Science.gov

Sample records for metastatic carcinomatous cell

  1. Two-color cytofluorometry and cellular properties of the urokinase receptor associated with a human metastatic carcinomatous cell line

    SciTech Connect

    Takahashi, K.; Gojobori, T.; Tanifuji, M. )

    1991-02-01

    Purified human urokinase was labeled with either fluorescein isothiocyanate or iodine-125 and used as a probe for binding to the human metastatic carcinomatous cell line, Detroit 562. Cytofluorometry showed that the ligand bound preferentially to cells that had been exposed to acidic pH. The binding was competitive and decreased after mild tryptic digestion. The bound ligand could be removed by restoration of the cells to a low pH. Therefore, the cells had specific binding sites. The bound urokinase was involved in the breakdown of fibrin. Two-color cytofluorometric maps were constructed by counterstaining with propidium iodide. Results suggested that there were different cell populations that had different numbers of receptors and amounts of DNA. We cloned cells and found that single clones had homogeneous levels of receptors with different dissociation constants (from 10(-13) to 10(-11) mol/mg protein) for different clones. Cells of one clone, C5, which had high levels of receptor production, moved characteristically on a glass substratum coated with gold particles and reacted with wheat germ agglutinin, but not with concanavalin A. The receptors were found together with adhesion proteins at the sites where the cells adhered to the substrate. These results and the data obtained by zymography of the cellular proteins suggested that the urokinase-type plasminogen activators were bound to the receptors. The membrane-associated activator may stimulate local proteolysis, facilitating the migration of the tumor cell across the substrate.

  2. Carcinomatous Meningitis: The Natural History of Successfully Treated Metastatic Bladder Cancer

    PubMed Central

    Tadepalli, S.; Coleman, T.; Hacket, L.A.; Liles, G.B.

    2011-01-01

    Carcinomatous meningitis due to bladder cancer is a rare entity reported only in case reports. Optimal therapy is thus poorly defined with earlier cases reporting an unsuccessful outcome. Here we report a case of late carcinomatous meningitis secondary to transitional cell carcinoma (TCC) of the bladder occurring in a patient in complete remission. He was successfully treated with intrathecal methotrexate and whole brain irradiation and experienced prolonged survival after treatment. With modern chemotherapy increasing complete remissions and survival rates in patients with TCC, more and more patients are being reported with carcinomatous meningitis. We raise the question of whether central nervous system prophylaxis should be considered in patients with TCC achieving a complete remission to chemotherapy in the metastatic setting. PMID:21941490

  3. Acute monocular visual loss in carcinomatous hypertrophic pachymeningitis mimicking giant cell arteritis.

    PubMed

    Chan, Jane W

    2006-05-01

    This report describes a 69-year-old woman who presented with acute monocular visual loss, ipsilateral headache, and elevated sedimentation rate (ESR) and C-reactive protein (CRP). Both temporal artery biopsies were negative. Neuroimaging, dural biopsy, and breast biopsy all confirmed the diagnosis of carcinomatous hypertrophic pachymeningitis associated with metastatic breast carcinoma. After treatment with corticosteroids, her vision improved. Her clinical presentation initially mimicked the symptoms and signs of giant cell arteritis. Acute monocular visual loss without other cranial nerve palsies may be an uncommon presentation of hypertrophic pachymeningitis from metastatic breast carcinoma.

  4. Acute monocular visual loss in carcinomatous hypertrophic pachymeningitis mimicking giant cell arteritis.

    PubMed

    Chan, Jane W

    2006-02-01

    This report describes a 69-year-old woman who presented with acute monocular visual loss, ipsilateral headache, and elevated sedimentation rate and C-reactive protein. Both temporal artery biopsies were negative. Neuroimaging, dural biopsy, and breast biopsy all confirmed the diagnosis of carcinomatous hypertrophic pachymeningitis associated with metastatic breast carcinoma. After treatment with corticosteroids, her vision improved. Her clinical presentation initially mimicked the symptoms and signs of giant cell arteritis. Acute monocular visual loss without other cranial nerve palsies may be an uncommon presentation of hypertrophic pachymeningitis from metastatic breast carcinoma.

  5. Small cell carcinoma of the ureter with squamous cell and transitional cell carcinomatous components associated with ureteral stone.

    PubMed

    Kim, T S; Seong, D H; Ro, J Y

    2001-12-01

    We report a case of primary small cell carcinoma of the ureter with squamous cell and transitional cell carcinomatous components associated with ureteral stone, which is unique in that the patient has remained free of tumor recurrence for 36 months after the surgery without adjuvant chemotherapy or radiotherapy. A 60-yr-old man presented himself with a right flank pain. Computed tomography revealed an ill-defined mass and a stone in the lower one third of the right ureter, and hydronephroureterosis above the stone-impacted site. The patient underwent right nephroureterectomy and stone removal. Upon gross examination, a 3.8 x 1.8 x 1.2 cm white and partly yellow mass was noted in the anterior part of the ureter, resulting in indentation of the ureteral lumen on the posterior side. Light microscopic examination revealed that the mass was mainly composed of small cell carcinoma, and partly squamous cell and transitional cell carcinomatous components. The overlying ureteral mucosa and renal pelvis also contained multifocal dysplastic transitional epithelium and transitional cell carcinoma in situ. There was no vascular invasion, and the surgical margins were free of tumor. The small cell carcinomatous component was positive for chromogranin, neuron specific enolase, synaptophysin, and pancytokeratin but negative for high molecular-weight cytokeratin (K-903) by immunohistochemistry.

  6. Composite renal cell carcinoma with clear cell renal cell carcinomatous and carcinoid tumoral elements: a first case report.

    PubMed

    Bressenot, A; Delaunay, C; Gauchotte, G; Oliver, A; Boudrant, G; Montagne, K

    2010-02-01

    Renal endocrine tumours are extremely rare, and carcinoid tumoral elements in renal cell carcinoma have never been reported. This is the first report of a composite renal cell carcinoma containing a clear cell renal cell carcinoma associated with carcinoid tumoral elements, in a patient with synchronous metastatic disease. In the absence of specific radiological and clinical manifestations, typical morphological features as well as an immunostaining profile of neuroendocrine differentiation were identified by microscopy. Secondary nodal and liver localisations were characterised by carcinoid elements only. Despite antiangiogenic therapy, liver metastasis progressed, suggesting that adjuvant therapy cannot be based on the presence of the clear cell renal cell carcinoma component. In this context, extensive tissue sampling is recommended to reveal the endocrine component that is the most aggressive element of such a composite carcinoma.

  7. Renal cell carcinoma metastatic to a pituitary FSH/LH adenoma: case report and review of the literature.

    PubMed

    Magnoli, Francesca; Finzi, Giovanna; Riva, Cristina; Capella, Carlo

    2014-12-01

    Abstract Metastases to the pituitary occur more frequently in patients with widespread cancer and mainly involve the posterior lobe. A few cases of metastatic carcinoma to a pituitary adenoma have been described so far. Here, the authors present an additional case of a clear cell renal cell carcinoma (CCRCC) metastatic to a FSH/LH/α-subunit pituitary adenoma and systematically review the literature. Immunohistochemistry and electron microscopy were performed to characterize both neoplastic components at the morphological level. Moreover, it was hypothesized that expression of VEGF and of the corresponding receptor VEGFR1 could be implicated in the development of the carcinomatous metastasis within the adenoma.

  8. Comparison of Class II HLA antigen expression in normal and carcinomatous human breast cells

    SciTech Connect

    Bernard, D.J.; Maurizis, J.C.; Chassagne, J.; Chollet, P.; Plagne, R.

    1985-03-01

    Class II HLA antigen expression in breast carcinoma and normal breast gland cells was compared using a method more accurate than immunofluorescence. This new method involves labeling membrane proteins with /sup 131/I and the anti-Class II HLA monoclonal antibody with /sup 125/I. The isolation and purification of the doubly labeled (/sup 125/I-/sup 131/I) immune complex was performed by affinity chromatography and chromatofocusing successively. When the specific activity of glycoproteins is known, the amount of glycoprotein which bind specifically to the anti-Class II HLA monoclonal antibody can be deduced. In breast carcinoma cells, 1.5 to 2% of the purified glycoproteins bind specifically to the monoclonal antibody, whereas less than 0.3% of normal breast gland cells binds. In contrast, leukemic cells, of which 80 to 90% possess Class II HLA antigens, 2 to 3% of Class II HLA glycoproteins bind specifically with the anti-Class II HLA monoclonal antibody.

  9. [Ulceration of the heel in a woman from Djibouti: squamous cell carcinoma with carcinomatous lymphangitis].

    PubMed

    Bertani, A; Massoure, P L; Menguy, P; Lamblin, G; Eve, O; Morand, J J

    2011-02-01

    The purpose of this report is to describe a case in which a heel ulcer with atypical features, i.e., large size and rapid progression, led to diagnosis of squamous cell carcinoma. Patient management was based on specialist advice obtained by "tele-dermatology" based on pictures and comments transmitted over the Internet. However, due to the risk of spreading and impossibility of providing other medical treatment (radiotherapy-chemotherapy), the lower limb was amputated at the top of the thigh.

  10. Computed tomography in metastatic renal cell carcinoma.

    PubMed

    Griffin, Nyree; Grant, Lee Alexander; Bharwani, Nishat; Sohaib, S Aslam

    2009-08-01

    Recent developments in chemotherapy have resulted in several new drug treatments for metastatic renal cell carcinoma (RCC). These therapies have shown improved progression-free survival and are applicable to many more patients than the conventional cytokine-based treatments for metastatic RCC. Consequently imaging is playing a greater part in the management of such patients. Computed tomography (CT) remains the primary imaging modality with other imaging modalities playing a supplementary role. CT is used in the diagnosis and staging of metastatic RCC. It is used in the follow-up of patients after nephrectomy, in assessing the extent of metastatic disease, and in evaluating response to treatment. This review looks at the role of CT in patients with metastatic RCC and describes the appearances of metastatic RCC before and following systemic therapy.

  11. [Long-term survival of a breast cancer patient with carcinomatous pleuritis and carcinomatous cardiac tamponade successfully treated by multimodality therapy].

    PubMed

    Tanaka, Yosuke; Tsuboi, Kaori; Yamamoto, Akira; Tsuda, Shoichi; Tsujii, Shigehiro; Yagi, Ken; Kitamura, Tatsuhiko

    2015-04-01

    A 69-year old woman was admitted to our hospital because of dyspnea and pain in her left breast. Computed tomography revealed a massive quantity of left pleural effusion, a tumor in the left breast(5 cm in diameter), left cervical and supraclavicular lymph node metastasis, and a large left axillary metastatic mass. Based on a core needle biopsy, her breast tumor was diagnosed pathologically as scirrhous carcinoma, which was positive for estrogen receptor/progesterone receptor and negative for HER2 using the FISH assay, and left pleural metastasis was diagnosed cytologically. The carcinomatous pleural effusion was successfully controlled using pleural instillations of pirarubicin HCl and OK-432 after pleural drainage. A near clinical complete response was achieved by EC systemic chemotherapy(6 months)followed by endocrine therapy(letrozole), but 3 months later she was diagnosed cytologically with carcinomatous cardiac tamponade. After operative pericardial drainage, intrapericardial instillations of cisplatin and OK-432 successfully prevented re-accumulation of pericardial effusion. Systemic chemotherapy(weekly paclitaxel)for 11 months and endocrine therapy(letrozole)resulted in a clinical complete response. One year and 10 months after pericardial drainage, she underwent surgery(mastectomy and axillary lymph node dissection level II)because of two small tumors in the left breast which were found to be malignant using PET-CT. One tumor(diameter 1.6 cm)was found pathologically to consist of degenerated cancer cells, and another tumor(diameter 2 cm)was diagnosed as recurrent cancer. There was no lymph node metastasis in the axilla except for a single mass(1.4×0.7×0.3 cm), which was composed of extremely degenerative and necrotic non-lymphoid cancerous tissue. Since having the surgery, she has not experienced recurrence on hormone therapy with fulvestrant, and to date she is still alive, 3 years and 5 months since the left pleural metastasis episode.

  12. Perioperative Considerations in Metastatic Renal Cell Carcinoma

    PubMed Central

    Flavin, Kate; Vasdev, Nikhil; Ashead, Jim; Lane, Tim; Hanbury, Damian; Nathan, Paul; Gowrie-Mohan, Shanmugasundaram

    2016-01-01

    Patients with metastatic renal cell carcinoma are complex, with the potential for significant complications, and require extensive pre-, peri-, and postoperative management. This article discusses, in depth, the necessary considerations in the treatment of these patients. PMID:27833463

  13. Brain May Prime Metastatic Cell Growth.

    PubMed

    2016-01-01

    Metastasizing tumor cells lose expression of the tumor suppressor PTEN at a much higher rate when they enter the brain compared to other organs, suggesting that the brain's unique microenvironment may prime metastatic cells for aggressive growth, a recent study reports. The findings may have implications for developing targeted therapies for brain metastases. ©2015 American Association for Cancer Research.

  14. Single cell metastatic phenotyping using pulsed nanomechanical indentations

    NASA Astrophysics Data System (ADS)

    Babahosseini, Hesam; Strobl, Jeannine S.; Agah, Masoud

    2015-09-01

    The existing approach to characterize cell biomechanical properties typically utilizes switch-like models of mechanotransduction in which cell responses are analyzed in response to a single nanomechanical indentation or a transient pulsed stress. Although this approach provides effective descriptors at population-level, at a single-cell-level, there are significant overlaps in the biomechanical descriptors of non-metastatic and metastatic cells which precludes the use of biomechanical markers for single cell metastatic phenotyping. This study presents a new promising marker for biosensing metastatic and non-metastatic cells at a single-cell-level using the effects of a dynamic microenvironment on the biomechanical properties of cells. Two non-metastatic and two metastatic epithelial breast cell lines are subjected to a pulsed stresses regimen exerted by atomic force microscopy. The force-time data obtained for the cells revealed that the non-metastatic cells increase their resistance against deformation and become more stiffened when subjected to a series of nanomechanical indentations. On the other hand, metastatic cells become slightly softened when their mechanical microenvironment is subjected to a similar dynamical changes. This distinct behavior of the non-metastatic and metastatic cells to the pulsed stresses paradigm provided a signature for single-cell-level metastatic phenotyping with a high confidence level of ∼95%.

  15. Secretome identification of immune cell factors mediating metastatic cell homing

    PubMed Central

    Aguado, Brian A.; Wu, Jia J.; Azarin, Samira M.; Nanavati, Dhaval; Rao, Shreyas S.; Bushnell, Grace G.; Medicherla, Chaitanya B.; Shea, Lonnie D.

    2015-01-01

    Metastatic cell homing is a complex process mediated in part by diffusible factors secreted from immune cells found at a pre-metastatic niche. We report on connecting secretomics and TRanscriptional Activity CEll aRray (TRACER) data to identify functional paracrine interactions between immune cells and metastatic cells as novel mediators of homing. Metastatic breast cancer mouse models were used to generate a diseased splenocyte conditioned media (D-SCM) containing immune cell secreted factors. MDA-MB-231 metastatic cell activity including cell invasion, migration, transendothelial migration, and proliferation were increased in D-SCM relative to control media. Our D-SCM secretome analysis yielded 144 secreted factor candidates that contribute to increased metastatic cell activity. The functional mediators of homing were identified using MetaCore software to determine interactions between the immune cell secretome and the TRACER-identified active transcription factors within metastatic cells. Among the 5 candidate homing factors identified, haptoglobin was selected and validated in vitro and in vivo as a key mediator of homing. Our studies demonstrate a novel systems biology approach to identify functional signaling factors associated with a cellular phenotype, which provides an enabling tool that complements large-scale protein identification provided by proteomics. PMID:26634905

  16. Measuring the metastatic potential of cancer cells

    NASA Technical Reports Server (NTRS)

    Morrison, Dennis R.; Gratzner, Howard; Atassi, M. Z.

    1993-01-01

    Cancer cells must secrete proteolytic enzymes to invade adjacent tissues and migrate to a new metastatic site. Urokinase (uPA) is a key enzyme related to metastasis in cancers of the lung, colon, gastric, uterine, breast, brain, and malignant melanoma. A NASA technology utilization project has combined fluorescence microscopy, image analysis, and flow cytometry, using fluorescent dyes, and urokinase-specific antibodies to measure uPA and abnormal DNA levels (related to cancer cell proliferation) inside the cancer cells. The project is focused on developing quantitative measurements to determine if a patient's tumor cells are actively metastasizing. If a significant number of tumor cells contain large amounts of uPA (esp. membrane-bound) then the post-surgical chemotherapy or radiotherapy can be targeted for metastatic cells that have already left the primary tumor. These analytical methods have been applied to a retrospective study of biopsy tissues from 150 node negative, stage 1 breast cancer patients. Cytopathology and image analysis has shown that uPA is present in high levels in many breast cancer cells, but not found in normal breast. Significant amounts of uPA also have been measured in glioma cell lines cultured from brain tumors. Commercial applications include new diagnostic tests for metastatic cells, in different cancers, which are being developed with a company that provides a medical testing service using flow cytometry for DNA analysis and hormone receptors on tumor cells from patient biopsies. This research also may provide the basis for developing a new 'magic bullet' treatment against metastasis using chemotherapeutic drugs or radioisotopes attached to urokinase-specific monoclonal antibodies that will only bind to metastatic cells.

