrast, GPIIb did not regulate local melanoma proliferation in a subcutaneous tumor model. Our data suggest that the platelet fibrinogen receptor has a differential role in the modulation of hematogenic melanoma metastasis. While platelets clearly support early steps in pulmonary metastasis via GPIIb-dependent formation of platelet-tumor-aggregates, at a later stage its absence is associated with an accelerated development of melanoma metastases. PMID:28253287

Platelet GPIIb supports initial pulmonary retention but inhibits subsequent proliferation of melanoma cells during hematogenic metastasis.

PubMed

Echtler, Katrin; Konrad, Ildiko; Lorenz, Michael; Schneider, Simon; Hofmaier, Sebastian; Plenagl, Florian; Stark, Konstantin; Czermak, Thomas; Tirniceriu, Anca; Eichhorn, Martin; Walch, Axel; Enders, Georg; Massberg, Steffen; Schulz, Christian

2017-01-01

Platelets modulate the process of cancer metastasis. However, current knowledge on the direct interaction of platelets and tumor cells is mostly based on findings obtained in vitro. We addressed the role of the platelet fibrinogen receptor glycoprotein IIb (integrin αIIb) for experimental melanoma metastasis in vivo. Highly metastatic B16-D5 melanoma cells were injected intravenously into GPIIb-deficient (GPIIb-/-) or wildtype (WT) mice. Acute accumulation of tumor cells in the pulmonary vasculature was assessed in real-time by confocal videofluorescence microscopy. Arrest of tumor cells was dramatically reduced in GPIIb-/- mice as compared to WT. Importantly, we found that mainly multicellular aggregates accumulated in the pulmonary circulation of WT, instead B16-D5 aggregates were significantly smaller in GPIIb-/- mice. While pulmonary arrest of melanoma was clearly dependent on GPIIb in this early phase of metastasis, we also addressed tumor progression 10 days after injection. Inversely, and unexpectedly, we found that melanoma metastasis was now increased in GPIIb-/- mice. In contrast, GPIIb did not regulate local melanoma proliferation in a subcutaneous tumor model. Our data suggest that the platelet fibrinogen receptor has a differential role in the modulation of hematogenic melanoma metastasis. While platelets clearly support early steps in pulmonary metastasis via GPIIb-dependent formation of platelet-tumor-aggregates, at a later stage its absence is associated with an accelerated development of melanoma metastases.

MET network in PubMed: a text-mined network visualization and curation system.

PubMed

Dai, Hong-Jie; Su, Chu-Hsien; Lai, Po-Ting; Huang, Ming-Siang; Jonnagaddala, Jitendra; Rose Jue, Toni; Rao, Shruti; Chou, Hui-Jou; Milacic, Marija; Singh, Onkar; Syed-Abdul, Shabbir; Hsu, Wen-Lian

2016-01-01

Metastasis is the dissemination of a cancer/tumor from one organ to another, and it is the most dangerous stage during cancer progression, causing more than 90% of cancer deaths. Improving the understanding of the complicated cellular mechanisms underlying metastasis requires investigations of the signaling pathways. To this end, we developed a METastasis (MET) network visualization and curation tool to assist metastasis researchers retrieve network information of interest while browsing through the large volume of studies in PubMed. MET can recognize relations among genes, cancers, tissues and organs of metastasis mentioned in the literature through text-mining techniques, and then produce a visualization of all mined relations in a metastasis network. To facilitate the curation process, MET is developed as a browser extension that allows curators to review and edit concepts and relations related to metastasis directly in PubMed. PubMed users can also view the metastatic networks integrated from the large collection of research papers directly through MET. For the BioCreative 2015 interactive track (IAT), a curation task was proposed to curate metastatic networks among PubMed abstracts. Six curators participated in the proposed task and a post-IAT task, curating 963 unique metastatic relations from 174 PubMed abstracts using MET.Database URL: http://btm.tmu.edu.tw/metastasisway. © The Author(s) 2016. Published by Oxford University Press.

Epoxyeicosanoids stimulate multiorgan metastasis and tumor dormancy escape in mice

PubMed Central

Panigrahy, Dipak; Edin, Matthew L.; Lee, Craig R.; Huang, Sui; Bielenberg, Diane R.; Butterfield, Catherine E.; Barnés, Carmen M.; Mammoto, Akiko; Mammoto, Tadanori; Luria, Ayala; Benny, Ofra; Chaponis, Deviney M.; Dudley, Andrew C.; Greene, Emily R.; Vergilio, Jo-Anne; Pietramaggiori, Giorgio; Scherer-Pietramaggiori, Sandra S.; Short, Sarah M.; Seth, Meetu; Lih, Fred B.; Tomer, Kenneth B.; Yang, Jun; Schwendener, Reto A.; Hammock, Bruce D.; Falck, John R.; Manthati, Vijaya L.; Ingber, Donald E.; Kaipainen, Arja; D’Amore, Patricia A.; Kieran, Mark W.; Zeldin, Darryl C.

2011-01-01

Epoxyeicosatrienoic acids (EETs) are small molecules produced by cytochrome P450 epoxygenases. They are lipid mediators that act as autocrine or paracrine factors to regulate inflammation and vascular tone. As a result, drugs that raise EET levels are in clinical trials for the treatment of hypertension and many other diseases. However, despite their pleiotropic effects on cells, little is known about the role of these epoxyeicosanoids in cancer. Here, using genetic and pharmacological manipulation of endogenous EET levels, we demonstrate that EETs are critical for primary tumor growth and metastasis in a variety of mouse models of cancer. Remarkably, we found that EETs stimulated extensive multiorgan metastasis and escape from tumor dormancy in several tumor models. This systemic metastasis was not caused by excessive primary tumor growth but depended on endothelium-derived EETs at the site of metastasis. Administration of synthetic EETs recapitulated these results, while EET antagonists suppressed tumor growth and metastasis, demonstrating in vivo that pharmacological modulation of EETs can affect cancer growth. Furthermore, inhibitors of soluble epoxide hydrolase (sEH), the enzyme that metabolizes EETs, elevated endogenous EET levels and promoted primary tumor growth and metastasis. Thus, our data indicate a central role for EETs in tumorigenesis, offering a mechanistic link between lipid signaling and cancer and emphasizing the critical importance of considering possible effects of EET-modulating drugs on cancer. PMID:22182838

Epoxyeicosanoids stimulate multiorgan metastasis and tumor dormancy escape in mice.

PubMed

Panigrahy, Dipak; Edin, Matthew L; Lee, Craig R; Huang, Sui; Bielenberg, Diane R; Butterfield, Catherine E; Barnés, Carmen M; Mammoto, Akiko; Mammoto, Tadanori; Luria, Ayala; Benny, Ofra; Chaponis, Deviney M; Dudley, Andrew C; Greene, Emily R; Vergilio, Jo-Anne; Pietramaggiori, Giorgio; Scherer-Pietramaggiori, Sandra S; Short, Sarah M; Seth, Meetu; Lih, Fred B; Tomer, Kenneth B; Yang, Jun; Schwendener, Reto A; Hammock, Bruce D; Falck, John R; Manthati, Vijaya L; Ingber, Donald E; Kaipainen, Arja; D'Amore, Patricia A; Kieran, Mark W; Zeldin, Darryl C

2012-01-01

Epoxyeicosatrienoic acids (EETs) are small molecules produced by cytochrome P450 epoxygenases. They are lipid mediators that act as autocrine or paracrine factors to regulate inflammation and vascular tone. As a result, drugs that raise EET levels are in clinical trials for the treatment of hypertension and many other diseases. However, despite their pleiotropic effects on cells, little is known about the role of these epoxyeicosanoids in cancer. Here, using genetic and pharmacological manipulation of endogenous EET levels, we demonstrate that EETs are critical for primary tumor growth and metastasis in a variety of mouse models of cancer. Remarkably, we found that EETs stimulated extensive multiorgan metastasis and escape from tumor dormancy in several tumor models. This systemic metastasis was not caused by excessive primary tumor growth but depended on endothelium-derived EETs at the site of metastasis. Administration of synthetic EETs recapitulated these results, while EET antagonists suppressed tumor growth and metastasis, demonstrating in vivo that pharmacological modulation of EETs can affect cancer growth. Furthermore, inhibitors of soluble epoxide hydrolase (sEH), the enzyme that metabolizes EETs, elevated endogenous EET levels and promoted primary tumor growth and metastasis. Thus, our data indicate a central role for EETs in tumorigenesis, offering a mechanistic link between lipid signaling and cancer and emphasizing the critical importance of considering possible effects of EET-modulating drugs on cancer.

Breast as an unusual site of metastasis- series of 3 cases and review of literature.

PubMed

Hebbar, Ashwin K; Shashidhar, K; S, Krishna Murthy; Kumar, Veerendra; Arjunan, Ravi

2014-09-01

Background and objectives Metastasis to the breast from extra mammary sites is uncommon with an incidence ranging from 1.2 to 2 % in clinical reports. Approximately 300 cases of breast metastasis from extra mammary sites have been reported, mostly in small series or as a single case report. Gastrointestinal adenocarcinoma metastasising to the breast is also very rare and only 30 cases have been reported in the literature. Metastatic deposits within the breast may be difficult to distinguish from primary breast carcinoma. Radiological features and immunohistochemistry especially for steroid hormone receptors (ER/PR) and expression of gross cystic disease fluid protein (GCDFP) and presence of other immunohistochemistry protein factors in breast metastasis which are specific to primary site may be helpful in differentiating these two conditions. Materials and methods In this series of 3 cases of breast as an unusual site of metastasis, we present different cases of adenocarcinoma of stomach, sigmoid colon and kidney with metastasis to the breast and discuss the differential diagnosis and management plans. Conclusion In conclusion, secondary tumors to the breast are rare and thus differentiating primary tumors from metastatic breast carcinoma is important for rational and optimum therapy and avoidance of unnecessary radical surgery. Palpable breast lump without typical radiological signs of primary breast carcinoma in patients with known primary should be suspected of representing metastasis.

Tumor cell migration screen identifies SRPK1 as breast cancer metastasis determinant.

PubMed

van Roosmalen, Wies; Le Dévédec, Sylvia E; Golani, Ofra; Smid, Marcel; Pulyakhina, Irina; Timmermans, Annemieke M; Look, Maxime P; Zi, Di; Pont, Chantal; de Graauw, Marjo; Naffar-Abu-Amara, Suha; Kirsanova, Catherine; Rustici, Gabriella; Hoen, Peter A C 't; Martens, John W M; Foekens, John A; Geiger, Benjamin; van de Water, Bob

2015-04-01

Tumor cell migration is a key process for cancer cell dissemination and metastasis that is controlled by signal-mediated cytoskeletal and cell matrix adhesion remodeling. Using a phagokinetic track assay with migratory H1299 cells, we performed an siRNA screen of almost 1,500 genes encoding kinases/phosphatases and adhesome- and migration-related proteins to identify genes that affect tumor cell migration speed and persistence. Thirty candidate genes that altered cell migration were validated in live tumor cell migration assays. Eight were associated with metastasis-free survival in breast cancer patients, with integrin β3-binding protein (ITGB3BP), MAP3K8, NIMA-related kinase (NEK2), and SHC-transforming protein 1 (SHC1) being the most predictive. Examination of genes that modulate migration indicated that SRPK1, encoding the splicing factor kinase SRSF protein kinase 1, is relevant to breast cancer outcomes, as it was highly expressed in basal breast cancer. Furthermore, high SRPK1 expression correlated with poor breast cancer disease outcome and preferential metastasis to the lungs and brain. In 2 independent murine models of breast tumor metastasis, stable shRNA-based SRPK1 knockdown suppressed metastasis to distant organs, including lung, liver, and spleen, and inhibited focal adhesion reorganization. Our study provides comprehensive information on the molecular determinants of tumor cell migration and suggests that SRPK1 has potential as a drug target for limiting breast cancer metastasis.

pH-Responsive Wormlike Micelles with Sequential Metastasis Targeting Inhibit Lung Metastasis of Breast Cancer.

PubMed

He, Xinyu; Yu, Haijun; Bao, Xiaoyue; Cao, Haiqiang; Yin, Qi; Zhang, Zhiwen; Li, Yaping

2016-02-18

Cancer metastasis is the main cause for the high mortality in breast cancer patients. Herein, we first report succinobucol-loaded pH-responsive wormlike micelles (PWMs) with sequential targeting capability to inhibit lung metastasis of breast cancer. PWMs can in a first step be delivered specifically to the sites of metastases in the lungs and then enable the intracellular pH-stimulus responsive drug release in cancer cells to improve the anti-metastatic effect. PWMs are identified as nanofibrillar assemblies with a diameter of 19.9 ± 1.9 nm and a length within the 50-200 nm range, and exhibited pH-sensitive drug release behavior in response to acidic intracellular environments. Moreover, PWMs can obviously inhibit the migration and invasion abilities of metastatic 4T1 breast cancer cells, and reduce the expression of the metastasis-associated vascular cell adhesion molecule-1 (VCAM-1) at 400 ng mL(-1) of succinobucol. In particular, PWMs can induce a higher specific accumulation in lung and be specifically delivered to the sites of metastases in lung, thereby leading to an 86.6% inhibition on lung metastasis of breast cancer. Therefore, the use of sequentially targeting PWMs can become an encouraging strategy for specific targeting and effective treatment of cancer metastasis. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Suppression for lung metastasis by depletion of collagen I and lysyl oxidase via losartan assisted with paclitaxel-loaded pH-sensitive liposomes in breast cancer.

PubMed

Zhang, Li; Wang, Yang; Xia, Tai; Yu, Qianwen; Zhang, Qianyu; Yang, Yuting; Cun, Xingli; Lu, Libao; Gao, Huile; Zhang, Zhirong; He, Qin

2016-10-01

Tumor metastasis would seriously impair the efficacy of chemotherapy. Our previous studies showed losartan combined with paclitaxel-loaded pH-sensitive cleavable liposomes (PTX-Cl-Lip) facilitated paclitaxel accumulation and led to enhanced antitumor efficacy in 4T1 bearing mice. Since losartan could inhibit the level of collagen I which was related to tumor metastasis, this strategy was further applied to suppress tumor metastasis this time. Our in vivo anti-metastatic study manifested losartan could lower the colonies occupied in lungs by 76.4% compared with that of saline group. When losartan and PTX-Cl-Lip were combined, anti-metastatic efficiency reached to 88.2%, which was the best among all the groups. In vitro 3D tumor spheroids studies proved losartan could significantly suppress the invasion of tumor cells. Losartan plus PTX-Cl-Lip could further weaken the metastasis of tumor cells. Mechanism study showed the declination of collagen I level via losartan was caused by inhibition of active transforming growth factor-β1. Western-blot study showed losartan could decrease the level of lysyl oxidase, then inhibit the cross-linking of collagen I, finally weakened the cell signaling transmit via integrin and the metastasis of tumor cells was restrained. All above studies illustrated this combined tactic could achieve favorable effect on suppression of lung tumor metastasis.

The effect of midline crossing of lateral supraglottic cancer on contralateral cervical lymph node metastasis.

PubMed

Yılmaz, Taner; Süslü, Nilda; Atay, Gamze; Günaydın, Rıza Önder; Bajin, Münir Demir; Özer, Serdar

2015-05-01

The degree of midline crossing of lateral supraglottic cancer does not significantly change its rate of contralateral cervical metastasis. The rate of occult metastasis is too high to take the risk of contralateral regional recurrence. We support routine bilateral neck dissection even in lateral supraglottic cancers with no or minimal midline crossing. Data on the rate of contralateral cervical metastasis of laterally located supraglottic cancer, the effect of its degree of midline crossing on contralateral cervical metastasis, and its treatment are still controversial. This was a retrospective cohort, chart review involving 305 surgically treated patients with T1-3 squamous cell carcinoma of the supraglottic larynx. In all, 184 patients had bilateral neck dissection; 86 N0 contralateral necks were followed up. Thirty-five patients who needed postoperative radiation therapy because of the primary tumor or ipsilateral neck dissection specimen also received radiation therapy to the contralateral neck. The degree of midline crossing at the epiglottis was measured on a laryngectomy specimen with a ruler and expressed as 'no,' '<5 mm' or '≥5 mm.' The rates of occult and overall contralateral metastasis in our series were 16% and 28%, respectively. There was no statistically significant difference between contralateral neck metastasis and recurrence rates in the neck dissection, follow-up, and irradiation groups according to the degree of midline crossing.

NF-κB-Dependent Lymphoid Enhancer Co-option Promotes Renal Carcinoma Metastasis.

PubMed

Rodrigues, Paulo; Patel, Saroor A; Harewood, Louise; Olan, Ioana; Vojtasova, Erika; Syafruddin, Saiful E; Zaini, M Nazhif; Richardson, Emma K; Burge, Johanna; Warren, Anne Y; Stewart, Grant D; Saeb-Parsy, Kourosh; Samarajiwa, Shamith A; Vanharanta, Sakari

2018-06-06

Metastases, the spread of cancer cells to distant organs, cause the majority of cancer-related deaths. Few metastasis-specific driver mutations have been identified, suggesting aberrant gene regulation as a source of metastatic traits. However, how metastatic gene expression programs arise is poorly understood. Here, using human-derived metastasis models of renal cancer, we identify transcriptional enhancers that promote metastatic carcinoma progression. Specific enhancers and enhancer clusters are activated in metastatic cancer cell populations, and the associated gene expression patterns are predictive of poor patient outcome in clinical samples. We find that the renal cancer metastasis-associated enhancer complement consists of multiple coactivated tissue-specific enhancer modules. Specifically, we identify and functionally characterize a coregulatory enhancer cluster, activated by the renal cancer driver HIF2A and an NF-κB-driven lymphoid element, as a mediator of metastasis in vivo We conclude that oncogenic pathways can acquire metastatic phenotypes through cross-lineage co-option of physiologic epigenetic enhancer states. SIGNIFICANCE: Renal cancer is associated with significant mortality due to metastasis. We show that in metastatic renal cancer, functionally important metastasis genes are activated via co-option of gene regulatory enhancer modules from distant developmental lineages, thus providing clues to the origins of metastatic cancer. Cancer Discov; 8(7); 1-16. ©2018 AACR. ©2018 American Association for Cancer Research.

Preventing Prostate Cancer Metastasis by Targeting Exosome Secretion

DTIC Science & Technology

2014-10-01

Exosome Secretion PRINCIPAL INVESTIGATOR: Christine Vogel CONTRACTING ORGANIZATION: New York University, New York, NY 10012...30 Sep 2013 - 29 Sep 2014 4. TITLE AND SUBTITLE Preventing Prostate Cancer Metastasis by Targeting Exosome Secretion 5a. CONTRACT...NUMBER Preventing Prostate Cancer Metastasis by Targeting Exosome Secretion 5b. GRANT NUMBER W81XWH-13-1-0467 5c. PROGRAM ELEMENT

Asparagine and Glutamine: Co-conspirators Fueling Metastasis.

PubMed

Luo, Ming; Brooks, Michael; Wicha, Max S

2018-05-01

Cancer cells frequently hijack normal metabolic pathways to promote their growth and metastasis. Two recent papers by Knott et al. (2018) and Pavlova et al. (2018) demonstrate that asparagine and glutamine work in concert to drive tumor growth and metastasis through modulation of cell survival, growth, and EMT regulatory pathways. Copyright © 2018. Published by Elsevier Inc.

[Highly metastatic nude mouse model of human primary gastric lymphoma constructed by surgical orthotopic transplantation and in vivo continuous screening method].

PubMed

Yang, Bo; Tuo, Shuai; Tuo, Chao-wei; Zhang, Ning; Liu, Qiu-zhen

2010-02-09

To develop a series of high metastatic models of human gastric malignant lymphoma in nude mice by orthotopic transplantation. Two histologically intact primary and hepatic metastatic fragments derived from surgical specimen of a patient with primary gastric lymphoma were implanted into the submucosa of stomach in nude mice. Highly metastatic and specific organ metastatic models were screened by selective orthotopic passage in nude mice. Transplantability, invasion, metastasis, morphological characteristics (light microscopy, electron microscopy and immunohistochemistry), karyotypic analysis and DNA content of orthotopically transplanted tumors were studied. Primary and hepatic metastatic fragments of primary gastric lymphoma were successfully transplanted in nude mice. Two nude mouse models of human primary gastric lymphoma, termed HGBL-0304 (hepatic metastasis model) and HGBL-0305 (high metastasis model), were developed, exhibiting different metastasis biology. Histopathology of transplanted tumors showed primary gastric diffuse large B cell lymphoma. Two models have been maintained for 45 generations by orthotopic passage in nude mice. A total of 419 nude mice were used for transplantation. The growth rate and resuscitation rate of liquid nitrogen cryopreservation of transplanted tumors were both 100%. Significant difference in metastasis biology was exhibited in four aspects of metastasis time, organ metastatic rate, the extent of hepatic metastasis and survival of cancer-bearing mice. The metastatic rates of liver, spleen, lymph nodes and peritoneal seeding in HGBL-0304 and HGBL-0305 models were 100% and 69.5%, 94.3% and 55.6%, 62.6% and 45.7%, and 43.5% and 30.5%. The onset time for metastases of liver, spleen, lymph nodes and peritoneal seeding was 2 w and 5 w, 3 w and 6 w, 2 w and 3 w, 3 w and 6 w respectively. The extent of hepatic metastasis in HGBL-0304 and HGBL-0305 models displayed diffuse involvement of the whole liver and mainly right lobe invasion of liver respectively. The mean survival time of HGBL-0304 and HGBL-0305 models was 54.3d and 106.9 d respectively. Surgical orthotopic implantation combined with in vivo selective passage screening is an effective method for establishing highly metastatic and specific organ metastatic models of human malignant lymphoma in nude mice. The study is the first time to establish hepatic metastasis and high metastasis nude mouse models of human primary gastric lymphoma with the same original patient and different potentials of invasion and metastasis.

Inhibition of Late and Early Phases of Cancer Metastasis by the NF-κB Inhibitor DHMEQ Derived from Microbial Bioactive Metabolite Epoxyquinomicin: A Review.

PubMed

Lin, Yinzhi; Ukaji, Tamami; Koide, Naoki; Umezawa, Kazuo

2018-03-03

We previously designed and synthesized dehydroxyepoxyquinomicin (DHMEQ) as an inhibitor of NF-κB based on the structure of microbial secondary metabolite epoxyquinomicin C. DHMEQ showed anti-inflammatory and anticancer activity in various in vivo disease models without toxicity. On the other hand, the process of cancer metastasis consists of cell detachment from the primary tumor, invasion, transportation by blood or lymphatic vessels, invasion, attachment, and formation of secondary tumor. Cell detachment from the primary tumor and subsequent invasion are considered to be early phases of metastasis, while tumor cell attachment to the tissue and secondary tumor formation the late phases. The assay system for the latter phase was set up with intra-portal-vein injection of pancreatic cancer cells. Intraperitoneal administration of DHMEQ was found to inhibit liver metastasis possibly by decreasing the expression of MMP-9 and IL-8. Also, when the pancreatic cancer cells treated with DHMEQ were inoculated into the peritoneal cavity of mice, the metastatic foci formation was inhibited. These results indicate that DHMEQ is likely to inhibit the late phase of metastasis. Meanwhile, we have recently employed three-dimensional (3D) culture of breast cancer cells for the model of early phase metastasis, since the 3D invasion just includes cell detachment and invasion into the matrix. DHMEQ inhibited the 3D invasion of breast cancer cells at 3D-nontoxic concentrations. In this way, DHMEQ was shown to inhibit the late and early phases of metastasis. Thus, DHMEQ is likely to be useful for the suppression of cancer metastasis.

Invasiveness is associated with metastasis and decreased survival in hemangiopericytoma of the central nervous system.

PubMed

Kinslow, Connor J; Rajpara, Raj S; Wu, Cheng-Chia; Bruce, Samuel S; Canoll, Peter D; Wang, Shih-Hsiu; Sonabend, Adam M; Sheth, Sameer A; McKhann, Guy M; Sisti, Michael B; Bruce, Jeffrey N; Wang, Tony J C

2017-06-01

Meningeal hemangiopericytoma (m-HPC) is a rare tumor of the central nervous system (CNS), which is distinguished clinically from meningioma by its tendency to recur and metastasize. The histological classification and grading scheme for m-HPC is still evolving and few studies have identified tumor features that are associated with metastasis. All patients at our institution with m-HPC were assessed for patient, tumor, and treatment characteristics associated with survival, recurrence, and metastasis. New findings were validated using the SEER database. Twenty-seven patients were identified in our institutional records with m-HPC with a median follow-up time of 85 months. Invasiveness was the strongest predictor of decreased overall survival (OS) and decreased metastasis-free survival (MFS) (p = 0.004 and 0.001). On subgroup analysis, bone invasion trended towards decreased OS (p = 0.056). Bone invasion and soft tissue invasion were significantly associated with decreased MFS (p = 0.001 and 0.012). An additional 315 patients with m-HPC were identified in the SEER database that had information on tumor invasion and 263 with information on distant metastasis. Invasion was significantly associated with decreased survival (HR = 5.769, p = 0.007) and metastasis (OR 134, p = 0.000) in the SEER data. In this study, the authors identified a previously unreported tumor characteristic, invasiveness, as the strongest factor associated with decreased survival and metastasis. The association of invasion with decreased survival and metastasis was confirmed in a separate, larger, publicly available database. Invasion may be a useful parameter in the histological grading and clinical management of hemangiopericytoma of the CNS.

Complement component 1, q subcomponent binding protein (C1QBP) in lipid rafts mediates hepatic metastasis of pancreatic cancer by regulating IGF-1/IGF-1R signaling.

PubMed

Shi, Haojun; Fang, Winston; Liu, Minda; Fu, Deliang

2017-10-01

Pancreatic cancer shows a remarkable predilection for hepatic metastasis. Complement component 1, q subcomponent binding protein (C1QBP) can mediate growth factor-induced cancer cell chemotaxis and distant metastasis by activation of receptor tyrosine kinases. Coincidentally, insulin-like growth factor-1 (IGF-1) derived from the liver and cancer cells itself has been recognized as a critical inducer of hepatic metastasis. However, the mechanism underlying IGF-1-dependent hepatic metastasis of pancreatic cancer, in which C1QBP may be involved, remains unknown. In the study, we demonstrated a significant association between C1QBP expression and hepatic metastasis in patients with pancreatic cancer. IGF-1 induced the translocation of C1QBP from cytoplasm to lipid rafts and further drove the formation of CD44 variant 6 (CD44v6)/C1QBP complex in pancreatic cancer cells. C1QBP interacting with CD44v6 in lipid rafts promoted phosphorylation of IGF-1R and thus activated downstream PI3K and MAPK signaling pathways which mediated metastatic potential of pancreatic cancer cells including proliferation, apoptosis, invasion, adhesion and energy metabolism. Furthermore, C1QBP knockdown suppressed hepatic metastasis of pancreatic cancer cells in nude mice. We therefore conclude that C1QBP in lipid rafts serves a key regulator of IGF-1/IGF-1R-induced hepatic metastasis from pancreatic cancer. Our findings about C1QBP in lipid rafts provide a novel strategy to block IGF-1/IGF-1R signaling in pancreatic cancer and a reliable premise for more efficient combined modality therapies. © 2017 UICC.

Diesel exhaust particle promotes tumor lung metastasis via the induction of BLT1-mediated neutrophilic lung inflammation.

PubMed

Li, Wenjing; Liu, Ting; Xiong, Yingluo; Lv, Jiaoyan; Cui, Xinyi; He, Rui

2018-06-05

BLT1, the primary functional receptor of Leukotriene B4 (LTB4), is involved in tissue inflammation by mediating leukocyte recruitment, and recently LTB4-dependent inflammation was reported to promote lung tumor growth. Exposure to diesel exhaust particle (DEP), the major component of particulate matter 2.5 (PM 2.5 ), can elicit lung inflammation, which may increase the risk of lung cancer. However, it remains unknown about the critical factors mediating DEP-induced lung inflammation and the subsequent effect on tumor metastasis. In this study, we found that DEP exposure led to acute lung inflammation, characterized by abundant infiltration of neutrophils and elevated lung levels in LTB4, as well as several pro-inflammatory cytokines and chemokines, including IL-1β, IL-6, TNF-α, CXCL1/2. Furthermore, DEP exposure promoted lung metastasis of 3LL and 4T1 cells. BLT1 blockade by its specific antagonist U75302 significantly inhibited neutrophilic lung inflammation following DEP exposure. Importantly, BLT1 blockade before the onset of inflammation significantly reduced DEP-enhanced lung metastasis, which was associated with greatly decreased infiltrating neutrophils in lungs. Interestingly, BLT1 blockade after the occurrence of lung metastases had no effect on the magnitude of lung metastasis, suggesting that inhibition of BLT1-mediated lung inflammation was insufficient to suppress established metastatic tumor. Administration of BLT2 inhibitor LY255283 fails to inhibit DEP-induced lung inflammation and tumor metastasis. Collectively, our results demonstrate that DEP exposure causes BLT1-mediated lung neutrophilic inflammation, which is critical for tumor lung metastasis, and suggest that interruption of the LTB4-BLT1 axis could be useful for preventing PM 2.5 -induced inflammation and subsequent susceptible to lung metastasis. Copyright © 2018 Elsevier Ltd. All rights reserved.

Risk Factors for Predicting Occult Lymph Node Metastasis in Patients with Clinical Stage I Non-small Cell Lung Cancer Staged by Integrated Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography.

PubMed

Kaseda, Kaoru; Asakura, Keisuke; Kazama, Akio; Ozawa, Yukihiko

2016-12-01

Lymph nodes in patients with non-small cell lung cancer (NSCLC) are often staged using integrated 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT). However, this modality has limited ability to detect micrometastases. We aimed to define risk factors for occult lymph node metastasis in patients with clinical stage I NSCLC diagnosed by preoperative integrated FDG-PET/CT. We retrospectively reviewed the records of 246 patients diagnosed with clinical stage I NSCLC based on integrated FDG-PET/CT between April 2007 and May 2015. All patients were treated by complete surgical resection. The prevalence of occult lymph node metastasis in patients with clinical stage I NSCLC was analysed according to clinicopathological factors. Risk factors for occult lymph node metastasis were defined using univariate and multivariate analyses. Occult lymph node metastasis was detected in 31 patients (12.6 %). Univariate analysis revealed CEA (P = 0.04), SUV max of the primary tumour (P = 0.031), adenocarcinoma (P = 0.023), tumour size (P = 0.002) and pleural invasion (P = 0.046) as significant predictors of occult lymph node metastasis. Multivariate analysis selected SUV max of the primary tumour (P = 0.049), adenocarcinoma (P = 0.003) and tumour size (P = 0.019) as independent predictors of occult lymph node metastasis. The SUV max of the primary tumour, adenocarcinoma and tumour size were risk factors for occult lymph node metastasis in patients with NSCLC diagnosed as clinical stage I by preoperative integrated FDG-PET/CT. These findings would be helpful in selecting candidates for mediastinoscopy or endobronchial ultrasound-guided transbronchial needle aspiration.

Experimental evidence of Migfilin as a new therapeutic target of hepatocellular carcinoma metastasis

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

Gkretsi, Vasiliki, E-mail: vasso.gkretsi@gmail.com; Bogdanos, Dimitrios P.; Department of Rheumatology, School of Medicine, University of Thessaly, University Hospital of Larissa, 41110 Larissa

Migfilin is a novel cell–matrix adhesion protein known to interact with Vasodilator Stimulated Phosphoprotein (VASP) and be localized both at cell–matrix and cell–cell adhesions. To date there is nothing known about its role in hepatocellular carcinoma (HCC). As matrix is important in metastasis, we aimed to investigate the Migfilin's role in HCC metastasis using two human HCC cell lines that differ in their metastatic potential; non-invasive Alexander cells and the highly invasive HepG2 cells. We silenced Migfilin by siRNA and studied its effect on signaling and metastasis-related cellular properties. We show that Migfilin's expression is elevated in HepG2 cells andmore » its silencing leads to upregulation of actin reorganization-related proteins, namely phosphor-VASP (Ser157 and Ser239), Fascin-1 and Rho-kinase-1, promoting actin polymerization and inhibiting cell invasion. Phosphor-Akt (Ser473) is decreased contributing to the upregulation of free and phosphor-β-catenin (Ser33/37Thr41) and inducing proliferation. Migfilin elimination upregulates Extracellular Signal–regulated kinase, which increases cell adhesion in HepG2 and reduces invasiveness. This is the first study to reveal that Migfilin inhibition can halt HCC metastasis in vitro, providing the molecular mechanism involved and presenting Migfilin as potential therapeutic target against HCC metastasis. - Highlights: • Migfilin is a cell–matrix and cell–cell adhesion protein known to interact with VASP. • Nothing is known about Migfilin's role in hepatocellular carcinoma (HCC). • We eliminated Migfilin from 2 HCC cell lines and studied in vitro metastasis. • Its silencing inhibits cell invasion and promotes adhesion in HepG2 invasive cells. • We provide molecular mechanism by which Migfilin elimination halts HCC metastasis.« less

The histone demethylase KDM3A, and its downstream target MCAM, promote Ewing Sarcoma cell migration and metastasis

PubMed Central

Sechler, Marybeth; Parrish, Janet K.; Birks, Diane K.; Jedlicka, Paul

2017-01-01

Ewing Sarcoma is the second most common solid pediatric malignant neoplasm of bone and soft tissue. Driven by EWS/Ets, or rarely variant, oncogenic fusions, Ewing Sarcoma is a biologically and clinically aggressive disease with a high propensity for metastasis. However, the mechanisms underpinning Ewing Sarcoma metastasis are currently not well understood. In the present study, we identify and characterize a novel metastasis-promotional pathway in Ewing Sarcoma, involving the histone demethylase KDM3A, previously identified by our laboratory as a new cancer-promoting gene in this disease. Using global gene expression profiling, we show that KDM3A positively regulates genes and pathways implicated in cell migration and metastasis, and demonstrate, using functional assays, that KDM3A promotes migration in vitro and experimental, post-intravasation, metastasis in vivo. We further identify the Melanoma Cell Adhesion Molecule (MCAM) as a novel KDM3A target gene in Ewing Sarcoma, and an important effector of KDM3A pro-metastatic action. Specifically, we demonstrate that MCAM depletion, like KDM3A depletion, inhibits cell migration in vitro and experimental metastasis in vivo, and that MCAM partially rescues impaired migration due to KDM3A knock-down. Mechanistically, we show that KDM3A regulates MCAM expression both through a direct mechanism, involving modulation of H3K9 methylation at the MCAM promoter, and an indirect mechanism, via the Ets1 transcription factor. Lastly, we identify an association between high MCAM levels in patient tumors and poor survival, in two different Ewing Sarcoma clinical cohorts. Taken together, our studies uncover a new metastasis-promoting pathway in Ewing Sarcoma, with therapeutically targetable components. PMID:28319067

Quantitative proteomics analysis of early recurrence/metastasis of huge hepatocellular carcinoma following radical resection

PubMed Central

2014-01-01

Background Hepatic resection is the preferred treatment for huge hepatocellular carcinoma (>10 cm in diameter; H-HCC). However, the patients with H-HCC suffer from poor prognosis due to the early recurrence/metastasis. The underlying mechanism of H-HCC’s early recurrence/metastasis is currently not well understood. Results Here, we describe an Isobaric Tags for relative and absolute quantification (iTRAQ)-based quantitative proteomics approach to analyze the early recurrence/metastasis related proteins of H-HCC after radical resection through multidimensional chromatography coupled with tandem mass spectrometry (2DLC-MS/MS). The different protein expression profiles between the early recurrence/metastasis within 6 months(R/M≤6months) and late recurrence/metastasis within 6–12 months after surgery (R/M6-12months) were confirmed and might reveal different underlying molecular mechanisms. We identified 44 and 49 significantly differentially expressed proteins in the R/M≤6months group and the R/M6-12months group compared to the group who had no recurrence within 2 years post surgery (the NR/M group), respectively. Moreover, among those proteins, S100A12 and AMACR were down regulated in the R/M≤6months group but up-regulated in the R/M6-12months group; and this regulation was further confirmed in mRNA and protein level by Q-PCR, Western-Blot and Immunohistochemistry (IHC). Conclusions This current study presents the first proteomic profile of the early recurrence/metastasis of H-HCC. The results suggest that S100A12 and AMACR might be potential prognostic markers for predicting the early recurrence/metastasis of H-HCC after hepatectomy. PMID:24839399

αB-crystallin: a Novel Regulator of Breast Cancer Metastasis to the Brain

PubMed Central

Malin, Dmitry; Strekalova, Elena; Petrovic, Vladimir; Deal, Allison M.; Ahmad, Abraham Al; Adamo, Barbara; Miller, C. Ryan; Ugolkov, Andrey; Livasy, Chad; Fritchie, Karen; Hamilton, Erika; Blackwell, Kimberly; Geradts, Joseph; Ewend, Matt; Carey, Lisa; Shusta, Eric V.; Anders, Carey K.; Cryns, Vincent L.

2013-01-01

Purpose Basal-like breast tumors are typically (ER/PR/HER2) triple-negative and are associated with a high incidence of brain metastases and poor clinical outcomes. The molecular chaperone αB-crystallin is predominantly expressed in triple-negative breast cancer (TNBC) and contributes to an aggressive tumor phenotype in preclinical models. We investigated the potential role of αB-crystallin in brain metastasis in TNBC. Experimental Design αB-crystallin expression in primary breast carcinomas and brain metastases was analyzed by immunohistochemistry among breast cancer patients with brain metastases. αB-crystallin was overexpressed or silenced in two different TNBC cell lines. The effects on cell adhesion to human brain microvascular endothelial cells (HBMECs) or extracellular matrix proteins, transendothelial migration, and transmigration across a HBMEC/astrocyte co-culture blood-brain barrier (BBB) model were examined. Additionally, the effects of overexpressing or silencing αB-crystallin on brain metastasis in vivo were investigated using orthotopic TNBC models. Results In a cohort of women with breast cancer brain metastasis, αB-crystallin expression in primary breast carcinomas was associated with poor overall survival and poor survival after brain metastasis, even among TNBC patients. Stable overexpression of αB-crystallin in TNBC cells enhanced adhesion to HBMECs, transendothelial migration, and BBB transmigration in vitro, while silencing αB-crystallin inhibited these events. αB-crystallin promoted adhesion of TNBC cells to HBMECs at least in part through an α3β1 integrin-dependent mechanism. αB-crystallin overexpression promoted brain metastasis, while silencing αB-crystallin inhibited brain metastasis in orthotopic TNBC models. Conclusion αB-crystallin is a novel regulator of brain metastasis in TNBC and represents a potential biomarker and drug target for this aggressive disease. PMID:24132917

αB-crystallin: a novel regulator of breast cancer metastasis to the brain.

PubMed

Malin, Dmitry; Strekalova, Elena; Petrovic, Vladimir; Deal, Allison M; Al Ahmad, Abraham; Adamo, Barbara; Miller, C Ryan; Ugolkov, Andrey; Livasy, Chad; Fritchie, Karen; Hamilton, Erika; Blackwell, Kimberly; Geradts, Joseph; Ewend, Matt; Carey, Lisa; Shusta, Eric V; Anders, Carey K; Cryns, Vincent L

2014-01-01

Basal-like breast tumors are typically (ER/PR/HER2) triple-negative and are associated with a high incidence of brain metastases and poor clinical outcomes. The molecular chaperone αB-crystallin is predominantly expressed in triple-negative breast cancer (TNBC) and contributes to an aggressive tumor phenotype in preclinical models. We investigated the potential role of αB-crystallin in brain metastasis in TNBCs. αB-crystallin expression in primary breast carcinomas and brain metastases was analyzed by immunohistochemistry among patients with breast cancer with brain metastases. αB-crystallin was overexpressed or silenced in two different TNBC cell lines. The effects on cell adhesion to human brain microvascular endothelial cells (HBMEC) or extracellular matrix proteins, transendothelial migration, and transmigration across a HBMEC/astrocyte coculture blood-brain barrier (BBB) model were examined. In addition, the effects of overexpressing or silencing αB-crystallin on brain metastasis in vivo were investigated using orthotopic TNBC models. In a cohort of women with breast cancer brain metastasis, αB-crystallin expression in primary breast carcinomas was associated with poor overall survival and poor survival after brain metastasis, even among patients with TNBC. Stable overexpression of αB-crystallin in TNBC cells enhanced adhesion to HBMECs, transendothelial migration, and BBB transmigration in vitro, whereas silencing αB-crystallin inhibited these events. αB-crystallin promoted adhesion of TNBC cells to HBMECs, at least in part, through an α3β1 integrin-dependent mechanism. αB-crystallin overexpression promoted brain metastasis, whereas silencing αB-crystallin inhibited brain metastasis in orthotopic TNBC models. αB-crystallin is a novel regulator of brain metastasis in TNBC and represents a potential biomarker and drug target for this aggressive disease.

Angiopoietin-1 deficiency increases tumor metastasis in mice.

PubMed

Michael, Iacovos P; Orebrand, Martina; Lima, Marta; Pereira, Beatriz; Volpert, Olga; Quaggin, Susan E; Jeansson, Marie

2017-08-11

Angipoietin-1 activation of the tyrosine kinase receptor Tek expressed mainly on endothelial cells leads to survival and stabilization of endothelial cells. Studies have shown that Angiopoietin-1 counteracts permeability induced by a number of stimuli. Here, we test the hypothesis that loss of Angiopoietin-1/Tek signaling in the vasculature would increase metastasis. Angiopoietin-1 was deleted in mice just before birth using floxed Angiopoietin-1 and Tek mice crossed to doxycycline-inducible bitransgenic ROSA-rtTA/tetO-Cre mice. By crossing Angiopoietin-1 knockout mice to the MMTV-PyMT autochthonous mouse breast cancer model, we investigated primary tumor growth and metastasis to the lung. Furthermore, we utilized B16F10 melanoma cells subcutaneous and experimental lung metastasis models in Angiopoietin-1 and Tek knockout mice. We found that primary tumor growth in MMTV-PyMT mice was unaffected, while metastasis to the lung was significantly increased in Angiopoietin-1 knockout MMTV-PyMT mice. In addition, angiopoietin-1 deficient mice exhibited a significant increase in lung metastasis of B16F10 melanoma cells, compared to wild type mice 3 weeks after injection. Additional experiments showed that this was likely an early event due to increased attachment or extravasation of tumor cells, since seeding of tumor cells was significantly increased 4 and 24 h post tail vein injection. Finally, using inducible Tek knockout mice, we showed a significant increase in tumor cell seeding to the lung, suggesting that Angiopoietin-1/Tek signaling is important for vascular integrity to limit metastasis. This study show that loss of the Angiopoietin-1/Tek vascular growth factor system leads to increased metastasis without affecting primary tumor growth.

Arachidonic Acid Metabolite as a Novel Therapeutic Target in Breast Cancer Metastasis

PubMed Central

Borin, Thaiz F.; Angara, Kartik; Rashid, Mohammad H.; Achyut, Bhagelu R.; Arbab, Ali S.

2017-01-01

Metastatic breast cancer (BC) (also referred to as stage IV) spreads beyond the breast to the bones, lungs, liver, or brain and is a major contributor to the deaths of cancer patients. Interestingly, metastasis is a result of stroma-coordinated hallmarks such as invasion and migration of the tumor cells from the primary niche, regrowth of the invading tumor cells in the distant organs, proliferation, vascularization, and immune suppression. Targeted therapies, when used as monotherapies or combination therapies, have shown limited success in decreasing the established metastatic growth and improving survival. Thus, novel therapeutic targets are warranted to improve the metastasis outcomes. We have been actively investigating the cytochrome P450 4 (CYP4) family of enzymes that can biosynthesize 20-hydroxyeicosatetraenoic acid (20-HETE), an important signaling eicosanoid involved in the regulation of vascular tone and angiogenesis. We have shown that 20-HETE can activate several intracellular protein kinases, pro-inflammatory mediators, and chemokines in cancer. This review article is focused on understanding the role of the arachidonic acid metabolic pathway in BC metastasis with an emphasis on 20-HETE as a novel therapeutic target to decrease BC metastasis. We have discussed all the significant investigational mechanisms and put forward studies showing how 20-HETE can promote angiogenesis and metastasis, and how its inhibition could affect the metastatic niches. Potential adjuvant therapies targeting the tumor microenvironment showing anti-tumor properties against BC and its lung metastasis are discussed at the end. This review will highlight the importance of exploring tumor-inherent and stromal-inherent metabolic pathways in the development of novel therapeutics for treating BC metastasis. PMID:29292756

Differentiation of Glioblastoma from Brain Metastasis: Qualitative and Quantitative Analysis Using Arterial Spin Labeling MR Imaging.

PubMed

Sunwoo, Leonard; Yun, Tae Jin; You, Sung-Hye; Yoo, Roh-Eul; Kang, Koung Mi; Choi, Seung Hong; Kim, Ji-Hoon; Sohn, Chul-Ho; Park, Sun-Won; Jung, Cheolkyu; Park, Chul-Kee

2016-01-01

To evaluate the diagnostic performance of cerebral blood flow (CBF) by using arterial spin labeling (ASL) perfusion magnetic resonance (MR) imaging to differentiate glioblastoma (GBM) from brain metastasis. The institutional review board of our hospital approved this retrospective study. The study population consisted of 128 consecutive patients who underwent surgical resection and were diagnosed as either GBM (n = 89) or brain metastasis (n = 39). All participants underwent preoperative MR imaging including ASL. For qualitative analysis, the tumors were visually graded into five categories based on ASL-CBF maps by two blinded reviewers. For quantitative analysis, the reviewers drew regions of interest (ROIs) on ASL-CBF maps upon the most hyperperfused portion within the tumor and upon peritumoral T2 hyperintensity area. Signal intensities of intratumoral and peritumoral ROIs for each subject were normalized by dividing the values by those of contralateral normal gray matter (nCBFintratumoral and nCBFperitumoral, respectively). Visual grading scales and quantitative parameters between GBM and brain metastasis were compared. In addition, the area under the receiver-operating characteristic curve was used to evaluate the diagnostic performance of ASL-driven CBF to differentiate GBM from brain metastasis. For qualitative analysis, GBM group showed significantly higher grade compared to metastasis group (p = 0.001). For quantitative analysis, both nCBFintratumoral and nCBFperitumoral in GBM were significantly higher than those in metastasis (both p < 0.001). The areas under the curve were 0.677, 0.714, and 0.835 for visual grading, nCBFintratumoral, and nCBFperitumoral, respectively (all p < 0.001). ASL perfusion MR imaging can aid in the differentiation of GBM from brain metastasis.

microRNA-200c/141 upregulates SerpinB2 to promote breast cancer cell metastasis and reduce patient survival.

PubMed

Jin, Tiefeng; Suk Kim, Hoe; Ki Choi, Sul; Hye Hwang, Eun; Woo, Jisu; Suk Ryu, Han; Kim, Kwangsoo; Moon, Aree; Kyung Moon, Woo

2017-05-16

The microRNA-200 (miR-200) family is associated with tumor metastasis and poor patient prognosis. We found that miR-200c/141 cluster overexpression upregulated SerpinB2 in the MDA-MB-231 triple-negative (TN) breast cancer cell line. We observed transcription factor (c-Jun, c-Fos, and FosB) upregulation, nuclear localization of c-Jun, and increased SerpinB2 promoter-directed chloramphenicol acetyltransferase activity in miR-200c/141 cluster-overexpressing cells relative to controls. Additionally, miR-124a and miR-26b, which directly target SepinB2, were downregulated compared to controls. In mouse xenograft models, miR-200c/141 cluster overexpression promoted lymph node and lung metastasis, and siRNA-mediated SerpinB2 knockdown decreased lung metastasis, suggesting that SerpinB2 mediates miR-200c/141-induced lung metastasis. We also explored the clinical significance of SerpinB2 protein status through analysis of primary breast tumor samples and The Cancer Genome Atlas (TCGA) data. High SerpinB2 levels were associated with reduced survival and increased lymph node metastasis in breast cancer patients. SerpinB2 was overexpressed in the TN breast cancer subtype as compared to the luminal subtype. The present study demonstrates that SerpinB2 promotes miR-200c/141 cluster overexpression-induced breast cancer cell metastasis, and SerpinB2 overexpression correlates with increased metastatic potential and unfavorable outcomes in breast cancer patients. SerpinB2 may be a useful biomarker for assessing metastasis risk in breast cancer patients.

NDRG2 correlated with favorable recurrence-free survival inhibits metastasis of mouse breast cancer cells via attenuation of active TGF-β production.

PubMed

Oh, Sang-seok; Kim, Donghyeok; Kim, Dong-Hee; Chang, Hong Hee; Sohn, Kyung-Cheol; Kim, Kyo Hyun; Jung, Sung Hoo; Lee, Byoung Kil; Kim, Joo Heon; Kim, Kwang Dong

2012-10-01

N-myc downstream-regulated gene 2 (NDRG2) has been studied for its inhibitory effects against growth and metastasis of many tumor cell types. In this study, we showed NDRG2 expression was correlated with favorable recurrence-free survival of patients with breast cancer and inhibited metastasis of breast cancer cells (4T1). NDRG2 expression was examined in 189 breast carcinoma tissues and paired normal breast tissues using immunohistochemistry. Histological and clinicopathological data were correlated using Pearson's chi-square test of independence. NDRG2 expression in human breast cancer tissues was inversely associated with lymph node metastasis and pTNM stage. Furthermore, patients with breast cancer with a high level of NDRG2 expression showed favorable recurrence-free survival (P = 0.038). To study the effect of NDRG2 on metastasis in vivo, we established an NDRG2-overexpressing mouse breast cancer cell line (4T1-NDRG2) and measured the metastasis and survival of 4T1-NDRG2 tumor-bearing mice. To test whether transforming growth factor β (TGF-β)- mediated metastasis of 4T1 was inhibited by NDRG2 expression, TGF-Smad-binding element (SBE)-luciferase activity and/or measurement of active TGF-β were performed in cell or tumor tissue level. 4T1-NDRG2 cells grew gradually and showed less metastatic activity in vivo and low invasiveness in vitro. 4T1-NDRG2 cells showed lower SBE-luciferase activity and lower level of active autocrine TGF-β than 4T1-Mock did. Correctly, our data show that NDRG2 significantly suppress tumor metastasis by attenuating active autocrine TGF-β production, and the attenuation might be typically associated with the favorable recurrence-free survival of patients clinically.

Phosphatidylethanolamine-binding protein 4 is associated with breast cancer metastasis through Src-mediated Akt tyrosine phosphorylation.

PubMed

Li, H; Huang, F; Fan, L; Jiang, Y; Wang, X; Li, J; Wang, Q; Pan, H; Sun, J; Cao, X; Wang, X

2014-09-11

Metastasis is responsible for more than 90% of the mortality observed among patients with breast cancer. Human phosphatidylethanolamine-binding protein 4 (hPEBP4) is a novel member of the PEBP family and functions as an anti-apoptotic molecule. Here, we found that the metastatic MDA-MB-231 breast cancer cells expressed much higher levels of hPEBP4 than the nonmetastatic MCF-7 breast cancer cells and that the expression levels of hPEBP4 were positively correlated with the metastasis of clinical breast cancer. The hPEBP4 overexpression in the MDA-MB-231 cells significantly promoted cell invasion in vitro and increased the development of lymph node metastasis in vivo. Conversely, the silencing of hPEBP4 suppressed the cell-invasive ability both in vitro and in vivo. Further investigation showed that hPEBP4 promoted the expression or activity of the metastasis-related proteinases MMP (matrix metalloproteinase) 2, MMP9 and MMP13. This hPEBP4-potentiated cell invasion and MMP expression is due to an increase in Akt activation. Knockdown of Akt restored hPEBP4-induced breast tumor metastasis in the hPEBP4-MDA-MB-231 xenograft mouse model. Moreover, we found that hPEBP4 functioned as a scaffolding molecule and enhanced the association of Akt with Src to promote Akt tyrosine phosphorylation, a prerequisite for the full activation of Akt, in a phosphatidylethanolamine-binding domain-dependent manner. Given the present information about human breast cancer, these functional data from cell culture and animal studies suggest that, in human breast cancer hPEBP4 is a novel and clinically relevant metastasis accelerator gene and may be a new diagnostic marker and therapeutic target for breast cancer metastasis.

Weighted gene co-expression network analysis of colorectal cancer liver metastasis genome sequencing data and screening of anti-metastasis drugs.

PubMed

Gao, Bo; Shao, Qin; Choudhry, Hani; Marcus, Victoria; Dong, Kung; Ragoussis, Jiannis; Gao, Zu-Hua

2016-09-01

Approximately 9% of cancer-related deaths are caused by colorectal cancer (CRC). CRC patients are prone to liver metastasis, which is the most important cause for the high CRC mortality rate. Understanding the molecular mechanism of CRC liver metastasis could help us to find novel targets for the effective treatment of this deadly disease. Using weighted gene co-expression network analysis on the sequencing data of CRC with and with metastasis, we identified 5 colorectal cancer liver metastasis related modules which were labeled as brown, blue, grey, yellow and turquoise. In the brown module, which represents the metastatic tumor in the liver, gene ontology (GO) analysis revealed functions including the G-protein coupled receptor protein signaling pathway, epithelial cell differentiation and cell surface receptor linked signal transduction. In the blue module, which represents the primary CRC that has metastasized, GO analysis showed that the genes were mainly enriched in GO terms including G-protein coupled receptor protein signaling pathway, cell surface receptor linked signal transduction, and negative regulation of cell differentiation. In the yellow and turquoise modules, which represent the primary non-metastatic CRC, 13 downregulated CRC liver metastasis-related candidate miRNAs were identified (e.g. hsa-miR-204, hsa-miR-455, etc.). Furthermore, analyzing the DrugBank database and mining the literature identified 25 and 12 candidate drugs that could potentially block the metastatic processes of the primary tumor and inhibit the progression of metastatic tumors in the liver, respectively. Data generated from this study not only furthers our understanding of the genetic alterations that drive the metastatic process, but also guides the development of molecular-targeted therapy of colorectal cancer liver metastasis.

Huntingtin-Interacting Protein-1 Is an Early-Stage Prognostic Biomarker of Lung Adenocarcinoma and Suppresses Metastasis via Akt-mediated Epithelial-Mesenchymal Transition.

PubMed

Hsu, Che-Yu; Lin, Cheng-Han; Jan, Yi-Hua; Su, Chia-Yi; Yao, Yun-Chin; Cheng, Hui-Chuan; Hsu, Tai-I; Wang, Po-Shun; Su, Wen-Pin; Yang, Chih-Jen; Huang, Ming-Shyan; Calkins, Marcus J; Hsiao, Michael; Lu, Pei-Jung

2016-04-15

Non-small cell lung cancer (NSCLC) carries a poor survival rate mainly because of metastasis. However, the molecular mechanisms that govern NSCLC metastasis have not been described. Because huntingtin-interacting protein-1 (HIP1) is known to play a role in tumorigenesis, we tested the involvement of HIP1 in NSCLC progression and metastasis. HIP1 expression was measured in human NSCLC tumors, and correlation with survival outcome was evaluated. Furthermore, we investigated the ability of HIP1 to suppress metastasis. The molecular mechanism by which HIP1 contributes to suppress metastasis was investigated. We used tissue arrays containing samples from 121 patients with NSCLC to analyze HIP1 expression by immunohistochemistry. To investigate the role of HIP1 expression on metastasis, we evaluated cellular mobility, migration, and invasion using lung adenocarcinoma (AdCA) cells with modified HIP1 expression levels. The human disease mouse models with the same cells were applied to evaluate the HIP1 suppressing metastasis and its mechanism in vivo. HIP1 expression in AdCA progression was found to be an early-stage prognostic biomarker, with low expression correlated to poor prognosis. We also found HIP1 to be a metastatic suppressor in AdCA. HIP1 significantly repressed the mobility of lung cancer cells in vitro and in vivo and regulated the epithelial-mesenchymal transition by repressing AKT/glycogen synthase kinase-3β/β-catenin signaling. HIP1 serves as an early-stage prognostic biomarker and a metastatic suppressor. Reduced expression during AdCA progression can relieve HIP1 suppression of Akt-mediated epithelial-mesenchymal transition and thereby lead to development of late metastases and poor prognosis.

Chromosomal instability drives metastasis through a cytosolic DNA response.

PubMed

Bakhoum, Samuel F; Ngo, Bryan; Laughney, Ashley M; Cavallo, Julie-Ann; Murphy, Charles J; Ly, Peter; Shah, Pragya; Sriram, Roshan K; Watkins, Thomas B K; Taunk, Neil K; Duran, Mercedes; Pauli, Chantal; Shaw, Christine; Chadalavada, Kalyani; Rajasekhar, Vinagolu K; Genovese, Giulio; Venkatesan, Subramanian; Birkbak, Nicolai J; McGranahan, Nicholas; Lundquist, Mark; LaPlant, Quincey; Healey, John H; Elemento, Olivier; Chung, Christine H; Lee, Nancy Y; Imielenski, Marcin; Nanjangud, Gouri; Pe'er, Dana; Cleveland, Don W; Powell, Simon N; Lammerding, Jan; Swanton, Charles; Cantley, Lewis C

2018-01-25

Chromosomal instability is a hallmark of cancer that results from ongoing errors in chromosome segregation during mitosis. Although chromosomal instability is a major driver of tumour evolution, its role in metastasis has not been established. Here we show that chromosomal instability promotes metastasis by sustaining a tumour cell-autonomous response to cytosolic DNA. Errors in chromosome segregation create a preponderance of micronuclei whose rupture spills genomic DNA into the cytosol. This leads to the activation of the cGAS-STING (cyclic GMP-AMP synthase-stimulator of interferon genes) cytosolic DNA-sensing pathway and downstream noncanonical NF-κB signalling. Genetic suppression of chromosomal instability markedly delays metastasis even in highly aneuploid tumour models, whereas continuous chromosome segregation errors promote cellular invasion and metastasis in a STING-dependent manner. By subverting lethal epithelial responses to cytosolic DNA, chromosomally unstable tumour cells co-opt chronic activation of innate immune pathways to spread to distant organs.

SOX5 predicts poor prognosis in lung adenocarcinoma and promotes tumor metastasis through epithelial-mesenchymal transition

PubMed Central

Chen, Xin; Fu, Yufei; Xu, Hongfei; Teng, Peng; Xie, Qiong; Zhang, Yiran; Yan, Caochong; Xu, Yiqiao; Li, Chunqi; Zhou, Jianying; Ni, Yiming; Li, Weidong

2018-01-01

Lung cancer is the leading cause of cancer-related death worldwide. Epithelial-mesenchymal transition (EMT) promotes lung cancer progression and metastasis, especially in lung adenocarcinoma. Sex determining region Y-box protein 5 (SOX5) is known to stimulate the progression of various cancers. Here, we used immunohistochemical analysis to reveal that SOX5 levels were increased in 90 lung adenocarcinoma patients. The high SOX5 expression in lung adenocarcinoma and non-tumor counterparts correlated with the patients’ poor prognosis. Inhibiting SOX5 expression attenuated metastasis and progression in lung cancer cells, while over-expressing SOX5 accelerated lung adenocarcinoma progression and metastasis via EMT. An in vivo zebrafish xenograft cancer model also showed SOX5 knockdown was followed by reduced lung cancer cell proliferation and metastasis. Our results indicate SOX5 promotes lung adenocarcinoma tumorigenicity and can be a novel diagnosis and prognosis marker of the disease. PMID:29541384

Circulating Tumor Cell Analysis in Preclinical Mouse Models of Metastasis.

PubMed

Kitz, Jenna; Lowes, Lori E; Goodale, David; Allan, Alison L

2018-04-28

The majority of cancer deaths occur because of metastasis since current therapies are largely non-curative in the metastatic setting. The use of in vivo preclinical mouse models for assessing metastasis is, therefore, critical for developing effective new cancer biomarkers and therapies. Although a number of quantitative tools have been previously developed to study in vivo metastasis, the detection and quantification of rare metastatic events has remained challenging. This review will discuss the use of circulating tumor cell (CTC) analysis as an effective means of tracking and characterizing metastatic disease progression in preclinical mouse models of breast and prostate cancer and the resulting lessons learned about CTC and metastasis biology. We will also discuss how the use of clinically-relevant CTC technologies such as the CellSearch ® and Parsortix™ platforms for preclinical CTC studies can serve to enhance the study of cancer biology, new biomarkers, and novel therapies from the bench to the bedside.

Metastasis of hepatocellular carcinoma to the heart: unusual patterns in three cases with antemortem diagnosis.

PubMed

Lei, M H; Ko, Y L; Kuan, P; Lien, W P; Chen, D S

1992-04-01

Unusual patterns of cardiac metastasis were noted in three cases of hepatocellular carcinoma (HCC): one patient was noted to have a large right ventricular (RV) tumor mass with intracavitary growth and myocardial invasion; the second had massive pulmonary and left atrial (LA) metastasis; and the third patient had a right atrial tumor mass with concomitant RV and LA involvement. Tumor implantation to the RV without right atrial involvement and extensive myocardial invasion is unusual in HCC. The LA involvement is probably related to tumor growth from the pulmonary veins following massive metastasis to the lung, direct invasion of the atrial septum or tumor implantation via a subclinical right-to-left shunt through the patent foramen ovale. To the best of our knowledge, such unusual intracavitary metastases in HCC have not been reported previously. Cardiac metastasis, without local gross recurrence, may be one of the presentations after lobectomy in patients with HCC.

Thyroid Gland Metastasis from Cancer of the Uterine Cervix: An Extremely Rare Case Report.

PubMed

Celik, Suleyman Utku; Besli, Dilara; Sak, Serpil Dizbay; Genc, Volkan

The thyroid gland is a relatively uncommon site for a metastatic disease, although it is richly supplied with blood. The metastases may originate from various primary sites, mainly kidney, lung, head and neck, and breast. Thyroid metastasis from cervical carcinomas is extremely rare; and only a few cases have been previously reported in the literature. In patient with thyroid nodules and an oncological history, the possibility of thyroid metastasis should be seriously considered. Despite the rarity of the metastasis of cervical carcinoma to the thyroid, it is difficult to say appropriate treatment approach for these lesions. When managing such patients, decision-making should balance the possibility of gaining long-term survival against estimation of the aggressiveness of the disease and its possible complications. Here, a case of thyroid metastasis from a squamous cell carcinoma of the uterine cervix presenting with cervical mass and difficulty in swallowing and its treatment is reported.

Lipid Osteoclastokines Regulate Breast Cancer Bone Metastasis

PubMed Central

Krzeszinski, Jing Y.; Schwaid, Adam G.; Cheng, Wing Yin; Jin, Zixue; Gallegos, Zachary R.; Saghatelian, Alan

2017-01-01

Bone metastasis is a deadly consequence of cancers, in which osteoclast forms a vicious cycle with tumor cells. Bone metastasis attenuation by clinical usage of osteoclast inhibitors and in our osteopetrotic mouse genetic models with β-catenin constitutive activation or peroxisome proliferator-activated receptor γ deficiency fully support the important role of osteoclast in driving the bone metastatic niche. However, the mechanisms for this “partnership in crime” are underexplored. Here we show that osteoclasts reprogram their lipid secretion to support cancer cells. Metabolomic profiling reveals elevated prometastatic arachidonic acid (AA) but reduced antimetastatic lysophosphatidylcholines (LPCs). This shift in lipid osteoclastokines synergistically stimulates tumor cell proliferation, migration, survival, and expression of prometastatic genes. Pharmacologically, combined treatment with LPCs and BW-755C, an inhibitor of AA signaling via blocking lipoxygenase and cyclooxygenase, impedes breast cancer bone metastasis. Our findings elucidate key paracrine mechanisms for the osteoclast-cancer vicious cycle and uncover important therapeutic targets for bone metastasis. PMID:27967239

Solitary small bowel metastasis from breast cancer.

PubMed

Choi, Jung Eun; Park, Shin Young; Jeon, Myung Hoon; Kang, Su Hwan; Lee, Soo Jung; Bae, Young Kyung; Kim, Min Kyoung

2011-03-01

The common sites of metastasis of breast cancer are bone, lung, and liver, but gastrointestinal metastasis from breast cancer is rare. We experienced a case of solitary ileal metastasis from breast cancer. A 45-years-old woman presented with melena for several weeks. She showed no other abdominal symptoms. Colonoscopy findings showed an ulcerative mucosal lesion in the terminal ileum, and biopsy was performed. Pathologic examination revealed metastatic carcinoma, originated from breast. The tumor cells were positive for estrogen receptor and negative for Cdx-2. She had had a previous medical history of bilateral breast cancer and undergone breast conserving surgery with sentinel lymph node biopsy for both breasts. The torso positron emission tomography scan at 19 months after surgery showed mildly increased uptake in the terminal ileum which was considered as inflammation. Finally, she was diagnosed with solitary ileal metastasis from breast cancer at 22 months after surgery.

Support Vector Machines Model of Computed Tomography for Assessing Lymph Node Metastasis in Esophageal Cancer with Neoadjuvant Chemotherapy.

PubMed

Wang, Zhi-Long; Zhou, Zhi-Guo; Chen, Ying; Li, Xiao-Ting; Sun, Ying-Shi

The aim of this study was to diagnose lymph node metastasis of esophageal cancer by support vector machines model based on computed tomography. A total of 131 esophageal cancer patients with preoperative chemotherapy and radical surgery were included. Various indicators (tumor thickness, tumor length, tumor CT value, total number of lymph nodes, and long axis and short axis sizes of largest lymph node) on CT images before and after neoadjuvant chemotherapy were recorded. A support vector machines model based on these CT indicators was built to predict lymph node metastasis. Support vector machines model diagnosed lymph node metastasis better than preoperative short axis size of largest lymph node on CT. The area under the receiver operating characteristic curves were 0.887 and 0.705, respectively. The support vector machine model of CT images can help diagnose lymph node metastasis in esophageal cancer with preoperative chemotherapy.

Indocyanine Green Fluorescence Navigation Thoracoscopic Metastasectomy for Pulmonary Metastasis of Hepatocellular Carcinoma.

PubMed

Kawakita, Naoya; Takizawa, Hiromitsu; Kondo, Kazuya; Sakiyama, Shoji; Tangoku, Akira

2016-12-20

Indocyanine green can selectively accumulate in primary hepatocellular carcinoma (HCC) and extrahepatic metastases. We report a patient who underwent resection of pulmonary metastasis of HCC using a thoracoscopic near-infrared imaging system and fluorescent navigation surgery. A 66-year-old man with suspicion of pulmonary metastasis of HCC was referred to our hospital. Indocyanine green was injected intravenously at a dose of 0.5 mg/kg body weight, 20 h before thoracoscopic surgery. An endoscopic indocyanine green near-infrared fluorescence imaging system showed clear blue fluorescence, indicating pulmonary metastasis of HCC in a lingular segment. We performed wide wedge resection using the fluorescence image for navigation to confirm the surgical margins. The specimen was histologically confirmed as a pulmonary metastasis of HCC. In conclusion, thoracoscopic indocyanine green near-infrared fluorescence imaging for pulmonary metastases of HCC is useful in identifying tumor locations and ensuring resection margins.

Isolated splenic vein thrombosis secondary to splenic metastasis: A case report

PubMed Central

Hiraiwa, Kunihiko; Morozumi, Kyoei; Miyazaki, Hiroshi; Sotome, Keiichi; Furukawa, Akio; Nakamaru, Makoto; Tanaka, Yoichi; Iri, Hisami

2006-01-01

A 49-year-old, previously healthy woman sought treatment for abdominal pain. Colonoscopy revealed ascending colon cancer. Computed tomography and angiography showed splenic metastasis and thrombosis extending from the splenic vein to the portal vein. She underwent right hemicolectomy, splenectomy, and distal pancreatomy. Histological findings showed no malignant cell in the splenic vein which was filled with organizing thrombus. We postulate the mechanism of splenic vein thrombosis in our case to be secondary to the extrinsic compression of the splenic vein by the splenic metastasis or by the inflammatory process produced by the splenic metastasis. In conclusion, we suggest that splenic metastasis should be added to the list of differential diagnosis which causes splenic vein thrombosis. In the absence of other sites of neoplastic disease, splenectomy seems to be the preferred therapy because it can be performed with low morbidity and harbors the potential for long-term survival. PMID:17072993

Intracranial meningioma as primary presentation for an undiagnosed collision metastatic breast cancer: Case report and literature review

PubMed Central

Farrag, Ashraf; Ansari, Jawaher; Ali, Muhammad; Sunbuli, Ghanem; Kassem, Hassan; Al Hamad, Abdul-Aziz

2018-01-01

Intracranial metastasis from breast cancer is a relatively common finding, however, the appearance of breast cancer metastasis in a meningioma is very rare. Several cases of tumor-to-tumor metastasis and collision tumors have been reported previously, with meningioma being implicated as the most common benign intracranial neoplasm to harbour the metastasis. Occasionally, the discovery of a tumor-to-meningioma metastasis may herald the diagnosis of an occult primary malignancy. Careful histopathological assessment of the resected meningioma specimen is pivotal to the management of these patients, as this will alter the treatment plan and prognosis considerably. Intracranial meningioma with collision breast cancer as primary presentation of an undiagnosed metastatic breast cancer is extremely rare. The current study presents a case of intracranial meningioma with collision breast cancer as a primary presentation, and reviews the available evidence for this unusual disease entity. PMID:29725531

Intracranial meningioma as primary presentation for an undiagnosed collision metastatic breast cancer: Case report and literature review.

PubMed

Farrag, Ashraf; Ansari, Jawaher; Ali, Muhammad; Sunbuli, Ghanem; Kassem, Hassan; Al Hamad, Abdul-Aziz

2018-05-01

Intracranial metastasis from breast cancer is a relatively common finding, however, the appearance of breast cancer metastasis in a meningioma is very rare. Several cases of tumor-to-tumor metastasis and collision tumors have been reported previously, with meningioma being implicated as the most common benign intracranial neoplasm to harbour the metastasis. Occasionally, the discovery of a tumor-to-meningioma metastasis may herald the diagnosis of an occult primary malignancy. Careful histopathological assessment of the resected meningioma specimen is pivotal to the management of these patients, as this will alter the treatment plan and prognosis considerably. Intracranial meningioma with collision breast cancer as primary presentation of an undiagnosed metastatic breast cancer is extremely rare. The current study presents a case of intracranial meningioma with collision breast cancer as a primary presentation, and reviews the available evidence for this unusual disease entity.

Stat3 orchestrates interaction between endothelial and tumor cells and inhibition of Stat3 suppresses brain metastasis of breast cancer cells.

PubMed

Lee, Hsueh-Te; Xue, Jianfei; Chou, Ping-Chieh; Zhou, Aidong; Yang, Phillip; Conrad, Charles A; Aldape, Kenneth D; Priebe, Waldemar; Patterson, Cam; Sawaya, Raymond; Xie, Keping; Huang, Suyun

2015-04-30

Brain metastasis is a major cause of morbidity and mortality in patients with breast cancer. Our previous studies indicated that Stat3 plays an important role in brain metastasis. Here, we present evidence that Stat3 functions at the level of the microenvironment of brain metastases. Stat3 controlled constitutive and inducible VEGFR2 expression in tumor-associated brain endothelial cells. Furthermore, inhibition of Stat3 by WP1066 decreased the incidence of brain metastases and increased survival in a preclinical model of breast cancer brain metastasis. WP1066 inhibited Stat3 activation in tumor-associated endothelial cells, reducing their infiltration and angiogenesis. WP1066 also inhibited breast cancer cell invasion. Our results indicate that WP1066 can inhibit tumor angiogenesis and brain metastasis mediated by Stat3 in endothelial and tumor cells.

Arctigenin Inhibits Lung Metastasis of Colorectal Cancer by Regulating Cell Viability and Metastatic Phenotypes.

PubMed

Han, Yo-Han; Kee, Ji-Ye; Kim, Dae-Seung; Mun, Jeong-Geon; Jeong, Mi-Young; Park, Sang-Hyun; Choi, Byung-Min; Park, Sung-Joo; Kim, Hyun-Jung; Um, Jae-Young; Hong, Seung-Heon

2016-08-27

Arctigenin (ARC) has been shown to have an anti-cancer effect in various cell types and tissues. However, there have been no studies concerning metastatic colorectal cancer (CRC). In this study, we investigated the anti-metastatic properties of ARC on colorectal metastasis and present a potential candidate drug. ARC induced cell cycle arrest and apoptosis in CT26 cells through the intrinsic apoptotic pathway via MAPKs signaling. In several metastatic phenotypes, ARC controlled epithelial-mesenchymal transition (EMT) through increasing the expression of epithelial marker E-cadherin and decreasing the expressions of mesenchymal markers; N-cadherin, vimentin, β-catenin, and Snail. Moreover, ARC inhibited migration and invasion through reducing of matrix metalloproteinase-2 (MMP-2) and MMP-9 expressions. In an experimental metastasis model, ARC significantly inhibited lung metastasis of CT26 cells. Taken together, our study demonstrates the inhibitory effects of ARC on colorectal metastasis.

Organtropic Metastatic Secretomes and Exosomes in Breast Cancer

DTIC Science & Technology

2014-10-01

An understanding of secreted metastasis regulators (extracellular proteins, cell-free nucleic acids and small vesicles – exosomes -) has tremendous...and exosomal proteins and miRNAs to promote organotropic metastasis. Therapeutic disruptions of these communication pathways may significantly increase...secreted and exosomal proteins and miRNAs that are regulators of bone and lung metastasis, to characterize their function in mediating tumor-stroma

Dangerous Liaisons: Deviant Endothelium NOTCHes toward Tumor Metastasis.

PubMed

Guo, Peipei; Rafii, Shahin

2017-03-13

In this issue of Cancer Cell, Wieland et al. uncover a feedback loop in which tumor cells, by augmenting Notch signaling, provoke a senescent and pro-inflammatory state in endothelial cells, promoting neutrophil infiltration, tumor cell adhesion, and metastasis. Interfering with this Notch-dependent crosstalk may be a therapeutic approach to block metastasis. Copyright © 2017 Elsevier Inc. All rights reserved.

Non-motorized voluntary running does not affect experimental and spontaneous metastasis in mice

USDA-ARS?s Scientific Manuscript database

The present study investigated the effects of non-motorized voluntary running on experimental metastasis of B16BL/6 melanoma and spontaneous metastasis of Lewis lung carcinoma (LLC) in male C57BL/6 mice. After 9 weeks of running, mice (n = 30 per group) received an intravenous injection of B16BL/6 c...

Orbital Metastasis: Rare Initial Presentation of an Occult Gall Bladder Carcinoma.

PubMed

Jain, Tarun Kumar; Parihar, Ashwin Singh; Sood, Ashwani; Basher, Rajender Kumar; Bollampally, Neeraja; Shekhawat, Amit Singh; Mittal, Bhagwant Rai

2018-03-01

Orbital metastases are known to arise from primary breast carcinoma followed by prostate, malignant melanoma, and lung carcinoma. We report a case of orbital metastasis as the initial presentation of an occult primary gall bladder carcinoma. The FDG PET/CT helped in localizing the occult distant primary site, which previously escaped detection, and also enabled the evaluation of orbital metastasis.