  17. Aural carcinoma with chondroid metaplasia at metastatic sites in a dog.

    PubMed

    Romanucci, Mariarita; Malatesta, Daniela; Marinelli, Alessia; Di Lorenzo, Pierluigi; Della Salda, Leonardo

    2011-08-01

    A case of aural carcinoma with chondroid metaplasia at metastatic foci in an 8-year-old male pug is described. Multiple metastases in both lungs and the right submandibular, parotid, retropharyngeal, cervical and prescapular lymph nodes were detected. Histologically, the skin of the right ear canal appeared to be diffusely infiltrated by cords and nests of neoplastic epithelial cells, showing multifocal contiguity with the overlying hyperplastic squamous epithelium. Most of the carcinomatous cells were arranged in a glandular-like pattern, with formation of lumens containing epithelial cells attached to the peripheral cell layer by elongated intercellular bridges. Scattered foci of keratinization with central accumulations of compact, laminated keratin were also observed, and histochemical stains failed to detect mucinous secretory material. Even though histological and histochemical findings were compatible with a diagnosis of acantholytic squamous cell carcinoma, CAM5.2 immunostaining was detectable in the majority, although not all, neoplastic cells, confirming a diagnosis of poorly differentiated ceruminous gland carcinoma. Pulmonary metastatic nodules revealed multifocal areas of cartilaginous metaplasia with apparent transition of carcinomatous cells to chondroid cells, showing nuclear atypia and focal cytokeratin immunostaining. Carcinomatous cells surrounding chondroid areas also revealed focal vimentin and S100 immunoreactivity. Histological evidence of transition between the two components, as well as the presence of intermediate cells displaying both epithelial and mesenchymal immunohistochemical features, strongly indicated a final diagnosis of carcinosarcoma, in which chondrosarcomatous elements were derived from carcinoma cells.

  18. Curing metastatic cancer: lessons from testicular germ-cell tumours.

    PubMed

    Masters, John R W; Köberle, Beate

    2003-07-01

    Most metastatic cancers are fatal. More than 80% of patients with metastatic testicular germ-cell tumours (TGCTs), however, can be cured using cisplatin-based combination chemotherapy. Why are TGCTs more sensitive to chemotherapeutics than most other tumour types? Answers to this question could lead to new treatments for metastatic cancers.

  19. Comparative proteomic investigation of metastatic and non-metastatic osteosarcoma cells of human and canine origin.

    PubMed

    Roy, Jahnabi; Wycislo, Kathryn L; Pondenis, Holly; Fan, Timothy M; Das, Aditi

    2017-01-01

    Osteosarcoma is the most common bone cancer in dogs and people. In order to improve clinical outcomes, it is necessary to identify proteins that are differentially expressed by metastatic cells. Membrane bound proteins are responsible for multiple pro-metastatic functions. Therefore characterizing the differential expression of membranous proteins between metastatic and non-metastatic clonal variants will allow the discovery of druggable targets and consequently improve treatment methodology. The objective of this investigation was to systemically identify the membrane-associated proteomics of metastatic and non-metastatic variants of human and canine origin. Two clonal variants of divergent in vivo metastatic potential from human and canine origins were used. The plasma membranes were isolated and peptide fingerprinting was used to identify differentially expressed proteins. Selected proteins were further validated using western blotting, flow cytometry, confocal microscopy and immunohistochemistry. Over 500 proteins were identified for each cell line with nearly 40% of the proteins differentially regulated. Conserved between both species, metastatic variants demonstrated significant differences in expression of membrane proteins that are responsible for pro-metastatic functions. Additionally, CD147, CD44 and vimentin were validated using various biochemical techniques. Taken together, through a comparative proteomic approach we have identified several differentially expressed cell membrane proteins that will help in the development of future therapeutics.

  20. Giant metastatic Merkel cell carcinoma.

    PubMed

    Bognet, Rachel; Thompson, Christina; Campanelli, Carmen

    2013-01-01

    A 68-year-old man presented with a rapidly growing, asymptomatic mass on his left mid-back for the past 3 months. The patient's medical history revealed an intentional 60-pound weight loss over the previous 2 years along with smoking approximately 1 pack of cigarettes per day. On physical examination, a fungating, 11-cm red tumor with palpable broader underlying extension (23 cm total) was present on the left mid-back with distinct red dermal nodules in a dermatomal distribution. In close proximity were two ulcerated nodules, proven histologically to be basal cell carcinomas. In the left groin was massive, fixed lymphadenopathy. A punch biopsy of the tumor was performed, which showed a dense infiltrate of small, round hyperchromatic blue cells that stained positive for CD 56 and pancytokeratin in a perinuclear dot pattern. Tumor cells were negative for CK20, TTF, CK7, and LCA.

  1. Renal Cell Carcinoma Metastatic to the Scalp

    PubMed Central

    Errami, Mounir; Margulis, Vitali; Huerta, Sergio

    2016-01-01

    Because of the asymptomatic natural history of renal cell carcinoma (RCC), by the time a diagnosis is made, metastatic disease is present in about one third of the cases. Thus, the overall survival of patients with RCC remains poor. Ultimately up to 50% of patients with RCC will develop metastases. Metastatic lesions from RCC are usually observed in the lungs, liver or bone. Metastases to the brain or the skin from RCC are rare. Here we present a patient diagnosed with RCC, found to have no evidence of metastases at the time of nephrectomy, who presented two years later with metastases to the scalp. We review the literature of patients with this rare site of metastasis and outline the overall prognosis of this lesion compared to other site of metastases from RCC. PMID:28191289

  2. Metastatic Basal cell carcinoma accompanying gorlin syndrome.

    PubMed

    Bilir, Yeliz; Gokce, Erkan; Ozturk, Banu; Deresoy, Faik Alev; Yuksekkaya, Ruken; Yaman, Emel

    2014-01-01

    Gorlin-Goltz syndrome or basal cell nevus syndrome is an autosomal dominant syndrome characterized by skeletal anomalies, numerous cysts observed in the jaw, and multiple basal cell carcinoma of the skin, which may be accompanied by falx cerebri calcification. Basal cell carcinoma is the most commonly skin tumor with slow clinical course and low metastatic potential. Its concomitance with Gorlin syndrome, resulting from a mutation in a tumor suppressor gene, may substantially change morbidity and mortality. A 66-year-old male patient with a history of recurrent basal cell carcinoma was presented with exophthalmus in the left eye and the lesions localized in the left lateral orbita and left zygomatic area. His physical examination revealed hearing loss, gapped teeth, highly arched palate, and frontal prominence. Left orbital mass, cystic masses at frontal and ethmoidal sinuses, and multiple pulmonary nodules were detected at CT scans. Basal cell carcinoma was diagnosed from biopsy of ethmoid sinus. Based on the clinical and typical radiological characteristics (falx cerebri calcification, bifid costa, and odontogenic cysts), the patient was diagnosed with metastatic skin basal cell carcinoma accompanied by Gorlin syndrome. Our case is a basal cell carcinoma with aggressive course accompanying a rarely seen syndrome.

  3. [Surgical treatment of lung cancer with carcinomatous pleuritis].

    PubMed

    Yokoi, Kohei; Matsuguma, Haruhisa

    2013-07-01

    Carcinomatous pleuritis in patients with lung cancer is usually found to accompany frank malignant effusion and/or multiple pleural tumors and is associated with poor outcomes. The disease condition is now classified as stage IV (M1a) in the present TNM staging system and is generally considered to be a contraindication for surgical resection. However, this condition is sometimes discovered, with or without a small amount of pleural effusion, at thoracotomy in patients with resectable non-small cell lung cancer. The incidence was reported to be approximately 3%, and in such patients surgical treatment has been performed in some institutions. The surgical procedures employed are diverse, including limited resection, lobectomy, pneumonectomy, and extrapleural pneumonectomy. The median postoperative survival times and 5-year survival rates were reported to be 17-30 months and 13-24%, respectively. We performed extrapleural pneumonectomy in 23 patients from 1988 to 2012, and the median survival time and 5-year survival rate are 34 months and 34%, respectively. Among 12 patients with pathologic N0-1 disease, 6 patients are alive without disease 4 to 288 months after surgery, for a median survival time and 5-year survival rate of 126 months and 61%, respectively. Our results indicate that carefully selected patients with carcinomatous pleuritis may be candidates for curative extrapleural pneumonectomy.

  4. Microenvironment -Programmed Metastatic Prostate Cancer Stem Cells (mPCSCs)

    DTIC Science & Technology

    2016-10-01

    AWARD NUMBER: W81XWH-13-1-0352 TITLE: Microenvironment-Programmed Metastatic Prostate Cancer Stem Cells (mPCSCs) PRINCIPAL INVESTIGATOR: Dean...Sep 2016 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Microenvironment-Programmed Metastatic Prostate Cancer Stem Cells (mPCSCs) 5b. GRANT NUMBER 5c...that eventually kills the patient. Although many PCa cell -intrinsic molecules and end-organ factors have been implicated in the metastatic

  5. Combination therapy for metastatic renal cell carcinoma

    PubMed Central

    Buonerba, Carlo; Di Lorenzo, Giuseppe

    2016-01-01

    Current therapy for metastatic clear cell renal cell carcinoma (RCC) consists of the serial administration of single agents. Combinations of VEGF and mTOR inhibitors have been disappointing in previous randomized trials. However, the combination of lenvatinib, a multitargeted agent that inhibits VEGF as well as FGF receptors, and everolimus demonstrated promising results in a randomized phase II trial. Moreover, the emergence of programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitors has spawned the investigation of combinations of these agents with VEGF inhibitors and cytotoxic T-lymphocyte antigen 4 (CTLA-4) inhibitors. These ongoing phase III trials in conjunction with the development of predictive biomarkers and agents inhibiting novel therapeutic targets may provide much needed advances in this still largely incurable disease. PMID:27047959

  6. Contemporary Treatment of Metastatic Renal Cell Carcinoma

    PubMed Central

    Stukalin, Igor; Alimohamed, Nimira; Heng, Daniel Y.C.

    2016-01-01

    The introduction of targeted therapy has revolutionized the treatment of patients with metastatic renal cell carcinoma (mRCC). The current standard of care focuses on the inhibition of angiogenesis through the targeting of the vascular endothelial growth factor receptor (VEGFR) and the mammalian target of rapamycin (mTOR). Over the past few years, research exploring novel targeted agents has blossomed, leading to the approval of various targeted therapies. Furthermore, results from the CheckMate025 and the METEOR trials have brought about two additional novel options: the programmed cell death 1 (PD-1) checkpoint inhibitor nivolumab and the MET/VEGFR/AXL inhibitor cabozantinib, respectively. With the variety of therapeutic agents available for treatment of mRCC, research examining appropriate sequencing and combinations of the drugs is ongoing. This review discusses the role of prognostic criteria, such as those from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria. It also covers the current standard of treatment for mRCC with targeted therapy in first-, second-, and third-line setting. Additionally, the novel mechanism of action of nivolumab and cabozantinib, therapeutic sequencing and ongoing clinical trials are discussed. PMID:27471582

  7. Metastatic squamous cell carcinoma in a cat.

    PubMed

    Dhaliwal, Ravinder S; Kufuor-Mensah, Eric

    2007-02-01

    A 7-year-old, spayed female Persian cat was referred for evaluation of progressive paraplegia. The cat was thin, cachectic and paraplegic on presentation. The survey radiographs showed a left caudal pulmonary lesion and lytic skeletal lesions at the right iliac crest and left distal scapula. Due to a poor prognosis for complete recovery, the owner opted for euthanasia. Post-mortem examination revealed bilaterally small and irregular kidneys, lysis of the left iliac crest and left distal scapula and a dilated left ventricular lumen with a thin interventricular septum. Histologically, all the lesions were determined to be squamous cell carcinoma. It appears that the origin or the primary site of the malignancy in this case is pulmonary as cardiac and skeletal tissues are primarily mesenchymal in origin and are less likely to develop a primary epithelial malignancy. To the best of our knowledge, there is no description of cardiac or skeletal metastatic squamous cell carcinoma in a cat.

  8. Differential Expression of Ccn4 and Other Genes Between Metastatic and Non-metastatic EL4 Mouse Lymphoma Cells

    PubMed Central

    S. CHAHAL, MANPREET; TERESA KU, H.; ZHANG, ZHIHONG; M. LEGASPI, CHRISTIAN; LUO, ANGELA; M. HOPKINS, MANDI; E. MEIER, KATHRYN

    2016-01-01

    Background: Previous work characterized variants of the EL4 murine lymphoma cell line. Some are non-metastatic, and others metastatic, in syngenic mice. In addition, metastatic EL4 cells were stably transfected with phospholipase D2 (PLD2), which further enhanced metastasis. Materials and Methods: Microarray analyses of mRNA expression was performed for non-metastatic, metastatic, and PLD2-expressing metastatic EL4 cells. Results: Many differences were observed between non-metastatic and metastatic cell lines. One of the most striking new findings was up-regulation of mRNA for the matricellular protein WNT1-inducible signaling pathway protein 1 (CCN4) in metastatic cells; increased protein expression was verified by immunoblotting and immunocytochemistry. Other differentially expressed genes included those for reproductive homeobox 5 (Rhox5; increased in metastatic) and cystatin 7 (Cst7; decreased in metastatic). Differences between PLD2-expressing and parental cell lines were limited but included the signaling proteins Ras guanyl releasing protein 1 (RGS18; increased with PLD2) and suppressor of cytokine signaling 2 (SOCS2; decreased with PLD2). Conclusion: The results provide insights into signaling pathways potentially involved in conferring metastatic ability on lymphoma cells. PMID:27807066

  9. Sequential Therapy in Metastatic Renal Cell Carcinoma

    PubMed Central

    Burke, John M.; Agrawal, Manish; Hauke, Ralph J.; Hutson, Thomas E.; Doshi, Gury; Fleming, Mark T.; Vogelzang, Nicholas J.

    2016-01-01

    The treatment of metastatic renal cell carcinoma (mRCC) has changed dramatically in the past decade. As the number of available agents, and related volume of research, has grown, it is increasingly complex to know how to optimally treat patients. The authors are practicing medical oncologists at the US Oncology Network, the largest community-based network of oncology providers in the country, and represent the leadership of the Network’s Genitourinary Research Committee. We outline our thought process in approaching sequential therapy of mRCC and the use of real-world data to inform our approach. We also highlight the evolving literature that will impact practicing oncologists in the near future. PMID:28326277

  10. [Treatment of metastatic renal cell carcinoma].

    PubMed

    Thuret, R; Maurin, C; Sun, M; Perrotte, P; Karakiewicz, P I

    2011-04-01

    The median survival of patients with metastatic renal cell carcinoma (mRCC) increased from 10 to more than 40 months since the advent of targeted therapy. The transformation of mRCC from an initially lethal disease to a more favorable entity, albeit incurable, occurred with the transition from best supportive care, to cytokines, to finally sequential targeted therapies. Sunitinib and bevacizumab (level 1b) represent the first-line standard of care for patients with clear-cell mRCC vs temsirolimus (level 2) for those with high-risk features. Additionally, exploratory analyses of the temsirolimus data indicate important benefits for those with nonclear-cell mRCC histological subtypes. In second-line, everolimus proved its efficacy (level 1b). Nonetheless, sunitinib and sorafenib are also effective for nonclear-cell histological subtypes and after failure of other first-line treatment. The PFS benefits of first- and subsequent treatment-lines were confirmed in virtually all subgroup analyses. Potential survival benefits can be derived from cytoreductive nephrectomy (CNT), as was shown for cytokines in the general population, in sunitinib and bevacizumab-exposed patients. Phase III studies are ongoing to address the importance of CNT. This information is crucial to ensure timely delivery of a combination of medical and surgical therapies in this patient population.

  11. Single-cell analysis reveals a stem-cell program in human metastatic breast cancer cells.

    PubMed

    Lawson, Devon A; Bhakta, Nirav R; Kessenbrock, Kai; Prummel, Karin D; Yu, Ying; Takai, Ken; Zhou, Alicia; Eyob, Henok; Balakrishnan, Sanjeev; Wang, Chih-Yang; Yaswen, Paul; Goga, Andrei; Werb, Zena

    2015-10-01

    Despite major advances in understanding the molecular and genetic basis of cancer, metastasis remains the cause of >90% of cancer-related mortality. Understanding metastasis initiation and progression is critical to developing new therapeutic strategies to treat and prevent metastatic disease. Prevailing theories hypothesize that metastases are seeded by rare tumour cells with unique properties, which may function like stem cells in their ability to initiate and propagate metastatic tumours. However, the identity of metastasis-initiating cells in human breast cancer remains elusive, and whether metastases are hierarchically organized is unknown. Here we show at the single-cell level that early stage metastatic cells possess a distinct stem-like gene expression signature. To identify and isolate metastatic cells from patient-derived xenograft models of human breast cancer, we developed a highly sensitive fluorescence-activated cell sorting (FACS)-based assay, which allowed us to enumerate metastatic cells in mouse peripheral tissues. We compared gene signatures in metastatic cells from tissues with low versus high metastatic burden. Metastatic cells from low-burden tissues were distinct owing to their increased expression of stem cell, epithelial-to-mesenchymal transition, pro-survival, and dormancy-associated genes. By contrast, metastatic cells from high-burden tissues were similar to primary tumour cells, which were more heterogeneous and expressed higher levels of luminal differentiation genes. Transplantation of stem-like metastatic cells from low-burden tissues showed that they have considerable tumour-initiating capacity, and can differentiate to produce luminal-like cancer cells. Progression to high metastatic burden was associated with increased proliferation and MYC expression, which could be attenuated by treatment with cyclin-dependent kinase (CDK) inhibitors. These findings support a hierarchical model for metastasis, in which metastases are initiated

  12. Gene expression profiling allows distinction between primary and metastatic squamous cell carcinomas in the lung.

    PubMed

    Talbot, Simon G; Estilo, Cherry; Maghami, Ellie; Sarkaria, Inderpal S; Pham, Duy Khanh; O-charoenrat, Pornchai; Socci, Nicholas D; Ngai, Ivan; Carlson, Diane; Ghossein, Ronald; Viale, Agnes; Park, Bernard J; Rusch, Valerie W; Singh, Bhuvanesh

    2005-04-15

    Lung neoplasms commonly develop in patients previously treated for head and neck carcinomas. The derivation of these tumors, either as new primary lung cancers or as metastatic head and neck cancers, is difficult to establish based on clinical or histopathologic criteria since both are squamous cell carcinomas and have identical features under light microscopy. However, this distinction has significant treatment and prognostic implications. Gene expression profiling was performed on a panel of 52 sequentially collected patients with either primary lung (n = 21) or primary head and neck (n = 31) carcinomas using the Affymetrix HG_U95Av2 high-density oligonucleotide microarray. Unsupervised hierarchical clustering with Ward linkage and the Pearson correlation metric was performed. To assess robustness, bootstrap resampling was performed with 1,000 iterations. A t test of the normalized values for each gene was used to determine the genes responsible for segregating head and neck from lung primary carcinomas, and those with the most differential expression were used for later analyses. In the absence of a large "test" set of tumors, we used a supervised leave-one-out cross-validation to test how well we could predict the tumor origin. Once a gene expression profile was established, 12 lung lesions taken from patients with previously treated head and neck cancers were similarly analyzed by gene expression profiling to determine their sites of origin. Unsupervised clustering analysis separated the study cohort into two distinct groups which reliably remained segregated with bootstrap resampling. Group 1 consisted of 30 tongue carcinomas. Group 2 consisted of 21 lung cancers and 1 tongue carcinoma. The clustering was not changed even when normal lung or tongue profiles were subtracted from the corresponding carcinomatous lesions, and a leave-one-out cross-validation showed a 98% correct prediction (see Supplementary Data 1). A minimum set of 500 genes required to

  13. Intraventricular metastatic clear cell renal carcinoma.

    PubMed

    Sava, I; Sava, Anca; Şapte, Elena; Mihailov, Claudia; Dumitrescu, Gabriela; Poeată, I; Sava, Florina; Haba, Danisia

    2013-01-01

    Intraventricular tumors represent a diagnostic problem, due to a wide range of differential diagnosis, with an important variability of tumoral histological types in adult and pediatric population. Patient, Our case is represented by a patient, aged 48 years, without any history of significant personal pathology, accusing nausea, vomiting, and intensive headache. In the morning, he became confused, having hallucinations for a short period of time, and has accused drowsiness for several weeks. Imaging (CT and MRI) shows a neoformation in the third ventricle, accompanied by bilateral lateral ventricles dilatation, with predominantly annular enhancement. During surgery, through the middle third transcallosal interhemispheric approach, it was revealed a reddish, well-demarcated intraventricular mass, well vascularized and with a firm consistency. Final pathologic diagnosis was metastatic clear cell renal carcinoma. Initial postoperative evolution was good, and then neurological and respiratory condition worsened as a bronchopneumonia lead to patient's death in 12 days after surgery. Clear cell carcinoma metastasis located in the third ventricle should be taken into consideration for patients presenting a single intraventricular lesion even they have no documented primary malignancy.