Inhibitory Effects of Megakaryocytes in Prostate Cancer Bone Metastasis

DTIC Science & Technology

2010-04-01

meeting, Feb. 2010, Seattle, WA) 3. Inhibitory effects of megakaryocytes in prostate cancer bone metastasis. (Oral presentation and Young ...cancer bone metastasis. (Oral presentation and ASBMR-Harold M. Frost Young Investigator Award, Aug. 2009, Sun Valley, ID) 5. Career development...valuable new scientific information and also provided critical career development support for an a spiring young scientist. References Please refer

Restricted feeding of a high-fat diet reduces spontaneous metastases of Lewis lung carcinoma in C57BL/6 mice

USDA-ARS?s Scientific Manuscript database

Obesity is a risk factor for cancer. We previously reported that consumption of a high-fat diet enhances metastasis in mice (Yan, Clin Exp Metastasis 2010). The present study investigated the effects of restricted feeding of a high-fat diet on spontaneous metastasis of Lewis lung carcinoma (LLC) i...

Preventing Prostate Cancer Metastasis by Targeting Exosome Secretion

DTIC Science & Technology

2015-12-01

extensive and painful metastasis of the bone. We proposed compare the impact of exosomes derived from advanced stage prostate cancer on bone stromal cells...The revised report including additional figures, tables, and text, is attached below. 1. INTRODUCTION Bone metastasis is a painful and often lethal...UT) supplemented with 10% fetal bovine serum (Atlanta Biologicals, Lawrenceville, GA) plus penicillin/streptomycin (Gibco, Gaithersburg, MD

Intramedullary spinal metastasis of a carcinoid tumor.

PubMed

Kumar, Jay I; Yanamadala, Vijay; Shin, John H

2015-12-01

We report an intramedullary spinal cord metastasis from a bronchial carcinoid, and discuss its mechanisms and management. Intramedullary spinal cord metastases from any cancer are rare, and bronchial carcinoids account for only a small fraction of lung cancers. To our knowledge, an intramedullary spinal cord metastasis from a bronchial carcinoid has been described only once previously. Copyright © 2015 Elsevier Ltd. All rights reserved.

Macrophage Efferocytosis and Prostate Cancer Bone Metastasis

DTIC Science & Technology

2015-10-01

prostate cancer bone metastasis through the phagocytosis of apoptotic tumor cells (efferocytosis). Specific Aims: 1. To identify the phagocytic ...2: To identify the phagocytic /efferocytic macrophage population in the tumor microenvironment of prostate bone metastases and determine its ability...preparation for Cancer Research. We obtained an array of prostate cancer tissue including bone metastasis (N=72) and stained the tissue for the phagocytic

Global Gene Expression Profiles Identify Metastasis Regulatory Networks | Center for Cancer Research

Cancer.gov

Metastasis is a systemic disease in which cancer cells break away from a tumor and migrate to other parts of the body, usually via the blood or lymphatic systems, to form new tumors. Metastatic tumors are difficult to treat and account for the majority of cancer-related deaths. Susceptibility to metastasis is known to have a genetic component, with some individuals more predisposed than others. However, because of the complex interchange between random genomic and epigenetic events that contribute to the disease, characterization of individual genes or small numbers of genes is not sufficient to understand the processes leading up to metastasis.

Cutaneous metastasis of transitional cell bladder carcinoma: a rare presentation and literature review.

PubMed

Salemis, Nikolaos S; Gakis, Christos; Zografidis, Andreas; Gourgiotis, Stavros

2011-01-01

Cutaneous metastasis from transitional cell bladder carcinoma is a rare clinical entity associated with poor prognosis. We present a case of cutaneous metastasis arising from a transitional cell bladder carcinoma in a male patient who had undergone a radical cystectomy and bilateral ureterostomy 17 months previously. The cutaneous metastasis became evident 3 months before the manifestations of generalized recurrent disease. An awareness of this rare clinical entity and high index of suspicion is needed to rule out metastatic spread in patients with a previous history of transitional cell bladder carcinoma presenting with cutaneous nodules. Definitive diagnosis requires a histological confirmation, but prognosis is generally poor.

Oleamide derivatives are prototypical anti-metastasis drugs that act by inhibiting Connexin 26.

PubMed

Nojima, Hiroshi; Ohba, Yusuke; Kita, Yasuyuki

2007-09-01

Despite considerable research, metastasis remains a major challenge in the clinical management of cancer. Recent reports show that abnormally augmented expression of Cx26 is responsible for the enhanced spontaneous metastasis of mouse BL6 melanoma cells. The function of Cx26 appears to be responsible for this phenotype since exogenous expression of a dominant-negative form of Cx26 and oleamide derivatives called MI-18 and MI-22 that specifically inhibit Cx26-mediated gap junction-mediated intercellular communications (GJIC) prevent the spontaneous metastasis of BL6 cells. As expected from their structural similarity to oleic acid (the major component of olive oil), both MI-18 and MI-22 are safe drugs; nonetheless, they are potent inhibitors of the spontaneous metastasis of BL6 mouse melanoma cells. Thus, they are a novel prototype of an anti-metastasis drug that has minimal side effects. While the primary tumors do not necessarily show strong Cx26-immunostaining signals, pronounced Cx26 expression is detected in the highly invasive tumor regions; it is also more frequently observed in metastasized tumors. Thus, Cx26 expression may be useful as a prognostic tool that can predict the existence of highly metastatic cancer cells in clinical samples.

Interleukin-6 enhances cancer stemness and promotes metastasis of hepatocellular carcinoma via up-regulating osteopontin expression.

PubMed

Wang, Chao-Qun; Sun, Hao-Ting; Gao, Xiao-Mei; Ren, Ning; Sheng, Yuan-Yuan; Wang, Zheng; Zheng, Yan; Wei, Jin-Wang; Zhang, Kai-Li; Yu, Xin-Xin; Zhu, Yin; Luo, Qin; Yang, Lu-Yu; Dong, Qiong-Zhu; Qin, Lun-Xiu

2016-01-01

Interleukin-6 (IL-6), one of the most important inflammatory cytokines, plays a pivotal role in metastasis and stemness of solid tumors. However, the underlying mechanisms of IL-6 in HCC metastasis remain unclear. In the present study, we demonstrated that stemness and metastatic potential of HCC cells were significantly enhanced after IL-6 stimulation. IL-6 could induce expression of osteopontin (OPN), along with other stemness-related genes, including HIF1α, BMI1, and HEY1. Block of OPN induction could significantly abrogate the effect of IL-6 on stemness and metastasis of HCC cells. Furthermore, IL-6 level was positively correlated with OPN in HCC. Patients with high plasma IL-6 or OPN level had poorer prognosis. In multivariate analysis, IL-6 and OPN were demonstrated to be independent prognostic indicators for HCC patients, and their combination had a better prognostic performance than IL-6 or OPN alone. Collectively, our findings indicate that IL-6 could enhance stemness and promote metastasis of HCC via up-regulating OPN expression, which can be a potential therapeutic target for combating HCC metastasis, and the combination of IL-6 and OPN serves as a promising prognostic predictor for HCC.

A new semiquantitative method for evaluation of metastasis progression.

PubMed

Volarevic, A; Ljujic, B; Volarevic, V; Milovanovic, M; Kanjevac, T; Lukic, A; Arsenijevic, N

2012-01-01

Although recent technical advancements are directed toward developing novel assays and methods for detection of micro and macro metastasis, there are still no reports of reliable, simple to use imaging software that could be used for the detection and quantification of metastasis in tissue sections. We herein report a new semiquantitative method for evaluation of metastasis progression in a well established 4T1 orthotopic mouse model of breast cancer metastasis. The new semiquantitative method presented here was implemented by using the Autodesk AutoCAD 2012 program, a computer-aided design program used primarily for preparing technical drawings in 2 dimensions. By using the Autodesk AutoCAD 2012 software- aided graphical evaluation we managed to detect each metastatic lesion and we precisely calculated the average percentage of lung and liver tissue parenchyma with metastasis in 4T1 tumor-bearing mice. The data were highly specific and relevant to descriptive histological analysis, confirming reliability and accuracy of the AutoCAD 2012 software as new method for quantification of metastatic lesions. The new semiquantitative method using AutoCAD 2012 software provides a novel approach for the estimation of metastatic progression in histological tissue sections.

Pericyte–fibroblast transition promotes tumor growth and metastasis

PubMed Central

Hosaka, Kayoko; Yang, Yunlong; Seki, Takahiro; Fischer, Carina; Dubey, Olivier; Fredlund, Erik; Hartman, Johan; Religa, Piotr; Ishii, Yoko; Sasahara, Masakiyo; Larsson, Ola; Cossu, Giulio; Cao, Renhai; Lim, Sharon; Cao, Yihai

2016-01-01

Vascular pericytes, an important cellular component in the tumor microenvironment, are often associated with tumor vasculatures, and their functions in cancer invasion and metastasis are poorly understood. Here we show that PDGF-BB induces pericyte–fibroblast transition (PFT), which significantly contributes to tumor invasion and metastasis. Gain- and loss-of-function experiments demonstrate that PDGF-BB-PDGFRβ signaling promotes PFT both in vitro and in in vivo tumors. Genome-wide expression analysis indicates that PDGF-BB–activated pericytes acquire mesenchymal progenitor features. Pharmacological inhibition and genetic deletion of PDGFRβ ablate the PDGF-BB–induced PFT. Genetic tracing of pericytes with two independent mouse strains, TN-AP-CreERT2:R26R-tdTomato and NG2-CreERT2:R26R-tdTomato, shows that PFT cells gain stromal fibroblast and myofibroblast markers in tumors. Importantly, coimplantation of PFT cells with less-invasive tumor cells in mice markedly promotes tumor dissemination and invasion, leading to an increased number of circulating tumor cells and metastasis. Our findings reveal a mechanism of vascular pericytes in PDGF-BB–promoted cancer invasion and metastasis by inducing PFT, and thus targeting PFT may offer a new treatment option of cancer metastasis. PMID:27608497

Extracellular and Intracellular Mechanisms Mediating Metastatic Activity of Exogenous Osteopontin

PubMed Central

Mandelin, Jami; Lin, Emme C. K.; Hu, Dana D.; Knowles, Susan K.; Do, Kim-Anh; Wang, Xuemei; Sage, E. Helene; Smith, Jeffrey W.; Arap, Wadih; Pasqualini, Renata

2009-01-01

BACKGROUND Osteopontin affects several steps of the metastatic cascade. Despite direct correlation with metastasis in experimental systems and in patient studies, the extracellular and intracellular basis for these observations remains unsolved. We used human melanoma and sarcoma cell lines to evaluate the effects of soluble osteopontin on metastasis. METHODS Exogenous osteopontin or negative controls, including a site-directed mutant osteopontin, were used in functional assays in vitro, ex vivo, and in vivo designed to test extracellular and intracellular mechanisms involved in experimental metastasis. RESULTS In the extracellular environment, we confirm that soluble osteopontin is required for its pro-metastatic effects; this phenomenon is specific, RGD-dependent, and evident in experimental models of metastasis. In the intracellular environment, osteopontin initially induces rapid Tyr-418 dephosphorylation of c-Src, with decreases in actin stress fibers and increased binding to the vascular endothelium. This heretofore undescribed Tyr dephosphorylation is followed by a tandem c-Src phosphorylation after tumor cell attachment to the metastatic site. CONCLUSION Our results reveal a complex molecular interaction as well as a dual role for osteopontin in metastasis that is dependent on whether tumor cells are in circulation or attached. Such context-dependent functional insights may contribute to anti-metastasis strategies. PMID:19224553

Case report of metastatic invasive breast lobular carcinoma to the urinary bladder.

PubMed

Al Ibraheemi, Ahmed A

2016-01-01

Breast cancer is the most common cancer in women except skin cancer. The common metastatic sites include lymph node, lung, liver and bone. However, metastasis to the bladder is extremely rare. To our knowledge, this is the first case of breast cancer metastasis to urinary bladder in Jordan which is reported. Nine years after the initial diagnosis of lobular breast carcinoma, the patient suffered from left side leg edema; Ultrasonography and Computed tomography scanning showed thickening of posterior bladder wall and bilateral hydronephrosis. The biopsy of the bladder confirmed metastatic lesion from the breast. In contrast to the primary tumor, bladder metastasis showed negative expression of estrogen (ER) and progesterone (PR) receptors. However, Her2neu test was negative in both. The reported case confirms that bladder metastasis from breast cancer tend to occur late after the diagnosis of the primary tumor. Furthermore, bladder metastasis can be asymptomatic and heterogeneous in ER and PR expression in comparison with the primary tumor. This report supports the need for careful follow-up and early intervention whenever such clinical situation is suspected. This report supports further evaluation of receptor status at time of metastasis.

Friend leukemia virus integration 1 activates the Rho GTPase pathway and is associated with metastasis in breast cancer.

PubMed

Song, Wei; Li, Wei; Li, Lingyu; Zhang, Shilin; Yan, Xu; Wen, Xue; Zhang, Xiaoying; Tian, Huimin; Li, Ailing; Hu, Ji-Fan; Cui, Jiuwei

2015-09-15

Breast cancer is the most prevalent malignant disease in women worldwide. In patients with breast cancer, metastasis to distant sites directly determines the survival outcome. However, the molecular mechanism underlying metastasis in breast cancer remains to be defined. In this report, we found that Friend leukemia virus integration 1 (FLI1) proto-oncogene was differentially expressed between the aggressive MDA-MB231 and the non-aggressive MCF-7 breast cancer cells. Congruently, immunohistochemical staining of clinical samples revealed that FLI1 was overexpressed in breast cancers as compared with the adjacent tissues. The abundance of FLI1 protein was strongly correlated with the advanced stage, poor differentiation, and lymph node metastasis in breast cancer patients. Knockdown of FLI1 with small interfering RNAs significantly attenuated the potential of migration and invasion in highly metastatic human breast cancer cells. FLI1 oncoprotein activated the Rho GTPase pathway that is known to play a role in tumor metastasis. This study for the first time identifies FLI1 as a clinically and functionally important target gene of metastasis, providing a rationale for developing FLI1 inhibitors in the treatment of breast cancer.

Innate immune cell-derived microparticles facilitate hepatocarcinoma metastasis by transferring integrin α(M)β₂ to tumor cells.

PubMed

Ma, Jingwei; Cai, Wenqian; Zhang, Yi; Huang, Chunmei; Zhang, Huafeng; Liu, Jing; Tang, Ke; Xu, Pingwei; Katirai, Foad; Zhang, Jianmin; He, Wei; Ye, Duyun; Shen, Guan-Xin; Huang, Bo

2013-09-15

Mechanisms by which tumor cells metastasize to distant organs still remain enigmatic. Immune cells have been assumed to be the root of metastasis by their fusing with tumor cells. This fusion theory, although interpreting tumor metastasis analogically and intriguingly, is arguable to date. We show in this study an alternative explanation by immune cell-derived microparticles (MPs). Upon stimulation by PMA or tumor cell-derived supernatants, immune cells released membrane-based MPs, which were taken up by H22 tumor cells, leading to tumor cell migration in vitro and metastasis in vivo. The underlying molecular basis was involved in integrin α(M)β₂ (CD11b/CD18), which could be effectively relayed from stimulated innate immune cells to MPs, then to tumor cells. Blocking either CD11b or CD18 led to significant decreases in MP-mediated tumor cell metastasis. This MP-mediated transfer of immune phenotype to tumor cells might also occur in vivo. These findings suggest that tumor cells may usurp innate immune cell phenotypes via MP pathway for their metastasis, providing new insight into tumor metastatic mechanism.

Collagen induced arthritis increases secondary metastasis in MMTV-PyV MT mouse model of mammary cancer.

PubMed

Roy, Lopamudra Das; Ghosh, Sriparna; Pathangey, Latha B; Tinder, Teresa L; Gruber, Helen E; Mukherjee, Pinku

2011-08-22

Several studies have demonstrated that sites of chronic inflammation are often associated with the establishment and growth of various malignancies. A common inflammatory condition in humans is autoimmune arthritis (AA). Although AA and cancer are different diseases, many of the underlying processes that contribute to the disorders of the joints and connective tissue that characterize AA also affect cancer progression and metastasis. Systemically, AA can lead to cellular infiltration and inflammation of the lungs. Several studies have reported statistically significant risk ratios between AA and breast cancer. Despite this knowledge being available, there has been minimal research linking breast cancer, arthritis, and metastasis associated with breast cancer. Notably both diseases are extremely prevalent in older post-menopausal women. To establish the novel link between arthritis induced inflammation and secondary metastasis associated with breast cancer, PyV MT mice that spontaneously develop mammary gland carcinoma were injected with Type II collagen (CII) to induce arthritis at 9 and 18 weeks of age for pre-metastatic and metastatic condition. The sites of secondary metastasis and the associated inflammatory microenvironment were evaluated. A significant increase in breast cancer-associated secondary metastasis to the lungs and bones was observed in the arthritic versus the non-arthritic PyV MT mice along with an increase in primary tumor burden. We report significant increases in the levels of interstitial cellular infiltrates and pro-inflammatory cytokines such as interleukin-17 (IL-17), interleukin-6 (IL-6), Pro- Matrix metallopeptidase 9 (Pro-MMP9), insulin like growth factor-II (GF-II) and macrophage colony stimulating factor (M-CSF) in the arthritic lung and bone milieu as well as in the circulation. These pro-inflammatory cytokines along with the inflammatory microenvironment may be the underlying factors facilitating tumor progression and metastasis in arthritic PyV MT mice. This was further substantiated by treatment with celecoxib, an anti-inflammatory drug + αIL-17 antibody that significantly reduced the secondary metastasis to lung and bone. The data generated not only reveal the underlying mechanism of high susceptibility to bone and lung metastasis in an arthritic condition but our combination therapies may lead to treatment modalities that will be capable of reducing tumor burden, and preventing relapse and metastasis in arthritic patients with breast cancer.

Collagen induced arthritis increases secondary metastasis in MMTV-PyV MT mouse model of mammary cancer

PubMed Central

2011-01-01

Background Several studies have demonstrated that sites of chronic inflammation are often associated with the establishment and growth of various malignancies. A common inflammatory condition in humans is autoimmune arthritis (AA). Although AA and cancer are different diseases, many of the underlying processes that contribute to the disorders of the joints and connective tissue that characterize AA also affect cancer progression and metastasis. Systemically, AA can lead to cellular infiltration and inflammation of the lungs. Several studies have reported statistically significant risk ratios between AA and breast cancer. Despite this knowledge being available, there has been minimal research linking breast cancer, arthritis, and metastasis associated with breast cancer. Notably both diseases are extremely prevalent in older post-menopausal women. Methods To establish the novel link between arthritis induced inflammation and secondary metastasis associated with breast cancer, PyV MT mice that spontaneously develop mammary gland carcinoma were injected with Type II collagen (CII) to induce arthritis at 9 and 18 weeks of age for pre-metastatic and metastatic condition. The sites of secondary metastasis and the associated inflammatory microenvironment were evaluated. Results A significant increase in breast cancer-associated secondary metastasis to the lungs and bones was observed in the arthritic versus the non-arthritic PyV MT mice along with an increase in primary tumor burden. We report significant increases in the levels of interstitial cellular infiltrates and pro-inflammatory cytokines such as interleukin-17 (IL-17), interleukin-6 (IL-6), Pro- Matrix metallopeptidase 9 (Pro-MMP9), insulin like growth factor-II (GF-II) and macrophage colony stimulating factor (M-CSF) in the arthritic lung and bone milieu as well as in the circulation. These pro-inflammatory cytokines along with the inflammatory microenvironment may be the underlying factors facilitating tumor progression and metastasis in arthritic PyV MT mice. This was further substantiated by treatment with celecoxib, an anti-inflammatory drug + αIL-17 antibody that significantly reduced the secondary metastasis to lung and bone. Conclusions The data generated not only reveal the underlying mechanism of high susceptibility to bone and lung metastasis in an arthritic condition but our combination therapies may lead to treatment modalities that will be capable of reducing tumor burden, and preventing relapse and metastasis in arthritic patients with breast cancer. PMID:21859454

Tumor cell migration screen identifies SRPK1 as breast cancer metastasis determinant

PubMed Central

van Roosmalen, Wies; Le Dévédec, Sylvia E.; Golani, Ofra; Smid, Marcel; Pulyakhina, Irina; Timmermans, Annemieke M.; Look, Maxime P.; Zi, Di; Pont, Chantal; de Graauw, Marjo; Naffar-Abu-Amara, Suha; Kirsanova, Catherine; Rustici, Gabriella; Hoen, Peter A.C. ‘t; Martens, John W.M.; Foekens, John A.; Geiger, Benjamin; van de Water, Bob

2015-01-01

Tumor cell migration is a key process for cancer cell dissemination and metastasis that is controlled by signal-mediated cytoskeletal and cell matrix adhesion remodeling. Using a phagokinetic track assay with migratory H1299 cells, we performed an siRNA screen of almost 1,500 genes encoding kinases/phosphatases and adhesome- and migration-related proteins to identify genes that affect tumor cell migration speed and persistence. Thirty candidate genes that altered cell migration were validated in live tumor cell migration assays. Eight were associated with metastasis-free survival in breast cancer patients, with integrin β3–binding protein (ITGB3BP), MAP3K8, NIMA-related kinase (NEK2), and SHC-transforming protein 1 (SHC1) being the most predictive. Examination of genes that modulate migration indicated that SRPK1, encoding the splicing factor kinase SRSF protein kinase 1, is relevant to breast cancer outcomes, as it was highly expressed in basal breast cancer. Furthermore, high SRPK1 expression correlated with poor breast cancer disease outcome and preferential metastasis to the lungs and brain. In 2 independent murine models of breast tumor metastasis, stable shRNA-based SRPK1 knockdown suppressed metastasis to distant organs, including lung, liver, and spleen, and inhibited focal adhesion reorganization. Our study provides comprehensive information on the molecular determinants of tumor cell migration and suggests that SRPK1 has potential as a drug target for limiting breast cancer metastasis. PMID:25774502

Pulmonary Metastasis After Resection of Cholangiocarcinoma: Incidence, Resectability, and Survival.

PubMed

Yamada, Mihoko; Ebata, Tomoki; Yokoyama, Yukihiro; Igami, Tsuyoshi; Sugawara, Gen; Mizuno, Takashi; Yamaguchi, Junpei; Nagino, Masato

2017-06-01

There are few reports on pulmonary metastasis from cholangiocarcinoma; therefore, its incidence, resectability, and survival are unclear. Patients who underwent surgical resection for cholangiocarcinoma, including intrahepatic, perihilar, and distal cholangiocarcinoma were retrospectively reviewed, and this study focused on patients with pulmonary metastasis. Between January 2003 and December 2014, 681 patients underwent surgical resection for cholangiocarcinoma. Of these, 407 patients experienced disease recurrence, including 46 (11.3%) who developed pulmonary metastasis. Of these 46 patients, 9 underwent resection for pulmonary metastasis; no resection was performed in the remaining 37 patients. R0 resection was achieved in all patients, and no complications related to pulmonary metastasectomy were observed. The median time to recurrence was significantly longer in the 9 patients who underwent surgery than in the 37 patients without surgery (2.5 vs 1.0 years, p < 0.010). Survival after surgery for primary cancer and survival after recurrence were significantly better in the former group than in the latter group (after primary cancer: 66.7 vs 0% at 5 years, p < 0.001; after recurrence: 40.0 vs 8.7% at 3 years, p = 0.003). Multivariate analysis identified the time to recurrence and resection for pulmonary metastasis as independent prognostic factors for survival after recurrence. Resection for pulmonary metastasis originating from cholangiocarcinoma can be safely performed and confers survival benefits for select patients, especially those with a longer time to recurrence after initial surgery.

Extract of Ginkgo biloba exacerbates liver metastasis in a mouse colon cancer Xenograft model.

PubMed

Wang, Huan; Wu, Xia; Lezmi, Stephane; Li, Qian; Helferich, William G; Xu, Yueqing; Chen, Hong

2017-12-02

Metastasis refers to the spread of a primary tumor cell from the primary site to other locations in the body and it is generally associated with the severity of a tumor. Extract of Ginkgo biloba (EGb) contains various bioactive compounds and it exerts beneficial effects including improvements in brain function and reduced risk of cardiovascular diseases. On the other hand, increased risk of thyroid and liver cancers by EGb have been reported in animals. A colon cancer metastasis model was established using intrasplenic injection of a human colon cancer cell line, SW620-luc in athymic mice to investigate the potential impact of EGb on colon cancer progression. After tumor establishment, EGb was intraperitonically injected daily for 5 wks. EGb significantly increased the rate of metastasis in mouse liver and decreased the number of necrotic and apoptotic cells in the metastatic liver when compared to the control. Meanwhile, EGb significantly induced proliferation of tumor cells in the metastatic liver, indicated by increased staining of Ki67 and H3S10p. mRNA expression of genes involved in cell cycle, metastasis, apoptosis, and oxidative stress were altered by EGb treatment in livers with tumors. Moreover, EGb activated the stress-responsive MAPK pathways in the liver with metastatic tumors. EGb exacerbated liver metastasis in a mouse colon cancer metastasis model. This is potentially due to the increased tumor cell proliferation involving stimulated MAPK pathways.

Effects of raf kinase inhibitor protein expression on metastasis and progression of human breast cancer.

PubMed

Li, Hong Zhao; Gao, Yan; Zhao, Xiu Lan; Liu, Yi Xin; Sun, Bao Cun; Yang, Jie; Yao, Zhi

2009-06-01

Raf kinase inhibitor protein (RKIP) has been shown to be a metastasis suppressor in many kinds of malignant tumors. But its function in breast cancer was not yet clarified completely. We detected RKIP expression in clinical samples of primary breast cancer, breast cancer metastases, and in different breast cancer cells. Compared with the normal breast epithelia, benign breast epithelia, or in situ ductal carcinoma, the expression level of RKIP is decreased in invasive carcinoma and significantly reduced or lost in the metastasis lymph node matched to the invasive carcinoma. To explore the potential role of RKIP in breast cancer metastasis, we studied the effect of RKIP on the malignant phenotypes of the breast cancer cells with ectopically overexpression or knockdown of RKIP. Cell proliferation, soft-agar colony formation, in vitro adhesion assay, invasion, and migation assays were done to examine the malignant phenotypes of the transfected cells. Consequently, RKIP has no effect on in vitro proliferation rate or colony-forming ability of MDA-MB-435 cells. In vitro cell invasion and migration assays indicated that the RKIP expression was inversely associated with the invasiveness of MDA-MB-435 cells. Consistent with these results, in the orthotopic murine models, we observed that overexpression of RKIP in breast cancer cells impaired invasiveness and metastasis, whereas down-regulation of RKIP expression promoted invasiveness and metastasis. These results indicate that RKIP is a metastasis suppressor gene of human breast cancer.

Suppression of breast cancer metastasis through the inactivation of ADP-ribosylation factor 1.

PubMed

Xie, Xiayang; Tang, Shou-Ching; Cai, Yafei; Pi, Wenhu; Deng, Libin; Wu, Guangyu; Chavanieu, Alain; Teng, Yong

2016-09-06

Metastasis is the major cause of cancer-related death in breast cancer patients, which is controlled by specific sets of genes. Targeting these genes may provide a means to delay cancer progression and allow local treatment to be more effective. We report for the first time that ADP-ribosylation factor 1 (ARF1) is the most amplified gene in ARF gene family in breast cancer, and high-level amplification of ARF1 is associated with increased mRNA expression and poor outcomes of patients with breast cancer. Knockdown of ARF1 leads to significant suppression of migration and invasion in breast cancer cells. Using the orthotopic xenograft model in NSG mice, we demonstrate that loss of ARF1 expression in breast cancer cells inhibits pulmonary metastasis. The zebrafish-metastasis model confirms that the ARF1 gene depletion suppresses breast cancer cells to metastatic disseminate throughout fish body, indicating that ARF1 is a very compelling target to limit metastasis. ARF1 function largely dependents on its activation and LM11, a cell-active inhibitor that specifically inhibits ARF1 activation through targeting the ARF1-GDP/ARNO complex at the Golgi, significantly impairs metastatic capability of breast cancer cell in zebrafish. These findings underline the importance of ARF1 in promoting metastasis and suggest that LM11 that inhibits ARF1 activation may represent a potential therapeutic approach to prevent or treat breast cancer metastasis.

Cutaneous metastasis: clinicopathological study of 72 patients from a tertiary care center in Lebanon.

PubMed

El Khoury, Jinane; Khalifeh, Ibrahim; Kibbi, Abdul-Ghani; Abbas, Ossama

2014-02-01

Cutaneous metastasis is the result of malignant cell spread from primary malignancy to the skin. This is not uncommon, and rates reported in the literature are as high as 10.4%. To the best of our knowledge, there are no studies assessing the epidemiologic, clinical, and histopathological features of cutaneous metastasis in our region. To assess the clinical and histopathological findings of all patients diagnosed with cutaneous metastasis at the American University of Beirut - Medical Center (AUB-MC) and to compare our findings with those published in the literature. Retrospective clinical and histopathologic evaluation of all cases diagnosed as cutaneous metastasis at AUB-MC between 1992 and 2010. A total of 72 patients (50 females and 22 males) were identified. The mean age at diagnosis was 55.2 years. The most common primary cancer was breast cancer in women and laryngeal cancer in men. The most common clinical presentation was a single nodule in 27% of cases followed by multiple nodules in 23%. Cutaneous metastasis lesions were asymptomatic in the majority. The chest was the most commonly affected site. On microscopy, the majority of metastatic cases were adenocarcinomas (74%). This is, to our knowledge, the first study characterizing the epidemiological, clinical, and histopathological features of cutaneous metastasis in the Lebanese population. The clinical and histopathological features observed were in concordance with the published literature, with minor differences. © 2013 The International Society of Dermatology.

Tumor suppressor miR-1 inhibits tumor growth and metastasis by simultaneously targeting multiple genes

PubMed Central

Liu, Cuilian; Zhang, Song; Wang, Qizhi; Zhang, Xiaobo

2017-01-01

Cancer progression depends on tumor growth and metastasis, which are activated or suppressed by multiple genes. An individual microRNA may target multiple genes, suggesting that a miRNA may suppress tumor growth and metastasis via simultaneously targeting different genes. However, thus far, this issue has not been explored. In the present study, the findings showed that miR-1 could simultaneously inhibit tumor growth and metastasis of gastric and breast cancers by targeting multiple genes. The results indicated that miR-1 was significantly downregulated in cancer tissues compared with normal tissues. The miR-1 overexpression led to cell cycle arrest in the G1 phase in gastric and breast cancer cells but not in normal cells. Furthermore, the miR-1 overexpression significantly inhibited the metastasis of gastric and breast cancer cells. An analysis of the underlying mechanism revealed that the simultaneous inhibition of tumor growth and metastasis mediated by miR-1 was due to the synchronous targeting of 6 miR-1 target genes encoding cyclin dependent kinase 4, twinfilin actin binding protein 1, calponin 3, coronin 1C, WAS protein family member 2 and thymosin beta 4, X-linked. In vivo assays demonstrated that miR-1 efficiently inhibited tumor growth and metastasis of gastric and breast cancers in nude mice. Therefore, our study contributed novel insights into the miR-1′s roles in tumorigenesis of gastric and breast cancers. PMID:28159933

MUC1 Predicts Colorectal Cancer Metastasis: A Systematic Review and Meta-Analysis of Case Controlled Studies

PubMed Central

Lu, Minxun; Liu, Yang; Zheng, Tianying; Feng, Shijian; Hao, Meiqin; Shi, Huashan

2015-01-01

Objective To evaluate the predicting value of MUC1 expression in lymph node and distant metastasis of colorectal cancer (CRC). Methods Pubmed/ MEDLINE and EMBASE were searched to identify eligible studies that evaluated the correlation between MUC1 and CRC. A meta-analysis was conducted to evaluate the impact of MUC1 expression on CRC metastasis. Results A total of 18 studies (n = 3271) met inclusion criteria and the mean Newcastle-Ottawa Scale (NOS) score was 6.3 with a range from 4 to 8. The pooled OR in the meta-analysis of 15 studies indicated that positive MUC1 expression correlated with more CRC node metastasis (OR = 2.32, 95% CI = 1.63–3.29). The data synthesis of 6 studies suggested that MUC1 expression predicted more possibility of CRC distant metastasis (OR = 2.22, 95% CI = 1.23–4.00). In addition, the combined OR of 7 studies showed that MUC1 expression indicated higher Duke’s stage (OR = 3.02, 95% CI = 2.11–4.33). No publication bias was found in the mate-analysis by Begg’s test or Egger’s test with the exception of the meta-analysis of MUC1 with CRC node metastasis (Begg’s test p = 0.729, Egger’s test p = 0.000). Conclusions Despite of some modest bias, the pooled evidence suggested that MUC1 expression was significantly correlated with CRC metastasis. PMID:26367866

Tumor suppressor miR-1 inhibits tumor growth and metastasis by simultaneously targeting multiple genes.

PubMed

Liu, Cuilian; Zhang, Song; Wang, Qizhi; Zhang, Xiaobo

2017-06-27

Cancer progression depends on tumor growth and metastasis, which are activated or suppressed by multiple genes. An individual microRNA may target multiple genes, suggesting that a miRNA may suppress tumor growth and metastasis via simultaneously targeting different genes. However, thus far, this issue has not been explored. In the present study, the findings showed that miR-1 could simultaneously inhibit tumor growth and metastasis of gastric and breast cancers by targeting multiple genes. The results indicated that miR-1 was significantly downregulated in cancer tissues compared with normal tissues. The miR-1 overexpression led to cell cycle arrest in the G1 phase in gastric and breast cancer cells but not in normal cells. Furthermore, the miR-1 overexpression significantly inhibited the metastasis of gastric and breast cancer cells. An analysis of the underlying mechanism revealed that the simultaneous inhibition of tumor growth and metastasis mediated by miR-1 was due to the synchronous targeting of 6 miR-1 target genes encoding cyclin dependent kinase 4, twinfilin actin binding protein 1, calponin 3, coronin 1C, WAS protein family member 2 and thymosin beta 4, X-linked. In vivo assays demonstrated that miR-1 efficiently inhibited tumor growth and metastasis of gastric and breast cancers in nude mice. Therefore, our study contributed novel insights into the miR-1's roles in tumorigenesis of gastric and breast cancers.

Selective efficacy of zoledronic acid on metastasis in a patient-derived orthotopic xenograph (PDOX) nude-mouse model of human pancreatic cancer.

PubMed

Hiroshima, Yukihiko; Maawy, Ali A; Katz, Matthew H G; Fleming, Jason B; Bouvet, Michael; Endo, Itaru; Hoffman, Robert M

2015-03-01

Patient-derived orthotopic xenograft (PDOX) nude-mouse models replicate the behavior of clinical cancer, including metastasis. The objective of the study was to determine the efficacy of zoledronic acid (ZA) on metastasis of a patient-derived orthotopic xenograft (PDOX) nude-mouse model of pancreatic cancer. In the present study, we examined the efficacy of ZA on pancreatic cancer growth and metastasis in a PDOX nude-mouse model. ZA monotherapy did not significantly suppress primary tumor growth. However, the primary tumor weight of gemcitabine (GEM) and combination GEM + ZA-treated mice was significantly decreased compared to the control group (GEM: P = 0.003; GEM + ZA: P = 0.002). The primary tumor weight of GEM + ZA-treated mice was significantly decreased compared to GEM-treated mice (P = 0.016). The metastasis weight decreased in ZA- or GEM-treated mice compared to the control group (ZA: P = 0.009; GEM: P = 0.007. No metastasis was detected in combination GEM + ZA-treated mice compared to the control group (GEM + ZA; P = 0.005). The results of the present study indicate that ZA can selectively target metastasis in a pancreatic cancer PDOX model and that the combination of ZA and GEM should be evaluated clinically in the near future for this highly treatment-resistant disease. © 2014 Wiley Periodicals, Inc.

Genome wide copy number analyses of superficial esophageal squamous cell carcinoma with and without metastasis.

PubMed

Wang, Pengjiao; Shan, Ling; Xue, Liyan; Zheng, Bo; Ying, Jianming; Lu, Ning

2017-01-17

Superficial esophageal squamous cell carcinoma (ESCC) is generally considered a subtype of less invasive ESCC. Yet a subset of these superficial ESCC would have metastasis after esophagostomy or endoscopic resection and lead to poor prognosis. The objective of this study is to determine biomarkers that can identify such subset of superficial ESCC that would have metastasis after surgery using genome wide copy number alteration (CNA) analyses. The CNAs of 38 cases of superficial ESCCs originated from radical surgery, including 19 without metastasis and 19 with metastasis within 5 years' post-surgery, were analyzed using Affymetrix OncoScan™ FFPE Assay. A 39-gene signature was identified which characterized the subset of superficial ESCC with high risk of metastasis after surgery. In addition, recurrent CNAs of superficial ESCC were also investigated in the study. Amplification of 11q13.3 (FGF4) and deletion of 9p21.3 (CDKN2A) were found to be recurrent in all 38 superficial ESCCs analyzed. Notably amplifications of 3p26.33 (SOX2OT), 8q24.21 (MYC), 14q21.1 (FOXA1) and deletion of 3p12.1 (GBE1) were only found to be recurrent in metastaic superficial ESCCs. In conclusion, using CNAs analyses, we identify a 39-gene signature which characterizes the high risk metastatic superficial ESCCs and discover several recurrent CNAs that might be the driver alterations in metastasis among superficial ESCCs.

Genome wide copy number analyses of superficial esophageal squamous cell carcinoma with and without metastasis

PubMed Central

Xue, Liyan; Zheng, Bo; Ying, Jianming; Lu, Ning

2017-01-01

Superficial esophageal squamous cell carcinoma (ESCC) is generally considered a subtype of less invasive ESCC. Yet a subset of these superficial ESCC would have metastasis after esophagostomy or endoscopic resection and lead to poor prognosis. The objective of this study is to determine biomarkers that can identify such subset of superficial ESCC that would have metastasis after surgery using genome wide copy number alteration (CNA) analyses. The CNAs of 38 cases of superficial ESCCs originated from radical surgery, including 19 without metastasis and 19 with metastasis within 5 years’ post-surgery, were analyzed using Affymetrix OncoScan™ FFPE Assay. A 39-gene signature was identified which characterized the subset of superficial ESCC with high risk of metastasis after surgery. In addition, recurrent CNAs of superficial ESCC were also investigated in the study. Amplification of 11q13.3 (FGF4) and deletion of 9p21.3 (CDKN2A) were found to be recurrent in all 38 superficial ESCCs analyzed. Notably amplifications of 3p26.33 (SOX2OT), 8q24.21 (MYC), 14q21.1 (FOXA1) and deletion of 3p12.1 (GBE1) were only found to be recurrent in metastaic superficial ESCCs. In conclusion, using CNAs analyses, we identify a 39-gene signature which characterizes the high risk metastatic superficial ESCCs and discover several recurrent CNAs that might be the driver alterations in metastasis among superficial ESCCs. PMID:27974698

Biological behavior of oral and perioral mast cell tumors in dogs: 44 cases (1996-2006).

PubMed

Hillman, Lorin A; Garrett, Laura D; de Lorimier, Louis-Philippe; Charney, Sarah C; Borst, Luke B; Fan, Timothy M

2010-10-15

To describe clinical outcome of dogs with mast cell tumors (MCTs) arising from the oral mucosa, oral mucocutaneous junction, or perioral region of the muzzle and evaluate the potential role of the chemokine receptor type 7 (CCR7) in the biological behavior of these tumors. Retrospective case series. 44 dogs with MCTs of the oral mucosa (n=14), oral mucocutaneous junction (19), or perioral region of the muzzle (11). Medical records were reviewed for information on signalment, regional metastasis, treatments, cause of death, and survival time. Twenty of the 44 cases had stored histologic samples available for immunohistochemical staining for CCR7 For all dogs, median survival time was 52 months. Twenty-six (59%) dogs had regional lymph node metastasis on admission. Median survival time for dogs with lymph node metastasis was 14 months, whereas median survival time was not reached for dogs without lymph node metastasis. Intensity of staining for CCR7 was not significantly associated with the presence of regional lymph node metastasis or survival time. Results suggested that in dogs with MCTs arising from the oral mucosa, oral mucocutaneous junction, or perioral region of the muzzle, the presence of regional lymph node metastasis at the time of diagnosis was a negative prognostic factor. However, prolonged survival times could be achieved with treatment. In addition, CCR7 expression in the primary tumor was not significantly associated with the presence of regional lymph node metastasis or survival time.

Impact of pathologic diagnosis of internal mammary lymph node metastasis in clinical N2b and N3b breast cancer patients.

PubMed

Joo, Ji Hyeon; Kim, Su Ssan; Ahn, Seung-Do; Choi, Eun Kyung; Jung, Jin Hong; Jeong, Yuri; Ahn, Sei Hyun; Son, Byung Ho; Lee, Jong Won; Kim, Hee Jung; Go, Beom Seok; Kim, Hak Hee; Cha, Joo Hee; Shin, Hee Jung; Chae, Eun Young

2017-11-01

To analyze the prognostic role of pathologic confirmation of internal mammary lymph nodes (IMNs) for breast cancer patients who received neoadjuvant chemotherapy. Of the patients who were treated with neoadjuvant chemotherapy, surgery, and radiation therapy between 2009 and 2013, 114 women had suspicious IMNs and FNAB was attempted. Clinical IMN metastasis was diagnosed by 18F-FDG PET/CT positivity or pathologic confirmation (N = 70). Patients were divided into the FNAB(+) or FNAB(-) IMN group. The pathologic confirmation rate was 57% (40 of 70 patients). Rates were 74% in US-positive, 70% in MRI-positive, and 55% in PET-positive patients. Nodal stage was cN2b (6%) or cN3b (94%). Five-year progression-free survival (PFS) was significantly worse in patients with FNAB(+) IMN metastasis than FNAB(-) IMN metastasis (61% vs. 87%, P = 0.03). FNAB(+) IMN patients showed worse distant metastasis and regional recurrence-free survival without statistical significance (69% vs. 86%, P = 0.06, and 81% vs. 96%, P = 0.06). With median follow-up of 50.5 months (13.0-97.0 months), overall survival at 5 years was 77%, and PFS was 72%. Patients with FNAB-proven IMN metastasis had worse treatment outcomes compared to patients with clinically diagnosed IMN metastasis in cN2b/N3b breast cancer.

[Diagnostic values of serum type III procollagen N-terminal peptide in type IV gastric cancer].

PubMed

Akazawa, S; Fujiki, T; Kanda, Y; Kumai, R; Yoshida, S

1985-04-01

Since increased synthesis of collagen has been demonstrated in tissue of type IV gastric cancer, we attempted to distinguish type IV gastric cancer from other cancers by measuring serum levels of type III procollagen N-terminal peptide (type III-N-peptide). Mean serum levels in type IV gastric cancer patients without metastasis were found to be elevated above normal values and developed a tendency to be higher than those in types I, II and III gastric cancer patients without metastasis. Highly positive ratios were found in patients with liver diseases including hepatoma and colon cancer, biliary tract cancer, and esophageal cancer patients with liver, lung or bone metastasis, but only 2 out of 14 of these cancer patients without such metastasis showed positive serum levels of type III-N-peptide. Positive cases in patients with type IV gastric cancer were obtained not only in the group with clinical stage IV but also in the groups with clinical stages II and III. In addition, high serum levels of type III-N-peptide in patients with type IV gastric cancer were seen not only in the cases with liver, lung or bone metastasis but also in cases with disseminated peritoneal metastasis alone. These results suggest that if the serum level of type III-N-peptide is elevated above normal values, type IV gastric cancer should be suspected after ruling out liver diseases, myelofibrosis and liver, lung or bone metastasis.

[A Case Report of Disappearance of Gastric Metastasis of Breast Cancer Treated with Combination Therapy Consisting of Paclitaxel and Cisplatin].

PubMed

Nakajima, Tooru; Taniwaka, Koichi; Goto, Hideki; Kawamura, Shunji

2017-04-01

A 63-year-old postmenopausal woman was treated with combination therapy consisting of paclitaxel(PTX)and cisplatin (CDDP)for gastric metastasis of breast cancer; she achieved a complete response as revealed by pathological examination. Combination therapy with PTX and CDDP seems to be an optional treatment for gastric metastasis of breast cancer.

Global Gene Expression Profiles Identify Metastasis Regulatory Networks | Center for Cancer Research

Cancer.gov

Metastasis is a systemic disease in which cancer cells break away from a tumor and migrate to other parts of the body, usually via the blood or lymphatic systems, to form new tumors. Metastatic tumors are difficult to treat and account for the majority of cancer-related deaths. Susceptibility to metastasis is known to have a genetic component, with some individuals more

SU-E-J-115: Using Markov Chain Modeling to Elucidate Patterns in Breast Cancer Metastasis Over Time and Space

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

Comen, E; Mason, J; Kuhn, P

2014-06-01

Purpose: Traditionally, breast cancer metastasis is described as a process wherein cancer cells spread from the breast to multiple organ systems via hematogenous and lymphatic routes. Mapping organ specific patterns of cancer spread over time is essential to understanding metastatic progression. In order to better predict sites of metastases, here we demonstrate modeling of the patterned migration of metastasis. Methods: We reviewed the clinical history of 453 breast cancer patients from Memorial Sloan Kettering Cancer Center who were non-metastatic at diagnosis but developed metastasis over time. We used the variables of organ site of metastases as well as time tomore » create a Markov chain model of metastasis. We illustrate the probabilities of metastasis occurring at a given anatomic site together with the probability of spread to additional sites. Results: Based on the clinical histories of 453 breast cancer patients who developed metastasis, we have learned (i) how to create the Markov transition matrix governing the probabilities of cancer progression from site to site; (ii) how to create a systemic network diagram governing disease progression modeled as a random walk on a directed graph; (iii) how to classify metastatic sites as ‘sponges’ that tend to only receive cancer cells or ‘spreaders’ that receive and release them; (iv) how to model the time-scales of disease progression as a Weibull probability distribution function; (v) how to perform Monte Carlo simulations of disease progression; and (vi) how to interpret disease progression as an entropy-increasing stochastic process. Conclusion: Based on our modeling, metastatic spread may follow predictable pathways. Mapping metastasis not simply by organ site, but by function as either a ‘spreader’ or ‘sponge’ fundamentally reframes our understanding of metastatic processes. This model serves as a novel platform from which we may integrate the evolving genomic landscape that drives cancer metastasis. PS-OC Trans-Network Project Grant Award for “Data Assimilation and ensemble statistical forecasting methods applied to the MSKCC longitudinal metastatic breast cancer cohort.”.« less

PAI-1, a target gene of miR-143, regulates invasion and metastasis by upregulating MMP-13 expression of human osteosarcoma.

PubMed

Hirahata, Mio; Osaki, Mitsuhiko; Kanda, Yusuke; Sugimoto, Yui; Yoshioka, Yusuke; Kosaka, Nobuyoshi; Takeshita, Fumitaka; Fujiwara, Tomohiro; Kawai, Akira; Ito, Hisao; Ochiya, Takahiro; Okada, Futoshi

2016-05-01

Despite recent improvements in the therapy for osteosarcoma, 30-40% of osteosarcoma patients die of this disease, mainly due to its lung metastasis. We have previously reported that intravenous injection of miR-143 significantly suppresses lung metastasis of human osteosarcoma cells (143B) in a mouse model. In this study, we examined the biological role and mechanism of miR-143 in the metastasis of human osteosarcoma cells. We identified plasminogen activator inhibitor-1 (PAI-1) as a direct target gene of miR-143. To determine the role of PAI-1 in human osteosarcoma cells, siRNA was transfected into 143B cells for knockdown of PAI-1 expression. An in vitro study showed that downregulation of PAI-1 suppressed cell invasion activity, but not proliferation. Moreover, injection of PAI-1 siRNA into a primary lesion in the osteosarcoma mouse model inhibited lung metastasis compared to control siRNA-injected mice, without influencing the proliferative activity of the tumor cells. Subsequent examination using 143B cells revealed that knockdown of PAI-1 expression resulted in downregulation of the expression and secretion of matrix metalloproteinase-13 (MMP-13), which is also a target gene of miR-143 and a proteolytic enzyme that regulates tumor-induced osteolysis. Immunohistochemical analysis using clinical samples showed that higher miR-143 expressing cases showed poor expression of PAI-1 in the primary tumor cells. All such cases belonged to the lung metastasis-negative group. Moreover, the frequency of lung metastasis-positive cases was significantly higher in PAI-1 and MMP-13 double-positive cases than in PAI-1 or MMP-13 single-positive or double-negative cases (P < 0.05). These results indicated that PAI-1, a target gene of miR-143, regulates invasion and lung metastasis via enhancement of MMP-13 expression and secretion in human osteosarcoma cells, suggesting that these molecules could be potential therapeutic target genes for preventing lung metastasis in osteosarcoma patients. © 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Breast cancer-associated metastasis is significantly increased in a model of autoimmune arthritis

PubMed Central

Das Roy, Lopamudra; Pathangey, Latha B; Tinder, Teresa L; Schettini, Jorge L; Gruber, Helen E; Mukherjee, Pinku

2009-01-01

Introduction Sites of chronic inflammation are often associated with the establishment and growth of various malignancies including breast cancer. A common inflammatory condition in humans is autoimmune arthritis (AA) that causes inflammation and deformity of the joints. Other systemic effects associated with arthritis include increased cellular infiltration and inflammation of the lungs. Several studies have reported statistically significant risk ratios between AA and breast cancer. Despite this knowledge, available for a decade, it has never been questioned if the site of chronic inflammation linked to AA creates a milieu that attracts tumor cells to home and grow in the inflamed bones and lungs which are frequent sites of breast cancer metastasis. Methods To determine if chronic inflammation induced by autoimmune arthritis contributes to increased breast cancer-associated metastasis, we generated mammary gland tumors in SKG mice that were genetically prone to develop AA. Two breast cancer cell lines, one highly metastatic (4T1) and the other non-metastatic (TUBO) were used to generate the tumors in the mammary fat pad. Lung and bone metastasis and the associated inflammatory milieu were evaluated in the arthritic versus the non-arthritic mice. Results We report a three-fold increase in lung metastasis and a significant increase in the incidence of bone metastasis in the pro-arthritic and arthritic mice compared to non-arthritic control mice. We also report that the metastatic breast cancer cells augment the severity of arthritis resulting in a vicious cycle that increases both bone destruction and metastasis. Enhanced neutrophilic and granulocytic infiltration in lungs and bone of the pro-arthritic and arthritic mice and subsequent increase in circulating levels of proinflammatory cytokines, such as macrophage colony stimulating factor (M-CSF), interleukin-17 (IL-17), interleukin-6 (IL-6), vascular endothelial growth factor (VEGF), and tumor necrosis factor-alpha (TNF-alpha) may contribute to the increased metastasis. Treatment with anti-IL17 + celecoxib, an anti-inflammatory drug completely abrogated the development of metastasis and significantly reduced the primary tumor burden. Conclusions The data clearly has important clinical implications for patients diagnosed with metastatic breast cancer, especially with regards to the prognosis and treatment options. PMID:19643025

Breast-cancer-associated metastasis is significantly increased in a model of autoimmune arthritis.

PubMed

Das Roy, Lopamudra; Pathangey, Latha B; Tinder, Teresa L; Schettini, Jorge L; Gruber, Helen E; Mukherjee, Pinku

2009-01-01

Sites of chronic inflammation are often associated with the establishment and growth of various malignancies including breast cancer. A common inflammatory condition in humans is autoimmune arthritis (AA) that causes inflammation and deformity of the joints. Other systemic effects associated with arthritis include increased cellular infiltration and inflammation of the lungs. Several studies have reported statistically significant risk ratios between AA and breast cancer. Despite this knowledge, available for a decade, it has never been questioned if the site of chronic inflammation linked to AA creates a milieu that attracts tumor cells to home and grow in the inflamed bones and lungs which are frequent sites of breast cancer metastasis. To determine if chronic inflammation induced by autoimmune arthritis contributes to increased breast cancer-associated metastasis, we generated mammary gland tumors in SKG mice that were genetically prone to develop AA. Two breast cancer cell lines, one highly metastatic (4T1) and the other non-metastatic (TUBO) were used to generate the tumors in the mammary fat pad. Lung and bone metastasis and the associated inflammatory milieu were evaluated in the arthritic versus the non-arthritic mice. We report a three-fold increase in lung metastasis and a significant increase in the incidence of bone metastasis in the pro-arthritic and arthritic mice compared to non-arthritic control mice. We also report that the metastatic breast cancer cells augment the severity of arthritis resulting in a vicious cycle that increases both bone destruction and metastasis. Enhanced neutrophilic and granulocytic infiltration in lungs and bone of the pro-arthritic and arthritic mice and subsequent increase in circulating levels of proinflammatory cytokines, such as macrophage colony stimulating factor (M-CSF), interleukin-17 (IL-17), interleukin-6 (IL-6), vascular endothelial growth factor (VEGF), and tumor necrosis factor-alpha (TNF-alpha) may contribute to the increased metastasis. Treatment with anti-IL17 + celecoxib, an anti-inflammatory drug completely abrogated the development of metastasis and significantly reduced the primary tumor burden. The data clearly has important clinical implications for patients diagnosed with metastatic breast cancer, especially with regards to the prognosis and treatment options.

Mena deficiency delays tumor progression and decreases metastasis in polyoma middle-T transgenic mouse mammary tumors.

PubMed

Roussos, Evanthia T; Wang, Yarong; Wyckoff, Jeffrey B; Sellers, Rani S; Wang, Weigang; Li, Jiufeng; Pollard, Jeffrey W; Gertler, Frank B; Condeelis, John S

2010-01-01

The actin binding protein Mammalian enabled (Mena), has been implicated in the metastatic progression of solid tumors in humans. Mena expression level in primary tumors is correlated with metastasis in breast, cervical, colorectal and pancreatic cancers. Cells expressing high Mena levels are part of the tumor microenvironment for metastasis (TMEM), an anatomical structure that is predictive for risk of breast cancer metastasis. Previously we have shown that forced expression of Mena adenocarcinoma cells enhances invasion and metastasis in xenograft mice. Whether Mena is required for tumor progression is still unknown. Here we report the effects of Mena deficiency on tumor progression, metastasis and on normal mammary gland development. To investigate the role of Mena in tumor progression and metastasis, Mena deficient mice were intercrossed with mice carrying a transgene expressing the polyoma middle T oncoprotein, driven by the mouse mammary tumor virus. The progeny were investigated for the effects of Mena deficiency on tumor progression via staging of primary mammary tumors and by evaluation of morbidity. Stages of metastatic progression were investigated using an in vivo invasion assay, intravital multiphoton microscopy, circulating tumor cell burden, and lung metastases. Mammary gland development was studied in whole mount mammary glands of wild type and Mena deficient mice. Mena deficiency decreased morbidity and metastatic dissemination. Loss of Mena increased mammary tumor latency but had no affect on mammary tumor burden or histologic progression to carcinoma. Elimination of Mena also significantly decreased epidermal growth factor (EGF) induced in vivo invasion, in vivo motility, intravasation and metastasis. Non-tumor bearing mice deficient for Mena also showed defects in mammary gland terminal end bud formation and branching. Deficiency of Mena decreases metastasis by slowing tumor progression and reducing tumor cell invasion and intravasation. Mena deficiency during development causes defects in invasive processes involved in mammary gland development. These findings suggest that functional intervention targeting Mena in breast cancer patients may provide a valuable treatment option to delay tumor progression and decrease invasion and metastatic spread leading to an improved prognostic outcome.

Reduction of metastasis, cell invasion, and adhesion in mouse osteosarcoma by YM529/ONO-5920-induced blockade of the Ras/MEK/ERK and Ras/PI3K/Akt pathway

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

Tsubaki, Masanobu; Satou, Takao; Itoh, Tatsuki

Osteosarcoma is one of the most common primary malignant bone tumors in children and adolescents. Some patients continue to have a poor prognosis, because of the metastatic disease. YM529/ONO-5920 is a nitrogen-containing bisphosphonate that has been used for the treatment of osteoporosis. YM529/ONO-5920 has recently been reported to induce apoptosis in various tumors including osteosarcoma. However, the mode of metastasis suppression in osteosarcoma by YM529/ONO-5920 is unclear. In the present study, we investigated whether YM529/ONO-5920 inhibited tumor cell migration, invasion, adhesion, or metastasis in the LM8 mouse osteosarcoma cell line. We found that YM529/ONO-5920 significantly inhibited metastasis, cell migration, invasion,more » and adhesion at concentrations that did not have antiproliferative effects on LM8 cells. YM529/ONO-5920 also inhibited the mRNA expression and protein activities of matrix metalloproteinases (MMPs). In addition, YM529/ONO-5920 suppressed phosphorylated extracellular signal-regulated kinase 1/2 (ERK1/2) and the serine/threonine protein kinase B (Akt) by the inhibition of Ras prenylation. Moreover, U0126, a mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor, and LY294002, a phosphatidylinositol 3-kinase (PI3K) inhibitor, also inhibited LM8 cell migration, invasion, adhesion, and metastasis, as well as the mRNA expression and protein activities of MMP-1, MMP-2, MMP-9, and MT1-MMP. The results indicated that YM529/ONO-5920 suppressed the Ras/MEK/ERK and Ras/PI3K/Akt pathways, thereby inhibiting LM8 cell migration, invasion, adhesion, and metastasis. These findings suggest that YM529/ONO-5920 has potential clinical applications for the treatment of tumor cell metastasis in osteosarcoma. -- Highlights: ► We investigated whether YM529/ONO-5920 inhibited tumor metastasis in osteosarcoma. ► YM529/ONO-5920 inhibited metastasis, cell migration, invasion, and adhesion. ► YM529/ONO-5920 suppressed Ras signalings. ► YM529/ONO-5920 has potential clinical applications for the treatment in osteosarcoma.« less

Identification of single nucleotide polymorphisms of the PI3K-AKT-mTOR pathway as a risk factor of central nervous system metastasis in metastatic breast cancer.

PubMed

Le Rhun, Emilie; Bertrand, Nicolas; Dumont, Aurélie; Tresch, Emmanuelle; Le Deley, Marie-Cécile; Mailliez, Audrey; Preusser, Matthias; Weller, Michael; Revillion, Françoise; Bonneterre, Jacques

2017-12-01

The PI3K-AKT-mTOR pathway may be involved in the development of central nervous system (CNS) metastasis from breast cancer. Accordingly, herein we explored whether single nucleotide polymorphisms (SNPs) of this pathway are associated with altered risk of CNS metastasis formation in metastatic breast cancer patients. The GENEOM study (NCT00959556) included blood sample collection from breast cancer patients treated in the neoadjuvant, adjuvant or metastatic setting. We identified patients with CNS metastases for comparison with patients without CNS metastasis, defined as either absence of neurological symptoms or normal brain magnetic resonance imaging (MRI) before death or during 5-year follow-up. Eighty-eight SNPs of phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian (or mechanistic) target of rapamycin (mTOR) pathway genes were selected for analysis: AKT1 (17 SNPs), AKT2 (4), FGFR1 (2), mTOR (7), PDK1 (4), PI3KR1 (11), PI3KCA (20), PTEN (17), RPS6KB1 (6). Of 342 patients with metastases, 207 fulfilled the inclusion criteria: One-hundred-and-seven patients remained free of CNS metastases at last follow-up or date of death whereas 100 patients developed CNS metastases. Among clinical parameters, hormonal and human epidermal growth factor receptor-2 (HER2) status as well as vascular tumour emboli was associated with risk of CNS metastasis. Only PI3KR1-rs706716 was associated with CNS metastasis in univariate analysis after Bonferroni correction (p < 0.00085). Multivariate analysis showed associations between AKT1-rs3803304, AKT2-rs3730050, PDK1-rs11686903 and PI3KR1-rs706716 and CNS metastasis . PI3KR1-rs706716 may be associated with CNS metastasis in metastatic breast cancer patients and could be included in a predictive composite score to detect early CNS metastasis irrespective of breast cancer subtype. Copyright © 2017 Elsevier Ltd. All rights reserved.

[Survival after cutaneous metastasis: a study of 200 cases].

PubMed

Schoenlaub, P; Sarraux, A; Grosshans, E; Heid, E; Cribier, B

2001-12-01

Cutaneous metastatic disease is uncommon and the outcome after cutaneous metastasis has rarely been thoroughly studied. The objective of this work was to study the survival after diagnosis of cutaneous metastasis in a large series of patients and to evaluate survival according to the type of cancer. This retrospective study was conducted out in the Laboratoire d'Histo-pathologie Cutanée of Strasbourg. Between 1950 to 1996, 228 patients with cutaneous metastasis were diagnosed on the basis of typical histopathology, confirmed by two dermatopathologists. We excluded lymphoma or leukaemia with secondary skin involvement. Medical and demographic data were collected from hospital data, and the "Registre du Cancer du Bas-Rhin". The type of neoplasm, the time of diagnosis of primary cancer and the time of death (or survival at 12/31/1996) was established in 200 patients, 99 men and 101 women with a mean age 62.4 +/- 13 years. We found 64 cases of breast carcinoma, 36 cases of lung carcinoma, 31 cases of melanoma and 69 cases of other cancers. Long term actuarial survival after cutaneous metastasis was calculated using by the Kaplan-Meier method. The median survival after cutaneous metastasis was 6.5 months (mean 22.8 +/- 43.8 months). The mortality rate was 13 p. 100 at 1 month, 48 p. 100 at 6 months and 64.5 p. 100 at 12 months. Median survival was calculated according to the primary neoplasm: breast carcinoma: 13.8 months, melanoma: 13.5 months, lung carcinoma: 2.9 months (36 cases). The outcome of patients with cutaneous metastasis of lung carcinoma was worse than those with melanoma (p < 10(-4)) and breast cancer (p < 10(-4)). Survival after cutaneous metastasis of other cancers could not be compared because of the small size of the subgroups: median survival after cutaneous metastasis of non cutaneous squamous cell carcinoma of the head and neck: 8.8 months (5 cases), cutaneous squamous cell carcinoma: 6.5 months (12 cases), carcinoma of oesophagus: 4.7 months (2 cases), colo-rectal cancer: 4.4 months (9 cases), pancreatic cancer: 3.3 months (2 cases), stomach cancer: 1.2 months (7 cases) and liver and gall bladder carcinoma: < 1 month (3 cases). Survival beyond 10 years was observed in 9 patients: 3 melanoma, 2 breast cancers, 2 prostatic carcinomas, 1 larynx carcinoma and 1 cutaneous squamous cell carcinoma. This is the first study in which the survival after the occurrence of skin metastasis was systematically analysed in a large series of patients. It shows that half of patients with cutaneous metastasis die within the first 6 months after the diagnosis. Those cases due to lung carcinoma have the poorest prognosis.

Hypoxia and the extracellular matrix: drivers of tumour metastasis

PubMed Central

Gilkes, Daniele M.; Semenza, Gregg L.; Wirtz, Denis

2014-01-01

Of the deaths attributed to cancer, 90% are due to metastasis, and treatments that prevent or cure metastasis remain elusive. Emerging data indicate that hypoxia and the extracellular matrix (ECM) might have crucial roles in metastasis. During tumour evolution, changes in the composition and the overall content of the ECM reflect both its biophysical and biological properties and these strongly influence tumour and stromal cell properties, such as proliferation and motility. Originally thought of as independent contributors to metastatic spread, recent studies have established a direct link between hypoxia and the composition and the organization of the ECM, which suggests a new model in which multiple microenvironmental signals might converge to synergistically influence metastatic outcome. PMID:24827502

Estrogen Receptors in Breast and Bone: from Virtue of Remodeling to Vileness of Metastasis

PubMed Central

Bado, Igor; Gugala, Zbigniew; Fuqua, Suzanne A. W.; Zhang, Xiang H.-F.

2017-01-01

Bone metastasis is a prominent cause of morbidity and mortality in cancer. High rates of bone colonization in breast cancer, especially in the subtype expressing estrogen receptors (ERs), suggests tissue-specific proclivities for metastatic tumor formation. The mechanisms behind this subtype-specific organ-tropism remains largely elusive. Interestingly, as the major driver of ER+ breast cancer, ERs also play important roles in bone development and homeostasis. Thus, any agents targeting ER will also inevitably affect the microenvironment, i.e., the osteoblasts and osteoclasts. Yet, how such microenvironmental effects are integrated with direct therapeutic responses of cancer cells remain poorly understood. Recent findings on ER mutations, especially their enrichment in bone metastasis, raised even more provocative questions on the role of ER in cancer-bone interaction. In this review, we evaluate the importance of estrogen receptors (ERs) in bone metastasis and discuss new avenues of investigation for bone metastasis treatment based on current knowledge. PMID:28368409

Role of monocyte recruitment in hemangiosarcoma metastasis in dogs.

PubMed

Regan, D P; Escaffi, A; Coy, J; Kurihara, J; Dow, S W

2017-12-01

Canine hemangiosarcoma (HSA) is a highly malignant tumour associated with short survival times because of early and widespread metastasis. In humans and rodents, monocytes play key roles in promoting tumour metastasis through stimulating tumour cell extravasation, seeding, growth and angiogenesis. Therefore, we investigated the potential association between monocyte infiltration and tumour metastasis in HSA and other common canine tumours. Immunohistochemistry was used to quantify CD18 + monocytes within metastases. We found that HSA metastases had significantly greater numbers of CD18 + monocytes compared with metastases from other tumour types. HSA cells were the highest producers of the monocyte chemokine CCL2, and stimulated canine monocyte migration in a CCL2 dependent manner. These results are consistent with the hypothesis that overexpression of CCL2 and recruitment of large numbers of monocytes may explain in part the aggressive metastatic nature of canine HSA. Thus, therapies designed to block monocyte recruitment may be an effective adjuvant strategy for suppressing HSA metastasis in dogs. © 2016 John Wiley & Sons Ltd.

Epigenomic reprogramming during pancreatic cancer progression links anabolic glucose metabolism to distant metastasis.

PubMed

McDonald, Oliver G; Li, Xin; Saunders, Tyler; Tryggvadottir, Rakel; Mentch, Samantha J; Warmoes, Marc O; Word, Anna E; Carrer, Alessandro; Salz, Tal H; Natsume, Sonoko; Stauffer, Kimberly M; Makohon-Moore, Alvin; Zhong, Yi; Wu, Hao; Wellen, Kathryn E; Locasale, Jason W; Iacobuzio-Donahue, Christine A; Feinberg, Andrew P

2017-03-01

During the progression of pancreatic ductal adenocarcinoma (PDAC), heterogeneous subclonal populations emerge that drive primary tumor growth, regional spread, distant metastasis, and patient death. However, the genetics of metastases largely reflects that of the primary tumor in untreated patients, and PDAC driver mutations are shared by all subclones. This raises the possibility that an epigenetic process might operate during metastasis. Here we report large-scale reprogramming of chromatin modifications during the natural evolution of distant metastasis. Changes were targeted to thousands of large chromatin domains across the genome that collectively specified malignant traits, including euchromatin and large organized chromatin histone H3 lysine 9 (H3K9)-modified (LOCK) heterochromatin. Remarkably, distant metastases co-evolved a dependence on the oxidative branch of the pentose phosphate pathway (oxPPP), and oxPPP inhibition selectively reversed reprogrammed chromatin, malignant gene expression programs, and tumorigenesis. These findings suggest a model whereby linked metabolic-epigenetic programs are selected for enhanced tumorigenic fitness during the evolution of distant metastasis.

The Androgen-Regulated Protease TMPRSS2 Activates aProteolytic Cascade Involving Components of the Tumor Microenvironment and Promotes Prostate Cancer Metastasis

PubMed Central

Lucas, Jared M.; Heinlein, Cynthia; Kim, Tom; Hernandez, Susana A.; Malik, Muzdah S.; True, Lawrence D.; Morrissey, Colm; Corey, Eva; Montgomery, Bruce; Mostaghel, Elahe; Clegg, Nigel; Coleman, Ilsa; Brown, Christopher M.; Schneider, Eric L.; Craik, Charles; Simon, Julian; Bedalov, Tony; Nelson, Peter S.

2014-01-01

TMPRSS2 is an androgen-regulated cell surface serine protease expressed predominantly in prostate epithelium. TMPRSS2 is expressed highly in localized high-grade prostate cancers and in the majority of human prostate cancer metastasis. Through the generation of mouse models with a targeted deletion of Tmprss2, we demonstrate that the activity of this protease regulates cancer cell invasion and metastasis to distant organs. By screening combinatorial peptide libraries we identified a spectrum of TMPRSS2 substrates that include pro-hepatocyte growth factor (HGF). HGF activated by TMPRSS2 promoted c-Met receptor tyrosine kinase signaling, and initiated a pro-invasive EMT phenotype. Chemical library screens identified a potent bioavailable TMPRSS2 inhibitor that suppressed prostate cancer metastasis in vivo. Together, these findings provide a mechanistic link between androgen-regulated signaling programs and prostate cancer metastasis that operate via context-dependent interactions with extracellular constituents of the tumor microenvironment. PMID:25122198

Tumor-stroma interactions a trademark for metastasis.

PubMed

Morales, Monica; Planet, Evarist; Arnal-Estape, Anna; Pavlovic, Milica; Tarragona, Maria; Gomis, Roger R

2011-10-01

We aimed to unravel genes that are significantly associated with metastasis in order to identify functions that support disseminated disease. We identify genes associated with metastasis and verify its clinical correlations using publicly available primary tumor expression profile data sets. We used facilities in R and Bioconductor (GSEA). Specific data structures and functions were imported. Our results show that genes associated with metastasis in primary tumor enriched for pathways associated with immune infiltration or cytokine-cytokine receptor interaction. As an example, we focus on the enrichment of TGFBR2 and TGF|X A set of communication tools capital for tumor-stroma interactions that define metastasis to the lung and support bone colonization. We showed that tumor-stroma communication through cytokine-cytokine receptor interaction pathway is selected in primary tumors with high risk of relapse. High levels of these factors support systemic instigation of the far metastatic nest as well as local metastatic-specific functions that provide solid ground for metastatic development. Copyright © 2011 Elsevier Ltd. All rights reserved.

Long noncoding RNA DANCR promotes colorectal cancer proliferation and metastasis via miR-577 sponging.

PubMed

Wang, Yong; Lu, Zhi; Wang, Ningnin; Feng, Jianzhou; Zhang, Junjie; Luan, Lan; Zhao, Wei; Zeng, Xiandong

2018-05-01

Long non-coding RNAs (lncRNAs) play key roles in various malignant tumors, including colorectal cancer (CRC). Long non-coding RNA differentiation antagonizing non-protein coding RNA (DANCR) is overexpressed in CRC patients, but whether it affects CRC proliferation and metastasis via regulation of heat shock protein 27 (HSP27) remains unclear. In the present study, we found that DANCR was highly expressed and correlated with proliferation and metastasis in CRC. In addition, we demonstrated that DANCR and HSP27 were both targets of microRNA-577 (miR-577) and shared the same binding site. Furthermore, we revealed that DANCR promoted HSP27 expression and its mediation of proliferation/metastasis via miR-577 sponging. Finally, using an in vivo study, we confirmed that overexpression of DANCR promoted CRC tumor growth and liver metastasis. The present study demonstrated the function of DANCR in CRC and might provide a new target in the treatment of CRC.

Myogenic transcription factors regulate pro-metastatic miR-182.

PubMed

Dodd, R D; Sachdeva, M; Mito, J K; Eward, W C; Brigman, B E; Ma, Y; Dodd, L; Kim, Y; Lev, D; Kirsch, D G

2016-04-07

Approximately 30% of patients with soft-tissue sarcoma die from pulmonary metastases. The mechanisms that drive sarcoma metastasis are not well understood. Recently, we identified miR-182 as a driver of sarcoma metastasis in a primary mouse model of soft-tissue sarcoma. We also observed elevated miR-182 in a subset of primary human sarcomas that metastasized to the lungs. Here, we show that myogenic differentiation factors regulate miR-182 levels to contribute to metastasis in mouse models. We find that MyoD directly binds the miR-182 promoter to increase miR-182 expression. Furthermore, mechanistic studies revealed that Pax7 can promote sarcoma metastasis in vivo through MyoD-dependent regulation of pro-metastatic miR-182. Taken together, these results suggest that sarcoma metastasis can be partially controlled through Pax7/MyoD-dependent activation of miR-182 and provide insight into the role that myogenic transcription factors have in sarcoma progression.

Serpins promote cancer cell survival and vascular co-option in brain metastasis.

PubMed

Valiente, Manuel; Obenauf, Anna C; Jin, Xin; Chen, Qing; Zhang, Xiang H-F; Lee, Derek J; Chaft, Jamie E; Kris, Mark G; Huse, Jason T; Brogi, Edi; Massagué, Joan

2014-02-27

Brain metastasis is an ominous complication of cancer, yet most cancer cells that infiltrate the brain die of unknown causes. Here, we identify plasmin from the reactive brain stroma as a defense against metastatic invasion, and plasminogen activator (PA) inhibitory serpins in cancer cells as a shield against this defense. Plasmin suppresses brain metastasis in two ways: by converting membrane-bound astrocytic FasL into a paracrine death signal for cancer cells, and by inactivating the axon pathfinding molecule L1CAM, which metastatic cells express for spreading along brain capillaries and for metastatic outgrowth. Brain metastatic cells from lung cancer and breast cancer express high levels of anti-PA serpins, including neuroserpin and serpin B2, to prevent plasmin generation and its metastasis-suppressive effects. By protecting cancer cells from death signals and fostering vascular co-option, anti-PA serpins provide a unifying mechanism for the initiation of brain metastasis in lung and breast cancers. Copyright © 2014 Elsevier Inc. All rights reserved.

The Italian cross-sectional survey of the management of bone metastasis: ZeTa study

PubMed Central

Santini, Daniele; Bertoldo, Francesco; Dell'Aquila, Emanuela; Cecchini, Isabella; Fregosi, Stefania; Bortolussi, Paolo

2012-01-01

Background Several studies have emphasized the importance of the maintenance of bone health in a comprehensive cancer care. However, no survey about approach to bone metastasis care is currently available. The ZeTa study provides a picture of the Italian oncologists' therapeutics habits in this area, in a real clinical-practice scenario. Design This study was based on online questionnaire-based interviews to Italian oncologists that included 145 questions. The aim was to collect information on the treatment of bone metastasis, the current use of bisphosphonates, the awareness of guidelines and the concerns about ONJ, the use of vitamin D supplementation. Results 445 oncologists were contacted, 283 agreed to participate. The results show that the current management of bone metastasis is still sub-optimal, as the recommendations from current clinical guidelines are not completely followed by all specialists. Conclusions This survey highlights the urgent need to improve management of bone metastasis in cancer patients. PMID:26909253

Uterine cervical cancer with brain metastasis as the initial site of presentation.