  14. Lobular Carcinoma of the Breast Metastatic to the Spleen and Accessory Spleen: Report of a Case

    PubMed Central

    2016-01-01

    Despite the fact that accessory spleen (also known as supernumerary spleen, splenunculus, or splenule) can be found in 10–30% of patients undergoing autopsies, metastatic disease occurring in this organ has been barely reported. A case of lobular breast carcinoma metastatic to the spleen and accessory spleen found incidentally at therapeutic splenectomy for severe anemia and thrombocytopenia is described. On microscopic examination both organs revealed severe fibrocongestive changes and extramedullary hematopoiesis with no obvious carcinomatous involvement. Cytokeratin 7, estrogen receptors, and GATA3 immunohistochemistry disclosed the presence of numerous metastatic breast carcinoma cells infiltrating the splenic parenchyma. This case demonstrates that metastatic carcinoma can be encountered, although rarely, in accessory spleens and that cytokeratin stain should be performed in sections of spleens and/or accessory spleens excised from cancer patients in which the presence of malignant epithelial cells is not recognized on routine sections. PMID:27672468

  15. [A Case of Recurrent Breast Cancer with Carcinomatous Pleurisy Successfully Treated with Biweekly Paclitaxel and Bevacizumab].

    PubMed

    Yoshida, Takashi; Goto, Yoshinari; Sakiyama, Kana; Kimura, Morihiko

    2016-11-01

    A 72-year-old woman underwent mastectomy with axillary lymph node dissection for left breast cancer at the age of 43 years, and was diagnosed with breast cancer metastasis to the pleura at the age of 68 years. She had been sequentially treated with hormonal therapies, but complained of a cough and dyspnea after 4 years. Chest radiography showed right pleural effusion, and cytological examination of the pleural effusion revealed adenocarcinoma cells. Biweekly paclitaxel and bevacizumab therapy was administered. Two months later, the pleural effusion had disappeared. Biweekly paclitaxel and bevacizumab therapy was continued without any severe adverse events. After 30 months, the patient has remained free of carcinomatous pleurisy recurrence. Therefore, biweekly paclitaxel and bevacizumab therapy can be safely and effectively administered to elderly patients with carcinomatous pleurisy.

  16. [Antalgic radiotherapy in lumbosacral carcinomatous neuropathies].

    PubMed

    Russi, E G; Gaeta, M; Pergolizzi, S; Settineri, N; Frosina, P; De Renzis, C

    1994-06-01

    Lumbosacral carcinomatous neuropathy (LCN) may be caused by infiltration or compression of the lumbosacral plexi and nerves from intrapelvic or paraaortic neoplasms. The authors submitted 23 patients complaining of LCN with CT documented intrapelvic or paraaortic tumors to palliative radiotherapy. Megavoltage external beam irradiation was administered using a 6-MV linear accelerator. Treatment field sizes ranged from 56 cm2 to 235 cm2 (mean: 150.54 cm2) and encompassed only the site where the disease involved the lumbosacral plexus or its branches. > or = 3 Gy/day fractions were used. Twenty-one of 22 assessable patients (95.4%) obtained LCN pain relief; 19 (86.3%) obtained complete LCN pain relief. The median time to pain progression (TPP) was 150 days (range: 39-510 days). The median survival was 165 days. Seven patients were LCN pain-free at death. Two patients are alive and LCN pain-free. The remaining 12 patients had recurrent LCN pain: four of them were reirradiated at the site of previous neuropathy and only two had partial relief again. The authors conclude that it is advisable to submit to palliative radiotherapy the inoperable disseminated and/or recurrent cancer patients complaining of LCN, to use large fractions not to occupy the extant time of their already short life-expectancy, and to design small fields to avoid acute side-effects.

  17. Metastatic Renal Cell Carcinoma to the Pancreas: A Review.

    PubMed

    Cheng, Shaun Kian Hong; Chuah, Khoon Leong

    2016-06-01

    The pancreas is an unusual site for tumor metastasis, accounting for only 2% to 5% of all malignancies affecting the pancreas. The more common metastases affecting the pancreas include renal cell carcinomas, melanomas, colorectal carcinomas, breast carcinomas, and sarcomas. Although pancreatic involvement by nonrenal malignancies indicates widespread systemic disease, metastatic renal cell carcinoma to the pancreas often represents an isolated event and is thus amenable to surgical resection, which is associated with long-term survival. As such, it is important to accurately diagnose pancreatic involvement by metastatic renal cell carcinoma on histology, especially given that renal cell carcinoma metastasis may manifest more than a decade after its initial presentation and diagnosis. In this review, we discuss the clinicopathologic findings of isolated renal cell carcinoma metastases of the pancreas, with special emphasis on separating metastatic renal cell carcinoma and its various differential diagnoses in the pancreas.

  18. Metastatic Mechanisms in Follicular Cell-Derived Thyroid Cancer

    PubMed Central

    Phay, John E.; Ringel, Matthew D.

    2013-01-01

    Thyroid cancer incidence is rising annually largely related to enhanced detection and of early stage well-differentiated primary tumors. The prognosis for patients with early stage thyroid cancer is outstanding with most patients being cured with surgery. In selected cases, I-131 is administered to treat known or suspected residual or metastatic disease. Even patients with loco-regional metastases typically have an outstanding long-term prognosis, albeit with monitoring and occasional intervention for residual or recurrent disease. In contrast, individuals with distant metastases from thyroid cancer, particular older patients with larger metastatic burdens and those with poorly differentiated tumors, have a poor prognosis. Patients with metastatic anaplastic thyroid cancer have a particularly poor prognosis. Published clinical trials indicate that transient disease control and partial remissions can be achieved with kinase inhibitor therapy directed toward angiogenic targets, and that in some cases, I-131 uptake can be enhanced. However, the direct targets of activity in metastatic lesions are incompletely defined and clear evidence that these treatments increase the duration or quality of life of patients is lacking, underscoring the need for improved knowledge regarding the metastatic process to inform the development of new therapies. In this review, we will focus on current data and hypotheses regarding key regulators of metastatic dormancy, metastatic progression, and the role of putative cancer stem cells. PMID:24036131

  19. Mechanosensitive pannexin-1 channels mediate microvascular metastatic cell survival.

    PubMed

    Furlow, Paul W; Zhang, Steven; Soong, T David; Halberg, Nils; Goodarzi, Hani; Mangrum, Creed; Wu, Y Gloria; Elemento, Olivier; Tavazoie, Sohail F

    2015-07-01

    During metastatic progression, circulating cancer cells become lodged within the microvasculature of end organs, where most die from mechanical deformation. Although this phenomenon was first described over a half-century ago, the mechanisms enabling certain cells to survive this metastasis-suppressive barrier remain unknown. By applying whole-transcriptome RNA-sequencing technology to isogenic cancer cells of differing metastatic capacities, we identified a mutation encoding a truncated form of the pannexin-1 (PANX1) channel, PANX1(1-89), as recurrently enriched in highly metastatic breast cancer cells. PANX1(1-89) functions to permit metastatic cell survival during traumatic deformation in the microvasculature by augmenting ATP release from mechanosensitive PANX1 channels activated by membrane stretch. PANX1-mediated ATP release acts as an autocrine suppressor of deformation-induced apoptosis through P2Y-purinergic receptors. Finally, small-molecule therapeutic inhibition of PANX1 channels is found to reduce the efficiency of breast cancer metastasis. These data suggest a molecular basis for metastatic cell survival on microvasculature-induced biomechanical trauma.

  20. [A Case of Recurrent Breast Cancer with Carcinomatous Pleurisy Successfully Treated with Paclitaxel and Bevacizumab after Radical Mastectomy].

    PubMed

    Sakaguchi, Nanae; Moriya, Tomoyuki; Yamazaki, Tamio; Yamagishi, Youji; Hasegawa, Shou; Tsuda, Hitoshi; Hase, Kazuo; Yamamoto, Junji

    2015-06-01

    A 61-year-old postmenopausal woman with breast cancer and carcinomatous pleurisy was successfully treated with bevacizumab and paclitaxel. In December 2008, after receiving preoperative chemotherapy consisting of q3w 4 cycles of EC (E: 90 mg/m2, C: 600 mg/m2) and 12 cycles of weekly paclitaxel (80 mg/m2), the patient underwent modified radical mastectomy with axillary lymph node dissection for right breast cancer. Pathological examination showed residual tumor cells and lymph node metastasis (pT4bN2M0, Stage III b). In July 2012, 3 and a half years later, she complained of a cough and dyspnea. Chest X-ray and computed tomography scans showed a pleural effusion involving the entire left thoracic cavity, indicating carcinomatous pleurisy. Bevacizumab and paclitaxel therapy was initiated. Soon thereafter, the pleural fluid disappeared, tumor marker levels decreased, and symptoms were ameliorated. After 6 cycles of bevacizumab and paclitaxel therapy, the patient continuously received 3 cycles of weekly paclitaxel (80 mg/m2). Two years and 4 months since the diagnosis, she has remained free of carcinomatous pleurisy recurrence. She is currently receiving hormone therapy on an outpatient basis. Bevacizumab and paclitaxel therapy is potentially effective for the treatment of patients with carcinomatous pleurisy, providing a chance for long-term survival.

  1. Marine algal fucoxanthin inhibits the metastatic potential of cancer cells.

    PubMed

    Chung, Tae-Wook; Choi, Hee-Jung; Lee, Ji-Yeon; Jeong, Han-Sol; Kim, Cheorl-Ho; Joo, Myungsoo; Choi, Jun-Yong; Han, Chang-Woo; Kim, So-Yeon; Choi, Jae-Sue; Ha, Ki-Tae

    2013-10-04

    Metastasis is major cause of malignant cancer-associated mortality. Fucoxanthin has effect on various pharmacological activities including anti-cancer activity. However, the inhibitory effect of fucoxanthin on cancer metastasis remains unclear. Here, we show that fucoxanthin isolated from brown alga Saccharina japonica has anti-metastatic activity. To check anti-metastatic properties of fucoxanthin, in vitro models including assays for invasion, migration, actin fiber organization and cancer cell-endothelial cell interaction were used. Fucoxanthin inhibited the expression and secretion of MMP-9 which plays a critical role in tumor invasion and migration, and also suppressed invasion of highly metastatic B16-F10 melanoma cells as evidenced by transwell invasion assay. In addition, fucoxanthin diminished the expressions of the cell surface glycoprotein CD44 and CXC chemokine receptor-4 (CXCR4) which play roles in migration, invasion and cancer-endothelial cell adhesion. Fucoxanthin markedly suppressed cell migration in wound healing assay and inhibited actin fiber formation. The adhesion of B16-F10 melanoma cells to the endothelial cells was significantly inhibited by fucoxanthin. Moreover, in experimental lung metastasis in vivo assay, fucoxanthin resulted in significant reduction of tumor nodules. Taken together, we demonstrate, for the first time, that fucoxanthin suppresses metastasis of highly metastatic B16-F10 melanoma cells in vitro and in vivo.

  2. Multiple metastatic renal cell carcinoma isolated to pancreas.

    PubMed

    Comunoğlu, Cem; Altaca, Gülüm; Demiralay, Ebru; Moray, Gökhan

    2012-06-01

    Renal cell carcinoma (RCC) metastases to the pancreas are reported to be rare. Isolated multiple pancreatic metastases are even rarer. We report a 68-year-old asymptomatic male patient who presented with multiple metastatic nodular lesions in the pancreas demonstrated by computerized tomography 3.5 years after radical nephrectomy performed for clear cell RCC. Spleen-preserving total pancreatectomy was performed. Gross examination revealed five well-demarcated tumoral nodules in the head, body and tail of the pancreas. Histopathological examination revealed clusters of epithelial clear cells, immunohistochemically positive for CD10 and vimentin, and negative for CK19 and chromogranin, supporting a diagnosis of metastatic RCC. The patient has remained well at 29 months post-resection, in agreement with recent experience that radical resection for multiple isolated metastatic nodular lesions can achieve improved survival and better quality of life.

  3. (-)-Gossypol reduces invasiveness in metastatic prostate cancer cells

    USDA-ARS?s Scientific Manuscript database

    Acquisition of metastatic ability by prostatic cancer cells is the most lethal aspect of prostatic cancer progression. (-)-Gossypol, a polyphenolic compound present in cottonseeds, possesses anti-proliferation and pro-apoptotic effects in various cancer cells. In this study, the differences betwee...

  4. Cold Atmospheric Plasma for Selectively Ablating Metastatic Breast Cancer Cells

    PubMed Central

    Wang, Mian; Holmes, Benjamin; Cheng, Xiaoqian; Zhu, Wei; Keidar, Michael; Zhang, Lijie Grace

    2013-01-01

    Traditional breast cancer treatments such as surgery and radiotherapy contain many inherent limitations with regards to incomplete and nonselective tumor ablation. Cold atomospheric plasma (CAP) is an ionized gas where the ion temperature is close to room temperature. It contains electrons, charged particles, radicals, various excited molecules, UV photons and transient electric fields. These various compositional elements have the potential to either enhance and promote cellular activity, or disrupt and destroy them. In particular, based on this unique composition, CAP could offer a minimally-invasive surgical approach allowing for specific cancer cell or tumor tissue removal without influencing healthy cells. Thus, the objective of this research is to investigate a novel CAP-based therapy for selectively bone metastatic breast cancer treatment. For this purpose, human metastatic breast cancer (BrCa) cells and bone marrow derived human mesenchymal stem cells (MSCs) were separately treated with CAP, and behavioral changes were evaluated after 1, 3, and 5 days of culture. With different treatment times, different BrCa and MSC cell responses were observed. Our results showed that BrCa cells were more sensitive to these CAP treatments than MSCs under plasma dose conditions tested. It demonstrated that CAP can selectively ablate metastatic BrCa cells in vitro without damaging healthy MSCs at the metastatic bone site. In addition, our study showed that CAP treatment can significantly inhibit the migration and invasion of BrCa cells. The results suggest the great potential of CAP for breast cancer therapy. PMID:24040051

  5. Carcinomatous meningitis: Leptomeningeal metastases in solid tumors

    PubMed Central

    Le Rhun, Emilie; Taillibert, Sophie; Chamberlain, Marc C.

    2013-01-01

    Leptomeningeal metastasis (LM) results from metastatic spread of cancer to the leptomeninges, giving rise to central nervous system dysfunction. Breast cancer, lung cancer, and melanoma are the most frequent causes of LM among solid tumors in adults. An early diagnosis of LM, before fixed neurologic deficits are manifest, permits earlier and potentially more effective treatment, thus leading to a better quality of life in patients so affected. Apart from a clinical suspicion of LM, diagnosis is dependent upon demonstration of cancer in cerebrospinal fluid (CSF) or radiographic manifestations as revealed by neuraxis imaging. Potentially of use, though not commonly employed, today are use of biomarkers and protein profiling in the CSF. Symptomatic treatment is directed at pain including headache, nausea, and vomiting, whereas more specific LM-directed therapies include intra-CSF chemotherapy, systemic chemotherapy, and site-specific radiotherapy. A special emphasis in the review discusses novel agents including targeted therapies, that may be promising in the future management of LM. These new therapies include anti-epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors erlotinib and gefitinib in nonsmall cell lung cancer, anti-HER2 monoclonal antibody trastuzumab in breast cancer, anti-CTLA4 ipilimumab and anti-BRAF tyrosine kinase inhibitors such as vermurafenib in melanoma, and the antivascular endothelial growth factor monoclonal antibody bevacizumab are currently under investigation in patients with LM. Challenges of managing patients with LM are manifold and include determining the appropriate patients for treatment as well as the optimal route of administration of intra-CSF drug therapy. PMID:23717798

  6. Obstructive Jaundice from Metastatic Squamous Cell Carcinoma of the Lung.

    PubMed

    Seth, Abhishek; Palmer, Thomas R; Campbell, Jason

    2016-01-01

    Obstructive jaundice from metastatic lung cancer is extremely rare. Most reported cases have had small cell cancer of lung or adenocarcinoma of lung as primary malignancy metastasizing to the biliary system. We report the case of a patient presenting with symptoms of obstructive jaundice found to have metastatic involvement of hepatobiliary system from squamous cell cancer (SCC) of lung. ERCP (endoscopic retrograde cholangiopancreatography) with biliary stenting is the procedure of choice in such patients. Our case is made unique by the fact that technical difficulties made it difficult for the anesthesiologists to intubate the patient for an ERCP. As a result percutaneous transhepatic cholangiogram (PTC) with internal-external biliary drainage was performed.

  7. Immunotherapy for metastatic renal cell carcinoma.

    PubMed

    Unverzagt, Susanne; Moldenhauer, Ines; Nothacker, Monika; Roßmeißl, Dorothea; Hadjinicolaou, Andreas V; Peinemann, Frank; Greco, Francesco; Seliger, Barbara

    2017-05-15

    Since the mid-2000s, the field of metastatic renal cell carcinoma (mRCC) has experienced a paradigm shift from non-specific therapy with broad-acting cytokines to specific regimens, which directly target the cancer, the tumour microenvironment, or both.Current guidelines recommend targeted therapies with agents such as sunitinib, pazopanib or temsirolimus (for people with poor prognosis) as the standard of care for first-line treatment of people with mRCC and mention non-specific cytokines as an alternative option for selected patients.In November 2015, nivolumab, a checkpoint inhibitor directed against programmed death-1 (PD-1), was approved as the first specific immunotherapeutic agent as second-line therapy in previously treated mRCC patients. To assess the effects of immunotherapies either alone or in combination with standard targeted therapies for the treatment of metastatic renal cell carcinoma and their efficacy to maximize patient benefit. We searched the Cochrane Library, MEDLINE (Ovid), Embase (Ovid), ISI Web of Science and registers of ongoing clinical trials in November 2016 without language restrictions. We scanned reference lists and contacted experts in the field to obtain further information. We included randomized controlled trials (RCTs) and quasi-RCTs with or without blinding involving people with mRCC. We collected and analyzed studies according to the published protocol. Summary statistics for the primary endpoints were risk ratios (RRs) and mean differences (MD) with their 95% confidence intervals (CIs). We rated the quality of evidence using GRADE methodology and summarized the quality and magnitude of relative and absolute effects for each primary outcome in our 'Summary of findings' tables. We identified eight studies with 4732 eligible participants and an additional 13 ongoing studies. We categorized studies into comparisons, all against standard therapy accordingly as first-line (five comparisons) or second-line therapy (one comparison

  8. Signet cell adenocarcinoma of the rectum metastatic to the orbit.

    PubMed

    Charles, Norman C; Ng, Diana D; Zoumalan, Christopher I

    2012-01-01

    A 24-year-old man developed abdominal carcinomatosis from signet cell carcinoma of the rectum. His only distal metastasis involved the superior orbit. Orbital pathology showed signet cells with a characteristic immunopathologic pattern. No hereditary syndrome was found. The authors identified only 5 cases in the literature describing colorectal adenocarcinoma metastatic to the orbit, with 2 showing histopathology. The authors believe that this rare case represents the first illustrating bona fide signet cell colorectal cancer involving the orbit.

  9. Functionalization of nanotextured substrates for enhanced identification of metastatic breast cancer cells.

    PubMed

    Mansur, Nuzhat; Raziul Hasan, Mohammad; Kim, Young-Tae; Iqbal, Samir M

    2017-09-20

    Metastasis is the major cause of low survival rates among cancer patients. Once cancer cells metastasize, it is extremely difficult to contain the disease. We report on a nanotextured platform for enhanced detection of metastatic cells. We captured metastatic (MDA-MDB-231) and non-metastatic (MCF-7) breast cancer cells on anti-EGFR aptamer modified plane and nanotextured substrates. Metastatic cells were seen to change their morphology at higher rates when captured on nanotextured substrates than on plane substrates. Analysis showed statistically different morphological behaviors of metastatic cells that were very pronounced on the nanotextured substrates. Several distance matrices were calculated to quantify the dissimilarity of cell shape change. Nanotexturing increased the dissimilarity of the metastatic cells and as a result the contrast between metastatic and non-metastatic cells increased. Jaccard distance measurements found that the shape change ratio of the non-metastatic and metastatic cells was enhanced from 1:1.01 to 1:1.81, going from plane to nanotextured substrates. The shape change ratio of the non-metastatic to metastatic cells improved from 1:1.48 to 1:2.19 for the Hausdorff distance and from 1:1.87 to 1:4.69 for the Mahalanobis distance after introducing nanotexture. Distance matrix analysis showed that nanotexture increased the shape change ratios of non-metastatic and metastatic cells. Hence, the detectability of metastatic cells increased. These calculated matrices provided clear and explicit measures to discriminate single cells for their metastatic state on functional nanotextured substrates.

  10. Functionalization of nanotextured substrates for enhanced identification of metastatic breast cancer cells

    NASA Astrophysics Data System (ADS)

    Mansur, Nuzhat; Raziul Hasan, Mohammad; Kim, Young-tae; Iqbal, Samir M.

    2017-09-01

    Metastasis is the major cause of low survival rates among cancer patients. Once cancer cells metastasize, it is extremely difficult to contain the disease. We report on a nanotextured platform for enhanced detection of metastatic cells. We captured metastatic (MDA-MDB-231) and non-metastatic (MCF-7) breast cancer cells on anti-EGFR aptamer modified plane and nanotextured substrates. Metastatic cells were seen to change their morphology at higher rates when captured on nanotextured substrates than on plane substrates. Analysis showed statistically different morphological behaviors of metastatic cells that were very pronounced on the nanotextured substrates. Several distance matrices were calculated to quantify the dissimilarity of cell shape change. Nanotexturing increased the dissimilarity of the metastatic cells and as a result the contrast between metastatic and non-metastatic cells increased. Jaccard distance measurements found that the shape change ratio of the non-metastatic and metastatic cells was enhanced from 1:1.01 to 1:1.81, going from plane to nanotextured substrates. The shape change ratio of the non-metastatic to metastatic cells improved from 1:1.48 to 1:2.19 for the Hausdorff distance and from 1:1.87 to 1:4.69 for the Mahalanobis distance after introducing nanotexture. Distance matrix analysis showed that nanotexture increased the shape change ratios of non-metastatic and metastatic cells. Hence, the detectability of metastatic cells increased. These calculated matrices provided clear and explicit measures to discriminate single cells for their metastatic state on functional nanotextured substrates.

  11. Cell stiffness is a biomarker of the metastatic potential of ovarian cancer cells

    NASA Astrophysics Data System (ADS)

    Xu, Wenwei; Mezencev, Roman; Kim, Byungkyu; Wang, Lijuan; McDonald, John; Sulchek, Todd; Sulchek Team; McDonald Team

    2013-03-01

    The metastatic potential of cells is an important parameter in the design of optimal strategies for the personalized treatment of cancer. Using atomic force microscopy (AFM), we show that ovarian cancer cells are generally softer and display lower intrinsic variability in cell stiffness than non-malignant ovarian epithelial cells. A detailed study of highly invasive ovarian cancer cells (HEY A8) and their less invasive parental cells (HEY), demonstrates that deformability can serve as an accurate biomarker of metastatic potential. Comparative gene expression profiling indicate that the reduced stiffness of highly metastatic HEY A8 cells is associated with actin cytoskeleton remodeling, microscopic examination of actin fiber structure in these cell lines is consistent with this prediction. Our results indicate that cell stiffness not only distinguishes ovarian cancer cells from non-malignant cells, but may also be a useful biomarker to evaluate the relative metastatic potential of ovarian and perhaps other types of cancer cells.

  12. AFM-based analysis of human metastatic cancer cells

    NASA Astrophysics Data System (ADS)

    Cross, Sarah E.; Jin, Yu-Sheng; Tondre, Julianne; Wong, Roger; Rao, Jian Yu; Gimzewski, James K.

    2008-09-01

    Recently biomechanics of cancer cells, in particular stiffness or elasticity, has been identified as an important factor relating to cancer cell function, adherence, motility, transformation and invasion. We report on the nanomechanical responses of metastatic cancer cells and benign mesothelial cells taken from human body cavity fluids using atomic force microscopy. Following our initial study (Cross et al 2007 Nat. Nanotechnol. 2 780-3), we report on the biophysical properties of patient-derived effusion cells and address the influence of cell morphology on measured cell stiffness. Using a cytocentrifugation method, which yields morphologically indistinguishable cells that can be prepared in 1 min and avoids any possible artifacts due to 12 h ex vivo culture, we find that metastatic tumor cells are more than 80% softer than benign cells with a distribution over six times narrower than that of normal cells. Consistent with our previous study, which yielded distinguishable cell populations based on ex vivo growth and morphological characteristics, our results show it is unlikely that morphology alone is sufficient to explain the difference in elastic moduli for these two cell types. Moreover, analysis of non-specific cell adhesion inherent to tumor and normal cells collected from patients show surface adhesion of tumor cells is ~33% less adhesive compared to that of normal cells. Our findings indicate that biomechanical-based functional analysis may provide an additional platform for cytological evaluation and diagnosis of cancer in the future.

  13. Acute megakaryoblastic leukemia. Blast cell aggregates simulating metastatic tumor.

    PubMed

    Pui, C H; Rivera, G; Mirro, J; Stass, S; Peiper, S; Murphy, S B

    1985-11-01

    Acute megakaryoblastic leukemia is a rare leukemia that can present diagnostic problems. We describe two children who have this disease and had clumps of blast cells in their bone marrow, a finding usually attributed to metastatic tumor. The megakaryocytic origin of the cells was supported by their cytochemical staining pattern (positive alpha-naphthyl acetate esterase resistant to sodium fluoride inhibition and negative alpha-naphthyl butyrate esterase) and by the presence of factor VIII-related antigen. Ultrastructural studies of blast cells from one patient demonstrated platelet peroxidase. The mechanism of blast cell clump formation in these cases is unknown; nevertheless, awareness that this feature can occur in acute megakaryoblastic leukemia may avoid a misdiagnosis of metastatic solid tumor.

  14. Extracellular matrix mediators of metastatic cell colonization characterized using scaffold mimics of the pre-metastatic niche

    PubMed Central

    Aguado, Brian A.; Caffe, Jordan R.; Nanavati, Dhaval; Rao, Shreyas S.; Bushnell, Grace G.; Azarin, Samira M.; Shea, Lonnie D.

    2016-01-01

    Metastatic tumor cells colonize the pre-metastatic niche, which is a complex microenvironment consisting partially of extracellular matrix (ECM) proteins. We sought to identify and validate novel contributors to tumor cell colonization using ECM coated poly(ε-caprolactone) (PCL) scaffolds as mimics of the pre-metastatic niche. Utilizing orthotopic breast cancer mouse models, fibronectin and collagen IV-coated scaffolds implanted in the subcutaneous space captured colonizing tumor cells, showing a greater than 2-fold increase in tumor cell accumulation at the implant site compared to uncoated scaffolds. As a strategy to identify additional ECM colonization contributors, decellularized matrix (DCM) from lungs and livers containing metastatic tumors were characterized. In vitro, metastatic cell adhesion was increased on DCM coatings from diseased organs relative to healthy DCM. Furthermore, in vivo implantations of diseased DCM-coated scaffolds had increased tumor cell colonization relative to healthy DCM coatings. Mass-spectrometry proteomics was performed on healthy and diseased DCM to identify candidates associated with colonization. Myeloperoxidase was identified as abundantly present in diseased organs and validated as a contributor to colonization using myeloperoxidase-coated scaffold implants. This work identified novel ECM proteins associated with colonization using decellularization and proteomics techniques and validated candidates using a scaffold to mimic the pre-metastatic niche. PMID:26844426

  15. The dual role of TLR3 in metastatic cell line.

    PubMed

    Matijevic, Tanja; Pavelic, Jasminka

    2011-10-01

    Toll-like receptors (TLRs) are members of transmembrane proteins that recognize conserved molecular motifs of viral and bacterial origin and initiate innate immune response. As the role of TLRs in tumors cells is still not clear, our aim was to investigate the role of TLR3 in primary tumor and metastatic cells (SW480, SW620, FaDu and Detroit 562). We have reported here on the dual role of TLR3 in pharynx metastatic cell line (Detroit 562); on one hand TLR3 activation drove cells to apoptosis while on the other its stimulation contributed to tumor progression by altering the expression of tumor promoting genes (PLAUR, RORB) and enhancing the cell migration potential. In addition, we have shown TLR3 signaling pathway is functional in another metastatic cancer cell line (SW620) suggesting TLR3 might be important in the process of tumor metastasis. Since TLR3 agonists have been used in tumor therapy with the aim to activate immune system, scientific contribution of this work is drawing attention to the importance of further work on this topic, especially pro-tumor effect of TLR3, in order to avoid possible side-effects.

  16. Metastatic phenotype is regulated by estrogen in thyroid cells.

    PubMed

    Rajoria, Shilpi; Suriano, Robert; Shanmugam, Arulkumaran; Wilson, Yushan Lisa; Schantz, Stimson P; Geliebter, Jan; Tiwari, Raj K

    2010-01-01

    Over 200 million people worldwide are affected by thyroid proliferative diseases, including cancer, adenoma, and goiter, annually. The incidences of thyroid malignancies are three to four times higher in women, suggesting the possible involvement of estrogen. Based on this observed sex bias, we hypothesize that estrogen modulates the growth and metastatic propensity of thyroid cancer cells. In this study, two thyroid cell lines (Nthy-ori 3-1 and BCPAP) were evaluated for the presence of estrogen receptor (ER) by Western blot analysis and estrogen responsiveness by using a cell proliferation assay. In addition, the effect of estradiol (E(2)) on modulation of metastatic phenotype was determined by using in vitro adhesion, migration, and invasion assays. Thyroid cells expressed a functionally active ER-alpha and ER-beta as evidenced by 50-150% enhancement of proliferation in the presence of E(2). E(2) also enhanced adhesion, migration, and invasion of thyroid cells in an in vitro experimental model system that, based on our results, is modulated by beta-catenin. Our data provide evidence that the higher incidence of thyroid cancer in women is potentially attributed to the presence of a functional ER that participates in cellular processes contributing to enhanced mitogenic, migratory, and invasive properties of thyroid cells. These findings will enable and foster the possible development of antiestrogenic therapy targeting invasion and migration, thus affecting metastatic propensity.

  17. Cell stiffness is a biomarker of the metastatic potential of ovarian cancer cells.

    PubMed

    Xu, Wenwei; Mezencev, Roman; Kim, Byungkyu; Wang, Lijuan; McDonald, John; Sulchek, Todd

    2012-01-01

    The metastatic potential of cells is an important parameter in the design of optimal strategies for the personalized treatment of cancer. Using atomic force microscopy (AFM), we show, consistent with previous studies conducted in other types of epithelial cancer, that ovarian cancer cells are generally softer and display lower intrinsic variability in cell stiffness than non-malignant ovarian epithelial cells. A detailed examination of highly invasive ovarian cancer cells (HEY A8) relative to their less invasive parental cells (HEY), demonstrates that deformability is also an accurate biomarker of metastatic potential. Comparative gene expression analyses indicate that the reduced stiffness of highly metastatic HEY A8 cells is associated with actin cytoskeleton remodeling and microscopic examination of actin fiber structure in these cell lines is consistent with this prediction. Our results indicate that cell stiffness may be a useful biomarker to evaluate the relative metastatic potential of ovarian and perhaps other types of cancer cells.

  18. Murine macrophage heparanase: inhibition and comparison with metastatic tumor cells

    SciTech Connect

    Savion, N.; Disatnik, M.H.; Nevo, Z.

    1987-01-01

    Circulating macrophages and metastatic tumor cells can penetrate the vascular endothelium and migrate from the circulatory system to extravascular compartments. Both activated murine macrophages and different metastatic tumor cells attach, invade, and penetrate confluent vascular endothelial cell monolayer in vitro, by degrading heparan sulfate proteoglycans in the subendothelial extracellular matrix. The sensitivity of the enzymes from the various sources degrading the heparan sulfate proteoglycan was challenged and compared by a series of inhibitors. Activated macrophages demonstrate a heparanase with an endoglycosidase activity that cleaves from the (/sup 35/S)O/sub 4//sup -/-labeled heparan sulfate proteoglycans of the extracellular matrix 10 kDa glycosaminoglycan fragments. The degradation of (/sup 35/S)O/sub 4//sup -/-labeled extracellular matrix proteoglycans by the macrophages' heparanase is significantly inhibited in the presence of heparan sulfate (10..mu..g/ml), arteparon (10..mu..g/ml), and heparin at a concentration of 3 ..mu..g/ml. Degradation of this heparan sulfate proteoglycan is a two-step sequential process involving protease activity followed by heparanase activity. B16-BL6 metastatic melanoma cell heparanase, which is also a cell-associated enzyme, was inhibited by heparin to the same extent as the macrophage haparanase. On the other hand, heparanase of the highly metastatic variant (ESb) of a methylcholanthrene-induced T lymphoma, which is an extracellular enzyme released by the cells to the incubation medium, was more sensitive to heparin and arteparon than the macrophages' heparanase. These results may indicate the potential use of heparin or other glycosaminoglycans as specific and differential inhibitors for the formation in certain cases of blood-borne tumor metastasis.