PubMed

Sato, Yumi; Tanaka, Kei; Kobayashi, Yoichi; Shibuya, Hiromi; Nishigaya, Yoshiko; Momomura, Mai; Matsumoto, Hironori; Iwashita, Mitsutoshi

2015-07-01

Brain metastasis from uterine cervical cancer is rare, with an incidence of 0.5%, and usually occurs late in the course of the disease. We report a case of uterine cervical cancer with brain metastasis as the initial site of presentation. A 50-year-old woman with headache, vertigo, amnesia and loss of appetite was admitted for persistent vomiting. Contrast enhanced computed tomography showed a solitary right frontal cerebral lesion with ring enhancement and uterine cervical tumor. She was diagnosed with uterine cervical squamous cell carcinoma with parametrium invasion and no other distant affected organs were detected. The cerebral lesion was surgically removed and pathologically proved to be metastasis of uterine cervical squamous cell carcinoma. The patient underwent concurrent chemoradiotherapy, followed by cerebral radiation therapy, but multiple metastases to the liver and lung developed and the patient died 7 months after diagnosis of brain metastasis. © 2015 The Authors. Journal of Obstetrics and Gynaecology Research © 2015 Japan Society of Obstetrics and Gynecology.

Multi-targeted inhibition of tumor growth and lung metastasis by redox-sensitive shell crosslinked micelles loading disulfiram

NASA Astrophysics Data System (ADS)

Duan, Xiaopin; Xiao, Jisheng; Yin, Qi; Zhang, Zhiwen; Yu, Haijun; Mao, Shirui; Li, Yaping

2014-03-01

Metastasis, the main cause of cancer related deaths, remains the greatest challenge in cancer treatment. Disulfiram (DSF), which has multi-targeted anti-tumor activity, was encapsulated into redox-sensitive shell crosslinked micelles to achieve intracellular targeted delivery and finally inhibit tumor growth and metastasis. The crosslinked micelles demonstrated good stability in circulation and specifically released DSF under a reductive environment that mimicked the intracellular conditions of tumor cells. As a result, the DSF-loaded redox-sensitive shell crosslinked micelles (DCMs) dramatically inhibited cell proliferation, induced cell apoptosis and suppressed cell invasion, as well as impairing tube formation of HMEC-1 cells. In addition, the DCMs could accumulate in tumor tissue and stay there for a long time, thereby causing significant inhibition of 4T1 tumor growth and marked prevention in lung metastasis of 4T1 tumors. These results suggested that DCMs could be a promising delivery system in inhibiting the growth and metastasis of breast cancer.

[In-transit metastasis in melanoma: Efficacy of topical imiquimod combined with carbon dioxide laser or with electrocautery].

PubMed

Elfatoiki, F-Z; Longvert, C; Clerici, T; Bourgault-Villada, I; Roudier-Pujol, C; Vasseur, E; Saiag, P

2014-02-01

In-transit metastases in cutaneous melanoma are common and difficult to manage. Therapy is mainly palliative. Use of topical imiquimod has been assessed for surface metastases. We report on four patients with cutaneous melanoma metastases treated with topical imiquimod associated with carbon dioxide laser in the first two patients and with electrocoagulation in the two others. For two patients, we noted complete regression of the lesions after 15 and 18 months. For the two others, treatment was stopped after 9 to 10 months because of progression of subcutaneous metastasis and distant metastasis. Topical imiquimod is an alternative treatment used in superficial in-transit metastasis of melanoma. Its use as a monotherapy is sometimes ineffective. We elected to use combined pre-treatment with carbon dioxide laser or electrocoagulation in order to potentiate the action of imiquimod. This simple and inexpensive therapeutic strategy constitutes a palliative treatment that can allow prolonged local control of cutaneous metastasis. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Gastric tumor from metastasis of breast cancer.

PubMed

Yamamoto, D; Yoshida, H; Sumida, K; Ueyama, Y; Kanematsu, S; Shoji, T; Sueoka, N; Tanaka, K; Tsubota, Y; Kon, M

2010-09-01

Metastatic tumours of the stomach have been reported to result from various types of cancer. Among them, gastric metastasis from breast cancer has been recognised in 0.3-18% patients (1-4). Here, a rare case of metastatic gastric tumour derived from breast carcinoma is reported. Gastric endoscopy confirmed a large, friable mass (approximately 5 cm in diameter) in the upper part of the gastric body. The mass within the stomach was difficult to distinguish from primary gastric cancer, although biopsies of this lesion revealed the characteristics of adenocarcinoma. In addition, immunohistochemistry showed the positive expression of mammaglobin. Taken together, the evidence pointed to metastasis of breast cancer to the stomach. The patient was treated with hormonal therapy (letrozole), and the size of the metastasis in the stomach was markedly reduced. Therefore, a gastric metastasis from breast cancer was diagnosed successfully using immunohistochemistry and unnecessary surgery was avoided. In conclusion, although gastric metastatic tumours derived from breast carcinoma are rare, their accurate pre-operative diagnosis and appropriate systemic treatment is essential.

The seed and soil hypothesis revisited - the role of tumor-stroma interactions in metastasis to different organs

PubMed Central

Langley, Robert R.; Fidler, Isaiah J.

2011-01-01

The fact that certain tumors exhibit a predilection for metastasis to specific organs has been recognized for well over a century now. An extensive body of clinical data and experimental research has confirmed Stephen Paget's original “seed and soil” hypothesis that proposed the organ-preference patterns of tumor metastasis are the product of favorable interactions between metastatic tumor cells (the “seed”) and their organ microenvironment (the “soil”). Indeed, many of first-line therapeutic regimens currently in use for the treatment of human cancer are designed to target cancer cells (such as chemotherapy) and also to modulate the tumor microenvironment (such as anti-angiogenic therapy). While some types of tumors are capable of forming metastases in virtually every organ in the body, the most frequent target organs of metastasis are bone, brain, liver, and the lung. In this review, we discuss how tumor-stromal interactions influence metastasis in each of these organs. PMID:21365651

Metastatic melanoma to the pituitary gland.

PubMed

McCutcheon, Ian E; Waguespack, Steven G; Fuller, Gregory N; Couldwell, William T

2007-08-01

Metastasis to the pituitary gland is unusual, and occurs most often in patients with carcinomas of the breast or lung. Despite its propensity for spread to the brain, metastatic melanoma has rarely been described within the sella. We report two cases of malignant melanoma pathologically confirmed within the pituitary, both metastatic from a primary site on the chest wall. In each patient, transsphenoidal resection of the tumor was incomplete and each received local radiotherapy after surgery. One patient recurred quickly and developed brain metastasis as well. He died four months after resection of the pituitary metastasis, but the second patient survived six months without recurrence. As intrasellar metastasis portends widespread systemic disease and may be synchronous with parenchymal brain metastasis, survival in such patients is limited regardless of adjunctive therapy. Such cases are likely to arise more commonly in future due to the increasing incidence of melanoma. Identifying them by imaging alone is difficult due to inconsistent signal characteristics on MRI (as shown by these cases) and the confusion introduced by any associated intratumoral hemorrhage.

Targeting tumor cell motility to prevent metastasis

PubMed Central

Palmer, Trenis D.; Ashby, William J.; Lewis, John D.; Zijlstra, Andries

2011-01-01

Mortality and morbidity in patients with solid tumors invariably results from the disruption of normal biological function caused by disseminating tumor cells. Tumor cell migration is under intense investigation as the underlying cause of cancer metastasis. The need for tumor cell motility in the progression of metastasis has been established experimentally and is supported empirically by basic and clinical research implicating a large collection of migration-related genes. However, there are few clinical interventions designed to specifically target the motility of tumor cells and adjuvant therapy to specifically prevent cancer cell dissemination is severely limited. In an attempt to define motility targets suitable for treating metastasis, we have parsed the molecular determinants of tumor cell motility into five underlying principles including cell autonomous ability, soluble communication, cell-cell adhesion, cell-matrix adhesion, and integrating these determinants of migration on molecular scaffolds. The current challenge is to implement meaningful and sustainable inhibition of metastasis by developing clinically viable disruption of molecular targets that control these fundamental capabilities. PMID:21664937

The TWIST/Mi2/NuRD protein complex and its essential role in cancer metastasis.

PubMed

Fu, Junjiang; Qin, Li; He, Tao; Qin, Jun; Hong, Jun; Wong, Jiemin; Liao, Lan; Xu, Jianming

2011-02-01

The epithelial-mesenchymal transition (EMT) converts epithelial tumor cells into invasive and metastatic cancer cells, leading to mortality in cancer patients. Although TWIST is a master regulator of EMT and metastasis for breast and other cancers, the mechanisms responsible for TWIST-mediated gene transcription remain unknown. In this study, purification and characterization of the TWIST protein complex revealed that TWIST interacts with several components of the Mi2/nucleosome remodeling and deacetylase (Mi2/NuRD) complex, MTA2, RbAp46, Mi2 and HDAC2, and recruits them to the proximal regions of the E-cadherin promoter for transcriptional repression. Depletion of these TWIST complex components from cancer cell lines that depend on TWIST for metastasis efficiently suppresses cell migration and invasion in culture and lung metastasis in mice. These findings not only provide novel mechanistic and functional links between TWIST and the Mi2/NuRD complex but also establish new essential roles for the components of Mi2/NuRD complex in cancer metastasis.

Hepatectomy As A First Choice Treatment For Liver Metastasis From Gastric Cancer: A Single Center Experience.

PubMed

Sakamoto, Hirohiko; Amikura, Katsumi; Tanaka, Yoichi; Kawashima, Yoshiyuki

2014-05-01

Indication of hepatectomy for liver metastases from gastric cancer (LMGC) is still controversial despite many papers favoring surgery. The aim of this study is to claim that we should accept hepatectomy as first choice treatment for LMGC. It is important to have a consensus on this matter for surgeons to treat LMGC properly. Fifty three patients undergoing hepatectomy for LMGC from 1990 through 2010 were retrospectively analysed for survival and prognostic factors. Analyses were made on size, multiplicity, synchronicity and positive surgical margin as liver metastasis factors. Serosal invasion, node metastasis, histological differentiation and UICC stage were analysed as primary site factors. Multivariate analysis was performed for those positive for univariate analysis. Cumulative 5 year survival rate was 27%. Multiplicity, positive margin and node metastasis (N > 2) yielded significant difference on univariate analysis. On multivariate analysis multiplicity and node metastasis (N > 2) were significant. Hepatectomy for LMGC is potentially curative and should be regarded as first choice. Solitary and N < 3 are good prognostic factors.

The mRNA-edited form of GABRA3 suppresses GABRA3-mediated Akt activation and breast cancer metastasis

PubMed Central

Gumireddy, Kiranmai; Li, Anping; Kossenkov, Andrew V.; Sakurai, Masayuki; Yan, Jinchun; Li, Yan; Xu, Hua; Wang, Jian; Zhang, Paul J.; Zhang, Lin; Showe, Louise C.; Nishikura, Kazuko; Huang, Qihong

2016-01-01

Metastasis is a critical event affecting breast cancer patient survival. To identify molecules contributing to the metastatic process, we analysed The Cancer Genome Atlas (TCGA) breast cancer data and identified 41 genes whose expression is inversely correlated with survival. Here we show that GABAA receptor alpha3 (Gabra3), normally exclusively expressed in adult brain, is also expressed in breast cancer, with high expression of Gabra3 being inversely correlated with breast cancer survival. We demonstrate that Gabra3 activates the AKT pathway to promote breast cancer cell migration, invasion and metastasis. Importantly, we find an A-to-I RNA-edited form of Gabra3 only in non-invasive breast cancers and show that edited Gabra3 suppresses breast cancer cell invasion and metastasis. A-to-I-edited Gabra3 has reduced cell surface expression and suppresses the activation of AKT required for cell migration and invasion. Our study demonstrates a significant role for mRNA-edited Gabra3 in breast cancer metastasis. PMID:26869349

The mRNA-edited form of GABRA3 suppresses GABRA3-mediated Akt activation and breast cancer metastasis.

PubMed

Gumireddy, Kiranmai; Li, Anping; Kossenkov, Andrew V; Sakurai, Masayuki; Yan, Jinchun; Li, Yan; Xu, Hua; Wang, Jian; Zhang, Paul J; Zhang, Lin; Showe, Louise C; Nishikura, Kazuko; Huang, Qihong

2016-02-12

Metastasis is a critical event affecting breast cancer patient survival. To identify molecules contributing to the metastatic process, we analysed The Cancer Genome Atlas (TCGA) breast cancer data and identified 41 genes whose expression is inversely correlated with survival. Here we show that GABAA receptor alpha3 (Gabra3), normally exclusively expressed in adult brain, is also expressed in breast cancer, with high expression of Gabra3 being inversely correlated with breast cancer survival. We demonstrate that Gabra3 activates the AKT pathway to promote breast cancer cell migration, invasion and metastasis. Importantly, we find an A-to-I RNA-edited form of Gabra3 only in non-invasive breast cancers and show that edited Gabra3 suppresses breast cancer cell invasion and metastasis. A-to-I-edited Gabra3 has reduced cell surface expression and suppresses the activation of AKT required for cell migration and invasion. Our study demonstrates a significant role for mRNA-edited Gabra3 in breast cancer metastasis.

Nicaraven reduces cancer metastasis to irradiated lungs by decreasing CCL8 and macrophage recruitment.

PubMed

Yan, Chen; Luo, Lan; Urata, Yoshishige; Goto, Shinji; Li, Tao-Sheng

2018-04-01

Radiotherapy for cancer patients damages normal tissues, thereby inducing an inflammatory response and promoting cancer metastasis. We investigated whether nicaraven, a compound with radioprotective and anti-inflammatory properties, could attenuate radiation-induced cancer metastasis to the lungs of mice. Nicaraven and amifostine, another commercial radioprotective agent, had limited effects on both the radiosensitivity of Lewis lung carcinoma cells in vitro and radiation-induced tumor growth inhibition in vivo. Using experimental and spontaneous metastasis models, we confirmed that thorax irradiation with 5 Gy X-rays dramatically increased the number of tumors in the lungs. Interestingly, the number of tumors in the lungs was significantly reduced by administering nicaraven but not by administering amifostine daily after radiation exposure. Furthermore, nicaraven administration effectively inhibited CCL8 expression and macrophage recruitment in the lungs 1 day after thorax irradiation. Our data suggest that nicaraven attenuates radiation-induced lung metastasis, likely by regulating the inflammatory response after radiation exposure. Copyright © 2018 Elsevier B.V. All rights reserved.

Arsenite-loaded nanoparticles inhibit the invasion and metastasis of a hepatocellular carcinoma: in vitro and in vivo study

NASA Astrophysics Data System (ADS)

Chi, Xiaoqin; Yin, Zhenyu; Jin, Jianbin; Li, Hui; Zhou, Jian; Zhao, Zhenghuan; Zhang, Sheng; Zhao, Wenxiu; Xie, Chengrong; Li, Jie; Feng, Min; Lin, Hongyu; Wang, Xiaomin; Gao, Jinhao

2017-11-01

Postoperative recurrence and metastasis are the major problems for the current treatment of hepatocellular carcinomas (HCC) in the clinic, including hepatectomy and liver transplantation. Here, we report that arsentic-loaded nanoparticles (ALNPs) are able to reduce the invasion of HCC cells in vitro, and, more importantly, can strongly suppress the invasion and metastasis of HCC in vivo without adverse side effects. Compared to free drug arsenic trioxide , ALNPs can deliver the drug into cancer cells more efficiently, destroy the structure of microtubules and reduce the aggregation of microfilaments in cell membranes more significantly. Furthermore, our results also reveal that tumor cells in murine blood were reduced remarkably after intravenous injection of ALNPs, indicating that this nano-drug may efficiently kill circulating tumor cells in vivo. In conclusion, our nano-drug ALNPs have great potential for the suppression of metastasis of HCC, which may open up a new avenue for the effective treatment of HCC without metastasis and recurrence.

[A Curatively Resected Case of Lateral Lymph Node Metastasis Five-Years after Initial Surgery for Rectal Cancer].

PubMed

Miura, Takayuki; Tsunenari, Takazumi; Sasaki, Tsuyoshi; Yokoyama, Tadaaki; Fukuhara, Kenji

2017-11-01

A 74-year-old male had undergone laparoscopic abdominoperineal resection for lower rectal cancer in July 2009. The pathological diagnosis was T2, N0, M0, pStage I (TNM 7th). Because of pathological venous invasion, adjuvant chemotherapy with Tegafur-uracil(UFT)plus Leucovorin for a year was performed. A CT examination revealed slowly growing peripheral right internal iliaclymph node. PET-CT demonstrated a 20mm right lateral lymph node(LLN)metastasis without other distant metastases. On diagnosis of solitary LLN metastasis of rectal cancer, the patient underwent surgical lymph node resection in September 2014. The pathological diagnosis was lymph node metastasis from rectal cancer. Subsequently, the patient received mFOLFOX6 adjuvant chemotherapy for 6 months. The patient remains alive without any recurrence 31 months after the second surgical treatment. lt is important to consider that LLN metastasis of Stage I rectal cancer might still occur a long time after the curative operation.

Small cell lung cancer with metastasis to the thyroid in a patient with toxic multinodular goiter.

PubMed

Ozgu, Eylem Sercan; Gen, Ramazan; Ilvan, Ahmet; Ozge, Cengiz; Polat, Ayşe; Vayisoglu, Yusuf

2012-11-01

Thyroid metastasis of lung cancer is rarely observed in clinical practice. The primary cancers which metastasize to the thyroid gland are mostly renal cell carcinoma, lung cancer, and breast cancer. Transient destructive thyrotoxicosis is caused by massive metastasis of extrathyroid tumors. We herein present a case report of a patient with small cell carcinoma of lung with metastasis to the thyroid and thyrotoxicosis due to toxic multinodular goiter. A 66-year-old man complained of swelling around the right side of the neck, dyspnea, progressive weight loss, and palpitation starting since 3 months before his admission. The patient was diagnosed with small cell carcinoma of lung with metastasis to the thyroid and thyrotoxicosis due to toxic multinodular goiter. The case report presented here illustrates the challenge of making a definitive and adequate diagnosis, particularly if the patient presents with 2 potential causes of thyrotoxicosis. Thyroid scintigraphy is an important tool for differential diagnosis of thyrotoxicosis.

Characteristics of metastasis in the breast from extramammary malignancies.

PubMed

Lee, Se Kyung; Kim, Wan Wook; Kim, Sung Hoon; Hur, Sung Mo; Kim, Sangmin; Choi, Jae Hyuck; Cho, Eun Yoon; Han, Soo Yeon; Hahn, Boo-Kyung; Choe, Jun-Ho; Kim, Jung-Han; Kim, Jee Soo; Lee, Jeong Eon; Nam, Seok Jin; Yang, Jung-Hyun

2010-02-01

Breast metastasis from extramammary neoplasm is rare. We present the cases of metastasis to the breast after review of results in one institute and we want to show the difference of previous report. The surgical and pathology databases of Samsung Medical Center from November 1994 to March 2009 were investigated to identify all patients with a diagnosis of metastasis to the breast. Thirty-three patients with breast metastases from extramammary neoplasm were studied. Gastric carcinoma was most common metastatic origin in this study. There were four cases with microcalcifications in their metastatic lesions. This is the first report of microcalcification of metastatic lesions to the breast from hepatocellular carcinoma and gastric cancer. Pathologic examination and considering known clinical history may be helpful to differentiate the primary breast cancer and metastatic cancer. Metastasis to the breast from an extramammary neoplasm usually indicates disseminated metastatic disease and a poor prognosis. An accurate diagnosis of breast metastases, differentiating primary from metastatic breast carcinoma, is important for proper management.

Contralateral breast metastasis from pulmonary adenocarcinoma: two cases report and literature review

PubMed Central

Ji, Fang-Fang; Gao, Peng; Wang, Ji-Gang; Zhao, Jie

2012-01-01

Carcinoma metastatic to breast from extra-mammary malignancy is rare and only accounts for 0.4-1.3% of all breast cancer. Two rare cases of single breast metastasis from pulmonary adenocarcinoma were reported here with a brief review of the pertinent literature. The only complaint of the these two female patients was painless breast mass found recently. Most breast metastasis previously reported are present in the upper outer quadrant, however, in our study, one case was found to be located in the lower inner quadrant and the other in the upper inner quadrant. Tumor cells from breast biopsy were immune-positive for thyroid transcription factor-1. The two patients survived 5 and 8 months, respectively, following the diagnosis of both the primary lung tumor and the breast metastasis. Breast metastasis from lung adenocarcinoma is rare but does exist. The awareness of this possibility may help to differentiate the tumor from primary breast carcinoma. Clinical history and immunohistochemical studies are essential to reach the final diagnosis. PMID:22934141

Paraganglioma with intracranial metastasis: a case report and review of the literature.

PubMed

Cai, Peihao; Mahta, Ali; Kim, Ryan Y; Kesari, Santosh

2012-10-01

Paragangliomas are rare neuroendocrine tumors of neural crest origin. They are mostly benign, however; malignant tumors with aggressive behavior and distant metastasis can also occur. Intracranial involvement is extremely rare and has been sporadically reported in the literature. Here we report a case who presented with progressive neurologic deficits due to multiple intracranial lesions found to be metastasis from an occult retroperitoneal malignant paraganglioma.

Jejunal obstruction caused by metastasis from an undiagnosed breast cancer: a case report.

PubMed

Calò, Pietro Giorgio; Fanni, Daniela; Ionta, Maria Teresa; Medas, Fabio; Faa, Gavino; Atzori, Francesco

2012-01-01

Solitary metastasis from breast carcinoma to the gastrointestinal tract is an uncommon finding. We describe a female patient with a solitary jejunal metastasis from an undiagnosed breast cancer who presented to the emergency department with a bowel obstruction. Abdominal surgery was performed, revealing a jejunal stenosis from a metastatic lobular carcinoma. The primary tumor in the left breast was subsequently diagnosed and surgically removed.

Mint3 in bone marrow-derived cells promotes lung metastasis in breast cancer model mice.

PubMed

Hara, Toshiro; Murakami, Yoshinori; Seiki, Motoharu; Sakamoto, Takeharu

2017-08-26

Breast cancer is one of the most common cancers in women in the world. Although breast cancer is well treatable at the early stage, patients with distant metastases show a poor prognosis. Data from recent studies using transplantation models indicate that Mint3/APBA3 might promote breast cancer malignancy. However, whether Mint3 indeed contributes to tumor development, progression, or metastasis in vivo remains unclear. To address this, here we examined whether Mint3 depletion affects tumor malignancy in MMTV-PyMT breast cancer model mice. In MMTV-PyMT mice, Mint3 depletion did not affect tumor onset and tumor growth, but attenuated lung metastases. Experimental lung metastasis of breast cancer Met-1 cells derived from MMTV-PyMT mice also decreased in Mint3-depleted mice, indicating that host Mint3 expression affected lung metastasis of MMTV-PyMT-derived breast cancer cells. Further bone marrow transplant experiments revealed that Mint3 in bone marrow-derived cells promoted lung metastasis in MMTV-PyMT mice. Thus, targeting Mint3 in bone marrow-derived cells might be a good strategy for preventing metastasis and improving the prognosis of breast cancer patients. Copyright © 2017 Elsevier Inc. All rights reserved.

STAT3 labels a subpopulation of reactive astrocytes required for brain metastasis.

PubMed

Priego, Neibla; Zhu, Lucía; Monteiro, Cátia; Mulders, Manon; Wasilewski, David; Bindeman, Wendy; Doglio, Laura; Martínez, Liliana; Martínez-Saez, Elena; Cajal, Santiago Ramón Y; Megías, Diego; Hernández-Encinas, Elena; Blanco-Aparicio, Carmen; Martínez, Lola; Zarzuela, Eduardo; Muñoz, Javier; Fustero-Torres, Coral; Pineiro, Elena; Hernández-Laín, Aurelio; Bertero, Luca; Poli, Valeria; Sánchez-Martínez, Melchor; Menendez, Javier A; Soffietti, Riccardo; Bosch-Barrera, Joaquim; Valiente, Manuel

2018-06-11

The brain microenvironment imposes a particularly intense selective pressure on metastasis-initiating cells, but successful metastases bypass this control through mechanisms that are poorly understood. Reactive astrocytes are key components of this microenvironment that confine brain metastasis without infiltrating the lesion. Here, we describe that brain metastatic cells induce and maintain the co-option of a pro-metastatic program driven by signal transducer and activator of transcription 3 (STAT3) in a subpopulation of reactive astrocytes surrounding metastatic lesions. These reactive astrocytes benefit metastatic cells by their modulatory effect on the innate and acquired immune system. In patients, active STAT3 in reactive astrocytes correlates with reduced survival from diagnosis of intracranial metastases. Blocking STAT3 signaling in reactive astrocytes reduces experimental brain metastasis from different primary tumor sources, even at advanced stages of colonization. We also show that a safe and orally bioavailable treatment that inhibits STAT3 exhibits significant antitumor effects in patients with advanced systemic disease that included brain metastasis. Responses to this therapy were notable in the central nervous system, where several complete responses were achieved. Given that brain metastasis causes substantial morbidity and mortality, our results identify a novel treatment for increasing survival in patients with secondary brain tumors.

CXCR4 expression in papillary thyroid carcinoma: induction by nitric oxide and correlation with lymph node metastasis.

PubMed

Yasuoka, Hironao; Kodama, Rieko; Hirokawa, Mitsuyoshi; Takamura, Yuuki; Miyauchi, Akira; Sanke, Tokio; Nakamura, Yasushi

2008-09-30

Metastasis to regional lymph nodes is a common step in the progression of cancer. Recent evidence suggests that tumor production of CXCR4 promotes lymph node metastasis. Nitric oxide (NO) may also increase metastatic ability in human cancers. Nitrite/nitrate levels and functional CXCR4 expression were assessed in K1 and B-CPAP papillary thyroid carcinoma (PTC) cells after induction and/or inhibition of NO synthesis. CXCR4 expression was also analyzed in primary human PTC. The relationship between nitrotyrosine levels, which are a biomarker for peroxynitrate formation from NO in vivo, CXCR4 expression, and lymph node status was also analyzed. Production of nitrite/nitrate and functional CXCR4 expression in both cell lines was increased by treatment with the NO donor DETA NONOate. The NOS inhibitor L-NAME eliminated this increase. Positive CXCR4 immunostaining was observed in 60.7% (34/56) of PTCs. CXCR4 expression was significantly correlated with nitrotyrosine levels and lymph node metastasis in human PTC. Our data indicate that NO stimulates CXCR4 expression in vitro. Formation of the NO biomarker nitrotyrosine was also correlated with CXCR4 expression and lymph node metastasis in human PTC. NO may induce lymph node metastasis via CXCR4 induction in papillary thyroid carcinoma.

CXCR4 expression in papillary thyroid carcinoma: induction by nitric oxide and correlation with lymph node metastasis

PubMed Central

Yasuoka, Hironao; Kodama, Rieko; Hirokawa, Mitsuyoshi; Takamura, Yuuki; Miyauchi, Akira; Sanke, Tokio; Nakamura, Yasushi

2008-01-01

Background Metastasis to regional lymph nodes is a common step in the progression of cancer. Recent evidence suggests that tumor production of CXCR4 promotes lymph node metastasis. Nitric oxide (NO) may also increase metastatic ability in human cancers. Methods Nitrite/nitrate levels and functional CXCR4 expression were assessed in K1 and B-CPAP papillary thyroid carcinoma (PTC) cells after induction and/or inhibition of NO synthesis. CXCR4 expression was also analyzed in primary human PTC. The relationship between nitrotyrosine levels, which are a biomarker for peroxynitrate formation from NO in vivo, CXCR4 expression, and lymph node status was also analyzed. Results Production of nitrite/nitrate and functional CXCR4 expression in both cell lines was increased by treatment with the NO donor DETA NONOate. The NOS inhibitor L-NAME eliminated this increase. Positive CXCR4 immunostaining was observed in 60.7% (34/56) of PTCs. CXCR4 expression was significantly correlated with nitrotyrosine levels and lymph node metastasis in human PTC. Conclusion Our data indicate that NO stimulates CXCR4 expression in vitro. Formation of the NO biomarker nitrotyrosine was also correlated with CXCR4 expression and lymph node metastasis in human PTC. NO may induce lymph node metastasis via CXCR4 induction in papillary thyroid carcinoma. PMID:18826577

High-level SLP-2 expression and HER-2/neu protein expression are associated with decreased breast cancer patient survival.

PubMed

Cao, Wenfeng; Zhang, Bin; Liu, Yanxue; Li, Hongtao; Zhang, Shiwu; Fu, Li; Niu, Yun; Ning, Liansheng; Cao, Xuchen; Liu, Zhihua; Sun, Baocun

2007-09-01

There is sufficient evidence that human stomatin-like protein 2 (SLP-2) is a novel cancer-related gene. Its protein is overexpressed in many human cancers. SLP-2 can contribute to the promotion of cell growth, cell adhesion, and tumorigenesis in esophageal squamous cell carcinoma and lymph node metastasis in laryngeal squamous cell carcinoma. Immunohistochemical detection of SLP-2, estrogen and progesterone receptors, and HER-2/neu were performed on 263 cases of primary invasive breast cancer with a tissue microarray. Of 263 cases, 138 (52.5%) showed high expression of SLP-2 protein, and 125 (47.5%) showed low or absent expression. In addition, there were significant positive associations between tumor stage and size (P = .020), lymph node metastasis (P < .001), clinical stage (P < .001), distant metastasis (P = .002), and HER-2/neu protein expression (P = .037) and high-level SLP-2 expression. High-level SLP-2 expression was associated with decreased overall survival (P = .011) and was more often found in patients with tumors larger than 20 mm, lymph node metastasis, advanced clinical stage, distant metastasis, and HER-2/neu protein-positive expression. More important, lymph node metastasis, HER-2/neu-positive expression, and high-level SLP-2 expression were associated with significantly decreased survival.

Tumor-associated macrophages drive spheroid formation during early transcoelomic metastasis of ovarian cancer

PubMed Central

Yin, Mingzhu; Li, Xia; Tan, Shu; Zhou, Huanjiao Jenny; Ji, Weidong; Bellone, Stefania; Xu, Xiaocao; Zhang, Haifeng; Santin, Alessandro D.; Lou, Ge

2016-01-01

Tumor-associated macrophages (TAMs) can influence ovarian cancer growth, migration, and metastasis, but the detailed mechanisms underlying ovarian cancer metastasis remain unclear. Here, we have shown a strong correlation between TAM-associated spheroids and the clinical pathology of ovarian cancer. Further, we have determined that TAMs promote spheroid formation and tumor growth at early stages of transcoelomic metastasis in an established mouse model for epithelial ovarian cancer. M2 macrophage–like TAMs were localized in the center of spheroids and secreted EGF, which upregulated αMβ2 integrin on TAMs and ICAM-1 on tumor cells to promote association between tumor cells and TAM. Moreover, EGF secreted by TAMs activated EGFR on tumor cells, which in turn upregulated VEGF/VEGFR signaling in surrounding tumor cells to support tumor cell proliferation and migration. Pharmacological blockade of EGFR or antibody neutralization of ICAM-1 in TAMs blunted spheroid formation and ovarian cancer progression in mouse models. These findings suggest that EGF secreted from TAMs plays a critical role in promoting early transcoelomic metastasis of ovarian cancer. As transcoelomic metastasis is also associated with many other cancers, such as pancreatic and colon cancers, our findings uncover a mechanism for TAM-mediated spheroid formation and provide a potential target for the treatment of ovarian cancer and other transcoelomic metastatic cancers. PMID:27721235

Possible reduction of hepatoma formation by Smmu 7721 cells in SCID mice and metastasis formation by B16F10 melanoma cells in C57BL/6 mice by Agaricus blazei murill extract.

PubMed

Wu, Ming-Fang; Lu, Hsu-Feng; Hsu, Yu-Ming; Tang, Ming-Chu; Chen, Hsueh-Chin; Lee, Ching-Sung; Yang, Yi-Yuan; Yeh, Ming-Yang; Chung, Hsiung-Kwang; Huang, Yi-Ping; Wu, Chih-Chung; Chung, Jing-Gung

2011-01-01

Agaricus blazei Murill extract (ABM) has been reported to possess antitumor effects. In this study, the role of ABM in tumor growth and metastasis in vivo was evaluated in experimental Smmu 7721 hepatoma cells in severe combined immunodeficiency (SCID) mice and B16F10 melanoma cells lung metastasis in C57BL/6 mice. For the tumor growth model, the size of the liver tumor mass was about 10 mm to 20 mm in the control group. In comparison with the control group, the tumor mass seem to grow slowly with ABM treatment, especially at the high dose. For the tumor metastasis model, after a six-week treatment, the survival rates of B6 mice were 0%, 30%, 10% and 50% for control group, low, median and high concentration ABM treatment groups, respectively. The survival rate showed that pretreatment of C57BL/6 (B6) mice with ABM lengthened their lifespan after tumor cell inoculation, which supports the notion that ABM successfully reduced lung metastasis formation by B16F10 melanoma cells. The treatment effect was dependent on the concentration of ABM for tumor growth and metastasis in these models.

IRX1 hypomethylation promotes osteosarcoma metastasis via induction of CXCL14/NF-κB signaling

PubMed Central

Lu, Jinchang; Song, Guohui; Tang, Qinglian; Zou, Changye; Han, Feng; Zhao, Zhiqiang; Yong, Bicheng; Yin, Junqiang; Xu, Huaiyuan; Xie, Xianbiao; Kang, Tiebang; Lam, YingLee; Yang, Huiling; Shen, Jingnan; Wang, Jin

2015-01-01

Osteosarcoma is a common malignant bone tumor with a propensity to metastasize to the lungs. Epigenetic abnormalities have been demonstrated to underlie osteosarcoma development; however, the epigenetic mechanisms that are involved in metastasis are not yet clear. Here, we analyzed 2 syngeneic primary human osteosarcoma cell lines that exhibit disparate metastatic potential for differences in epigenetic modifications and expression. Using methylated DNA immunoprecipitation (MeDIP) and microarray expression analysis to screen for metastasis-associated genes, we identified Iroquois homeobox 1 (IRX1). In both human osteosarcoma cell lines and clinical osteosarcoma tissues, IRX1 overexpression was strongly associated with hypomethylation of its own promoter. Furthermore, experimental modulation of IRX1 in osteosarcoma cell lines profoundly altered metastatic activity, including migration, invasion, and resistance to anoikis in vitro, and influenced lung metastasis in murine models. These prometastatic effects of IRX1 were mediated by upregulation of CXCL14/NF-κB signaling. In serum from osteosarcoma patients, the presence of IRX1 hypomethylation in circulating tumor DNA reduced lung metastasis–free survival. Together, these results identify IRX1 as a prometastatic gene, implicate IRX1 hypomethylation as a potential molecular marker for lung metastasis, and suggest that epigenetic reversion of IRX1 activation may be beneficial for controlling osteosarcoma metastasis. PMID:25822025

Thioredoxin-1 promotes colorectal cancer invasion and metastasis through crosstalk with S100P.

PubMed

Lin, Feiyan; Zhang, Peili; Zuo, Zhigui; Wang, Fule; Bi, Ruichun; Shang, Wenjing; Wu, Aihua; Ye, Ju; Li, Shaotang; Sun, Xuecheng; Wu, Jianbo; Jiang, Lei

2017-08-10

Thioredoxin-1 (Trx-1) is a small redox-regulating protein, which plays an important role in several cellular functions. Despite recent advances in understanding the biology of Trx-1, the role of Trx-1 and its underlying signaling mechanism in colorectal cancer (CRC) metastasis have not been extensively studied. In this study, we observed that Trx-1 expression is increased in CRC tissues compared to the paired non-cancerous tissues and is significantly correlated with clinical staging, lymph node metastasis and poor survival. Overexpression of Trx-1 enhanced CRC cell invasion and metastasis in vitro and in vivo. Conversely, suppression of Trx-1 expression decreased cell invasion and metastasis in vitro and in vivo. Moreover, Trx-1 activates S100P gene transcription. S100P, in turn, promotes Trx-1 expression and nuclear localization by upregulating p-ERK1/2 and downregulating TXNIP expression. Our finding provides new insight into the mechanism of Trx-1/S100P axis in the promotion of CRC metastasis, and suggests that the Trx-1/S100P axis and their related signaling pathways could be novel targets for the treatment of metastatic CRC. Copyright © 2017 Elsevier B.V. All rights reserved.

Human brain metastatic stroma attracts breast cancer cells via chemokines CXCL16 and CXCL12.

PubMed

Chung, Brile; Esmaeili, Ali A; Gopalakrishna-Pillai, Sailesh; Murad, John P; Andersen, Emily S; Kumar Reddy, Naveen; Srinivasan, Gayathri; Armstrong, Brian; Chu, Caleb; Kim, Young; Tong, Tommy; Waisman, James; Yim, John H; Badie, Behnam; Lee, Peter P

2017-01-01

The tumor microenvironment is composed of heterogeneous populations of cells, including cancer, immune, and stromal cells. Progression of tumor growth and initiation of metastasis is critically dependent on the reciprocal interactions between cancer cells and stroma. Through RNA-Seq and protein analyses, we found that cancer-associated fibroblasts derived from human breast cancer brain metastasis express significantly higher levels of chemokines CXCL12 and CXCL16 than fibroblasts from primary breast tumors or normal breast. To further understand the interplay between cancer cells and cancer-associated fibroblasts from each site, we developed three-dimensional organoids composed of patient-derived primary or brain metastasis cancer cells with matching cancer-associated fibroblasts. Three-dimensional CAF aggregates generated from brain metastasis promote migration of cancer cells more effectively than cancer-associated fibroblast aggregates derived from primary tumor or normal breast stromal cells. Treatment with a CXCR4 antagonist and/or CXCL16 neutralizing antibody, alone or in combination, significantly inhibited migration of cancer cells to brain metastatic cancer-associated fibroblast aggregates. These results demonstrate that human brain metastasis cancer-associated fibroblasts potently attract breast cancer cells via chemokines CXCL12 and CXCL16, and blocking CXCR6-CXCL16/CXCR4-CXCL12 receptor-ligand interactions may be an effective therapy for preventing breast cancer brain metastasis.

The T-LAK Cell-originated Protein Kinase Signal Pathway Promotes Colorectal Cancer Metastasis.