  19. Immunotherapy in Metastatic Renal Cell Carcinoma: A Comprehensive Review.

    PubMed

    Raman, Rachna; Vaena, Daniel

    2015-01-01

    Localized renal cell carcinoma (RCC) is often curable by surgery alone. However, metastatic RCC is generally incurable. In the 1990s, immunotherapy in the form of cytokines was the mainstay of treatment for metastatic RCC. However, responses were seen in only a minority of highly selected patients with substantial treatment-related toxicities. The advent of targeted agents such as vascular endothelial growth factor tyrosine kinase inhibitors VEGF-TKIs and mammalian target of rapamycin (mTOR) inhibitors led to a change in this paradigm due to improved response rates and progression-free survival, a better safety profile, and the convenience of oral administration. However, most patients ultimately progress with about 12% being alive at 5 years. In contrast, durable responses lasting 10 years or more are noted in a minority of those treated with cytokines. More recently, an improved overall survival with newer forms of immunotherapy in other malignancies (such as melanoma and prostate cancer) has led to a resurgence of interest in immune therapies in metastatic RCC. In this review we discuss the rationale for immunotherapy and recent developments in immunotherapeutic strategies for treating metastatic RCC.

  20. Vismodegib: in locally advanced or metastatic basal cell carcinoma.

    PubMed

    Keating, Gillian M

    2012-07-30

    Vismodegib is the first Hedgehog pathway inhibitor to be approved in the US, where it is indicated for the treatment of adults with metastatic basal cell carcinoma (BCC), or with locally advanced BCC that has recurred following surgery or who are not candidates for surgery, and who are not candidates for radiation. Vismodegib selectively and potently inhibits the Hedgehog signalling pathway by binding to Smoothened, thereby inhibiting the activation of Hedgehog target genes. Oral vismodegib was effective in the treatment of patients with locally advanced (n = 63) or metastatic (n = 33) BCC, according to the results of an ongoing, noncomparative, multinational, pivotal, phase II trial (ERIVANCE BCC). In this trial (using a clinical cutoff date of 26 November 2010), the independent review facility overall response rate was 42.9% in patients with locally advanced BCC and 30.3% in patients with metastatic BCC. In both patients with locally advanced BCC and those with metastatic BCC, the median duration of response was 7.6 months and median progression-free survival was 9.5 months. Oral vismodegib had an acceptable tolerability profile in patients with advanced BCC.

  1. Adoptive Cell Therapy for Metastatic Melanoma.

    PubMed

    Merhavi-Shoham, Efrat; Itzhaki, Orit; Markel, Gal; Schachter, Jacob; Besser, Michal J

    Adoptive cell therapy (ACT) of tumor-infiltrating lymphocytes (TILs) is a powerful form of immunotherapy by inducing durable complete responses that significantly extend the survival of melanoma patients. Mutation-derived neoantigens were recently identified as key factors for tumor recognition and rejection by TILs. The isolation of T-cell receptor (TCR) genes directed against neoantigens and their retransduction into peripheral T cells may provide a new form of ACT.Genetic modifications of T cells with chimeric antigen receptors (CARs) have demonstrated remarkable clinical results in hematologic malignancies, but are so far less effective in solid tumors. Only very limited reports exist in melanoma. Progress in CAR T-cell engineering, including neutralization of inhibitory signals or additional safety switches, may open opportunities also in melanoma.We review clinical results and latest developments of adoptive therapies with TILs, T-cell receptor, and CAR-modified T cells and discuss future directions for the treatment of melanoma.

  2. Coexistence of microfilaria with metastatic adenocarcinomatous deposit from breast in axillary lymph node cytology: A rare association

    PubMed Central

    Sahoo, Nibedita; Saha, Arpita; Mishra, Pritinanda

    2017-01-01

    Filariasis is a global social health problem of tropical and sub tropical countries like India. W.bancrofti accounts for 95% of cases of lymphatic filariasis. Microfilaria in cytosmears are a rare finding. We report a case of 55 year old female presented with right axillary swelling with ipsilateral breast lump. Cytosmears from the lymph node aspirate showed metastatic adenocarcinomatous deposits and a bunch of microfilariae surrounding the tumor cells and the aspirate from the breast shows ductal carcinoma. We report an additional case of a rare association of microfilaria co-existing with carcinomatous deposit in the lymph node. PMID:28182075

  3. Quantitative method of measuring cancer cell urokinase and metastatic potential

    NASA Technical Reports Server (NTRS)

    Morrison, Dennis R. (Inventor)

    1993-01-01

    The metastatic potential of tumors can be evaluated by the quantitative detection of urokinase and DNA. The cell sample selected for examination is analyzed for the presence of high levels of urokinase and abnormal DNA using analytical flow cytometry and digital image analysis. Other factors such as membrane associated urokinase, increased DNA synthesis rates and certain receptors can be used in the method for detection of potentially invasive tumors.

  4. Association between shortage of energy supply and nuclear gene mutations leading to carcinomatous transformation.

    PubMed

    DU, Jianping

    2016-01-01

    Anaerobic bacteria use glycolysis, an oxygen-independent metabolic pathway, whereas energy metabolism in the evolved eukaryotic cell is performed via oxidative phosphorylation, with all eukaryotic cell activities depending upon high energy consumption. However, in cancer cells evolving from eukaryotic cells, the energy metabolism switches from oxidative phosphorylation to glycolysis. The shortage of energy supply induces cancer cells to acquire specific characteristics. Base pair renewal is the most energy-consuming process in the cell, and shortage of energy supply may lead to errors in this process; the more prominent the shortage in energy supply, the more errors are likely to occur in base pair renewal, resulting in gene mutations and expression of cancer cell characteristics. Thus, shortage of energy supply is associated with carcinomatous transformation.

  5. Postradiation lumbosacral radiculopathy with spinal root cavernomas mimicking carcinomatous meningitis

    PubMed Central

    Ducray, François; Guillevin, Rémy; Psimaras, Dimitri; Sanson, Marc; Mokhtari, Karima; Delanian, Sylvie; Navarro, Soledad; Maisonobe, Thierry; Cornu, Philippe; Hoang-Xuan, Khê; Delattre, Jean-Yves; Pradat, Pierre-François

    2008-01-01

    Lumbosacral radiculopathy is a rare complication of radiotherapy and may be challenging to differentiate from diagnosis of a tumor recurrence. We reviewed the records of three patients with a past history of cancer and radiotherapy who were referred for suspicion of carcinomatous meningitis on lumbar MRI, but whose final diagnosis was radiation-induced lumbosacral radiculopathy. The three patients developed a progressive lumbosacral radiculopathy at 20, 13, and 47 years after lumbar radiotherapy delivered for renal cancer, Hodgkin’s disease, and a seminoma, respectively. MRI showed a diffuse, nodular enhancement of the cauda equina nerve roots on T1 sequences, suggestive of leptomeningeal metastasis. A slowly progressive clinical course over several years and negative cerebrospinal fluid cytologic analysis ruled out the diagnosis of carcinomatous meningitis. Because of the radiologic findings, a biopsy was performed in two patients. In the first, a biopsy limited to the arachnoid excluded a malignant infiltration. In the second, a biopsy of the enhancing lesions demonstrated spinal root cavernomas. These observations, together with three recent case reports in the literature, delineate a syndrome of “radiation-induced lumbosacral radiculopathy with multiple spinal root cavernomas” that mimics carcinomatous meningitis on MRI. Its diagnosis is important in order to avoid inappropriate treatment and useless or dangerous spinal root biopsies. PMID:18755918

  6. Metastatic non-small cell lung cancer presenting with an orbital metastasis: a case report.

    PubMed

    Azad, Arun

    2008-08-13

    Metastatic disease to the orbit occurs in up to 7% of cancers. In approximately 20% of cases, there is no diagnosis of cancer at the time of presentation with orbital metastatic disease. This is a case of a 53-year-old female smoker whose initial presentation of metastatic non-small cell lung cancer was with an orbital metastasis.

  7. KLF4-dependent perivascular cell plasticity mediates pre-metastatic niche formation and metastasis.

    PubMed

    Murgai, Meera; Ju, Wei; Eason, Matthew; Kline, Jessica; Beury, Daniel W; Kaczanowska, Sabina; Miettinen, Markku M; Kruhlak, Michael; Lei, Haiyan; Shern, Jack F; Cherepanova, Olga A; Owens, Gary K; Kaplan, Rosandra N

    2017-10-01

    A deeper understanding of the metastatic process is required for the development of new therapies that improve patient survival. Metastatic tumor cell growth and survival in distant organs is facilitated by the formation of a pre-metastatic niche that is composed of hematopoietic cells, stromal cells and extracellular matrix (ECM). Perivascular cells, including vascular smooth muscle cells (vSMCs) and pericytes, are involved in new vessel formation and in promoting stem cell maintenance and proliferation. Given the well-described plasticity of perivascular cells, we hypothesized that perivascular cells similarly regulate tumor cell fate at metastatic sites. We used perivascular-cell-specific and pericyte-specific lineage-tracing models to trace the fate of perivascular cells in the pre-metastatic and metastatic microenvironments. We show that perivascular cells lose the expression of traditional vSMC and pericyte markers in response to tumor-secreted factors and exhibit increased proliferation, migration and ECM synthesis. Increased expression of the pluripotency gene Klf4 in these phenotypically switched perivascular cells promoted a less differentiated state, characterized by enhanced ECM production, that established a pro-metastatic fibronectin-rich environment. Genetic inactivation of Klf4 in perivascular cells decreased formation of a pre-metastatic niche and metastasis. Our data revealed a previously unidentified role for perivascular cells in pre-metastatic niche formation and uncovered novel strategies for limiting metastasis.

  8. Metastatic cancer stem cells: from the concept to therapeutics.

    PubMed

    Liao, Wen-Ting; Ye, Ya-Ping; Deng, Yong-Jian; Bian, Xiu-Wu; Ding, Yan-Qing

    2014-01-01

    Metastatic cancer stem cells (MCSCs) refer to a subpopulation of cancer cells with both stem cell properties and invasion capabilities that contribute to cancer metastasis. MCSCs have capability of self-renewal, potentials of multiple differentiation and development and/or reconstruction of cancer tissues. As compared with stationary cancer stem cells, MCSCs are capable of invasion to normal tissues such as vasculatures, resistance to chemo- and/or radio-therapies, escape from immune surveillance, survival in circulation and formation of metastasis. MCSCs are derived from invasive cancer stem cells (iCSCs) due to the plasticity of cancer stem cells, which is one of the characteristics of cancer cell heterogeneity. Both stages of iCSCs and MSCSs are the potential therapeutic targets for cancer metastasis in the future strategies of personalized cancer therapy.

  9. Immune cells in primary and metastatic gastrointestinal stromal tumors (GIST).

    PubMed

    Cameron, Silke; Gieselmann, Marieke; Blaschke, Martina; Ramadori, Giuliano; Füzesi, Laszlo

    2014-01-01

    We have previously described immune cells in untreated primary gastrointestinal stromal tumors (GIST). Here we compare immune cells in metastatic and primary GIST, and describe their chemoattractants. For this purpose, tissue microarrays from 196 patients, 188 primary and 51 metastasized GIST were constructed for paraffin staining. Quantitative analysis was performed for cells of macrophage lineage (Ki-M1P, CD68), T-cells (CD3, CD56) and B-cells (CD20). Chemokine gene-expression was evaluated by real-time RT-PCR. Immuno-localisation was verified by immunofluorescence. Ki-M1P+ cells were the predominant immune cells in both primary and metastatic GIST (2 8.8% ± 7.1, vs. 26.7% ± 6.3). CD68+ macrophages were significantly fewer, with no significant difference between primary GIST (3.6% ± 2.1) and metastases (4.6% ± 1.5). CD3+ T-cells were the most dominant lymphocytes with a significant increase in metastases (7.3% ± 2.3 vs. 2.2% ± 1.8 in primary GIST, P < 0.01). The percentage of CD56+ NK-cells was 1.1% ± 0.9 in the primary, and 2.4 ± 0.7 (P < 0.05) in the metastases. The number of CD20+ B-cells was generally low with 0.6% ± 0.7 in the primary and 1.8% ± 0.3 (P < 0.05) in the metastases. Analysis of the metastases showed significantly more Ki-M1P+ cells in peritoneal metastases (31.8% ± 7.4 vs. 18.2% ± 3.7, P < 0.01), whilst CD3+ T-cells were more common in liver metastases (11.7% ± 1.8 vs. 4.4% ± 2.6, P < 0.01). The highest transcript expression was seen for monocyte chemotactic protein 1 (MCP1/CCL2), macrophage inflammatory protein 1α (MIP-1α/CCL3) and the pro-angiogenic growth-related oncoprotein 1 (Gro-α/CXCL-1). Whilst the ligands were predominantly expressed in tumor cells, their receptors were mostly present in immune cells. This locally specific microenvironment might influence neoplastic progression of GIST at the different metastatic sites.

  10. Immune cells in primary and metastatic gastrointestinal stromal tumors (GIST)

    PubMed Central

    Cameron, Silke; Gieselmann, Marieke; Blaschke, Martina; Ramadori, Giuliano; Füzesi, Laszlo

    2014-01-01

    We have previously described immune cells in untreated primary gastrointestinal stromal tumors (GIST). Here we compare immune cells in metastatic and primary GIST, and describe their chemoattractants. For this purpose, tissue microarrays from 196 patients, 188 primary and 51 metastasized GIST were constructed for paraffin staining. Quantitative analysis was performed for cells of macrophage lineage (Ki-M1P, CD68), T-cells (CD3, CD56) and B-cells (CD20). Chemokine gene-expression was evaluated by real-time RT-PCR. Immuno-localisation was verified by immunofluorescence. Ki-M1P+ cells were the predominant immune cells in both primary and metastatic GIST (2 8.8% ± 7.1, vs. 26.7% ± 6.3). CD68+ macrophages were significantly fewer, with no significant difference between primary GIST (3.6% ± 2.1) and metastases (4.6% ± 1.5). CD3+ T-cells were the most dominant lymphocytes with a significant increase in metastases (7.3% ± 2.3 vs. 2.2% ± 1.8 in primary GIST, P < 0.01). The percentage of CD56+ NK-cells was 1.1% ± 0.9 in the primary, and 2.4 ± 0.7 (P < 0.05) in the metastases. The number of CD20+ B-cells was generally low with 0.6% ± 0.7 in the primary and 1.8% ± 0.3 (P < 0.05) in the metastases. Analysis of the metastases showed significantly more Ki-M1P+ cells in peritoneal metastases (31.8% ± 7.4 vs. 18.2% ± 3.7, P < 0.01), whilst CD3+ T-cells were more common in liver metastases (11.7% ± 1.8 vs. 4.4% ± 2.6, P < 0.01). The highest transcript expression was seen for monocyte chemotactic protein 1 (MCP1/CCL2), macrophage inflammatory protein 1α (MIP-1α/CCL3) and the pro-angiogenic growth-related oncoprotein 1 (Gro-α/CXCL-1). Whilst the ligands were predominantly expressed in tumor cells, their receptors were mostly present in immune cells. This locally specific microenvironment might influence neoplastic progression of GIST at the different metastatic sites. PMID:25120735

  11. Changes in cytoskeletal dynamics and nonlinear rheology with metastatic ability in cancer cell lines

    NASA Astrophysics Data System (ADS)

    Coughlin, Mark F.; Fredberg, Jeffrey J.

    2013-12-01

    Metastatic outcome is impacted by the biophysical state of the primary tumor cell. To determine if changes in cancer cell biophysical properties facilitate metastasis, we quantified cytoskeletal biophysics in well-characterized human skin, bladder, prostate and kidney cell line pairs that differ in metastatic ability. Using magnetic twisting cytometry with optical detection, cytoskeletal dynamics was observed through spontaneous motion of surface bound marker beads and nonlinear rheology was characterized through large amplitude forced oscillations of probe beads. Measurements of cytoskeletal dynamics and nonlinear rheology differed between strongly and weakly metastatic cells. However, no set of biophysical parameters changed systematically with metastatic ability across all cell lines. Compared to their weakly metastatic counterparts, the strongly metastatic kidney cancer cells exhibited both increased cytoskeletal dynamics and stiffness at large deformation which are thought to facilitate the process of vascular invasion.

  12. Changes in cytoskeletal dynamics and nonlinear rheology with metastatic ability in cancer cell lines.

    PubMed

    Coughlin, Mark F; Fredberg, Jeffrey J

    2013-12-01

    Metastatic outcome is impacted by the biophysical state of the primary tumor cell. To determine if changes in cancer cell biophysical properties facilitate metastasis, we quantified cytoskeletal biophysics in well-characterized human skin, bladder, prostate and kidney cell line pairs that differ in metastatic ability. Using magnetic twisting cytometry with optical detection, cytoskeletal dynamics was observed through spontaneous motion of surface bound marker beads and nonlinear rheology was characterized through large amplitude forced oscillations of probe beads. Measurements of cytoskeletal dynamics and nonlinear rheology differed between strongly and weakly metastatic cells. However, no set of biophysical parameters changed systematically with metastatic ability across all cell lines. Compared to their weakly metastatic counterparts, the strongly metastatic kidney cancer cells exhibited both increased cytoskeletal dynamics and stiffness at large deformation which are thought to facilitate the process of vascular invasion.

  13. Extracellular matrix mediators of metastatic cell colonization characterized using scaffold mimics of the pre-metastatic niche.

    PubMed

    Aguado, Brian A; Caffe, Jordan R; Nanavati, Dhaval; Rao, Shreyas S; Bushnell, Grace G; Azarin, Samira M; Shea, Lonnie D

    2016-03-01

    Metastatic tumor cells colonize the pre-metastatic niche, which is a complex microenvironment consisting partially of extracellular matrix (ECM) proteins. We sought to identify and validate novel contributors to tumor cell colonization using ECM-coated poly(ε-caprolactone) (PCL) scaffolds as mimics of the pre-metastatic niche. Utilizing orthotopic breast cancer mouse models, fibronectin and collagen IV-coated scaffolds implanted in the subcutaneous space captured colonizing tumor cells, showing a greater than 2-fold increase in tumor cell accumulation at the implant site compared to uncoated scaffolds. As a strategy to identify additional ECM colonization contributors, decellularized matrix (DCM) from lungs and livers containing metastatic tumors were characterized. In vitro, metastatic cell adhesion was increased on DCM coatings from diseased organs relative to healthy DCM. Furthermore, in vivo implantations of diseased DCM-coated scaffolds had increased tumor cell colonization relative to healthy DCM coatings. Mass-spectrometry proteomics was performed on healthy and diseased DCM to identify candidates associated with colonization. Myeloperoxidase was identified as abundantly present in diseased organs and validated as a contributor to colonization using myeloperoxidase-coated scaffold implants. This work identified novel ECM proteins associated with colonization using decellularization and proteomics techniques and validated candidates using a scaffold to mimic the pre-metastatic niche. The pre-metastatic niche consists partially of ECM proteins that promote metastatic cell colonization to a target organ. We present a biomaterials-based approach to mimic this niche and identify ECM mediators of colonization. Using murine breast cancer models, we implanted microporous PCL scaffolds to recruit colonizing tumor cells in vivo. As a strategy to modulate colonization, we coated scaffolds with various ECM proteins, including decellularized lung and liver matrix from

  14. Metastatic renal cell carcinoma in a meningioma: a case report.

    PubMed

    Han, H S; Kim, E Y; Han, J Y; Kim, Y B; Hwang, T S; Chu, Y C

    2000-10-01

    Tumor-to-tumor metastasis is rare. We report a case of metastatic renal cell carcinoma in meningioma. A 67-year-old woman presented a two-week history of motor dysphagia and decreased short-term memory. She had undergone a left radical nephrectomy for a renal cell carcinoma 7 years ago, and had not received any adjuvant therapy. MRI disclosed a 3.0 x 3.0 x 3.0-cm sized round tentorial-based extraaxial mass with peritumoral edema in the left posterior temporal lobe. During operation, the tumor was found to be an encapsulated mass firmly attached to the tentorium. Histologically, the tumor was a meningotheliomatous meningioma extensively infiltrated by metastatic renal cell carcinoma, accompanying widespread coagulative necrosis. Immunohistochemical staining for cytokeratin revealed strong positivity only in the renal cell carcinoma component. The patient's postoperative course was uneventful. Post-operative radiation therapy was applied to the whole brain. Three months after operation, the patient developed right hemiparesis and dysphagia. Brain MRI at that time did not reveal recurrence or any other causative lesions, although the whole body scan disclosed uptake at the second lumbar vertebra and rib. The patient refused further treatment.

  15. Management of metastatic renal cell carcinoma – mini review

    PubMed Central

    Pandey, Himanshu; Sood, Swapan

    2015-01-01

    The management of metastatic renal cell carcinoma (mRCC) has evolved considerably in the last decade. A number of different systemic molecular targeted agents that have been recently approved have improved the survival of patients with mRCC. This mini-review focuses on the implementation of multi-modality therapy in the management of mRCC and the approved indications of the various available novel agents. These novel agents have expanded our armamentarium and improved clinical outcomes of this challenging disease that has considerable biological heterogeneity and clinical variability. PMID:28326262

  16. EphA2 Is a Potential Player of Malignant Cellular Behavior in Non-Metastatic Renal Cell Carcinoma Cells but Not in Metastatic Renal Cell Carcinoma Cells.

    PubMed

    Cho, Min Chul; Cho, Sung Yong; Yoon, Cheol Yong; Lee, Seung Bae; Kwak, Cheol; Kim, Hyeon Hoe; Jeong, Hyeon

    2015-01-01

    To investigate the role of EphA2 in malignant cellular behavior in renal cell carcinoma (RCC) cells and whether FAK/RhoA signaling can act as downstream effectors of EphA2 on RCC cells. Expression of EphA2 protein in non-metastatic RCC (Caki-2 and A498), metastatic RCC cells (Caki-1 and ACHN), HEK-293 cells and prostate cancer cells (PC-3 and DU-145; positive controls of EphA2 expression) was evaluated by Western blot. Changes in mRNA or protein expression of EphA2, FAK or membrane-bound RhoA following EphA2, FAK or RhoA small interfering RNA (siRNA) transfection were determined by reverse transcription polymerase chain reaction or Western blot. The effect of siRNA treatment on cellular viability, apoptosis and invasion was analyzed by cell counting kit-8, Annexin-V and modified Matrigel-Boyden assays, respectively. In all RCC cell lines, the expression of EphA2 protein was detectable at variable levels; however, in HEK-293 cells, EphA2 expression was very low. Treatment with EphA2 siRNA significantly reduced the expression of EphA2 mRNA and protein in all RCC cell lines. For non-metastatic RCC cells (Caki-2 and A498) but not metastatic RCC cells (Caki-1 and ACHN), cellular viability, invasiveness, resistance to apoptosis, expression of membrane-bound RhoA protein and FAK phosphorylation were significantly decreased in EphA2 siRNA-treated cells compared to the control. In non-metastatic RCC cells, FAK siRNA significantly attenuated the invasiveness, resistance to apoptosis, as well as expression of membrane-bound RhoA protein without changing protein expression of EphA2. RhoA siRNA significantly decreased the malignant cellular behavior and expression of membrane-bound RhoA protein without changing EphA2 protein expression or FAK phosphorylation. Our data provide the first functional evidence that the EphA2/FAK/RhoA signaling pathway plays a critical role in the malignant cellular behavior of RCC and appears to be functional particularly in the early stage of

  17. Kinetics of metastatic breast cancer cell trafficking in bone

    PubMed Central

    Phadke, Pushkar A.; Mercer, Robyn R.; Harms, John F.; Jia, Yujiang; Frost, Andra R.; Jewell, Jennifer L.; Bussard, Karen M.; Nelson, Shakira; Moore, Cynthia; Kappes, John C.; Gay, Carol V.; Mastro, Andrea M.; Welch, Danny R.

    2006-01-01

    Purpose In vivo studies have focused on the latter stages of the bone metastatic process (osteolysis), while little is known about earlier events, e.g., arrival, localization, initial colonization. Defining these initial steps may potentially identify critical points susceptible to therapeutic intervention. Experimental Design MDA-MB-435 human breast cancer cells engineered with green fluorescent protein (GFP) were injected into the cardiac left ventricle of athymic mice. Femurs were analyzed by fluorescence microscopy, immunohistochemistry, real-time PCR, flow cytometry and histomorphometry at times ranging from 1 hr to 6 wk. Results Single cells were found in distal metaphyses at 1 hr post-injection and remained as single cells up to 72 hr. Diaphyseal arrest occurred rarely and few cells remained there after 24 hr. At 1 wk, numerous foci (2–10 cells) were observed, mostly adjacent to osteoblast-like cells. By 2 wk, fewer but larger foci (≥50 cells) were seen. Most bones had a single large mass at 4 wk (originating from a colony or coalescing foci) which extended into the diaphysis by 4–6 wk. Little change (<20%) in osteoblast or osteoclast numbers was observed at 2 wk; but, at 4–6 wk osteoblasts were dramatically reduced (8% of control), while osteoclasts were reduced modestly (to ~60% of control). Conclusions Early arrest in metaphysis and minimal retention in diaphysis highlight the importance of local milieu in determining metastatic potential. These results extend the Seed and Soil hypothesis by demonstrating both inter- and intra-tissue differences governing metastasis location. Ours is the first in vivo evidence that tumor cells influence not only osteoclasts, as widely believed, but also eliminate functional osteoblasts, thereby restructuring the bone microenvironment to favor osteolysis. The data also explain why bisphosphonates do heal bone despite inhibiting resorption, implying that concurrent strategies that restore osteoblast function are

  18. Biomarker utility of circulating tumor cells in metastatic cutaneous melanoma.

    PubMed

    Khoja, Leila; Lorigan, Paul; Zhou, Cong; Lancashire, Matthew; Booth, Jessica; Cummings, Jeff; Califano, Raffaele; Clack, Glen; Hughes, Andrew; Dive, Caroline

    2013-06-01

    The incidence of melanoma is increasing worldwide. Advances in targeted agents and immunotherapy have improved outcomes in metastatic disease, but biomarkers are required to optimize treatment. We determined the prevalence of circulating tumor cells (CTCs) and explored their utility as prognostic and pharmacodynamic biomarkers. A total of 101 patients with metastatic cutaneous melanoma were recruited prospectively. CTC number was determined using the CellSearch platform and melanoma kits in samples taken at baseline and serially during treatment. CTC numbers ranged between 0 and 36 per 7.5 ml blood; 26% of patients had ≥ 2 CTCs. Baseline CTC number was prognostic for median overall survival (OS) in univariate analysis (2.6 vs. 7.2 months (P<0.011) for patients with ≥ 2 CTCs vs. <2 CTCs, respectively). In multivariate analysis, CTC number was an independent prognostic biomarker of OS (hazard ratio (HR) 2.403, 95% confidence interval (CI) 1.303-4.430, P=0.005). Patients receiving treatment in whom CTC number remained ≥ 2 CTCs during treatment had shorter median OS than those who maintained <2 CTCs (7 vs. 10 months, HR 0.34, 95% CI 0.14-0.81, log-rank test P=0.015). In conclusion, CTC number in metastatic cutaneous melanoma patients is prognostic for OS with a cutoff of 2 CTCs per 7.5 ml blood. CTC number measured before and throughout treatment provided additional prognostic information. Larger studies are warranted to confirm CTC biomarker utility in melanoma patients.

  19. Renal cell carcinoma metastatic to gallbladder: a survival advantage to simultaneous nephrectomy and cholecystectomy.

    PubMed

    Hellenthal, Nicholas J; Stewart, Gregory S; Cambio, Angelo J; Delair, Sean M

    2007-01-01

    Renal cell carcinoma is a relatively uncommon cancer. Patients presenting with a renal adenocarcinoma are often found to have evidence of metastatic disease at the time of diagnosis. Herein, we describe the case of a 39-year-old male with renal cell carcinoma and a synchronous metastatic focus to the gallbladder. The patient underwent a successful simultaneous nephrectomy and cholecystectomy and is doing well 30 months after surgery without evidence of disease recurrence. A thorough metastatic work-up along with aggressive surgical intervention in patients with renal cell carcinoma and unusual metastatic foci can provide a long-term favorable outcome.

  20. Renal cell carcinoma metastatic to the nasal cavity.

    PubMed

    Terada, Tadashi

    2012-01-01

    Metastatic renal cell carcinoma of the nasal cavity is very rare. A 76-year-old man presented with epistaxis and admitted to our hospital. His past histories were right radical nephrectomy for renal cell carcinomas at the age of 68 years and brain infarction at the age of 75 years. Laryngoscopic examination revealed a red polyp of the right nasal cavity. Imaging modalities including CT and MRI also revealed a tumor measuring 2 x 3 x 2 cm. Angiography showed that the tumor is very hypervascular. Clinical diagnosis was angiogenic tumors including hemangioma, sinonasal hemangiopericytoma, and paraganglioma. A blood data showed anemia and low platerets, and bone marrow biopsy revealed myelodysplastic syndrome. A coiling embolization of the feeding artery was performed, and the tumor reduced markedly. The tumor was resected almost entirely. Pathologically, the tumor was 2 x 1.5 x 1.5 cm red tumor. The tumor cells had clear cytoplasm, and arranged in a trabecular pattern lined by a layer of endothelial cells. Atypia is mild. Immunohistochemically, the tumor cells were positive for pancytokeratin (AE1/3, CAM5.2), RCC ma, CD10, and Ki-67 (labeling=20%), but negative for CD34, factor-VIII-related antigen, CEA, EMA, melanosome (HMB45), S100 protein, p53, and HepPar-1. The pathological diagnosis was made without knowledge of kidney status. A pathological diagnosis of metastatic renal cell carcinoma of clear cell type (grade 1) was made. The patient is now free from tumor, and palliative chemoradiation is considered.

  1. Different growth and metastatic phenotypes associated with a cell-intrinsic change of Met in metastatic melanoma

    PubMed Central

    Adachi, Eri; Sakai, Katsuya; Nishiuchi, Takumi; Imamura, Ryu; Sato, Hiroki; Matsumoto, Kunio

    2016-01-01

    A dynamic phenotypic change contributes to the metastatic progression and drug resistance in malignant melanoma. Nevertheless, mechanisms for a phenotypic change have remained to be addressed. Here, we show that Met receptor expression changes in a cell-autonomous manner and can distinguish phenotypical differences in growth, as well as in metastatic and drug-resistant characteristics. In metastatic melanoma, the cells are composed of Met-low and Met-high populations. Met-low populations have stem-like gene expression profiles, are resistant to chemotherapeutic agents, and have shown abundant angiogenesis and rapid tumor growth in subcutaneous inoculation. Met-high populations have a differentiated phenotype, are relatively resistant to B-RAF inhibitor, and are highly metastatic to the lungs. Met plays a definitive role in lung metastasis because the lung metastasis of Met-high cells requires Met, and treatment of mice with the Met-containing exosomes from Met-high cells facilitates lung metastasis by Met-low cells. Clonal cell fate analysis showed the hierarchical phenotypical changes from Met-low to Met-high populations. Met-low cells either showed self-renewal or changed into Met-high cells, whereas Met-high cells remained Met-high. Clonal transition from Met-low to Met-high cells accompanied changes in the gene expression profile, in tumor growth, and in metastasis that were similar to those in Met-high cells. These findings indicate that malignant melanoma has the ability to undergo phenotypic change by a cell-intrinsic/autonomous mechanism that can be characterized by Met expression. PMID:27683122

  2. [Carcinomatous meningitis: The radiation therapist's point of view].

    PubMed

    Espenel, S; Vallard, A; Langrand-Escure, J; Ben Mrad, M; Méry, B; Rivoirard, R; Moriceau, G; Guy, J-B; Trone, J-C; Moncharmont, C; Wang, G; Diao, P; Bernichon, É; Chanal, É; Fournel, P; Magné, N

    2016-02-01

    Carcinomatous meningitis complicates 5 to 10% of cancers, essentially with breast cancers, lung cancers and melanomas. The incidence probably increased because of therapeutic advances in oncology. Treatment is based on external beam radiotherapy, systemic treatment, intrathecal chemotherapy and supportive care. The aim of this work was to review data on external radiation therapy and carcinomatous meningitis. There are few evidences on the subject, but it is a major topic of interest. A whole brain radiation therapy is indicated in case of brain metastases or clinical encephalitis. Focal radiation therapy is recommended on symptomatic, bulky or obstructive sites. The dose depends on performance status (20 to 40 Gy in five to 20 fractions), volume to treat and available techniques (classic fractionation or hypofractionation via stereotactic radiosurgery). The objective of radiation therapy is to improve quality of life. Association with systemic therapy improves overall survival. Administration of sequential intrathecal chemotherapy may also improve overall survival, but induces more toxicity. The use of new radiotherapy techniques and development of radiosensitizing molecules in patients with good performance status could improve survival in this frequent complication of cancer.

  3. Concordance of Pathologic Features Between Metastatic Sites and the Primary Tumor in Surgically Resected Metastatic Renal Cell Carcinoma.

    PubMed

    Psutka, Sarah P; Cheville, John C; Costello, Brian A; Stewart-Merrill, Suzanne B; Lohse, Christine M; Leibovich, Bradley C; Boorjian, Stephen A; Thompson, R Houston

    2016-10-01

    To evaluate the concordance of pathologic features in metastatic renal cell carcinoma (RCC) between the primary nephrectomy and metastasectomy specimens. Primary nephrectomy (n = 454) and matched metastasectomy specimens (n = 680) from patients treated between 1970 and 2009 for RCC were re-reviewed by 1 urologic pathologist in a blinded fashion. RCC histologic subtype, grade, coagulative necrosis, and the presence of sarcomatoid differentiation were compared between the primary and the metastatic tumor with kappa statistics. Concordance with the primary tumor was observed for subtype in 647 (95%, kappa = 0.71) of the metastases, for grade in 411 (60%, kappa = 0.35), necrosis in 460 (68%, kappa = 0.32), and sarcomatoid differentiation in 643 (95%, kappa = 0.60). Upgrading was observed in 100%, 63%, and 13% of patients with grades 1, 2, and 3 primary tumors, respectively (no patient had a grade 1 metastatic lesion). Metastatic tumors treated with metastasectomy within 30 days of nephrectomy (n = 145) had similar rates of concordant subtype, necrosis, and sarcomatoid differentiation to those undergoing metastasectomy beyond 30 days from nephrectomy (P >.05 for all), but had higher rates of concordant grade (71% vs 58%, P = .003). Pre-metastasectomy exposure to systemic targeted or immunotherapy was not associated with a change in concordance of histopathologic features. Among 454 surgically managed metastatic RCC patients, we observed a high degree of concordance for histologic subtype and sarcomatoid differentiation, and varying degrees of discordance for grade and coagulative tumor necrosis, between primary and metastatic tumors. Further investigation is warranted to understand the biologic and therapeutic implications of these observations. Published by Elsevier Inc.

  4. A mouse surgical model for metastatic ovarian granulosa cell tumor.

    PubMed

    Nadeau, Marie-Eve; Kaartinen, M Johanna; Laguë, Marie-Noëlle; Paquet, Marilène; Huneault, Louis M; Boerboom, Derek

    2009-12-01

    We recently described a genetically engineered mouse model that develops ovarian granulosa cell tumors (GCTs) that mimic many aspects of the advanced human disease, including distant dissemination. However, because the primary tumors killed their hosts before metastases were able to form, the use of these mice to study metastatic disease required the development of a simple, reliable, and humane surgical protocol for the excision of large GCTs from debilitated mice. Here we describe a protocol involving multimodal anesthesia, tumor removal through ventral midline celiotomy and perioperative fluid therapy, and analgesia that led to the postoperative survival of more than 90% of mice, despite the removal of tumors representing as much as 10% of the animal's body weight. Intraabdominal recurrence of the GCT did not occur in surviving animals, but most developed pulmonary or adrenal metastases (or both) by 12 wk after surgery. We propose that this mouse model of metastatic GCT will serve as a useful preclinical model for the development of novel treatment modalities and diagnostic techniques. Furthermore, our results delineate anesthetic and surgical principles for the removal of large abdominal tumors from mice that will be applicable to other models of human cancers.