PubMed

Zykova, Tatyana A; Zhu, Feng; Wang, Lei; Li, Haitao; Bai, Ruihua; Lim, Do Young; Yao, Ke; Bode, Ann M; Dong, Zigang

2017-04-01

Approximately 90% of all cancer deaths arise from the metastatic dissemination of primary tumors. Metastasis is the most lethal attribute of colorectal cancer. New data regarding the molecules contributing to the metastatic phenotype, the pathways they control and the genes they regulate are very important for understanding the processes of metastasis prognosis and prevention in the clinic. The purpose of this study was to investigate the role of T-LAK cell-originated protein kinase (TOPK) in the promotion of colorectal cancer metastasis. TOPK is highly expressed in human metastatic colorectal cancer tissue compared with malignant adenocarcinoma. We identified p53-related protein kinase (PRPK) as a new substrate of TOPK. TOPK binds with and phosphorylates PRPK at Ser250 in vitro and ex vivo. This site plays a critical role in the function of PRPK. Cell lines stably expressing mutant PRPK (S250A), knockdown TOPK, knockdown PRPK or knockdown of both TOPK and PRPK significantly inhibited liver metastasis of human HCT116 colon cancer cells in a xenograft mouse model. Therefore, we conclude that TOPK directly promotes metastasis of colorectal cancer by modulating PRPK. Thus, these findings may assist in the prediction of prognosis or development of new therapeutic strategies against colon cancer. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Regulation of the metastasis suppressor Nm23-H1 by tumor viruses

PubMed Central

Banerjee, Shuvomoy; Jha, Hem Chandra

2018-01-01

Metastasis is the most common cause of cancer mortality. To increase the survival of patients, it is necessary to develop more effective methods for treating as well as preventing metastatic diseases. Recent advancement of knowledge in cancer metastasis provides the basis for development of targeted molecular therapeutics aimed at the tumor cell or its interaction with the host microenvironment. Metastasis suppressor genes (MSGs) are promising targets for inhibition of the metastasis process. During the past decade, functional significance of these genes, their regulatory pathways, and related downstream effector molecules have become a major focus of cancer research. Nm23-H1, first in the family of Nm23 human homologues, is a well-characterized, anti-metastatic factor linked with a large number of human malignancies. Mounting evidence to date suggests an important role for Nm23-H1 in reducing virus-induced tumor cell motility and migration. A detailed understanding of the molecular association between oncogenic viral antigens with Nm23-H1 may reveal the underlying mechanisms for tumor virus-associated malignancies. In this review, we will focus on the recent advances to our understanding of the molecular basis of oncogenic virus-induced progression of tumor metastasis by deregulation of Nm23-H1. PMID:25199839

Real-time photoacoustic flow cytography and photothermolysis of single circulating melanoma cells in vivo

NASA Astrophysics Data System (ADS)

He, Yun; Wang, Lidai; Shi, Junhui; Yao, Junjie; Li, Lei; Zhang, Ruiying; Huang, Chih-Hsien; Zou, Jun; Wang, Lihong V.

2017-03-01

Metastasis is responsible for as many as 90% of cancer-related deaths, and the deadliest skin cancer, melanoma, has a high propensity for metastasis. Since hematogenous spread of circulating tumor cells (CTCs) is cancer's main route of metastasis, detecting and destroying CTCs can impede metastasis and improve patients' prognoses. Extensive studies employing exogenous agents to detect tumor-specific biomarkers and guide therapeutics to CTCs have achieved promising results, but biosafety remains a critical concern. Taking another approach, physical detection and destruction of CTCs is a safer way to evaluate and reduce metastasis risks. Melanoma cells strongly express melanosomes, providing a striking absorption contrast with the blood background in the red to near-infrared spectrum. Exploiting this intrinsic optical absorption contrast of circulating melanoma cells, we coupled dual-wavelength photoacoustic flow cytography with a nanosecond-pulsed laser killing mechanism that specifically targets melanoma CTCs. We have successfully achieved in vivo label-free imaging of rare single CTCs and CTC clusters in mice. Further, the photoacoustic signal from a CTC immediately hardware-triggers a lethal pinpoint laser irradiation that lyses it on the spot in a thermally confined manner. Our technology can facilitate early inhibition of metastasis by clearing circulating tumor cells from vasculature.

RNA Sequencing Analysis Reveals Interactions between Breast Cancer or Melanoma Cells and the Tissue Microenvironment during Brain Metastasis

PubMed Central

Hosonaga, Mari; Koya, Ikuko

2017-01-01

Metastasis is the main cause of treatment failure and death in cancer patients. Metastasis of tumor cells to the brain occurs frequently in individuals with breast cancer, non–small cell lung cancer, or melanoma. Despite recent advances in our understanding of the causes and in the treatment of primary tumors, the biological and molecular mechanisms underlying the metastasis of cancer cells to the brain have remained unclear. Metastasizing cancer cells interact with their microenvironment in the brain to establish metastases. We have now developed mouse models of brain metastasis based on intracardiac injection of human breast cancer or melanoma cell lines, and we have performed RNA sequencing analysis to identify genes in mouse brain tissue and the human cancer cells whose expression is associated specifically with metastasis. We found that the expressions of the mouse genes Tph2, Sspo, Ptprq, and Pole as well as those of the human genes CXCR4, PLLP, TNFSF4, VCAM1, SLC8A2, and SLC7A11 were upregulated in brain tissue harboring metastases. Further characterization of such genes that contribute to the establishment of brain metastases may provide a basis for the development of new therapeutic strategies and consequent improvement in the prognosis of cancer patients. PMID:28210624

Polyphenolic Nutrients in Cancer Chemoprevention and Metastasis: Role of the Epithelial-to-Mesenchymal (EMT) Pathway

PubMed Central

Amawi, Haneen; Ashby, Charles R.; Peraman, Ramalingam

2017-01-01

The epithelial-to-mesenchymal transition (EMT) has received significant interest as a novel target in cancer prevention, metastasis, and resistance. The conversion of cells from an epithelial, adhesive state to a mesenchymal, motile state is one of the key events in the development of cancer metastasis. Polyphenols have been reported to be efficacious in the prevention of cancer and reversing cancer progression. Recently, the antimetastatic efficacy of polyphenols has been reported, thereby expanding the potential use of these compounds beyond chemoprevention. Polyphenols may affect EMT pathways, which are involved in cancer metastasis; for example, polyphenols increase the levels of epithelial markers, but downregulate the mesenchymal markers. Polyphenols also alter the level of expression and functionality of important proteins in other signaling pathways that control cellular mesenchymal characteristics. However, the specific proteins that are directly affected by polyphenols in these signaling pathways remain to be elucidated. The aim of this review is to analyze current evidence regarding the role of polyphenols in attenuating EMT-mediated cancer progression and metastasis. We also discuss the role of the most important polyphenol subclasses and members of the polyphenols in reversing metastasis and targeting EMT. Finally, limitations and future directions to improve our understanding in this field are discussed. PMID:28825675

The Likely Sites of Nodal Metastasis Differs According to the Tumor Extent in Distal Bile Duct Cancer.

PubMed

Kato, Yuichiro; Takahashi, Shinichiro; Gotohda, Naoto; Konishi, Masaru

2016-09-01

In the revised Japanese and Worldwide TNM classification of distal bile duct cancer, the lymph node status is defined as N0 or N1 without reference to the tumor location or extent, according to the presence/absence of metastasis to the regional lymph nodes. Data of 94 patients with distal bile duct cancer who had undergone pancreaticoduodenectomy were reviewed retrospectively. In formalin-fixed specimens, we measured the longitudinal lengths from the papilla to the lower and upper margins of the tumor, in order to investigate the correlation of the tumor extent with the likely sites of nodal metastasis. The frequencies of metastasis to the posterior pancreaticoduodenal nodes (7.1 %) and superior mesenteric artery nodes (0.0 %) were significantly lower in the cases in which the length from the papilla to the lower margin of the tumor was ≥30 mm. The frequencies of nodal metastasis to the common hepatic artery nodes (0.0 %) and hepatoduodenal ligament nodes (6.7 %) were significantly lower in the cases in which the length from the papilla to the upper margin was <40 mm. The likely sites of nodal metastasis differ according to the extent of the tumor in cases of bile duct cancer.

Regulation of hematogenous tumor metastasis by acid sphingomyelinase

PubMed Central

Carpinteiro, Alexander; Becker, Katrin Anne; Japtok, Lukasz; Hessler, Gabriele; Keitsch, Simone; Požgajovà, Miroslava; Schmid, Kurt W; Adams, Constantin; Müller, Stefan; Kleuser, Burkhard; Edwards, Michael J; Grassmé, Heike; Helfrich, Iris; Gulbins, Erich

2015-01-01

Metastatic dissemination of cancer cells is the ultimate hallmark of malignancy and accounts for approximately 90% of human cancer deaths. We investigated the role of acid sphingomyelinase (Asm) in the hematogenous metastasis of melanoma cells. Intravenous injection of B16F10 melanoma cells into wild-type mice resulted in multiple lung metastases, while Asm-deficient mice (Smpd1−/− mice) were protected from pulmonary tumor spread. Transplanting wild-type platelets into Asm-deficient mice reinstated tumor metastasis. Likewise, Asm-deficient mice were protected from hematogenous MT/ret melanoma metastasis to the spleen in a mouse model of spontaneous tumor metastasis. Human and mouse melanoma cells triggered activation and release of platelet secretory Asm, in turn leading to ceramide formation, clustering, and activation of α5β1 integrins on melanoma cells finally leading to adhesion of the tumor cells. Clustering of integrins by applying purified Asm or C16 ceramide to B16F10 melanoma cells before intravenous injection restored trapping of tumor cells in the lung in Asm-deficient mice. This effect was revertable by arginine-glycine-aspartic acid peptides, which are known inhibitors of integrins, and by antibodies neutralizing β1 integrins. These findings indicate that melanoma cells employ platelet-derived Asm for adhesion and metastasis. PMID:25851537

DT-13 attenuates human lung cancer metastasis via regulating NMIIA activity under hypoxia condition.

PubMed

Wei, Xiao-Hui; Lin, Sen-Sen; Liu, Yang; Zhao, Ren-Ping; Khan, Ghulam Jilany; Du, Hong-Zhi; Mao, Ting-Ting; Yu, Bo-Yang; Li, Rui-Ming; Yuan, Sheng-Tao; Sun, Li

2016-08-01

Cancer metastasis plays a major role in tumor deterioration. Metastatic processes are known to be regulated by hypoxic microenvironment and non-muscle myosin IIA (NMIIA). DT-13, a bioactive saponin monomer isolated from Ophiopogon japonicus, has been reported to inhibit various cancer metastasis, but whether NMIIA is involved in the anti-metastatic activity of DT-13 under hypoxia remains to be determined. Thus, this study aims to clarify the role of DT-13 in regulating 95D cell metastasis under hypoxic microenvironment and to further investigate whether NMIIA is involved in the anti-metastatic mechanism of DT-13. We found that DT-13 significantly inhibited 95D cells metastasis in vitro and in vivo. Furthermore, hypoxia significantly inhibited the expression of NMIIA and redistributed NMIIA to the cell periphery, whereas DT-13 reversed the hypoxic effects by upregulating the expression of NMIIA. Moreover, DT-13 treatment redistributed NMIIA to the nuclear periphery and reduced the formation of F-actin in 95D cells. In addition, we found that the Raf-ERK1/2 signaling pathway is involved in regulation of NMIIA by DT-13. Collectively, these findings support NMIIA as a target of DT-13 to prevent lung cancer metastasis.

A critical role of Notch signaling in osteosarcoma invasion and metastasis

PubMed Central

Zhang, Pingyu; Yang, Yanwen; Zweidler-McKay, Patrick A.; Hughes, Dennis P.M.

2010-01-01

Purpose Notch signaling is an important mediator of growth and survival in several cancer types, with Notch pathway genes functioning as oncogenes or tumor suppressors in different cancers. However, the role of Notch in osteosarcoma is unknown. Experimental Design We assessed the expression of Notch pathway genes in human osteosarcoma cell lines and patient samples. We then employed pharmacologic and retroviral manipulation of the Notch pathway and studied the impact on osteosarcoma cell proliferation, survival, anchorage-independent growth, invasion and metastasis in vitro and in vivo. Results Notch pathway genes, including Notch ligand DLL1, Notch 1 and 2, and the Notch target gene HES1 were expressed in osteosarcoma cells, and expression of HES1 was associated with invasive and metastatic potential. Blockade of Notch pathway signaling with a small molecule inhibitor of gamma secretase eliminated invasion in matrigel without affecting cell proliferation, survival, or anchorage-independent growth. Manipulation of Notch and HES1 signaling demonstrated a crucial role for HES1 in osteosarcoma invasiveness and metastasis in vivo. Conclusion These studies identify a new invasion and metastasis-regulating pathway in osteosarcoma and define a novel function for the Notch pathway: regulation of metastasis. Since the Notch pathway can be inhibited pharmacologically, these findings point toward possible new treatments to reduce invasion and metastasis in osteosarcoma. PMID:18483362

Significant Prognostic Factors for Completely Resected pN2 Non-small Cell Lung Cancer without Neoadjuvant Therapy

PubMed Central

Nakao, Masayuki; Mun, Mingyon; Nakagawa, Ken; Nishio, Makoto; Ishikawa, Yuichi; Okumura, Sakae

2015-01-01

Purpose: To identify prognostic factors for pathologic N2 (pN2) non-small cell lung cancer (NSCLC) treated by surgical resection. Methods: Between 1990 and 2009, 287 patients with pN2 NSCLC underwent curative resection at the Cancer Institute Hospital without preoperative treatment. Results: The 5-year overall survival (OS), cancer-specific survival (CSS), and recurrence-free survival (RFS) rates were 46%, 55% and 24%, respectively. The median follow-up time was 80 months. Multivariate analysis identified four independent predictors for poor OS: multiple-zone mediastinal lymph node metastasis (hazard ratio [HR], 1.616; p = 0.003); ipsilateral intrapulmonary metastasis (HR, 1.042; p = 0.002); tumor size >30 mm (HR, 1.013; p = 0.002); and clinical stage N1 or N2 (HR, 1.051; p = 0.030). Multivariate analysis identified three independent predictors for poor RFS: multiple-zone mediastinal lymph node metastasis (HR, 1.457; p = 0.011); ipsilateral intrapulmonary metastasis (HR, 1.040; p = 0.002); and tumor size >30 mm (HR, 1.008; p = 0.032). Conclusion: Multiple-zone mediastinal lymph node metastasis, ipsilateral intrapulmonary metastasis, and tumor size >30 mm were common independent prognostic factors of OS, CSS, and RFS in pN2 NSCLC. PMID:25740454

Down-regulation of KIAA1199/CEMIP by miR-216a suppresses tumor invasion and metastasis in colorectal cancer.

PubMed

Zhang, Dejun; Zhao, Lei; Shen, Qiong; Lv, Qing; Jin, Min; Ma, Hong; Nie, Xiu; Zheng, Xiumei; Huang, Shaoyi; Zhou, Pengfei; Wu, Gang; Zhang, Tao

2017-05-15

Colorectal cancer is one of the major causes of death from cancer. Metastasis is the leading cause of treatment failure, in which cancer stem cells and circulating tumor cells play crucial roles. Identifying the involved metastatic biomarkers and clarifying the regulation mechanisms are of great importance for targeting tumor metastasis. In the current research, we discovered that KIAA1199, a cell-migration inducing protein, showed higher expression in CD44+ cancer cells from metastatic compared with the paired primary tissues, and was upregulated in colorectal cancer and positively correlated with numbers and mesenchymal phenotype of circulating tumor cells, and predicted shorter progress-free survival. Moreover, we indicated that down-regulation of KIAA1199 suppressed migration and invasion of colorectal cancer cells in vitro, and inhibited metastasis in vivo. Furthermore, we demonstrated that KIAA1199 was one of the direct and functional targets of miR-216a, and miR-216a overexpression led to decreased migration and invasion of colorectal cancer cells in vitro, and inhibited metastasis in vivo. Collectively, KIAA1199 plays a critical role in maintaining an aggressive phenotype of tumor cells, and suppression of KIAA1199-related motilities of tumor cells contributes to reduced tumor metastasis in colorectal cancer. © 2017 UICC.

Protein arginine methyltransferase 5 promotes lung cancer metastasis via the epigenetic regulation of miR-99 family/FGFR3 signaling.

PubMed

Jing, Pengyu; Zhao, Nan; Ye, Mingxiang; Zhang, Yong; Zhang, Zhipei; Sun, Jianyong; Wang, Zhengxin; Zhang, Jian; Gu, Zhongping

2018-07-28

Protein arginine methyltransferase 5 (PRMT5) functions as a tumor initiator to regulate several cancer progressions, such as proliferation and apoptosis, by catalyzing the symmetrical dimethylation (me2s) of arginine residues within targeted molecules. However, the exact role of PRMT5-mediated metastasis in lung cancer is not fully understood. Here, we illustrated its potential effects in lung cancer metastasis in vivo and vitro. PRMT5 was frequently overexpressed in lung tumors, and its expression was positively related to tumor stages, lymphatic metastasis and poor outcome. In this model, PRMT5 repressed the transcription of the miR-99 family by symmetrical dimethylation of histone H4R3, which increased FGFR3 expression and in turn activated Erk1/2 and Akt, leading to cell growth and metastasis in lung cancer. Furthermore, loss of PRMT5 exerted anti-metastasis effects on lung cancer progression by blocking histone-modification of miR-99 family. Overall, this study provides new insights into the PRMT5/miR-99 family/FGFR3 axis in regulating lung cancer progression and identifies PRMT5 as a promising prognostic biomarker and therapeutic target. Copyright © 2018 The Author(s). Published by Elsevier B.V. All rights reserved.

Molecular Mechanisms and Metabolomics of Natural Polyphenols Interfering with Breast Cancer Metastasis.

PubMed

Ci, Yingqian; Qiao, Jinping; Han, Mei

2016-12-17

Metastatic cancers are the main cause of cancer-related death. In breast primary cancer, the five-year survival rate is close to 100%; however, for metastatic breast cancer, that rate drops to a mere 25%, due in part to the paucity of effective therapeutic options for treating metastases. Several in vitro and in vivo studies have indicated that consumption of natural polyphenols significantly reduces the risk of cancer metastasis. Therefore, this review summarizes the research findings involving the molecular mechanisms and metabolomics of natural polyphenols and how they may be blocking breast cancer metastasis. Most natural polyphenols are thought to impair breast cancer metastasis through downregulation of MMPs expression, interference with the VEGF signaling pathway, modulation of EMT regulator, inhibition of NF-κB and mTOR expression, and other related mechanisms. Intake of natural polyphenols has been shown to impact endogenous metabolites and complex biological metabolic pathways in vivo. Breast cancer metastasis is a complicated process in which each step is modulated by a complex network of signaling pathways. We hope that by detailing the reported interactions between breast cancer metastasis and natural polyphenols, more attention will be directed to these promising candidates as effective adjunct therapies against metastatic breast cancer in the clinic.

Diagnosis and ultrasonographic appearance of hepatic metastasis in six cases of canine appendicular osteosarcoma (2005-2013).

PubMed

Cesario, L; Garrett, L D; Barger, A M; O'Brien, R T; Fan, T M

2016-05-01

The aims of this retrospective study were to identify clinical cases of dogs with appendicular osteosarcoma (OSA) in which hepatic metastasis was confirmed, to highlight the use of cytology for its diagnosis and to describe the radiographic and ultrasonographic appearances of the lesion. Medical records were retrospectively reviewed for dogs with appendicular OSA and hepatic metastases between January 2005 and January 2013. Reviews of radiographs, ultrasounds and cytology were performed. Six dogs with appendicular OSA and hepatic metastases were identified. The ultrasonographic appearance of metastatic lesions varied, including hyperechoic with shadowing, hyperechoic without shadowing, hypoechoic and mixed echogenicity. In two cases, the hepatic metastases were also evident on thoracic radiographs. The mean survival time from diagnosis of appendicular OSA was 188 days (range 69-363 days) and from diagnosis of hepatic metastases was 35 days (range 2-69 days). Death was tumour-related in all cases. Hepatic metastasis varies widely in its ultrasonographic appearance. In three of six cases, hepatic metastasis was identified without concurrent pulmonary metastasis; therefore, abdominal ultrasound may be useful at regular intervals for patient evaluation, especially in clinical trials where accurate identification of the disease-free interval is crucial. Once hepatic metastasis is confirmed, survival times appear limited. © 2016 Australian Veterinary Association.

Long Non-coding RNAs and their Role in Metastasis

PubMed Central

WEIDLE, ULRICH H; BIRZELE, FABIAN; KOLLMORGEN, GWEN; RÜGER, RÜDIGER

2017-01-01

The perception of long non-coding RNAs as chunk RNA and transcriptional noise has been steadily replaced by their role as validated targets for a diverse set of physiological processes in the past few years. However, for the vast majority of lncRNAs their precise mode of action and physiological function remain to be uncovered. A large body of evidence has revealed their essential role in all stages of cancirogenesis and metastasis. In this review we focus on the role of lncRNAs in metastasis. We grouped selected lncRNAs into three categories based on in vitro and in vivo mode of action-related studies and clinical relevance for metastasis. Grouped according to their mode of action, in category I we discuss lncRNAs such as CCAT2, DREH, LET, NKILA, treRNA, HOTAIR, H19, FENDRR, lincROR, MALAT, GClnc1, BCAR4, SCHLAP1 and lncRNA ATP, all lncRNAs with in vitro and in vivo metastasis-related data and clinical significance. In category II we discuss lncRNAs CCAT1, PCAT1, PTENgp1, GPLINC, MEG3, ZEB2-AS, LCT13, ANRIL, NBAT1 and lncTCF7 all characterized by their mode of action in vitro and clinical significance, but pending or preliminary in vivo data. Finally, under category III, we discuss lncRNAs BANCR, FRLnc1, SPRY4-IT1 and LIMT with partially or poorly-resolved mode of action and varying degree of validation in clinical metastasis. Finally we discuss metastasis-related translational aspects of lncRNAs. PMID:28446530

Expression of proliferation marker Ki67 correlates to occurrence of metastasis and prognosis, histological subtypes and HPV DNA detection in penile carcinomas.

PubMed

Protzel, C; Knoedel, J; Zimmermann, U; Woenckhaus, C; Poetsch, M; Giebel, J

2007-11-01

Clinical outcome of penile squamous cell carcinoma (PSCC) largely depends on the presence of lymph node metastasis. In search of a valuable marker predicting the risk for metastasis, the expression of Ki67 was investigated immunohistochemically in primary tumors and compared to presence of inguinal lymph node metastasis. As human papilloma virus (HPV) is thought to affect Ki67 expression, we evaluated whether occurrence of HPV DNA correlates to Ki67 score or metastatic potential. Samples originated from patients subjected to resection of invasive SCC of penis. Immunohistochemistry was done on paraffin-embedded sections using a monoclonal antibody against Ki67. After DNA isolation from paraffin embedded tissue the presence of HPV 6/11, HPV 16 and HPV 18 DNA was analyzed by PCR. Statistical analysis was done using two tail unpaired t test and Chi-square test. Four of 28 patients showed a weak Ki67 expression, without displaying lymph node metastasis. Among 17 patients showing an intermediate Ki67 index, eight exhibited metastases while in all seven patients with a strong expression of Ki67 lymph node metastases were found. The median Ki67 expression in metastastic lesions was significantly different (50.3%) from tumors without lymph node metastasis (31.8%) (p=0.024). Furthermore, a correlation between presence of HPV DNA and strong Ki67 expression was determined (p=0.009). Since our study demonstrated a strong Ki67 labeling index significantly associated to positive lymph nodes, we suggest Ki67 expression as a prognostic marker for lymph node metastasis in penile squamous carcinoma.

XCR1 promotes cell growth and migration and is correlated with bone metastasis in non-small cell lung cancer

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

Wang, Ting; Han, Shuai; Wu, Zhipeng

Bone metastasis occurs in approximately 30–40% patients with advanced non-small cell lung cancer (NSCLC), but the mechanism underlying this bone metastasis remains poorly understood. The chemokine super family is believed to play an important role in tumor metastasis in lung cancer. The chemokine receptor XCR1 has been identified to promote cell proliferation and migration in oral cancer and ovarian carcinoma, but the role of XCR1 in lung cancer has not been reported. In this study, we demonstrated for the first time that XCR1 was overexpressed in lung cancer bone metastasis as compared with that in patients with primary lung cancer.more » In addition, the XCR1 ligand XCL1 promoted the proliferation and migration of lung cancer cells markedly, and knockdown of XCR1 by siRNA abolished the effect of XCL1 in cell proliferation and migration. Furthermore, we identified JAK2/STAT3 as a novel downstream pathway of XCR1, while XCL1/XCR1 increased the mRNA level of the downstream of JAK2/STAT3 including PIM1, JunB, TTP, MMP2 and MMP9. These results indicate that XCR1 is a new potential therapeutic target for the treatment of lung cancer bone metastasis. - Highlights: • XCR1 is overexpressed in bone metastasis compared with primary NSCLC. • XCR1 activation by XCL1 promotes lung cancer cell proliferation and migration. • JAK2/STAT3 is a novel potential downstream pathway of XCR1.« less

Z-100, an immunomodulatory extract of Mycobacterium tuberculosis strain Aoyama B, prevents spontaneous lymphatic metastasis of B16-BL6 melanoma.

PubMed

Horii, Takayuki; Yoshinaga, Koji; Kobayashi, Nobuyoshi; Seto, Koichi; Orikawa, Yuki; Okamoto, Masahiro; Eta, Runa; Ohira, Yuta; Katsunuma, Kokichi; Hori, Yuko; Tanaka, Takao; Takei, Mineo

2014-01-01

Lymphatic metastasis is common in advanced-stage carcinoma and is associated with a poor prognosis. However, few effective treatments to inhibit it are available. Z-100 is an immunomodulatory extract of Mycobacterium tuberculosis strain Aoyama B that contains polysaccharides such as arabinomannan and mannan. Here, we investigated the inhibitory effect of Z-100 on spontaneous lymphatic metastasis. C57BL/6N mice injected subcutaneously with B16-BL6 melanoma cells in the right hind footpad were administered Z-100 subcutaneously in the right inguinal region on a daily basis. On day twenty-one after the injection, the right inguinal lymph nodes were excised, and the extent of metastasis, the number of immune cells, and the amount of granzyme B protein in the lymph nodes were examined. We also investigated the combined effect of Z-100 and irradiation in this model. Results showed that Z-100 reduced number of animals with metastasis, with respective metastasis rates of 85.7%, 42.9%, 7.1% and 0.0% in saline, 0.1 mg/kg Z-100, 1 mg/kg Z-100 and 10 mg/kg Z-100 group. Further, mice that had been given Z-100 were found to have more immune cells and granzyme B protein in the lymph nodes than control mice. The combination of low dose Z-100 and irradiation also inhibited spontaneous lymph node metastases. These findings suggest that Z-100 may be beneficial in preventing lymphatic metastasis by enhancing the immune response.

Inhibitory effect of BCG cell-wall skeletons (BCG-CWS) emulsified in squalane on tumor growth and metastasis in mice.

PubMed

Yoo, Yung Choon; Hata, Katsusuke; Lee, Kyung Bok; Azuma, Ichiro

2002-08-01

The antimetastatic effect of BCG-CWS, which was emulsified in an oil-in-water form with either Drakeol 6VR mineral oil (BCG-CWS/DK) or squalane (BCG-CWS/SQA), on lung metastasis produced by highly metastatic murine tumor cells, Colon26-M3.1 carcinoma cells and B16-BL6 melanoma cells, was investigated in syngeneic mice. An intravenous (i.v.) administration of BCG-CWS (100 mg/mouse) 1 day after tumor inoculation significantly inhibited tumor metastasis of both Colon26-M3.1 carcinoma and B16-BL6 melanoma cells in experimental lung metastasis models. No differences in the antitumor activity of the two oil-based formulations (BCG-CWS/DK and BCG-CWS/SQA) were obverved. However, BCG-CWS/SQA administered through subcutaneous (s.c.) route was shown to be effective only when it was consecutively injected (3 times) after tumor inoculation. An in vivo analysis for tumor-induced angiogenesis showed that a single i.v. administration of BCG-CWS/SQA inhibited the number of tumor-induced blood vessels and suppressed tumor growth. Furthermore, the multiple administration of BCG-CWS/SQA given at on week intervals led to a significant reduction in spontaneous lung metastasis of B16-BL6 melanoma cells in a spontaneous metastasis model. These results suggest that BCG-CWS emulsified with squalane is a potent inhibitory agent of lung metastasis, and that the antimetastatic effect of BCG-CWS is related to the suppression of tumor growth and the inhibition of tumor-induced angiogenesis.

Neck dissection after chemoradiotherapy for oropharyngeal and hypopharyngeal cancer: the correlation between cervical lymph node metastasis and prognosis.

PubMed

Hanai, Nobuhiro; Kawakita, Daisuke; Ozawa, Taijiro; Hirakawa, Hitoshi; Kodaira, Takeshi; Hasegawa, Yasuhisa

2014-02-01

Recently, the role of chemoradiotherapy (CRT) for preserving organs in the treatment of head and neck cancer has been increasing. However, the indication for post-CRT neck dissection (ND) and its surgical extent is still controversial. The purpose of this study was to discuss the indications for post-CRT ND and the proper extent of the surgical procedure. We performed a retrospective analysis on N2-3 oropharyngeal and hypopharyngeal squamous cell carcinoma (OHSCC) patients treated with CRT in our institute from 1995 to 2008, and determined the prognostic impact of post-CRT ND and the distribution of cervical lymph node (CLN) metastasis based on the pathological results of ND. The patients without pathological CLN metastases had good prognoses, whereas patients with pathological CLN metastases exhibited a significantly high recurrence rate (P = 0.033). Based on the pathological results of ND, performing selective ND at levels II-IV can contain 88 and 85 % of CLN metastasis of the oropharynx and hypopharynx, respectively. In all cases, when pathological CLN metastases were found at level V in ND following CRT, distant metastases developed. The presence of pathological CLN metastasis affects prognosis, but also a diffuse distribution of CLN metastasis worsens prognosis; that is, the presence of CLN metastasis at level V after CRT appears to be an indicator of distant metastasis. Post-CRT ND may not make sense as a salvage intervention for improving the prognosis in such situations. We concluded that the proper extent of post-CRT ND of OHSCC is selective ND including levels II-IV.

Crosstalk between stromal components and tumor cells of TNBC via secreted factors enhances tumor growth and metastasis

PubMed Central

Jin, Kideok; Pandey, Niranjan B.; Popel, Aleksander S.

2017-01-01

Triple negative breast cancer (TNBC) as a metastatic disease is currently incurable. Reliable and reproducible methods for testing drugs against metastasis are not available. Stromal cells may play a critical role in tumor progression and metastasis. In this study, we determined that fibroblasts and macrophages secreted IL-8 upon induction by tumor cell-conditioned media (TCM) from MDA-MB-231 cancer cells. Our data showed that the proliferation of MDA-MB-231 cells co-cultured with fibroblasts or macrophages was enhanced compared to the monoculture. Furthermore, TNBC cell migration, a key step in tumor metastasis, was promoted by conditioned media (CM) from TCM-induced fibroblasts or macrophages. Knockdown of the IL-8 receptor CXCR2 by CRISPR-Cas9 reduces MDA-MB-231 cell proliferation and migration compared to wild type. In a mouse xenograft tumor model, the growth of MDA-MB-231-CXCR2−/− tumor was significantly decreased compared to the growth of tumors from wild-type cells. In addition, the incidence of thoracic metastasis of MDA-MB-231-CXCR2−/− tumors was reduced compared to wild type. We found that the auto- and paracrine loop exists between TNBC cells and stroma, which results in enhanced IL-8 secretion from the stromal components. Significantly, inhibition of the IL-8 signaling pathway by reparixin, an inhibitor of the IL-8 receptor, CXCR1/2, reduced MDA-MB-231 tumor growth and metastasis. Taken together, these findings implicate IL-8 signaling as a critical event in TNBC tumor growth and metastasis via crosstalk with stromal components. PMID:28947965

Proteomic profiling of isogenic primary and metastatic medulloblastoma cell lines reveals differential expression of key metastatic factors.

PubMed

Gu, Shuo; Chen, Kai; Yin, Minzhi; Wu, Zhixiang; Wu, Yeming

2017-05-08

Medulloblastoma is the most common malignant brain tumor in children. Around 30% of medulloblastoma patients are diagnosed with metastasis, which often results in a poor prognosis. Unfortunately, molecular mechanisms of medulloblastoma metastasis remain largely unknown. In this study, we employed the recently developed deep proteome analysis approach to quantitatively profile the expression of >10,000 proteins from CHLA-01-MED and CHLA-01R-MED isogenic cell lines derived from the primary and metastatic tumor of the same patient diagnosed with a group IV medulloblastoma. Using statistical analysis, we identified ~1400 significantly altered proteins between the primary and metastatic cell lines including known factors such as placental growth factor (PLGF), LIM homeobox 1 (LHX1) and prominim 1 (PROM1), as well as the negative regulator secreted protein acidic and cysteine rich (SPARC). Additional transwell experiments and immunohistochemical analysis of clinical medulloblastoma samples implicated yes-associated protein 1 (YAP1) as a potential key factor contributing to metastasis. Taken together, our data broadly defines the metastasis-relevant regulated proteome and provides a precious resource for further investigating potential mechanisms of medulloblastoma metastasis. This study represented the first deep proteome analysis of metastatic medulloblastomas and provided a valuable candidate list of altered proteins in metastatic medulloblastomas. The primary data suggested YAP1 as a potential driver for the metastasis of medulloblastoma. These results open up numerous avenues for further investigating the underlying mechanisms of medulloblastoma metastasis and improving the prognosis of medulloblastoma patients. Copyright © 2017 Elsevier B.V. All rights reserved.

Development of a model with which to predict the life expectancy of patients with spinal epidural metastasis.

PubMed

Bartels, Ronald H M A; Feuth, Ton; van der Maazen, Richard; Verbeek, André L M; Kappelle, Arnoud C; André Grotenhuis, J; Leer, Jan Willem

2007-11-01

The surgical treatment of spinal epidural metastasis is evolving. To be a surgical candidate, a patient should have a life expectancy of at least 3 months. Estimation of survival by experienced specialists has proven to be unreliable. The Cox proportional hazards model was used to make a prediction model. To validate the model, Efron optimism correction by bootstrapping was performed. Retrospective data of patients treated for a spinal metastasis were used. Possible predictive factors were defined based on clinical experience and the literature. Statistical methods and clinical knowledge were also used to reveal an optimal set of predictors of survival. Data from patients treated at the Department of Radiation Oncology for spinal metastasis between 1998 and 2005 were evaluated. The case notes of 219 patients form the base of this study. In the final model, only 5 variables were required to predict the survival of a patient with spinal metastasis: sex, location of the primary lesion, intentional curative treatment of the primary tumor, cervical location of the spinal metastasis, and Karnofsky performance score. Examples with different predictors are given. The R(2) (N) index of Nagelkerke was 0.36 (95% confidence interval [95% CI], 0.28-0.48) and the c-index 0.72 (95% CI, 0.68-0.77). A reliable and simple model with which to predict the survival of a patient with spinal epidural metastasis is presented. Without the need for extensive investigations, survival can be predicted and only 5 easily obtainable parameters are required.

Screening and identification of gastric adenocarcinoma metastasis-related genes by using cDNA microarray coupled to FDD-PCR.

PubMed

Wang, Jian-Hua; Chen, Shi-Shu

2002-07-01

To clone gastric adenocarcinoma metastasis related genes, RF-1 cell line (primary tumor of a gastric adenocarcinoma patient ) and RF-48 cell line (its metastatic counterpart) were used as a model for studying the molecular mechanism of tumor metastasis. Two fluorescent cDNA probes, labeled with Cy3 and Cy5 dyes, were prepared from RF-1 and RF-48 mRNA samples by reverse transcription method. The two color probes were then mixed and hybridized to the cDNA chip constructed by double-dots of 4 096 human genes, and scanned at two wavelengths. The experiment was repeated for 2 times. Differential expression genes from the above two cells were analyzed using the computer. 138 in all genes (3.4%) revealed differential expression in RF-48 cells compared with RF-1 cells: 81(2.1%) genes revealed apparent up-regulation, and 56(1.3%) genes revealed down-regulation. 45 genes involved in gastric adenocarcinoma metastasis were cloned using fluorescent differential display-PCR (FDD-PCR), including 3 novel genes. There were 7 differential expression genes that agreed with each other in two detection methods. The possible roles of some differential expressed genes, which maybe involved in the mechanism of tumor metastasis, were discussed. cDNA chip was used to analyze gene expression in a high-throughput and large scale manner, in combination with FDD-PCR for cloning unknown novel genes. In conclusion, some genes related to metastasis were preliminarily scanned, which would contribute to disclose the molecular mechanism of gastric adenocarcinoma metastasis.

Twist promotes tumor metastasis in basal-like breast cancer by transcriptionally upregulating ROR1.