  5. Optical detection of metastatic cancer cells using a scanned laser pico-projection system

    NASA Astrophysics Data System (ADS)

    Huang, Chih-Ling; Chiu, Wen-Tai; Lo, Yu-Lung; Chuang, Chin-Ho; Chen, Yu-Bin; Chang, Shu-Jing; Ke, Tung-Ting; Cheng, Hung-Chi; Wu, Hua-Lin

    2015-03-01

    Metastasis is responsible for 90% of all cancer-related deaths in humans. As a result, reliable techniques for detecting metastatic cells are urgently required. Although various techniques have been proposed for metastasis detection, they are generally capable of detecting metastatic cells only once migration has already occurred. Accordingly, the present study proposes an optical method for physical characterization of metastatic cancer cells using a scanned laser pico-projection system (SLPP). The validity of the proposed method is demonstrated using five pairs of cancer cell lines and two pairs of non-cancer cell lines treated by IPTG induction in order to mimic normal cells with an overexpression of oncogene. The results show that for all of the considered cell lines, the SLPP speckle contrast of the high-metastatic cells is significantly higher than that of the low-metastatic cells. As a result, the speckle contrast measurement provides a reliable means of distinguishing quantitatively between low- and high-metastatic cells of the same origin. Compared to existing metastasis detection methods, the proposed SLPP approach has many advantages, including a higher throughput, a lower cost, a larger sample size and a more reliable diagnostic performance. As a result, it provides a highly promising solution for physical characterization of metastatic cancer cells in vitro.

  6. IGFBP‐3 inhibits Wnt signaling in metastatic melanoma cells

    PubMed Central

    Zingariello, Maria; Sancillo, Laura; Panasiti, Vincenzo; Polinari, Dorina; Martella, Marianna; Rosa Alba, Rana; Londei, Paola

    2016-01-01

    In previous works, we have shown that insulin‐like growth factor‐binding protein‐3 (IGFBP‐3), a tissue and circulating protein able to bind to IGFs, decreases drastically in the blood serum of patients with diffuse metastatic melanoma. In agreement with the clinical data, recombinant IGFBP‐3 was found to inhibit the motility and invasiveness of cultured metastatic melanoma cells and to prevent growth of grafted melanomas in mice. The present work was aimed at identifying the signal transduction pathways underlying the anti‐tumoral effects of IGFBP‐3. We show that the anti‐tumoral effect of IGFBP‐3 is due to inhibition of the Wnt pathway and depends upon the presence of CD44, a receptor protein known to modulate Wnt signaling. Once it has entered the cell, IGFBP‐3 binds the Wnt signalosome interacting specifically with its component GSK‐3β. As a consequence, the β‐catenin destruction complex dissociates from the LRP6 Wnt receptor and GSK‐3β is activated through dephosphorylation, becoming free to target cytoplasmic β‐catenin which is degraded by the proteasomal pathway. Altogether, the results suggest that IGFBP‐3 is a novel and effective inhibitor of Wnt signaling. As IGFBP‐3 is a physiological protein which has no detectable toxic effects either on cultured cells or live mice, it might qualify as an interesting new therapeutic agent in melanoma, and potentially many other cancers with a hyperactive Wnt signaling. © 2016 The Authors. Molecular Carcinogenesis Published by Wiley Periodicals, Inc. PMID:27377812

  7. Axitinib in metastatic renal cell carcinoma: single center experience

    PubMed Central

    Kardas, Joanna

    2017-01-01

    Aim of the study Due to the emergence of new therapeutic opportunities in the second-line treatment of metastatic renal cell carcinoma, the choice of the appropriate medication requires consideration. Making the selection one should take into account the likelihood of response, the probability of toxicity, properties of the drug and the clinical characteristics of the patient. Aim of the work was to confirm antitumor efficacy of axitinib in patients with metastatic clear-cell renal-cell carcinoma in the second line treatment remaining under the care of our institution. The primary objective was to determine antitumor activity, secondary – to evaluate progression free survival, safety of the treatment and to analyse clinical characteristics of treated population. Results Treatment records of 27 patients (9 females, 18 males) treated from October 2014 to the present (July 2016) were reviewed. The median duration of treatment which corresponds to the time to disease progression in observed population was 6 months (range: under 1 month – 16 months). 1 patient (3.7%) had got objective response (PR, partial remission). Clinical benefit rate (PR + SD (stable disease) was 66%. 9 patients (33.33%) experienced treatment toxicity only in the first degree of CTCAE (common toxicity criteria for adverse events), 11 patients (40.74%) presented the second degree toxicity and 5 patients (18.5%) – third degree. The most commonly reported treatment related adverse events were diarrhea (47%), fatigue (26%), hand-foot syndrome (26%), deterioration of blood pressure control (22.2%), abnormal liver function tests (18.5%), mucositis (11.1%). We observed 3 cases of unacceptable toxicity. Conclusions Axitinib confirms its effectiveness also in situation outside clinical trials, however, it is characterized by significant toxicity. Therefore, qualification for treatment should take into account the clinical patient characteristics. Effective diagnosis and treatment of side effects and

  8. Orbitofacial Metastatic Basal Cell Carcinoma: Report of 10 Cases.

    PubMed

    Branson, Sara V; McClintic, Elysa; Ozgur, Omar; Esmaeli, Bita; Yeatts, R Patrick

    To explore the clinical features, management, and prognosis of metastatic basal cell carcinoma originating in the orbitofacial region. Ten cases of orbitofacial metastatic basal cell carcinoma were identified by searching databases at 2 institutions from 1995 to 2015. A retrospective chart review was performed. Main outcome measures included patient demographics, lesion size, location of metastases, histologic subtype, recurrence rate, time between primary tumor diagnosis and metastasis, perineural invasion, treatment modalities, and survival from time of metastasis. The median tumor size at largest dimension was 3.3 cm (range, 1.9-11.5 cm), and 6 of 10 patients had at least 1 local recurrence before metastasis (range, 0-2 recurrences). The most common sites of metastasis included the ipsilateral parotid gland (n = 6) and cervical lymph nodes (n = 5). Histologic subtypes included infiltrative (n = 5), basosquamous (n = 2), nodular (n = 1), and mixed (n = 1). The median time from primary tumor diagnosis to metastasis was 7.5 years (range, 0-13). The median survival time from diagnosis of metastasis to last documented encounter or death was 5.3 years (range, 7 months-22.8 years). Treatment regimens included surgical excision, radiotherapy, and hedgehog inhibitors. Based on our findings, the following features may be markers of high risk orbitofacial basal cell carcinoma: 1) increasing tumor size, 2) local recurrence of the primary tumor, 3) aggressive histologic subtype, and 4) perineural invasion. Screening should include close observation of the primary site and tissues in the distribution of regional lymphatics, particularly the parotid gland and cervical lymph nodes.

  9. T Cells Induce Pre-Metastatic Osteolytic Disease and Help Bone Metastases Establishment in a Mouse Model of Metastatic Breast Cancer

    PubMed Central

    Monteiro, Ana Carolina; Leal, Ana Carolina; Gonçalves-Silva, Triciana; Mercadante, Ana Carolina T.; Kestelman, Fabiola; Chaves, Sacha Braun; Azevedo, Ricardo Bentes; Monteiro, João P.; Bonomo, Adriana

    2013-01-01

    Bone metastases, present in 70% of patients with metastatic breast cancer, lead to skeletal disease, fractures and intense pain, which are all believed to be mediated by tumor cells. Engraftment of tumor cells is supposed to be preceded by changes in the target tissue to create a permissive microenvironment, the pre-metastatic niche, for the establishment of the metastatic foci. In bone metastatic niche, metastatic cells stimulate bone consumption resulting in the release of growth factors that feed the tumor, establishing a vicious cycle between the bone remodeling system and the tumor itself. Yet, how the pre-metastatic niches arise in the bone tissue remains unclear. Here we show that tumor-specific T cells induce osteolytic bone disease before bone colonization. T cells pro-metastatic activity correlate with a pro-osteoclastogenic cytokine profile, including RANKL, a master regulator of osteoclastogenesis. In vivo inhibition of RANKL from tumor-specific T cells completely blocks bone loss and metastasis. Our results unveil an unexpected role for RANKL-derived from T cells in setting the pre-metastatic niche and promoting tumor spread. We believe this information can bring new possibilities for the development of prognostic and therapeutic tools based on modulation of T cell activity for prevention and treatment of bone metastasis. PMID:23935856

  10. Metastatic efficiency of tumour cells can be impaired by intraoperative cell salvage process: truth or conjecture?

    PubMed

    Kumar, N; Zaw, A S; Kantharajanna, S B; Khoo, B L; Lim, C T; Thiery, J P

    2017-08-23

    The use of salvaged blood in oncological surgery has been a matter of controversy over the years. This is due to the concern of systemic dissemination of reinfused tumour cells. Recent literature, across disciplines, has shed considerable light on its safety in terms of tumour recurrence, progression and overall survival rates. This clinical safety demonstrates the apparent metastatic inefficiency of reinfused tumour cells. The proof of this concept comes from various studies that have shown that salvaged blood has no tumour cells, or has a significantly lower count as compared to the patient's original circulatory tumour load. Recently, we took a step further and found that the tumour cells in the salvaged blood lose the capacity to replicate. In this review, we revisited the safety of salvaged blood from the point of view of metastatic potential. We have presented basic and applied science evidence regarding the innocuous nature of tumour cells that have been subjected to the cell salvage process. The understanding of the metastatic efficiency or the lack of it in tumour cells subjected to salvage process is key to allay the concerns conventionally associated with the use of salvaged blood in tumour surgery. Based on the available literature, we surmise that the prevalent apprehensions on the usage of salvaged blood are ill-founded and further substantiate why tumour cells in the salvaged blood could be regarded as cells with non-metastatic potential. © 2017 British Blood Transfusion Society.

  11. Fine needle aspiration cytology of metastatic Merkel cell carcinoma.

    PubMed

    Ostović, Karmen Trutin; Haris, Visnja; Miletić, Zorana; Lambasa, Smiljka; Lajtman, Zoran; Stoos-Veić, Tajana

    2010-06-01

    Merkel cell carcinoma (MCC) is uncommon cutaneous malignant neuroendocrine tumour of the elderly people with rapidly growing skin nodules found frequently on sun-exposed areas of the body. MCC is often an aggressive tumour with high tendency for local recurrence, lymph node involvement and distant metastases. This paper reports a case of metastatic MCC diagnosed by fine needle aspiration cytology (FNAC), flow cytometric deoxiribonucleated acid (DNA) analysis, pathohistology and electron microscopy. The cytological features in aspirate (stained with Papenheim and Papanicolaou staining) included increased cellularity, discohesive groups of small-to-medium size malignant cells with uniform, round-to-oval nuclei with moulding effect, fine chromatin, multiple micronucleoli and scanty cytoplasm. DNA flow cytometric analysis of the aspirate showed unexpected results for clinically aggressive behaviour of this tumour (the patient died after 21 months), and revealed that tumour contained diploid peak with DNA index of 1.1. The proliferation was high with elevated S-phase fraction (21%). The cytological diagnosis of possible metastatic MCC was confirmed by histological one as well as by electron microscopy presented the pathognomonic features for this tumour: dense-core neurosecretory granules with diameter of 100-250 nm surrounded by whorls of intermediate filaments. MCC provides an enormous challenge for the morphologist because of a wide range of differential diagnosis and for the clinician because this tumour has a highly malignant potential for local recurrence, nodal and distant spread and very often is combined with other tumours. Therefore it is important to perform FNAC of different lesions in the same patient because it can distinguish MCC from the other tumours.

  12. Metastatic Cutaneous Squamous Cell Carcinoma with Gastrointestinal Involvement: A Case Report.

    PubMed

    Schwartz, Brian; Schwartz, Mitchell

    2016-01-01

    Metastatic squamous cell carcinoma (SCC) involving the gastrointestinal tract as the sole site of metastatic disease is exceedingly rare. We report a patient with known cutaneous SCC that metastasized to regional lymph nodes who, after therapy, appeared to be disease free until a small metastatic lesion was identified on colonoscopy within a diverticular orifice. He was subsequently noted to have more diffuse gastrointestinal involvement, including a small bowel lesion not previously identified on imaging. The presence of a gastrointestinal metastatic lesion in this setting should prompt consideration to exclude other synchronous lesions and the need for possible additional systemic therapy.

  13. Germ cell tumor metastatic to the oral cavity.

    PubMed

    Lee, Luis; Oppenheimer, Randy; Jayaram, Lakshmi

    2012-04-01

    Neoplasms metastatic to the oral cavity are rare, accounting for less than 1% of all malignancies found there. When they do occur, they are usually found in the soft tissue or mandible. Metastatic malignancies involving the gingival, alveolar, or buccal mucosa are very rare. We present a case of what appeared to be a benign epulis in a 25-year-old man. Biopsy revealed that the lesion represented metastatic testicular cancer.

  14. Identification of an aptamer through whole cell-SELEX for targeting high metastatic liver cancers

    PubMed Central

    Rong, Yuan; Chen, Hao; Zhou, Xue-Feng; Yin, Chang-Qing; Wang, Bi-Cheng; Peng, Chun-Wei; Liu, Shao-Ping; Wang, Fu-Bing

    2016-01-01

    Hepatocellular carcinoma (HCC) is one of the most deadly human cancers due to its ability of invasion and metastasis. Thus, the approaches to identify potential compounds that inhibit invasion and metastasis of HCC are critical for treatment of this disease. In the present study, we used HCCLM9 cells with high metastatic potential and MHCC97L with low metastatic potential as a model system to study the molecular mechanisms of HCC metastasis. By applying cell- Systematic Evolution of Ligands by Exponential enrichment (SELEX) against living cells, we used HCCLM9 as target cells and MHCC97L cells as control to screen a group of HCC metastasis- and cell-specific DNA aptamers. One of selected aptamers, LY-1, could specifically bind to metastatic HCC with a dissociation constant (Kd) in nanomolar range. In vitro studies demonstrated that LY-1 can recognize and bind to membrane protein of metastatic HCC cells. Furthermore, QD605 labeled LY-1 aptamer could recognize HCC cells in both local liver cancer tissues and pulmonary metastatic sites in a xenograft model of HCC with pulmonary metastasis. Further biochemical and immunostaining studies showed that LY-1 could selectively bind to a subpopulation of more metastatic cells in HCCLM9 cells, which express more CK19 and vimentin. Finally, treatment of highly metastatic cells with LY-1 led to reduced migration and invasiveness of HCCLM9 cells in vitro and suppression of xenograft growth in vivo. Taken together, the present study demonstrated the tumor targeting and tumor suppressive effects of LY-1, which could be a promising molecular probe for metastatic HCC and a potential candidate of chemotherapy for metastatic HCC. PMID:26882565

  15. Overcoming Bone Marrow Stroma-Mediated Chemoresistance in Metastatic Breast Cancer Cells

    DTIC Science & Technology

    2004-08-01

    AD Award Number: DAMD17-03- 1 -0524 .TITLE: Overcoming Bone Marrow Stroma- Mediated Chemoresistance in Metastatic Breast Cancer Cells PRINCIPAL...SUBTITLE 5. FUNDING NUMBERS Overcoming Bone Marrow Stroma- Mediated Chemoresistance in DAMD17-03- 1 -0524 Metastatic Breast Cancer Cells 6. AUTHOR(S) Robert...the compound (Figure 1 ). The inhibitor was slightly more effective in T-47D cells than in MCF-7 cells, but did not eradicate dormant clones much past

  16. Update on the medical treatment of metastatic renal cell carcinoma.

    PubMed

    Ravaud, Alain; Wallerand, Hervé; Culine, Stéphane; Bernhard, Jean-Christophe; Fergelot, Patricia; Bensalah, Karim; Patard, Jean-Jacques

    2008-08-01

    Metastatic renal cell carcinoma (mRCC) has long been treated only by immunotherapy with good results only in a small population of patients. In recent years, major improvements in treatment possibilities have occurred with the advent of anti-angiogenic drugs. In the past 2 yr, pivotal phase III trials have confirmed this major breakthrough by increasing the progression-free survival rates and/or overall survival rates provided by sunitinib, sorafenib, and bevacizumab, and more recently by the mTOR (mammalian target of rapamycin) inhibitors temsirolimus and everolimus. To update the previous review on smart drugs published in the European Journal in 2006 (Patard JJ, et al. Understanding the importance of smart drugs in renal cell carcinoma. Eur Urol 2006; 49:633-43). Critical review of published literature 2006-2008 (Pubmed website search words: renal cell carcinoma and/or targeted therapy and prospective trials) and more recent meeting abstracts (American Society of Clinical Oncology 2007). Quality assessment included prospective phase I-III trials and critical evaluations with low numbers of patients, retrospective analyses, and slide presentations of meeting abstracts. This review presents the current situation and provides more recent data on sequential treatment, the association of targeted drugs, and the treatment of non-clear-cell histologies. Treatment of mRCC with targeted therapy centers on at least two major pathways: angiogenesis and mTOR involving inhibiting drugs that may be used alone, in combination, or sequentially.

  17. Axitinib in sequential therapy in metastatic renal cell carcinoma

    PubMed Central

    Hryciuk, Beata; Stec, Rafał; Mączewski, Michał; Szczylik, Cezary

    2016-01-01

    Efficacy of new molecularly targeted drugs in the treatment of renal cell carcinoma (RCC), confirmed in clinical studies in relation to survival and prolongation of time to progression, has became a big chance for patients with metastatic renal cell cancer. Axitinib is a potent and selective receptor tyrosine kinase for vascular endothelial growth factor (VEGFR-1, -2, -3), platelet-derived growth factor β (PDGRF-β) and c-KIT. This is a case report of a 57-year old female patient with a history of left nephrectomy due to clear cell renal cell carcinoma. The patient had received three prior systemic treatments (interferon – sorafenib – everolimus). After consecutive progression the patient was qualified to 4th line therapy – axitinib at a dose of 5 mg twice daily. Partial response to treatment was achieved. After 6 months therapy was stopped due to the disease progression. The total time to progression was 37.5 months. The total survival time from the disease diagnosis was 45 months. Based on literature date and own experience we showed that sequential treatment RCC is associated with improved survival. In summary, axitinib may be an effective drug after failure of tyrosine-kinase inhibitor (TKI) therapy in previous lines of therapy.