PubMed

Cao, Jingying; Wang, Xin; Dai, Tao; Wu, Yuanzhong; Zhang, Meifang; Cao, Renxian; Zhang, Ruhua; Wang, Gang; Jiang, Rou; Zhou, Binhua P; Shi, Jian; Kang, Tiebang

2018-01-01

Rationale: Twist is a key transcription factor for induction of epithelial-mesenchymal transition (EMT), which promotes cell migration, invasion, and cancer metastasis, confers cancer cells with stem cell-like characteristics, and provides therapeutic resistance. However, the functional roles and targeted genes of Twist in EMT and cancer progression remain elusive. Methods: The potential targeted genes of Twist were identified from the global transcriptomes of T47D/Twist cells by microarray analysis. EMT phenotype was detected by western blotting and immunofluorescence of marker proteins. The dual-luciferase reporter and chromatin immunoprecipitation assays were employed to observe the direct transcriptional induction of ROR1 by Twist. A lung metastasis model was used to study the pro-metastatic role of Twist and ROR1 by injecting MDA-MB-231 cells into tail vein of nude mice. Bio-informatics analysis was utilized to measure the metastasis-free survival of breast cancer patients. Results: Twist protein was proved to directly activate the transcription of ROR1 gene, a receptor of Wnt5a in non-canonical WNT signaling pathway. Silencing of ROR1 inhibited EMT process, cell migration, invasion, and cancer metastasis of basal-like breast cancer (BLBC) cells. Knockdown of ROR1 also ameliorated the pro-metastatic effect of Twist. Furthermore, analyses of clinical specimens indicated that high expression of both ROR1 and Twist tightly correlates with poor metastasis-free survival of breast cancer patients. Conclusion: ROR1 is a targeted gene of Twist. Twist/ROR1 signaling is critical for invasion and metastasis of BLBC cells.

Cystatin C takes part in melanoma-microglia cross-talk: possible implications for brain metastasis.

PubMed

Moshe, Adi; Izraely, Sivan; Sagi-Assif, Orit; Prakash, Roshini; Telerman, Alona; Meshel, Tsipi; Carmichael, Thomas; Witz, Isaac P

2018-05-02

The development of melanoma brain metastasis is largely dependent on mutual interactions between the melanoma cells and cells in the brain microenvironment. Here, we report that the extracellular cysteine protease inhibitor cystatin C (CysC) is involved in these interactions. Microglia-derived factors upregulated CysC secretion by melanoma. Similarly, melanoma-derived factors upregulated CysC secretion by microglia. Whereas CysC enhanced melanoma cell migration through a layer of brain endothelial cells, it inhibited the migration of microglia cells toward melanoma cells. CysC was also found to promote the formation of melanoma three-dimensional structures in matrigel. IHC analysis revealed increased expression levels of CysC in the brain of immune-deficient mice bearing xenografted human melanoma brain metastasis compared to the brain of control mice. Based on these in vitro and in vivo experiments we hypothesize that CysC promotes melanoma brain metastasis. Increased expression levels of CysC were detected in the regenerating brain of mice after stroke. Post-stroke brain with melanoma brain metastasis showed an even stronger expression of CysC. The in vitro induction of stroke-like conditions in brain microenvironmental cells increased the levels of CysC in the secretome of microglia cells, but not in the secretome of brain endothelial cells. The similarities between melanoma brain metastasis and stroke with respect to CysC expression by and secretion from microglia cells suggest that CysC may be involved in shared pathways between brain metastasis and post-stroke regeneration. This manifests the tendency of tumor cells to highjack physiological molecular pathways in their progression.

Diagnostic performance of a computer-assisted diagnosis system for bone scintigraphy of newly developed skeletal metastasis in prostate cancer patients: search for low-sensitivity subgroups.

PubMed

Koizumi, Mitsuru; Motegi, Kazuki; Koyama, Masamichi; Terauchi, Takashi; Yuasa, Takeshi; Yonese, Junji

2017-08-01

The computer-assisted diagnostic system for bone scintigraphy (BS) BONENAVI is used to evaluate skeletal metastasis. We investigated its diagnostic performance in prostate cancer patients with and without skeletal metastasis and searched for the problems. An artificial neural network (ANN) value was calculated in 226 prostate cancer patients (124 with skeletal metastasis and 101 without) using BS. Receiver operating characteristic curve analysis was performed and the sensitivity and specificity determined (cutoff ANN = 0.5). Patient's situation at the time of diagnosis of skeletal metastasis, computed tomography (CT) type, extent of disease (EOD), and BS uptake grade were analyzed. False-negative and false-positive results were recorded. BONENAVI showed 82% (102/124) of sensitivity and 83% (84/101) specificity for metastasis detection. There were no significant differences among CT types, although low EOD and faint BS uptake were associated with low ANN values and low sensitivity. Patients showed lower sensitivity during the follow-up period than staging work-up. False-negative lesions were often located in the pelvis or adjacent to it. They comprised not only solitary, faint BS lesions but also overlaying to urinary excretion. BONENAVI with BS has good sensitivity and specificity for detecting prostate cancer's osseous metastasis. Low EOD and faint BS uptake are associated with low sensitivity but not the CT type. Prostate cancer patients likely to have false-negative results during the follow-up period had a solitary lesion in the pelvis with faint BS uptake or lesions overlaying to urinary excretion.

Intratumor heterogeneity predicts metastasis of triple-negative breast cancer.

PubMed

Yang, Fang; Wang, Yucai; Li, Quan; Cao, Lulu; Sun, Zijia; Jin, Juan; Fang, Hehui; Zhu, Aiyu; Li, Yan; Zhang, Wenwen; Wang, Yanru; Xie, Hui; Gustafsson, Jan-Åke; Wang, Shui; Guan, Xiaoxiang

2017-09-01

Even with the identical clinicopathological features, the ability for metastasis is vastly different among triple-negative breast cancer (TNBC) patients. Intratumor heterogeneity (ITH), which is common in breast cancer, may be a key mechanism leading to the tumor progression. In this study, we studied whether a quantitative genetic definition of ITH can predict clinical outcomes in patients with TNBC. We quantified ITH by calculating Shannon index, a measure of diversity in a population, based on Myc, epidermal growth factor receptor/centromeric probe 7 (EGFR/CEP7) and cyclin D1/centromeric probe 11 (CCND1/CEP11) copy number variations (CNVs) in 300 cells at three different locations of a tumor. Among 75 TNBC patients, those who developed metastasis had significantly higher ITH, that is Shannon indices of EGFR/CEP7 and CCND1/CEP11 CNVs. Higher Shannon indices of EGFR/CEP7 and CCND1/CEP11 CNVs were significantly associated with the development of metastasis and were predictive of significantly worse metastasis-free survival (MFS). Regional heterogeneity, defined as the difference in copy numbers of Myc, EGFR or CCND1 at different locations, was found in 52 patients. However, the presence of regional heterogeneity did not correlate with metastasis or MFS. Our findings demonstrate that higher ITH of EGFR/CEP7 and CCND1/CEP11 CNVs is predictive of metastasis and is associated with significantly worse MFS in TNBC patients, suggesting that ITH is a very promising novel prognostic factor in TNBC. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Pulmonary metastasectomy in colorectal cancer patients with previously resected liver metastasis: pooled analysis.

PubMed

Salah, Samer; Ardissone, Francesco; Gonzalez, Michel; Gervaz, Pascal; Riquet, Marc; Watanabe, Kazuhiro; Zabaleta, Jon; Al-Rimawi, Dalia; Toubasi, Samar; Massad, Ehab; Lisi, Elena; Hamed, Osama H

2015-01-01

Data addressing the outcomes and patterns of recurrence after pulmonary metastasectomy (PM) in patients with colorectal cancer (CRC) and previously resected liver metastasis are limited. We searched the PubMed database for studies assessing PM in CRC and gathered individual data for patients who had PM and a previous curative liver resection. The influence of potential factors on overall survival (OS) was analyzed through univariate and multivariate analysis. Between 1983 and 2009, 146 patients from five studies underwent PM and had previous liver resection. The median interval from resection of liver metastasis until detection of lung metastasis and the median follow-up from PM were 23 and 48 months, respectively. Five-year OS and recurrence-free survival rates calculated from the date of PM were 54.4 and 29.3 %, respectively. Factors predicting inferior OS in univariate analysis included thoracic lymph node (LN) involvement and size of largest lung nodule ≥2 cm. Adjuvant chemotherapy and whether lung metastasis was detected synchronous or metachronous to liver metastasis had no influence on survival. In multivariate analysis, thoracic LN involvement emerged as the only independent factor (hazard ratio 4.86, 95 % confidence interval 1.56-15.14, p = 0.006). PM offers a chance for long-term survival in selected patients with CRC and previously resected liver metastasis. Thoracic LN involvement predicted poor prognosis; therefore, significant efforts should be undertaken for adequate staging of the mediastinum before PM. In addition, adequate intraoperative LN sampling allows proper prognostic stratification and enrollment in novel adjuvant therapy trials.

Association between US features of primary tumor and axillary lymph node metastasis in patients with clinical T1-T2N0 breast cancer.

PubMed

Bae, Min Sun; Shin, Sung Ui; Song, Sung Eun; Ryu, Han Suk; Han, Wonshik; Moon, Woo Kyung

2018-04-01

Background Most patients with early-stage breast cancer have clinically negative lymph nodes (LNs). However, 15-20% of patients have axillary nodal metastasis based on the sentinel LN biopsy. Purpose To assess whether ultrasound (US) features of a primary tumor are associated with axillary LN metastasis in patients with clinical T1-T2N0 breast cancer. Material and Methods This retrospective study included 138 consecutive patients (median age = 51 years; age range = 27-78 years) who underwent breast surgery with axillary LN evaluation for clinically node-negative T1-T2 breast cancer. Three radiologists blinded to the axillary surgery results independently reviewed the US images. Tumor distance from the skin and distance from the nipple were determined based on the US report. Association between US features of a breast tumor and axillary LN metastasis was assessed using a multivariate logistic regression model after controlling for clinicopathologic variables. Results Of the 138 patients, 28 (20.3%) had nodal metastasis. At univariate analysis, tumor distance from the skin ( P = 0.019), tumor size on US ( P = 0.023), calcifications ( P = 0.036), architectural distortion ( P = 0.001), and lymphovascular invasion ( P = 0.049) were associated with axillary LN metastasis. At multivariate analysis, shorter skin-to-tumor distance (odds ratio [OR] = 4.15; 95% confidence interval [CI] = 1.01-16.19; P = 0.040) and masses with associated architectural distortion (OR = 3.80; 95% CI = 1.57-9.19; P = 0.003) were independent predictors of axillary LN metastasis. Conclusion US features of breast cancer can be promising factors associated with axillary LN metastasis in patients with clinically node-negative early-stage breast cancer.

Occult lymph node metastasis and risk of regional recurrence in papillary thyroid cancer after bilateral prophylactic central neck dissection: A multi-institutional study.

PubMed

Lee, Young Chan; Na, Se Young; Park, Gi Cheol; Han, Ju Hyun; Kim, Seung Woo; Eun, Young Gyu

2017-02-01

The impact of occult lymph node metastasis on regional recurrence after prophylactic central neck dissection for preoperative, nodal-negative papillary thyroid cancer is controversial. We investigated risk factors for regional lymph node recurrence in papillary thyroid cancer patients who underwent total thyroidectomy and bilateral prophylactic central neck dissection. Analysis was according to clinicopathologic characteristics and occult lymph node metastasis patterns. This multicenter study enrolled 211 consecutive patients who underwent total thyroidectomy with bilateral prophylactic central neck dissection for papillary thyroid cancer without evidence of central lymph node metastasis on preoperative imaging. Clinicopathologic features and central lymph node metastasis patterns were analyzed for predicting regional recurrence. Multivariate Cox regression analysis was used to identify independent factors for recurrence. Median follow-up time was 43 months (24-95 months). Ten patients (4.7%) showed regional lymph node recurrence. The estimated 5-year, regional recurrence-free survival was 95.2%. Tumor size ≥1 cm, central lymph node metastasis, lymph node ratio, and prelaryngeal lymph node metastasis were associated with regional recurrence in univariate analysis (P < .05). In multivariate analysis, a lymph node ratio ≥ 0.26 was a significant risk factor for regional lymph node recurrence (odds ratio = 11.63, P = .003). Lymph node ratio ≥ 0.26 was an independent predictor of worse recurrence-free survival on Cox regression analysis (hazard ratio = 11.49, P = .002). Although no significant association was observed between the presence of occult lymph node metastasis and regional recurrence, lymph node ratio ≥ 0.26 was an independent predictor of regional lymph node recurrence in papillary thyroid cancer patients who underwent total thyroidectomy and bilateral prophylactic central neck dissection. Copyright © 2016 Elsevier Inc. All rights reserved.

Significance of SYT8 For the Detection, Prediction, and Treatment of Peritoneal Metastasis From Gastric Cancer.

PubMed

Kanda, Mitsuro; Shimizu, Dai; Tanaka, Haruyoshi; Tanaka, Chie; Kobayashi, Daisuke; Hayashi, Masamichi; Iwata, Naoki; Niwa, Yukiko; Yamada, Suguru; Fujii, Tsutomu; Sugimoto, Hiroyuki; Murotani, Kenta; Fujiwara, Michitaka; Kodera, Yasuhiro

2018-03-01

To develop novel diagnostic and therapeutic targets specific for peritoneal metastasis of gastric cancer (GC). Advanced GC frequently recurs because of undetected micrometastases even after curative resection. Peritoneal metastasis has been the most frequent recurrent pattern after gastrectomy and is incurable. We conducted a recurrence pattern-specific transcriptome analysis in an independent cohort of 16 patients with stage III GC who underwent curative gastrectomy and adjuvant S-1 for screening candidate molecules specific for peritoneal metastasis of GC. Next, another 340 patients were allocated to discovery and validation sets (1:2) to evaluate the diagnostic and predictive value of the candidate molecule. The results of quantitative reverse-transcription PCR and immunohistochemical analysis were correlated with clinical characteristics and survival. The effects of siRNA-mediated knockdown on phenotype and fluorouracil sensitivity of GC cells were evaluated in vitro, and the therapeutic effects of siRNAs were evaluated using a mouse xenograft model. Synaptotagmin VIII (SYT8) was identified as a candidate biomarker specific to peritoneal metastasis. In the discovery set, the optimal cut-off of SYT8 expression was established as 0.005. Expression levels of SYT8 mRNA in GC tissues were elevated in the validation set comprising patients with peritoneal recurrence or metastasis. SYT8 levels above the cut-off value were significantly and specifically associated with peritoneal metastasis, and served as an independent prognostic marker for peritoneal recurrence-free survival of patients with stage II/III GC. The survival difference between patients with SYT8 levels above and below the cut-off was associated with patients who received adjuvant chemotherapy. Inhibition of SYT8 expression by GC cells correlated with decreased invasion, migration, and fluorouracil resistance. Intraperitoneal administration of SYT8-siRNA inhibited the growth of peritoneal nodules and prolonged survival of mice engrafted with GC cells. SYT8 represents a promising target for the detection, prediction, and treatment of peritoneal metastasis of GC.

Vascular endothelial growth factor-C (VEGF-C) expression predicts lymph node metastasis of transitional cell carcinoma of the bladder.

PubMed

Suzuki, Kazumi; Morita, Tatsuo; Tokue, Akihiko

2005-02-01

It has been found that expression of vascular endothelial growth factor-C (VEGF-C) in several carcinomas is significantly associated with angiogenesis, lymphangiogenesis and regional lymph node metastasis. However, VEGF-C expression in bladder transitional cell carcinoma (TCC) has not yet been reported. To elucidate the role of VEGF-C in bladder TCC, we examined VEGF-C expression in bladder TCC and pelvic lymph node metastasis specimens obtained from patients who underwent radical cystectomy. Eighty-seven patients who underwent radical cystectomy for clinically organ-confined TCC of the bladder were enrolled in the present study. No neoadjuvant treatments, except transurethral resection of the tumor, were given to these patients. The VEGF-C expressions of 87 bladder tumors and 20 pelvic lymph node metastasis specimens were examined immunohistochemically and the association between VEGF-C expression and clinicopathological factors, including angiogenesis as evaluated by microvessel density (MVD), was also examined. Vascular endothelial growth factor-C expression was found in the cytoplasm of tumor cells, but not in the normal transitional epithelium. Vascular endothelial growth factor-C expression was significantly associated with the pathological T stage (P = 0.0289), pelvic lymph node metastasis (P < 0.0001), lymphatic involvement (P = 0.0008), venous involvement (P = 0.0002) and high MVD (P = 0.0043). The multivariate analysis demonstrated that VEGF-C expression and high MVD in bladder TCC were independent risk factors influencing the pelvic lymph node metastasis. Moreover, the patients with VEGF-C-positive tumors had significantly poorer prognoses than those with the VEGF-C-negative tumors (P = 0.0087) in the univariate analysis. The multivariate analysis based on Cox proportional hazard model showed that the independent prognostic factors were patient age (P = 0.0132) and pelvic lymph node metastasis (P = 0.0333). The present study suggests that VEGF-C expression is an important predictive factor of pelvic lymph node metastasis in bladder cancer patients.

Coronin 3 promotes gastric cancer metastasis via the up-regulation of MMP-9 and cathepsin K.

PubMed

Ren, Gui; Tian, Qifei; An, Yanxin; Feng, Bin; Lu, Yuanyuan; Liang, Jie; Li, Kai; Shang, Yulong; Nie, Yongzhan; Wang, Xin; Fan, Daiming

2012-09-14

Coronins are a family of highly evolutionary conserved proteins reportedly involved in the regulation of actin cytoskeletal dynamics, although only coronin 3 has been shown to be related to cancer cell migration. In glioblastoma cells, the knockdown of coronin 3 inhibits cell proliferation and invasion. Coronin 3 is also associated with the aggression and metastasis of hepatocellular carcinoma. In this paper, we analyze the migration, invasion and metastasis abilities of gastric cancer cells after up- or down-regulation of coronin 3, and explore the mechanism of coronin 3 in the process of gastric cancer metastasis. The expression of coronin 3 was higher in the highly metastatic sub-cell line MKN28-M, which we established in our laboratory. We also demonstrated that the expression of coronin 3 was remarkably higher in lymph lode metastases than in primary gastric cancer tissues, and over-expression of coronin 3 was correlated with the increased clinical stage and lymph lode metastasis. Recombinant lentiviral vectors encoding shRNAs were designed to down-regulate coronin 3 expression in gastric cancer cell lines. Stable knockdown of coronin 3 by this lentiviral vector could efficiently inhibit the migration and invasion of MKN45 gastric cancer cells. In contrast, up-regulation of coronin 3 significantly enhanced migration and invasion of MKN28-NM cells. In addition, knockdown of coronin 3 significantly reduced liver metastasis in mice after tail vein injection of gastric cancer cells. The Human Tumor Metastasis PCR Array was used to screen the metastasis-associated genes identified by the down-regulation of coronin 3, and the results suggested that, following the knockdown of coronin 3, the tumor cell migration and invasion were inhibited by the reduced expression of MMP-9 and cathepsin K. Coronin 3 is highly expressed in gastric cancer metastases and can promote the metastatic behaviors of gastric cancer cells, including their migration and invasion.

Skin metastasis on the neck: an unusual presentation of recurrence of papillary thyroid carcinoma

PubMed Central

Soylu, Selen; Teksoz, Serkan; Ozcan, Murat; Bukey, Yusuf

2017-01-01

Skin metastasis of papillary thyroid carcinoma (PTC) is rare. Here, two cases of skin metastases of PTC are presented. Both of the patients were females, one is 83 and the other is 65 years old. The patients were admitted to the hospital with a movable skin lesion on anterior neck region. Free T3 and T4 levels were in normal levels and TSH levels were low in both patients. The 83-year-old patient underwent total thyroidectomy due to papillary thyroid cancer and received 131I ablation therapy and then thyroid suppression therapy. After the surgery, the patient lived without evidence of disease for 3 years and then skin metastasis occurred. The 65-year-old patient had a total thyroidectomy 5 years ago due to PTC then neck dissection due to metastasis 3 years later and then received 131I ablation therapy. Thyroid ultrasonography of both patients showed hypoechoic nodules with central vascularization. In the histological examination of both patients, cystic lesions filled with papillary structures were seen. Fine needle aspiration biopsy (FNAB) taken from both patients were papillary carcinoma with solid trabecular pattern. PTC tends to metastasize to regional lymph nodes but distant metastasis is rare. When distant metastasis develops, prognosis of the disease is poor. Therefore, skin metastasis of papillary thyroid cancer is a poor prognostic factor. If the patient does not have a thyroid malignancy history, diagnosis of PTC metastatic to the skin may be difficult since primary skin tumors such as apocrine tumors have similar histopathological features. However, in the presented cases since there was a PTC history, the diagnosis was easier with the help of histopathological examination. Skin metastasis of PTC should be kept in mind when differential diagnosis of atypical skin lesions are made especially in the patients with thyroid malignancy history. PMID:29142854

An in vitro 3D model using collagen coated gelatin nanofibers for studying breast cancer metastasis.

PubMed

Janani, G; Pillai, Mamatha M; Selvakumar, R; Bhattacharyya, Amitava; Sabarinath, C

2017-02-07

The study of breast cancer metastasis is limited due to poor knowledge of molecular progression of breast tumor and varied heterogeneity. For a better understanding of tumor metastasis, a reliable 3D in vitro model bridging the gap between 2D cultures and in vivo animal model studies is essential. Our study is focused on two key points: (i) designing a 3D microenvironment for studying metastasis and (ii) simulating the metastasis milieu by inducing epithelial to mesenchymal transition (EMT) and mesenchymal to epithelial transition (MET). An electrospun gelatin nanofiber matrix (EGNF) was fabricated using electrospinning and further dip coated with different concentrations of collagen to obtain surface complexity and mechanical properties, similar to connective tissues. Nanofiber matrices were physically characterized by Fourier transform infrared spectroscopy (FTIR), atomic force microscopy (AFM), and field-emission scanning electron microscopy (FESEM). The FTIR, AFM, and FESEM results indicated the crosslinking and confirmed the presence of pores in the nanofiber matrices. Comparative studies on biocompatibility, cell attachment, and the proliferation of MCF-7 cells on EGNF and collagen coated gelatin nanofibrous matrix (CCGM) revealed higher cellular attachment and proliferation in CCGM. CCGM with human metastatic breast cancer cell line (MCF-7) was taken to study breast cancer metastasis using estrogen (induces EMT) and progesterone (induces MET) hormones for 24 h. Quantitative real-time PCR was used for quantifying the expression of metastasis related genes, and fluorescence microscopy for verifying the invasion of cells to the matrices. The expression of E-cadherin and matrix metalloproteinase 2 (MMP 2) confirmed the occurrence of EMT and MET. Live cell imaging and cellular attachment showed significant increase of cellular invasion in crosslinked 0.15% CCGM that serves as a suitable non-toxic, biocompatible, and affordable scaffold for studying breast cancer metastasis. Our findings suggested that CCGM can be used as a tissue-like 3D model for studying breast cancer metastatic events in vitro.

Tumor Microenvironment of Metastasis and Risk of Distant Metastasis of Breast Cancer

PubMed Central

Xue, Xiaonan; Lin, Hung-Mo; D’Alfonso, Timothy M.; Ginter, Paula S.; Oktay, Maja H.; Robinson, Brian D.; Ginsberg, Mindy; Gertler, Frank B.; Glass, Andrew G.; Sparano, Joseph A.; Condeelis, John S.; Jones, Joan G.

2014-01-01

Background Tumor microenvironment of metastasis (TMEM), consisting of direct contact between a macrophage, an endothelial cell, and a tumor cell, has been associated with metastasis in both rodent mammary tumors and human breast cancer. We prospectively examined the association between TMEM score and risk of distant metastasis and compared risk associated with TMEM score with that associated with IHC4. Methods We conducted a case–control study nested within a cohort of 3760 patients with invasive ductal breast carcinoma diagnosed between 1980 and 2000 and followed through 2010. Case patients were women who developed a subsequent distant metastasis; control subjects were matched (1:1) on age at and calendar year of primary diagnosis. TMEM was assessed by triple immunostain and IHC4 by standard methods; slides were read by pathologists blinded to outcome. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using logistic regression, adjusted for clinical variables. A Receiver Operating Characteristic analysis was performed, and the area under the curve was estimated. All statistical tests were two-sided. Results TMEM score was associated with increased risk of distant metastasis in estrogen receptor (ER)+/human epidermal growth factor receptor (HER2)− tumors (multivariable OR high vs low tertile = 2.70; 95% CI = 1.39 to 5.26; P trend = .004), whereas IHC4 score had a borderline positive association (OR10 unit increase = 1.06; 95% CI = 1.00 to 1.13); the association for TMEM score persisted after adjustment for IHC4 score. The area under the curve for TMEM, adjusted for clinical variables, was 0.78. Neither TMEM score nor IHC4 score was independently associated with metastatic risk overall or in the triple negative or HER2+ subgroups. Conclusions TMEM score predicted risk of distant metastasis in ER+/HER2− breast cancer independently of IHC4 score and classical clinicopathologic features. PMID:24895374

Tumor microenvironment of metastasis and risk of distant metastasis of breast cancer.

PubMed

Rohan, Thomas E; Xue, Xiaonan; Lin, Hung-Mo; D'Alfonso, Timothy M; Ginter, Paula S; Oktay, Maja H; Robinson, Brian D; Ginsberg, Mindy; Gertler, Frank B; Glass, Andrew G; Sparano, Joseph A; Condeelis, John S; Jones, Joan G

2014-08-01

Tumor microenvironment of metastasis (TMEM), consisting of direct contact between a macrophage, an endothelial cell, and a tumor cell, has been associated with metastasis in both rodent mammary tumors and human breast cancer. We prospectively examined the association between TMEM score and risk of distant metastasis and compared risk associated with TMEM score with that associated with IHC4. We conducted a case-control study nested within a cohort of 3760 patients with invasive ductal breast carcinoma diagnosed between 1980 and 2000 and followed through 2010. Case patients were women who developed a subsequent distant metastasis; control subjects were matched (1:1) on age at and calendar year of primary diagnosis. TMEM was assessed by triple immunostain and IHC4 by standard methods; slides were read by pathologists blinded to outcome. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using logistic regression, adjusted for clinical variables. A Receiver Operating Characteristic analysis was performed, and the area under the curve was estimated. All statistical tests were two-sided. TMEM score was associated with increased risk of distant metastasis in estrogen receptor (ER)(+)/human epidermal growth factor receptor (HER2)(-) tumors (multivariable OR high vs low tertile = 2.70; 95% CI = 1.39 to 5.26; P trend = .004), whereas IHC4 score had a borderline positive association (OR10 unit increase = 1.06; 95% CI = 1.00 to 1.13); the association for TMEM score persisted after adjustment for IHC4 score. The area under the curve for TMEM, adjusted for clinical variables, was 0.78. Neither TMEM score nor IHC4 score was independently associated with metastatic risk overall or in the triple negative or HER2(+) subgroups. TMEM score predicted risk of distant metastasis in ER(+)/HER2(-) breast cancer independently of IHC4 score and classical clinicopathologic features. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Targeting Tryptophan Catabolism: A Novel Method to Block Triple-Negative Breast Cancer Metastasis

DTIC Science & Technology

2017-04-01

AWARD NUMBER: W81XWH-15-1-0039 TITLE: Targeting Tryptophan Catabolism: A Novel Method to Block Triple- Negative Breast Cancer Metastasis...Mar 2017 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Targeting Tryptophan Catabolism: A Novel Method to Block Triple-Negative Breast Cancer...Tryptophan Catabolism: A Novel Method to Block Triple-Negative Breast Cancer Metastasis,” Submitted by Jennifer K. Richer, PhD, University of Colorado

Notch Signaling in Prostate Cancer Cells Promotes Osteoblastic Metastasis

DTIC Science & Technology

2017-06-01

in the tumor- bone microenvironment. Conversely, inhibition of Notch3 in PC3, 22rv1 and C42B cells with shRNA, promoted prostate cancer–induced...metastasis and thus may be a therapeutic target for such metastatic lesions. 15. SUBJECT TERMS Prostate Cancer; Notch3; MMP3; Bone -Tumor microenvironment...9 4 1. Introduction: To address the clinical problem of disease progression in prostate cancer- induced bone metastasis, the

Delphian node metastasis in head and neck cancers--oracle or myth?

PubMed

Iyer, N Gopalakrishna; Shaha, Ashok R; Ferlito, Alfio; Thomas Robbins, K; Medina, Jesus E; Silver, Carl E; Rinaldo, Alessandra; Takes, Robert P; Suárez, Carlos; Rodrigo, Juan P; Bradley, Patrick J; Werner, Jochen A

2010-09-15

Delphian node (DN) refers to the pre-laryngeal or pre-cricoid nodal tissue often identified during laryngeal or thyroid surgery. The original nomenclature is based on the assumption that metastasis to this node was predictive of aggressive disease and poor outcome for patients. In this article, we review the existing literature on the topic to determine the significance of DN metastasis in laryngeal, hypopharyngeal and thyroid cancers. (c) 2010 Wiley-Liss, Inc.

Durable remission of leptomeningeal metastases from hormone-responsive prostate cancer.

PubMed

Zhang, Meng; Mahta, Ali; Kim, Ryan Y; Akar, Serra; Kesari, Santosh

2012-06-01

Prostate cancer is rarely associated with leptomeningeal metastasis. An 87-year-old man with a history of prostate cancer presented with leptomeningeal metastasis. He received hormonal therapy with leuprolide. Subsequently, he achieved an impressive response, indicated by a constant fall in his PSA levels and by the stabilization of leptomeningeal disease and clinical improvement. Hormonal therapy may be effective in inducing remission in hormone-sensitive prostate cancer with leptomeningeal metastasis.

Malignant anterior uveal melanoma with diffuse metastasis in a dog.

PubMed

Minami, T; Patnaik, A K

1992-12-15

Enucleation was performed in 10-year-old sexually intact female mixed-breed German Shepherd Dog. Histologic examination revealed that the dog had an uveal amelanotic melanoma of the eye. The tumor consisted of anaplastic cells with a high mitotic index, indicating malignancy. On examination 3 months after enucleation, the dog had difficulty breathing and nasal discharge. Radiography revealed pulmonary metastasis. The dog was euthanatized. Necropsy revealed diffuse metastasis involving various organs.

Chemotherapeutic Targeting of Fibulin-5 to Suppress Breast Cancer Invasion and Metastasis Stimulated by Transforming Growth Factor-beta

DTIC Science & Technology

2011-01-01

Fibulin-5 as a potential marker for breast cancer metastasis and reinforces the need to target Fibulin-5 chemotherapeutically in patients with... potentiates TGF-β stimulation of invasion and epithelial-mesenchymal transition (EMT) in normal and malignant MECs in vitro, and more importantly...mechanisms that enable FBLN5 to enhance oncogenic TGF-β signaling has tremendous potential to neutralize the metastasis promoting activities of this

Metastatic adrenal cortical carcinoma to T12 vertebrae.

PubMed

Lee, Daniel; Yanamadala, Vijay; Shankar, Ganesh M; Shin, John H

2016-05-01

We report spinal metastasis of adrenal cortical carcinoma (ACC) to the T12 vertebrae with epidural extension. ACC is a rare malignancy with poor prognosis and high rates of metastasis. However, spinal lesions of ACC are rare, and few have been reported in the literature. We discuss our management of this lesion and review the current understanding and treatment of ACC and spinal metastasis. Copyright © 2015 Elsevier Ltd. All rights reserved.

Extradural Spinal Metastasis of Adenoid Cystic Carcinoma (ACC): A Case Report

PubMed Central

Nair, Rajesh; Upadhyaya, Sunil; Nayal, Bhavna; Shetty, Arjun

2015-01-01

Adenoid cystic carcinoma (ACC) is a rare malignant tumour of the major salivary glands. It accounts for 10-15% of all salivary gland tumours and 1% of all head and neck tumours. Surgical resection followed by radiation is the choice of treatment for ACC. However, late loco-regional recurrence and metastasis is often seen emphasizing the importance of long-term follow-up. We report an unusual case of extradural metastasis of ACC in the dorsal spine. The primary submandibular gland tumour was resected 11 y back. A recurrence had been detected two years prior to the occurrence of spinal metastasis. Surgical decompression was done which was followed by palliative radiotherapy. Patient is symptomatically better, ambulant and on regular follow-up. PMID:25738073

Stomach metastasis of breast carcinoma mimicking primary gastric neoplasm on fluorodeoxy glucose-positron emission tomography-computed tomography.

PubMed

Joshi, Prathamesh; Lele, Vikram; Jain, Reetu; Khubchandani, Shaila; Sinhasan, Shraddha

2013-04-01

We present fluorodeoxy glucose positron emission tomography-computed tomography (FDG-PET/CT) findings in a case of breast carcinoma. The PET/CT findings in this case were suspicious of second primary neoplasm in the stomach. However, on endoscopic biopsy, the lesion was found to be stomach metastasis of breast carcinoma with estrogen receptor positivity. Stomach is a rare site of breast carcinoma metastasis. Our case suggests that it is difficult to distinguish a stomach metastasis of breast cancer from a primary gastric cancer on the basis of clinical and imaging features. However, this differential diagnosis must be kept in mind and it is important to make such distinction because of its implications on patient management.

EACR-MRS conference on Seed and Soil: In Vivo Models of Metastasis.

PubMed

Teles Alves, I; Cohen, N; Ersan, P G; Eyre, R; Godet, I; Holovanchuk, D; Jackstadt, R; Kyjacova, L; Mahal, K; Noguera-Castells, A; Recalde-Percaz, L; Sleeman, J P

2017-12-01

New experimental tools are urgently required to better understand the metastatic process. The importance of such tools is underscored by the fact that many anti-cancer therapies are generally ineffective against established metastases. This makes a major contribution to the fact that metastatic spread is responsible for over 90% of cancer patient deaths. It was therefore timely that the recent "Seed and Soil: In Vivo Models of Metastasis" conference held in Berlin, Germany (27-29 of November 2017) aimed to give an in-depth overview of the latest research models and tools for studying metastasis, and to showcase recent findings from world-leading metastasis researchers. This Meeting Report summarises the major themes of this ground-breaking conference.

The radiosensitive effect of apatinib for hepatocellular carcinoma patient with big paraspinal metastasis

PubMed Central

Zhu, Hong; Zhao, Yaqin; Wang, Xin

2018-01-01

Abstract Rationale: Hepatocellular carcinoma (HCC) is a highly invasive cancer associated with great mortality rates. The prognosis of advanced HCC is very poor. Patient concerns: Here, we report a HCC patient with a big paraspinal metastasis with 10 cm in diameter who failed the treatment of sorafenib. Diagnoses: Sorafenib refractory HCC with big paraspinal metastasis. Interventions: The concurrent treatment of apatinib with stereotactic body radiotherapy (SBRT). Outcomes: The paraspinal metastasis with 10 cm in diameter showed nearly complete response. Lessons: We think that the apatinib may be a good choice for HCC and it may function as a radiosensitizer of HCC. However, it warrants further investigation in the future prospective clinical studies. PMID:29480860

Hypoxia induced E-cadherin involving regulators of Hippo pathway due to HIF-1α stabilization/nuclear translocation in bone metastasis from breast carcinoma

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

Maroni, Paola; Matteucci, Emanuela; Drago, Lorenzo

The present study deals with the molecular mechanisms involved in the regulation of E-cadherin expression under hypoxia, because the adjustment of the amount of E-cadherin due to physical stimuli of the microenvironment might influence the colonization of metastasis to skeleton. We analyzed the effect of 1% oxygen tension, that is similar to that encountered in the bone marrow by metastatic cells spreading from breast carcinoma. The purpose was to evaluate the hypoxia-orchestrated control of E-cadherin transactivation via hypoxia inducible factor-1 (HIF-1) and peroxisome proliferator activated receptor-γ (PPARγ), and the involvement of Hippo pathway members, as regulators of transcription factors. Tomore » give a translational significance to the study, we took into consideration human pair-matched ductal breast carcinoma and bone metastasis: E-cadherin and Wwox were expressed in bone metastasis but not in breast carcinoma, while HIF-1α and TAZ seemed localized principally in nuclei of metastasis and were found in all cell compartments of breast carcinoma. A close examination of the regulatory mechanisms underlying E-cadherin expression in bone metastasis was done in 1833 clone derived from MDA-MB231 cells. Hypoxia induced E-cadherin only in 1833 clone, but not in parental cells, through HIF-1 and PPARγ activities, while Wwox decreased. Since Wwox was highly expressed in bone metastasis, the effect of ectopic Wwox was evaluated, and we showed E-cadherin transactivation and enhanced invasiveness in WWOX transfected 1833 cells. Also, hypoxia was additive with ectopic Wwox remarkably enhancing HIF-1α nuclear shuttle and accumulation due to the lengthening of the half-life of HIF-1α protein; under this experimental condition HIF-1α appeared as a slower migrated band compared with control, in agreement with the phosphorylation state. The in vitro data strongly supported the almost exclusive presence of HIF-1α in nuclei of human-bone metastasis. Thus, we identified Wwox as a novel molecule in the HIF-1α-HDM2 regulatory loop, necessary for the dynamic regulation of the HIF-1α amount, and we suggested that the reduction of endogenous Wwox free pool under hypoxia might also be due to the interaction with HDM2, sequestering the E3 ubiquitin ligase. We highlighted the importance of nuclear HIF-1α in the biology of metastasis for the mesenchymal-epithelial transition: this phenotype was regulated by Wwox plus hypoxia through E-cadherin target gene, playing a pivotal role in bone metastasis colonization. - Highlights: • E-cadherin accumulates in hypoxic bone metastasis opposite to primary carcinoma. • HIF-1 and PPARγ cooperate in inducing E-cadherin under hypoxia in metastatic cells. • Wwox regulates HIF-1α phosphorylation and nuclear translocation. • Hypoxia plus Wwox prevent HIF-1α degradation via HDM2 forming a regulatory loop.« less

Combined overexpression of cadherin 6, cadherin 11 and cluster of differentiation 44 is associated with lymph node metastasis and poor prognosis in oral squamous cell carcinoma.

PubMed

Ma, Chao; Zhao, Ji-Zhi; Lin, Run-Tai; Zhou, Lian; Chen, Yong-Ning; Yu, Li-Jiang; Shi, Tian-Yin; Wang, Mu; Liu, Man-Man; Liu, Yao-Ran; Zhang, Tao

2018-06-01

Oral squamous cell carcinoma (OSCC) is a highly invasive lesion that frequently metastasizes to the cervical lymph nodes and is associated with a poor prognosis. Several adhesion factors, including cadherin 6 (CDH6), cadherin 11 (CDH11) and cluster of differentiation 44 (CD44), have been reported to be involved in the invasion and metastasis of multiple types of cancer. Therefore, the aim of the present study was to determine the expression of CDH6, CDH11 and CD44 in tumor tissues from patients with OSCC, and whether this was associated with the metastasis and survival of OSCC. The mRNA expression of the human tumor metastasis-related cytokines was examined by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) in OSCC tumors with or without lymph node metastasis (n=10/group). The expression of CDH6, CDH11 and CD44 in 101 OSCC and 10 normal oral mucosa samples was examined by immunohistochemical staining. The association between overall and disease-specific survival times of patients with OSCC and the expression of these three proteins was evaluated using Kaplan-Meier curves and the log-rank test. RT-qPCR results indicated that the mRNA expression of CDH6, CDH11 and CD44 was increased in OSCC patients with lymph node metastasis (2.93-, 2.01- and 1.92-fold; P<0.05). Overexpression of CDH6, CDH11 and CD44 was observed in 31/35 (89%), 25/35 (71%) and 31/35 (89%) patients, respectively. The number of OSCC patients with lymph node metastasis exhibiting CDH6, CDH11 and CD44 overexpression was significantly higher than the number of patients without lymph node metastasis exhibiting overexpression of these proteins (P=0.017, P=0.038 and P=0.007, respectively). OSCC patients with high co-expression of CDH6, CDH11 and CD44 exhibited lower disease-specific survival times (P=0.047; χ 2 =3.933) when compared with OSCC patients with low co-expression of these adhesion factors. CDH6, CDH11 and CD44 serve important roles in OSCC metastasis and the combined use of these factors as biomarkers may improve the accuracy of the prediction of cancer metastases and prognosis.

Pharmacological activation of estrogen receptor beta augments innate immunity to suppress cancer metastasis.

PubMed

Zhao, Linjie; Huang, Shuang; Mei, Shenglin; Yang, Zhengnan; Xu, Lian; Zhou, Nianxin; Yang, Qilian; Shen, Qiuhong; Wang, Wei; Le, Xiaobing; Lau, Wayne Bond; Lau, Bonnie; Wang, Xin; Yi, Tao; Zhao, Xia; Wei, Yuquan; Warner, Margaret; Gustafsson, Jan-Åke; Zhou, Shengtao

2018-04-17

Metastases constitute the greatest causes of deaths from cancer. However, no effective therapeutic options currently exist for cancer patients with metastasis. Estrogen receptor β (ERβ), as a member of the nuclear receptor superfamily, shows potent tumor-suppressive activities in many cancers. To investigate whether modulation of ERβ could serve as a therapeutic strategy for cancer metastasis, we examined whether the selective ERβ agonist LY500307 could suppress lung metastasis of triple-negative breast cancer (TNBC) and melanoma. Mechanistically, while we observed that LY500307 potently induced cell death of cancer cells metastasized to lung in vivo, it does not mediate apoptosis of cancer cells in vitro, indicating that the cell death-inducing effects of LY500307 might be mediated by the tumor microenvironment. Pathological examination combined with flow cytometry assays indicated that LY500307 treatment induced significant infiltration of neutrophils in the metastatic niche. Functional experiments demonstrated that LY500307-treated cancer cells show chemotactic effects for neutrophils and that in vivo neutrophil depletion by Ly6G antibody administration could reverse the effects of LY500307-mediated metastasis suppression. RNA sequencing analysis showed that LY500307 could induce up-regulation of IL-1β in TNBC and melanoma cells, which further triggered antitumor neutrophil chemotaxis. However, the therapeutic effects of LY500307 treatment for suppression of lung metastasis was attenuated in IL1B -/- murine models, due to failure to induce antitumor neutrophil infiltration in the metastatic niche. Collectively, our study demonstrated that pharmacological activation of ERβ could augment innate immunity to suppress cancer metastatic colonization to lung, thus providing alternative therapeutic options for cancer patients with metastasis.

Emodin suppresses pulmonary metastasis of breast cancer cells accompanied with decreased macrophage recruitment and M2 polarization in the lungs

PubMed Central

Jia, Xuemei; Yu, Fang; Wang, Junfeng; Iwanowycz, Stephen; Saaoud, Fatma; Wang, Yuzhen; Hu, Jun; Wang, Qian; Fan, Daping

2014-01-01

Purpose Breast cancer is the leading cause of death in female cancer patients due to the lack of effective treatment for metastasis. Macrophages are the most abundant immune cells in the primary and metastatic tumors, and contribute to tumor initiation, progression and metastasis. Emodin has been found to exert anti-tumor effects through promoting cell cycle arrest and apoptosis, and inhibiting angiogenesis, but its effects on tumor-associated macrophages during cancer metastasis have not been investigated. Methods Mice inoculated with 4T1 or EO771 breast cancer cells orthotopically were treated with Emodin after the primary tumors reached 200 mm3 in size. Primary tumor growth, lung metastasis, and macrophage infiltration in the lungs were analyzed. In vitro experiments were performed to examine the effects of Emodin on macrophage migration and M2 polarization, and the underlying mechanisms. Results Emodin significantly suppressed breast cancer lung metastasis in both orthotopic mouse models without apparent effects on primary tumors. Reduced infiltration of F4/80+ macrophages and Ym1+ M2 macrophages in lungs was observed in Emodin-treated mice. In vitro experiments demonstrated that Emodin decreased the migration of macrophages towards tumor cell conditioned medium (TCM) and inhibited macrophage M2 polarization induced by TCM. Mechanistically, Emodin suppressed STAT6 phosphorylation and C/EBPβ expression, two crucial signaling events in macrophage M2 polarization, in macrophages treated with IL-4 or TCM. Conclusion Taken together, our study, for the first time, demonstrated that Emodin suppressed pulmonary metastasis of breast cancer probably through inhibiting macrophage recruitment and M2 polarization in the lungs by reducing STAT6 phosphorylation and C/EBPβ expression. PMID:25311112

CXCR4-mediated osteosarcoma growth and pulmonary metastasis is promoted by mesenchymal stem cells through VEGF.

PubMed

Zhang, Peng; Dong, Ling; Yan, Kang; Long, Hua; Yang, Tong-Tao; Dong, Ming-Qing; Zhou, Yong; Fan, Qing-Yu; Ma, Bao-An

2013-10-01

Chemokines and chemokine receptor 4 (CXCR4) play an important role in metastasis. CXCR4 is also expressed in the human osteosarcoma cell line 9607-F5M2 (F5M2), which has a high tumorigenic ability and potential for spontaneous pulmonary metastasis. Mesenchymal stem cells (MSCs) contribute to the formation of the tumor stroma and promote metastasis. However, mechanisms underlying the promotion of osteosarcoma growth and pulmonary metastasis by MSCs are still elusive. Our study co-injected the human MSCs and F5M2 cells into the caudal vein of nude mice. The total number of tumor nodules per lung was significantly increased in the F5M2+MSC group compared to the other groups (control, F5M2 cells alone and MSCs alone) at week six. Moreover, a high number of Dil-labeled MSCs was present also at the osteosarcoma metastasis sites in the lung. Using Transwell assays, we found that F5M2 cells migrate towards MSCs, while the CXCR4 inhibitor AMD3100 decreased the migration potential of F5M2 cells towards MSCs. Furthermore, upon treatment with F5M2-conditioned medium, MSCs expressed and secreted higher levels of VEGF as determined by immunohistochemistry, western blotting and ELISA, respectively. Importantly, co-cultured with F5M2 cells, MSCs expressed and secreted higher VEGF levels, while AMD3100 dramatically decreased the VEGF secretion by MSCs. However, CXCR4 expression on F5M2 cells was not significantly increased in the co-culture system. Additionally, VEGF increased the proliferation of both MSCs and F5M2 cells. These findings suggest that CXCR4-mediated osteosarcoma growth and pulmonary metastasis are promoted by MSCs through VEGF.

IL-33 promotes growth and liver metastasis of colorectal cancer in mice by remodeling the tumor microenvironment and inducing angiogenesis.

PubMed

Zhang, Yu; Davis, Celestia; Shah, Sapana; Hughes, Daniel; Ryan, James C; Altomare, Diego; Peña, Maria Marjorette O

2017-01-01

Liver metastasis is the major cause of death from colorectal cancer (CRC). Understanding its mechanisms is necessary for timely diagnosis and development of effective therapies. Interleukin-33 (IL-33) is an IL-1 cytokine family member that uniquely functions as a cytokine and nuclear factor. It is released by necrotic epithelial cells and activated innate immune cells, functioning as an alarmin or an early danger signal. Its role in invoking type 2 immune response has been established; however, it has contrasting roles in tumor development and metastasis. We identified IL-33 as a potently upregulated cytokine in a highly metastatic murine CRC cell line and examined its role in tumor growth and metastasis to the liver. IL-33 was transgenically expressed in murine and human adenocarcinoma and carcinoma cell lines and their growth and spontaneous metastasis to the liver were assessed in orthotopic models of CRC in wild-type C57Bl/6 and Il33 knockout mice. The results showed that increased expression of IL-33 in CRC cells enhanced their tumor take, growth, and liver metastasis. Tumor- rather than host-derived IL-33 induced the enhanced recruitment of CD11b + GR1 + and CD11b + F4/80 + myeloid cells to remodel the tumor microenvironment by increased expression of mobilizing cytokines, and tumor angiogenesis by activating endothelial cells. IL-33 expression was elevated in patient tumor tissues, induced early in adenoma development, and activated by pro-inflammatory cytokines derived from the tumor microenvironment. The data suggest that tumor-derived IL-33 modulates the tumor microenvironment to potently promote colon carcinogenesis and liver metastasis, underscoring its potential as a therapeutic target. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Comparative membrane proteomics analyses of breast cancer cell lines to understand the molecular mechanism of breast cancer brain metastasis.

PubMed

Peng, Wenjing; Zhang, Yu; Zhu, Rui; Mechref, Yehia

2017-09-01

Breast cancer is the leading type of cancer in women. Breast cancer brain metastasis is currently considered an issue of concern among breast cancer patients. Membrane proteins play important roles in breast cancer brain metastasis, involving cell adhesion and penetration of blood-brain barrier. To understand the mechanism of breast cancer brain metastasis, liquid chromatography-tandem mass spectrometry (LC-MS/MS) was employed in conjunction with enrichment of membrane proteins to analyze the proteomes from five different breast cancer and a brain cancer cell lines. Quantitative proteomic data of all cell lines were compared with MDA-MB-231BR which is a brain seeking breast cancer cell line, thus representing brain metastasis characteristics. Label-free proteomics of the six cell lines facilitates the identification of 1238 proteins and the quantification of 899 proteins of which more than 70% were membrane proteins. Unsupervised principal component analysis (PCA) of the label-free proteomics data resulted in a distinct clustering of cell lines, suggesting quantitative differences in the expression of several proteins among the different cell lines. Unique protein expressions in 231BR were observed for 28 proteins. The up-regulation of STAU1, AT1B3, NPM1, hnRNP Q, and hnRNP K and the down-regulation of TUBB4B and TUBB5 were noted in 231BR relative to 231 (precursor cell lines from which 231BR is derived). These proteins might contribute to the breast cancer brain metastasis. Ingenuity pathway analysis (IPA) supported the great brain metastatic propensity of 231BR and suggested the importance of the up-regulation of integrin proteins and down-regulation of EPHA2 in brain metastasis. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

The Twist Box Domain is Required for Twist1-induced Prostate Cancer Metastasis

PubMed Central

Gajula, Rajendra P.; Chettiar, Sivarajan T.; Williams, Russell D.; Thiyagarajan, Saravanan; Kato, Yoshinori; Aziz, Khaled; Wang, Ruoqi; Gandhi, Nishant; Wild, Aaron T.; Vesuna, Farhad; Ma, Jinfang; Salih, Tarek; Cades, Jessica; Fertig, Elana; Biswal, Shyam; Burns, Timothy F.; Chung, Christine H.; Rudin, Charles M.; Herman, Joseph M.; Hales, Russell K.; Raman, Venu; An, Steven S.; Tran, Phuoc T.

2013-01-01

Twist1, a basic helix-loop-helix transcription factor, plays a key role during development and is a master regulator of the epithelial-mesenchymal transition (EMT) that promotes cancer metastasis. Structure-function relationships of Twist1 to cancer-related phenotypes are underappreciated, so we studied the requirement of the conserved Twist box domain for metastatic phenotypes in prostate cancer (PCa). Evidence suggests that Twist1 is overexpressed in clinical specimens and correlated with aggressive/metastatic disease. Therefore, we examined a transactivation mutant, Twist1-F191G, in PCa cells using in vitro assays which mimic various stages of metastasis. Twist1 overexpression led to elevated cytoskeletal stiffness and cell traction forces at the migratory edge of cells based on biophysical single-cell measurements. Twist1 conferred additional cellular properties associated with cancer cell metastasis including increased migration, invasion, anoikis resistance, and anchorage-independent growth. The Twist box mutant was defective for these Twist1 phenotypes in vitro. Importantly, we observed a high frequency of Twist1-induced metastatic lung tumors and extra-thoracic metastases in vivo using the experimental lung metastasis assay. The Twist box was required for PCa cells to colonize metastatic lung lesions and extra-thoracic metastases. Comparative genomic profiling revealed transcriptional programs directed by the Twist box that were associated with cancer progression, such as Hoxa9. Mechanistically, Twist1 bound to the Hoxa9 promoter and positively regulated Hoxa9 expression in PCa cells. Finally, Hoxa9 was important for Twist1-induced cellular phenotypes associated with metastasis. These data suggest that the Twist box domain is required for Twist1 transcriptional programs and PCa metastasis. PMID:23982216

Adenocarcinoma arising at a colostomy site with inguinal lymph node metastasis: report of a case.

PubMed

Iwamoto, Masayoshi; Kawada, Kenji; Hida, Koya; Hasegawa, Suguru; Sakai, Yoshiharu

2015-02-01

Inguinal lymph node metastasis from adenocarcinoma arising at a colostomy site is extremely rare, and the significance of surgical resection for metastatic inguinal lymph nodes has not been established. An 82-year-old woman who had undergone abdominoperineal resection 27 years earlier was admitted to our hospital complaining of bleeding from a colostomy. Physical examination revealed that a tumor at the colostomy site directly invaded into the peristomal skin, and that a left inguinal lymph node was firm and swollen. Positron emission tomography/computed tomography scan demonstrated accumulation of (18)F-fluorodeoxy glucose into both the colostomy tumor and the left swollen inguinal lymph node, while there was no evidence of metastasis to liver or lungs. She underwent open left hemicolectomy with wide local resection of the colostomy, and dissection of left inguinal lymph nodes. Histological diagnosis was a moderately differentiated adenocarcinoma that directly invaded into the surrounding skin and metastasized to the left inguinal lymph node. The patient has been followed up for >5 years without any sign of recurrence. In general, inguinal lymph node metastasis from colorectal cancers is regarded as a systemic disease with a poor prognosis, and so systemic chemotherapy and radiotherapy, but not surgical lymph node dissection, are recommended. Considering the lymphatic drainage route in the present case, inguinal lymph node metastasis does not represent a systemic disease but rather a sentinel nodal metastasis from adenocarcinoma at a colostomy site. Surgical dissection of metastatic inguinal lymph nodes should be considered to enable a favorable prognosis in the absence of distant metastasis to other organs. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Expression of Lipid Metabolism-Related Proteins in Metastatic Breast Cancer.

PubMed

Jung, Yoon Yang; Kim, Hye Min; Koo, Ja Seung

2015-01-01

The tumor biology of metastatic breast cancers differ according to the metastatic sites, and the features of cancer metabolism may also be different. The aim of this study is to investigate the expression of lipid metabolism-related proteins in metastatic breast cancer according to metastatic site and discuss the clinical significance thereof. Immunohistochemical staining for lipid metabolism-related proteins [fatty acid synthase (FASN), hormone-sensitive lipase (HSL), carnitine palmitoyltransferase IA (CPT-1A), acyl-CoA oxidase 1 (ACOX1), fatty acid binding protein 4 (FABP4,) and perilipin 1 (PLIN1)] was performed using a tissue microarray of 149 cases of metastatic breast cancer (bone metastasis = 39, brain metastasis = 37, liver metastasis = 21, and lung metastasis = 52). The expression levels of ACOX1 (p = 0.009) and FASN (p = 0.007) varied significantly according to metastatic site, with the highest expression in brain metastasis and the lowest expression in liver metastasis. ACOX1 positivity (p = 0.005) and FASN positivity (p = 0.003) correlated with HER-2 positivity. The expression of FASN was significantly higher in HER-2 type breast cancer, and lower in luminal A and TNBC type breast cancer (p<0.001). Among lipid metabolism-related proteins, PLIN1 positivity was found to be an independent poor prognostic factor on multivariate analysis (Hazard ratio: 4.979, 95% CI: 1.054-22.59, p = 0.043). Different expression levels of lipid metabolism-related proteins were observed according to metastatic site. The expression of ACOX1 and FASN was highest in brain metastasis. These results suggest that the metastatic site should be considered when using lipid metabolism inhibitors for targeted therapy.

The microRNA miR-34a inhibits prostate cancer stem cells and metastasis by directly repressing CD44.

PubMed

Liu, Can; Kelnar, Kevin; Liu, Bigang; Chen, Xin; Calhoun-Davis, Tammy; Li, Hangwen; Patrawala, Lubna; Yan, Hong; Jeter, Collene; Honorio, Sofia; Wiggins, Jason F; Bader, Andreas G; Fagin, Randy; Brown, David; Tang, Dean G

2011-02-01

Cancer stem cells (CSCs), or tumor-initiating cells, are involved in tumor progression and metastasis. MicroRNAs (miRNAs) regulate both normal stem cells and CSCs, and dysregulation of miRNAs has been implicated in tumorigenesis. CSCs in many tumors--including cancers of the breast, pancreas, head and neck, colon, small intestine, liver, stomach, bladder and ovary--have been identified using the adhesion molecule CD44, either individually or in combination with other marker(s). Prostate CSCs with enhanced clonogenic and tumor-initiating and metastatic capacities are enriched in the CD44(+) cell population, but whether miRNAs regulate CD44(+) prostate cancer cells and prostate cancer metastasis remains unclear. Here we show, through expression analysis, that miR-34a, a p53 target, was underexpressed in CD44(+) prostate cancer cells purified from xenograft and primary tumors. Enforced expression of miR-34a in bulk or purified CD44(+) prostate cancer cells inhibited clonogenic expansion, tumor regeneration, and metastasis. In contrast, expression of miR-34a antagomirs in CD44(-) prostate cancer cells promoted tumor development and metastasis. Systemically delivered miR-34a inhibited prostate cancer metastasis and extended survival of tumor-bearing mice. We identified and validated CD44 as a direct and functional target of miR-34a and found that CD44 knockdown phenocopied miR-34a overexpression in inhibiting prostate cancer regeneration and metastasis. Our study shows that miR-34a is a key negative regulator of CD44(+) prostate cancer cells and establishes a strong rationale for developing miR-34a as a novel therapeutic agent against prostate CSCs.

Amino-terminal enhancer of split gene AES encodes a tumor and metastasis suppressor of prostate cancer.

PubMed

Okada, Yoshiyuki; Sonoshita, Masahiro; Kakizaki, Fumihiko; Aoyama, Naoki; Itatani, Yoshiro; Uegaki, Masayuki; Sakamoto, Hiromasa; Kobayashi, Takashi; Inoue, Takahiro; Kamba, Tomomi; Suzuki, Akira; Ogawa, Osamu; Taketo, M Mark

2017-04-01

A major cause of cancer death is its metastasis to the vital organs. Few effective therapies are available for metastatic castration-resistant prostate cancer (PCa), and progressive metastatic lesions such as lymph nodes and bones cause mortality. We recently identified AES as a metastasis suppressor for colon cancer. Here, we have studied the roles of AES in PCa progression. We analyzed the relationship between AES expression and PCa stages of progression by immunohistochemistry of human needle biopsy samples. We then performed overexpression and knockdown of AES in human PCa cell lines LNCaP, DU145 and PC3, and determined the effects on proliferation, invasion and metastasis in culture and in a xenograft model. We also compared the PCa phenotypes of Aes/Pten compound knockout mice with those of Pten simple knockout mice. Expression levels of AES were inversely correlated with clinical stages of human PCa. Exogenous expression of AES suppressed the growth of LNCaP cells, whereas the AES knockdown promoted it. We also found that AES suppressed transcriptional activities of androgen receptor and Notch signaling. Notably, AES overexpression in AR-defective DU145 and PC3 cells reduced invasion and metastasis to lymph nodes and bones without affecting proliferation in culture. Consistently, prostate epithelium-specific inactivation of Aes in Pten flox/flox mice increased expression of Snail and MMP9, and accelerated growth, invasion and lymph node metastasis of the mouse prostate tumor. These results suggest that AES plays an important role in controlling tumor growth and metastasis of PCa by regulating both AR and Notch signaling pathways. © 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

The role of the tumor-microenvironment in lung cancer-metastasis and its relationship to potential therapeutic targets.

PubMed

Wood, Steven L; Pernemalm, Maria; Crosbie, Philip A; Whetton, Anthony D

2014-05-01

Non-small cell lung cancer (NSCLC) accounts for >80% of lung cancer cases and currently has an overall five-year survival rate of only 15%. Patients presenting with advanced stage NSCLC die within 18-months of diagnosis. Metastatic spread accounts for >70% of these deaths. Thus elucidation of the mechanistic basis of NSCLC-metastasis has potential to impact on patient quality of life and survival. Research on NSCLC metastasis has recently expanded to include non-cancer cell components of tumors-the stromal cellular compartment and extra-cellular matrix components comprising the tumor-microenvironment. Metastasis (from initial primary tumor growth through angiogenesis, intravasation, survival in the bloodstream, extravasation and metastatic growth) is an inefficient process and few released cancer cells complete the entire process. Micro-environmental interactions assist each of these steps and discovery of the mechanisms by which tumor cells co-operate with the micro-environment are uncovering key molecules providing either biomarkers or potential drug targets. The major sites of NSCLC metastasis are brain, bone, adrenal gland and the liver. The mechanistic basis of this tissue-tropism is beginning to be elucidated offering the potential to target stromal components of these tissues thus targeting therapy to the tissues affected. This review covers the principal steps involved in tumor metastasis. The role of cell-cell interactions, ECM remodeling and autocrine/paracrine signaling interactions between tumor cells and the surrounding stroma is discussed. The mechanistic basis of lung cancer metastasis to specific organs is also described. The signaling mechanisms outlined have potential to act as future drug targets minimizing lung cancer metastatic spread and morbidity. Copyright © 2013 Elsevier Ltd. All rights reserved.

Ligand-directed targeting of lymphatic vessels uncovers mechanistic insights in melanoma metastasis.

PubMed

Christianson, Dawn R; Dobroff, Andrey S; Proneth, Bettina; Zurita, Amado J; Salameh, Ahmad; Dondossola, Eleonora; Makino, Jun; Bologa, Cristian G; Smith, Tracey L; Yao, Virginia J; Calderone, Tiffany L; O'Connell, David J; Oprea, Tudor I; Kataoka, Kazunori; Cahill, Dolores J; Gershenwald, Jeffrey E; Sidman, Richard L; Arap, Wadih; Pasqualini, Renata

2015-02-24

Metastasis is the most lethal step of cancer progression in patients with invasive melanoma. In most human cancers, including melanoma, tumor dissemination through the lymphatic vasculature provides a major route for tumor metastasis. Unfortunately, molecular mechanisms that facilitate interactions between melanoma cells and lymphatic vessels are unknown. Here, we developed an unbiased approach based on molecular mimicry to identify specific receptors that mediate lymphatic endothelial-melanoma cell interactions and metastasis. By screening combinatorial peptide libraries directly on afferent lymphatic vessels resected from melanoma patients during sentinel lymphatic mapping and lymph node biopsies, we identified a significant cohort of melanoma and lymphatic surface binding peptide sequences. The screening approach was designed so that lymphatic endothelium binding peptides mimic cell surface proteins on tumor cells. Therefore, relevant metastasis and lymphatic markers were biochemically identified, and a comprehensive molecular profile of the lymphatic endothelium during melanoma metastasis was generated. Our results identified expression of the phosphatase 2 regulatory subunit A, α-isoform (PPP2R1A) on the cell surfaces of both melanoma cells and lymphatic endothelial cells. Validation experiments showed that PPP2R1A is expressed on the cell surfaces of both melanoma and lymphatic endothelial cells in vitro as well as independent melanoma patient samples. More importantly, PPP2R1A-PPP2R1A homodimers occur at the cellular level to mediate cell-cell interactions at the lymphatic-tumor interface. Our results revealed that PPP2R1A is a new biomarker for melanoma metastasis and show, for the first time to our knowledge, an active interaction between the lymphatic vasculature and melanoma cells during tumor progression.

The matricellular protein CYR61 promotes breast cancer lung metastasis by facilitating tumor cell extravasation and suppressing anoikis.

PubMed

Huang, Yu-Ting; Lan, Qiang; Lorusso, Girieca; Duffey, Nathalie; Rüegg, Curzio

2017-02-07

Matricellular proteins play multiple roles in primary tumor growth, local invasion and tumor angiogenesis. However, their contribution to metastasis and the putative mechanisms involved are less well characterized. In ER-negative human breast cancer, elevated expression levels of the matricellular protein Cysteine-rich angiogenic inducer 61 (CYR61) are associated with more aggressive progression. Here, we investigated the role of CYR61 in breast cancer lung metastasis using the triple negative human breast cancer cell lines MDA-MB-231 and SUM159. Silencing of CYR61 significantly decreased lung metastasis from tumors orthotopically implanted in pre-irradiated or naive mammary tissue and upon tail vein injection. Constitutive CYR61 silencing impaired cancer cell extravasation to the lung during the first 24 hours after tail vein injection. In contrast, CYR61 inducible silencing starting 24 hours after cancer cell injection had no impact on lung metastasis formation. In vitro experiments revealed that CYR61 silencing decreased cancer cell transendothelial migration and motility, reduced CYR61 levels present at the cell surface and sensitized cancer cells to anoikis. Furthermore, we demonstrate that CYR61-dependent cell survival under non-adhesive conditions relied, at least partially, on β1 integrin ligation and AMPKα signaling while it was independent of AKT, FAK and ERK1/2 activation. Our data provide the first evidence that CYR61 promotes breast cancer lung metastasis by facilitating tumor cell extravasation and protecting from anoikis during initial seeding to the lung. The uncovered CYR61-β1 integrin-AMPKα axis may serve as a potential therapeutic target to prevent breast cancer metastasis to the lung.

Enhanced depth imaging optical coherence tomography of choroidal metastasis in 14 eyes.

PubMed

Al-Dahmash, Saad A; Shields, Carol L; Kaliki, Swathi; Johnson, Timothy; Shields, Jerry A

2014-08-01

To describe the imaging features of choroidal metastasis using enhanced depth imaging optical coherence tomography (EDI-OCT). This retrospective observational case series included 31 eyes with choroidal metastasis. Spectral domain EDI-OCT was performed using Heidelberg Spectralis HRA + OCT. The main outcome measures were imaging features by EDI-OCT. Of 31 eyes with choroidal metastasis imaged with EDI-OCT, 14 (45%) eyes displayed image detail suitable for study. The metastasis originated from carcinoma of the breast (n = 7, 50%), lung (n = 5, 36%), pancreas (n = 1, 7%), and thyroid gland (n = 1, 7%). The mean tumor basal diameter was 6.4 mm, and mean thickness was 2.3 mm by B-scan ultrasonography. The tumor location was submacular in 6 (43%) eyes and extramacular in 8 (57%) eyes. By EDI-OCT, the mean tumor thickness was 987 μm. The most salient EDI-OCT features of the metastasis included anterior compression/obliteration of the overlying choriocapillaris (n = 13, 93%), an irregular (lumpy bumpy) anterior contour (n = 9, 64%), and posterior shadowing (n = 12, 86%). Overlying retinal pigment epithelial abnormalities were noted (n = 11, 78%). Outer retinal features included structural loss of the interdigitation of the cone outer segment tips (n = 9, 64%), the ellipsoid portion of photoreceptors (n = 8, 57%), external limiting membrane (n = 4, 29%), outer nuclear layer (n = 1, 7%), and outer plexiform layer (n = 1, 7%). The inner retinal layers (inner nuclear layer to nerve fiber layer) were normal. Subretinal fluid (n = 11, 79%), subretinal lipofuscin pigment (n = 1, 7%), and intraretinal edema (n = 2, 14%) were identified. The EDI-OCT of choroidal metastasis shows a characteristic lumpy bumpy anterior tumor surface and outer retinal layer disruption with preservation of inner retinal layers.

Clinical utility of TERT promoter mutations and ALK rearrangement in thyroid cancer patients with a high prevalence of the BRAF V600E mutation.

PubMed

Bae, Ja Seong; Kim, Yourha; Jeon, Sora; Kim, Se Hee; Kim, Tae Jung; Lee, Sohee; Kim, Min-Hee; Lim, Dong Jun; Lee, Youn Soo; Jung, Chan Kwon

2016-02-09

Mutations in the TERT promoter, ALK rearrangement, and the BRAF V600E mutation are associated with aggressive clinicopathologic features in thyroid cancers. However, little is known about the impact of TERT promoter mutations and ALK rearrangement in thyroid cancer patients with a high prevalence of BRAF mutations. We performed Sanger sequencing to detect BRAF V600E and TERT promoter mutations and both immunohistochemistry and fluorescence in situ hybridization to identify ALK rearrangement on 243 thyroid cancers. TERT promoter mutations were not present in 192 well-differentiated thyroid carcinomas (WDTC) without distant metastasis or in 9 medullary carcinomas. However, the mutations did occur in 40 % (12/30) of WDTC with distant metastasis, 29 % (2/7) of poorly differentiated carcinomas and 60 % (3/5) of anaplastic carcinomas. ALK rearrangement was not present in all thyroid cancers. The BRAF V600E mutation was more frequently found in WDTC without distant metastasis than in WDTC with distant metastasis (p = 0.007). In the cohort of WDTC with distant metastasis, patients with wild-type BRAF and TERT promoter had a significantly higher response rate after radioiodine therapy (p = 0.024), whereas the BRAF V600E mutation was significantly correlated with progressive disease (p = 0.025). The TERT promoter mutation is an independent predictor for distant metastasis of WDTC, but ALK testing is not useful for clinical decision-making in Korean patients with a high prevalence of the BRAF V600E mutation. Radioiodine therapy for distant metastasis of WDTC is most effective in patients without BRAF V600E and TERT promoter mutations.

Quantifying spontaneous metastasis in a syngeneic mouse melanoma model using real time PCR.

PubMed

Deng, Wentao; McLaughlin, Sarah L; Klinke, David J

2017-08-07

Modeling metastasis in vivo with animals is a priority for both revealing mechanisms of tumor dissemination and developing therapeutic methods. While conventional intravenous injection of tumor cells provides an efficient and consistent system for studying tumor cell extravasation and colonization, studying spontaneous metastasis derived from orthotopic tumor sites has the advantage of modeling more aspects of the metastatic cascade, but is challenging as it is difficult to detect small numbers of metastatic cells. In this work, we developed an approach for quantifying spontaneous metastasis in the syngeneic mouse B16 system using real time PCR. We first transduced B16 cells with lentivirus expressing firefly luciferase Luc2 gene for bioluminescence imaging. Next, we developed a real time quantitative PCR (qPCR) method for the detection of luciferase-expressing, metastatic tumor cells in mouse lungs and other organs. To illustrate the approach, we quantified lung metastasis in both spontaneous and experimental scenarios using B16F0 and B16F10 cells in C57BL/6Ncrl and NOD-Scid Gamma (NSG) mice. We tracked B16 melanoma metastasis with both bioluminescence imaging and qPCR, which were found to be self-consistent. Using this assay, we can quantitatively detect one Luc2 positive tumor cell out of 10 4 tissue cells, which corresponds to a metastatic burden of 1.8 × 10 4 metastatic cells per whole mouse lung. More importantly, the qPCR method was at least a factor of 10 more sensitive in detecting metastatic cell dissemination and should be combined with bioluminescence imaging as a high-resolution, end-point method for final metastatic cell quantitation. Given the rapid growth of primary tumors in many mouse models, assays with improved sensitivity can provide better insight into biological mechanisms that underpin tumor metastasis.

Screening and identification of gastric adenocarcinoma metastasis-related genes using cDNA microarray coupled to FDD-PCR.

PubMed

Wang, Jianhua; Chen, Shishu

2002-10-01

To identify certain gastric adenocarcinoma metastasis-related genes, an RF-1 cell line (primary tumor from a gastric adenocarcinoma patient) and an RF-48 cell line (its metastatic counterpart) were used as a model for studying the molecular mechanism of tumor metastasis. Two fluorescent cDNA probes, labeled with Cy3 and Cy5 dyes, were prepared from RF-1 and RF-48 mRNA samples by the reverse transcription method. The two color probes were then mixed and hybridized to a cDNA chip constructed with double-dots from 4,096 human genes, and scanned at two wavelengths. The experiment was repeated twice. Differentially expressedn genes from the above two cells were analyzed by use of computer. Of the total genes, 138 (3.4%) revealed differential expression in RF-48 cells compared with RF-1 cells: 81 (2.1%) genes revealed apparent up-regulation, and 56 (1.3%) genes revealed down-regulation. Forty-five genes involved in gastric adenocarcinoma metastasis were cloned using fluorescent differential display-PCR (FDD-PCR), including three novel genes. There were seven differentially expressed genes that presented the same behaviour under both detection methods. The possible roles of some differentially expressed genes, which may be involved in the mechanism of tumor metastasis, were discussed. cDNA chip was used to analyze gene expression in a high-throughput and large-scale manner in combination with FDD-PCR for cloning unknown novel genes. Some genes related to metastasis were preliminarily scanned, which would contribute to disclose the molecular mechanism of gastric adenocarcinoma metastasis and provide new targets for therapeutic intervention.

Plantamajoside, a potential anti-tumor herbal medicine inhibits breast cancer growth and pulmonary metastasis by decreasing the activity of matrix metalloproteinase-9 and -2.

PubMed

Pei, Shimin; Yang, Xu; Wang, Huanan; Zhang, Hong; Zhou, Bin; Zhang, Di; Lin, Degui

2015-12-16

Metastasis is the major cause of death in breast cancers. MMPs play a key role in tumor microenvironment that facilitates metastasis. The existing researches suggest that the high expression of gelatinase A and B (MMP2 and MMP9) promote the metastasis of breast cancer. Therefore, gelatinase inhibitor can effectively suppress tumor metastasis. However, at present, there is no dramatically effective gelatinase inhibitor against breast cancer. We screened gelatinase inhibitor among Chinese herbal medicine by molecular docking technology; investigated the proliferation, migration and invasion of MDA-MB-231 human breast cancer cell line and 4T1 mouse breast cancer cell line in response to the treatment with the screened inhibitor by wound assay, invasion assay and gelatin zymography; then further examined the effects of inhibitor on allograft mammary tumors of mice by immunohistochemistry. We successfully screened an Chinese herbal medicine-Plantamajoside(PMS)-which can reduce the gelatinase activity of MMP9 and MMP2. In vitro, PMS can inhibit the proliferation, migration and invasion of MDA-MB-231 human breast cancer cell line and 4T1 mouse breast cancer cell line by decreasing MMP9 and MMP2 activity. In vivo, oral administration of PMS to the mice bearing 4T1 cells induced tumors resulted in significant reduction in allograft tumor volume and weights, significant decrease in microvascular density and significant lower lung metastasis rate. Our results indicate that as a promising anti-cancer agent, PMS may inhibit growth and metastasis of breast cancer by inhibiting the activity of MMP9 and MMP2.

MicroRNA-409-3p suppresses colorectal cancer invasion and metastasis partly by targeting GAB1 expression.

PubMed

Bai, Rongpan; Weng, Chunhua; Dong, Haojie; Li, Siqi; Chen, Guangdi; Xu, Zhengping

2015-11-15

Colorectal cancer (CRC) is one of the most common cancers worldwide and its metastasis accounts for the majority of deaths. However, the molecular mechanisms underlying CRC progression are not well characterized. In this study, we identified miR-409-3p as a tumor suppressor of CRC. MiR-409-3p expression was significantly downregulated in CRC tissue compared to adjacent non-tumor tissue, and reduced miR-409-3p expression was correlated with CRC metastasis. In vitro and in vivo studies revealed that miR-409-3p negatively regulated CRC metastatic capacities, including suppressing cancer cell migration, invasion and metastasis. To explore the mechanism of action of miR-409-3p, we adopted a pathway and pathophysiological event-based target screening and validation approach, and found nine known metastasis-related genes as potential targets. The 3'-UTR binding assays between the candidates and miR-409-3p suggested that only GAB1, NR4A2 and LMO4 were directly regulated by the miRNA. However, endogenous expression analysis revealed that only GAB1 was modulated by miR-409-3p in CRC cells at both the mRNA and protein levels. Furthermore, we provided evidence to conclude that GAB1 was partially responsible for miR-409-3p-mediated metastasis. Taken together, our data demonstrate that miR-409-3p is a metastatic suppressor, and post-transcriptional inhibition of the oncoprotein GAB1 is one of the mechanisms of action of this miRNA. Our finding suggests miR-409-3p might be a novel target for CRC metastasis treatment. © 2015 UICC.