  18. Trial Watch: Therapeutic vaccines in metastatic renal cell carcinoma.

    PubMed

    Combe, Pierre; de Guillebon, Eleonore; Thibault, Constance; Granier, Clémence; Tartour, Eric; Oudard, Stéphane

    2015-05-01

    Despite the renaissance of cancer immunotherapy, no novel immunotherapy has been approved for the treatment of renal cell cancer (RCC) since the availability of recombinant cytokines (interleukin-2, interferon-α). All vaccine trials have failed to meet their endpoints although they have highlighted potential predictive biomarkers (e.g., pre-existing immune response, hematological parameters, tumor burden). Recent advances in immunomodulatory therapies have prompted the study of combination treatments targeting the tumor immunosuppressive microenvironment consisting of regulatory T-cells (Treg), myeloid suppressor cells, and cytokines. Approaches under investigation are use of inhibitors to curb the overexpression of immune checkpoint ligands by tumor cells (e.g., anti-CTLA-4, anti-PD-1/PD-L1) and exploiting the immunomodulatory effects of anti-angiogenic agents that are the current standard of metastatic RCC care. Phase III trials are focusing on the possible synergy between therapeutic vaccines (e.g., IMA-901 and AGS-003) and anti-angiogenic agents.

  19. Phenotypic screening of a library of compounds against metastatic and non-metastatic clones of a canine mammary gland tumour cell line.

    PubMed

    Saeki, K; Watanabe, M; Michishita, M; Tsuboi, M; Sugano, S; Yoshitake, R; Murai, K; Tanaka, Y; Ong, S M; Saito, T; Matsumoto, K; Fujita, N; Nishimura, R; Nakagawa, T

    2015-08-01

    Metastases are associated with a poor prognosis for canine mammary gland tumours (CMGTs). Metastatic and non-metastatic clones were isolated previously from a single malignant CMGT cell line. The difference in metastatic potential between the two cell lines was hypothesised to be associated with distinct cellular signalling. The aim of this study was to screen for compounds that specifically target metastatic cells in order to improve CMGT therapeutic outcomes. The two clonal cell lines were characterised by transcriptome analysis and their sensitivity to a library of 291 different compounds was compared. The metastatic clone exhibited elevated expression of molecules associated with degradation of the extracellular matrix, epithelial-mesenchymal transition and cancer stem cell phenotype. This was confirmed using a matrigel invasion assay and by assessment of aldehyde dehydrogenase activity. The mitochondrial respiratory chain complex inhibitors (MRCIs; rotenone, antimycin and oligomycin) significantly inhibited the growth of the metastatic clone. Although MRCIs similarly depleted mitochondrial ATP in both clones, the subsequent cellular response was different, with toxicity to the metastatic clone being independent of AMP-activated protein kinase activity. The results of this study suggest a potential utility of MRCIs as anti-tumour agents against metastatic CMGTs. Further studies are needed to investigate the clinical utility of MRCIs and to determine the association between MRCI sensitivity and malignancy.

  20. Optical redox ratio identifies metastatic potential-dependent changes in breast cancer cell metabolism

    PubMed Central

    Alhallak, Kinan; Rebello, Lisa G.; Muldoon, Timothy J.; Quinn, Kyle P.; Rajaram, Narasimhan

    2016-01-01

    The development of prognostic indicators of breast cancer metastatic risk could reduce the number of patients receiving chemotherapy for tumors with low metastatic potential. Recent evidence points to a critical role for cell metabolism in driving breast cancer metastasis. Endogenous fluorescence intensity of nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FAD) can provide a label-free method for assessing cell metabolism. We report the optical redox ratio of FAD/(FAD + NADH) of four isogenic triple-negative breast cancer cell lines with varying metastatic potential. Under normoxic conditions, the redox ratio increases with increasing metastatic potential (168FARN>4T07>4T1), indicating a shift to more oxidative metabolism in cells capable of metastasis. Reoxygenation following acute hypoxia increased the redox ratio by 43 ± 9% and 33 ± 4% in the 4T1 and 4T07 cells, respectively; in contrast, the redox ratio decreased 14 ± 7% in the non-metastatic 67NR cell line. These results demonstrate that the optical redox ratio is sensitive to the metabolic adaptability of breast cancer cells with high metastatic potential and could potentially be used to measure dynamic functional changes that are indicative of invasive or metastatic potential. PMID:27895979

  1. Functional significance of secreted Frizzled-related protein 1 in metastatic renal cell carcinomas.

    PubMed

    Saini, Sharanjot; Liu, Jan; Yamamura, Soichiro; Majid, Shahana; Kawakami, Kazumori; Hirata, Hiroshi; Dahiya, Rajvir

    2009-09-01

    The secreted Frizzled-related protein 1 (SFRP1) is a Wingless-type (Wnt) antagonist that has been associated with various malignancies, including renal cell carcinomas (RCC). However, the functional significance of SFRP1 has never been investigated in metastatic RCC. Here, we investigated the role of this molecule in kidney cancer progression and metastasis. Using Wnt pathway-focused cDNA expression profiling in normal renal, primary RCC, and metastatic RCC cell lines, we identified that SFRP1 is up-regulated in metastatic RCC. SFRP1 overexpression in metastatic RCC was confirmed by immunostaining in renal tissues. We explored the molecular mechanisms underlying SFRP1 up-regulation by analyzing DNA methylation and histone modification patterns on SFRP1 promoter. We found that this gene is unmethylated/hypomethylated and enriched in activating histone modifications in metastatic RCC. To understand the functional significance of SFRP1 overexpression in metastatic RCC with regard to tumorigenesis, we used a small interfering RNA-mediated approach to knockdown the gene and monitored cellular proliferation, apoptosis, and metastatic behavior. Proliferation was unaltered and apoptosis increased on attenuation of SFRP1 expression. Also, SFRP1 depletion decreased the invasive potential of the metastatic RCC cell line, suggesting that the overexpression of this Wnt antagonist may be related to invasiveness and metastatic behavior in RCC. We investigated the molecular basis of the role of SFRP1 in invasion and metastasis and found that matrix metalloproteinase MMP10 is regulated by SFRP1. In conclusion, our data suggest that SFRP1 plays a role in the metastatic potential of RCC. The present findings may be important in the design of treatment modalities for metastatic RCC.

  2. Metastatic Cancer

    MedlinePlus

    ... stop the growth of primary and metastatic cancer cells. This research includes finding ways to help your immune system ... the steps in the process that allow cancer cells to spread. Visit the Metastatic Cancer Research page to stay informed of ongoing research funded ...

  3. Organ-specific isogenic metastatic breast cancer cell lines exhibit distinct Raman spectral signatures and metabolomes.

    PubMed

    Winnard, Paul T; Zhang, Chi; Vesuna, Farhad; Kang, Jeon Woong; Garry, Jonah; Dasari, Ramachandra Rao; Barman, Ishan; Raman, Venu

    2017-03-21

    Molecular characterization of organ-specific metastatic lesions, which distinguish them from the primary tumor, will provide a better understanding of tissue specific adaptations that regulate metastatic progression. Using an orthotopic xenograft model, we have isolated isogenic metastatic human breast cancer cell lines directly from organ explants that are phenotypically distinct from the primary tumor cell line. Label-free Raman spectroscopy was used and informative spectral bands were ascertained as differentiators of organ-specific metastases as opposed to the presence of a single universal marker. Decision algorithms derived from the Raman spectra unambiguously identified these isogenic cell lines as unique biological entities - a finding reinforced through metabolomic analyses that indicated tissue of origin metabolite distinctions between the cell lines. Notably, complementarity of the metabolomics and Raman datasets was found. Our findings provide evidence that metastatic spread generates tissue-specific adaptations at the molecular level within cancer cells, which can be differentiated with Raman spectroscopy.

  4. Organ-specific isogenic metastatic breast cancer cell lines exhibit distinct Raman spectral signatures and metabolomes

    PubMed Central

    Winnard, Paul T.; Zhang, Chi; Vesuna, Farhad; Kang, Jeon Woong; Garry, Jonah; Dasari, Ramachandra Rao; Barman, Ishan; Raman, Venu

    2017-01-01

    Molecular characterization of organ-specific metastatic lesions, which distinguish them from the primary tumor, will provide a better understanding of tissue specific adaptations that regulate metastatic progression. Using an orthotopic xenograft model, we have isolated isogenic metastatic human breast cancer cell lines directly from organ explants that are phenotypically distinct from the primary tumor cell line. Label-free Raman spectroscopy was used and informative spectral bands were ascertained as differentiators of organ-specific metastases as opposed to the presence of a single universal marker. Decision algorithms derived from the Raman spectra unambiguously identified these isogenic cell lines as unique biological entities – a finding reinforced through metabolomic analyses that indicated tissue of origin metabolite distinctions between the cell lines. Notably, complementarity of the metabolomics and Raman datasets was found. Our findings provide evidence that metastatic spread generates tissue-specific adaptations at the molecular level within cancer cells, which can be differentiated with Raman spectroscopy. PMID:28145887

  5. Increased Secretory Leukocyte Protease Inhibitor (SLPI) Production by Highly Metastatic Mouse Breast Cancer Cells

    PubMed Central

    Sayers, Kevin T.; Brooks, Alan D.; Sayers, Thomas J.; Chertov, Oleg

    2014-01-01

    The precise molecular mechanisms enabling cancer cells to metastasize from the primary tumor to different tissue locations are still largely unknown. Secretion of some proteins by metastatic cells could facilitate metastasis formation. The comparison of secreted proteins from cancer cells with different metastatic capabilities in vivo might provide insight into proteins involved in the metastatic process. Comparison of the secreted proteins from the mouse breast cancer cell line 4T1 and its highly metastatic 4T1.2 clone revealed a prominent differentially secreted protein which was identified as SLPI (secretory leukocyte protease inhibitor). Western blotting indicated higher levels of the protein in both conditioned media and whole cell lysates of 4T1.2 cells. Additionally higher levels of SLPI were also observed in 4T1.2 breast tumors in vivo following immunohistochemical staining. A comparison of SLPI mRNA levels by gene profiling using microarrays and RT-PCR did not detect major differences in SLPI gene expression between the 4T1 and 4T1.2 cells indicating that SLPI secretion is regulated at the protein level. Our results demonstrate that secretion of SLPI is drastically increased in highly metastatic cells, suggesting a possible role for SLPI in enhancing the metastatic behavior of breast cancer cell line 4T1. PMID:25110884

  6. The utility of tetraspanin CD9 as a biomarker for metastatic clear cell renal cell carcinoma.

    PubMed

    Garner, Jo M; Herr, Michael J; Hodges, Kurt B; Jennings, Lisa K

    2016-02-26

    The use of tetraspanin CD9 as a biomarker for renal cell carcinomas (RCC) has been explored with minor conclusions. Identification of a biomarker that not only distinguishes between the different types of renal cell carcinomas, but also predicts the metastatic potential of these tumors would significantly advance diagnosis and prognosis of kidney cancers. We utilized established cell lines to better understand the contribution of CD9 to the metastatic potential of clear cell renal cell carcinomas, and then applied our findings to the TCGA database and immunohistochemical analysis of human samples based on tumor grading to determine the utility of CD9 as a biomarker for RCC. Clear cell renal cell carcinoma (ccRCC) cell expression of tetraspanin CD9 was compared to normal kidney cells and found to be elevated. Upon knockdown of CD9, ccRCC cells obtained a more metastatic phenotype. We found E-cadherin expression to be repressed and the endothelial to mesenchymal transition markers Snail, Twist1, and Zeb1 to be elevated upon CD9 knockdown. Upon observing these gene expression changes in the TCGA database and in 10 cases, we found that CD9 and E-cadherin expression was lowered in higher grade ccRCC tumors. There was a significant correlation between CD9 and either E-cadherin, Snail, or Zeb1 in these tumors. Collectively, using tetraspanin CD9 in tandem with E-cadherin as a biomarker in renal cell carcinoma will help to not only distinguish between types, but also predict the metastatic potential of RCC. Copyright © 2016 Elsevier Inc. All rights reserved.

  7. Targeting breast to brain metastatic tumours with death receptor ligand expressing therapeutic stem cells.

    PubMed

    Bagci-Onder, Tugba; Du, Wanlu; Figueiredo, Jose-Luiz; Martinez-Quintanilla, Jordi; Shah, Khalid

    2015-06-01

    Characterizing clinically relevant brain metastasis models and assessing the therapeutic efficacy in such models are fundamental for the development of novel therapies for metastatic brain cancers. In this study, we have developed an in vivo imageable breast-to-brain metastasis mouse model. Using real time in vivo imaging and subsequent composite fluorescence imaging, we show a widespread distribution of micro- and macro-metastasis in different stages of metastatic progression. We also show extravasation of tumour cells and the close association of tumour cells with blood vessels in the brain thus mimicking the multi-foci metastases observed in the clinics. Next, we explored the ability of engineered adult stem cells to track metastatic deposits in this model and show that engineered stem cells either implanted or injected via circulation efficiently home to metastatic tumour deposits in the brain. Based on the recent findings that metastatic tumour cells adopt unique mechanisms of evading apoptosis to successfully colonize in the brain, we reasoned that TNF receptor superfamily member 10A/10B apoptosis-inducing ligand (TRAIL) based pro-apoptotic therapies that induce death receptor signalling within the metastatic tumour cells might be a favourable therapeutic approach. We engineered stem cells to express a tumour selective, potent and secretable variant of a TRAIL, S-TRAIL, and show that these cells significantly suppressed metastatic tumour growth and prolonged the survival of mice bearing metastatic breast tumours. Furthermore, the incorporation of pro-drug converting enzyme, herpes simplex virus thymidine kinase, into therapeutic S-TRAIL secreting stem cells allowed their eradication post-tumour treatment. These studies are the first of their kind that provide insight into targeting brain metastasis with stem-cell mediated delivery of pro-apoptotic ligands and have important clinical implications. © The Author (2015). Published by Oxford University Press on

  8. Establishment and characterization of a new highly metastatic human osteosarcoma cell line derived from Saos2

    PubMed Central

    Du, Lin; Fan, Qiming; Tu, Bing; Yan, Wei; Tang, Tingting

    2014-01-01

    Osteosarcoma is the most common primary malignancy of bone in adolescents and young adults. There is a shortage of tumorigenic and highly metastatic human osteosarcoma cell lines that can be used for metastasis study. Here we establish and characterize a highly metastatic human osteosarcoma cell line that is derived from Saos2 cell line based on bioluminescence. The occasional pulmonary metastatic cells developed from Saos2 were isolated, harvested, characterized and named Saos2-l. The parental Saos2 and Saos2-l cells were further characterized both in vitro and in vivo. Results showed that Saos2-l cells demonstrated increased cell adhesion, migration and invasion compared to the parental Saos2 cells. Conversely, Saos2-l cells grew at a slightly slower rate than that of the parental cells. When injected into nude mice, Saos2-l cells had a greater increase in developing pulmonary metastases compared to the parental Saos2 cells. Further transcriptional profiling analysis revealed that some gene expression were up-regulated or down-regulated in the highly metastatic Saos2-l cells, indicating possible influencing factors of metastasis. Thus, we have established and characterized a highly metastatic human osteosarcoma cell line that should serve as a valuable tool for future investigations on the pathogenesis, metastasis and potential treatments of human osteosarcoma. PMID:25031706

  9. Metastatic pancreatic islet cell carcinoma to the orbit: a case report.

    PubMed

    Nasr, Amin M.; Teichmann, Klaus; Dabbagh, Najwa; Huaman, Antonio M.

    1998-03-01

    We report a rare case of pancreatic islet cell carcinoma metastatic to the orbit in a 29-year-old woman. The initial symptomatology, progression of the disease, and radiologic and histopathologic findings are presented and discussed.

  10. Tumor cells as cellular vehicles to deliver gene therapies to metastatic tumors.

    PubMed

    García-Castro, Javier; Martínez-Palacio, Jesús; Lillo, Rosa; García-Sánchez, Félix; Alemany, Ramón; Madero, Luis; Bueren, Juan A; Ramírez, Manuel

    2005-04-01

    A long-pursued goal in cancer treatment is to deliver a therapy specifically to metastases. As a result of the disseminated nature of the metastatic disease, carrying the therapeutic agent to the sites of tumor growth represents a major step for success. We hypothesized that tumor cells injected intravenously (i.v.) into an animal with metastases would respond to many of the factors driving the metastatic process, and would target metastases. Using a model of spontaneous metastases, we report here that i.v. injected tumor cells localized on metastatic lesions. Based on this fact, we used genetically transduced tumor cells for tumor targeting of anticancer agents such as a suicide gene or an oncolytic virus, with evident antitumoral effect and negligible systemic toxicity. Therefore, autologous tumor cells may be used as cellular vehicles for systemic delivery of anticancer therapies to metastatic tumors.

  11. Bone marrow-derived stem cell therapy for metastatic brain cancers.

    PubMed

    Kaneko, Yuji; Tajiri, Naoki; Staples, Meaghan; Reyes, Stephanny; Lozano, Diego; Sanberg, Paul R; Freeman, Thomas B; van Loveren, Harry; Kim, Seung U; Borlongan, Cesar V

    2015-01-01

    We propose that stem cell therapy may be a potent treatment for metastatic melanoma in the brain. Here we discuss the key role of a leaky blood-brain barrier (BBB) that accompanies the development of brain metastases. We review the need to characterize the immunological and inflammatory responses associated with tumor-derived BBB damage in order to reveal the contribution of this brain pathological alteration to the formation and growth of brain metastatic cancers. Next, we discuss the potential repair of the BBB and attenuation of brain metastasis through transplantation of bone marrow-derived mesenchymal stem cells with the endothelial progenitor cell phenotype. In particular, we review the need for evaluation of the efficacy of stem cell therapy in repairing a disrupted BBB in an effort to reduce neuroinflammation, eventually attenuating brain metastatic cancers. The demonstration of BBB repair through augmented angiogenesis and vasculogenesis will be critical to establishing the potential of stem cell therapy for the treatment/prevention of metastatic brain tumors. The overarching hypothesis we advanced here is that BBB breakdown is closely associated with brain metastatic cancers of melanoma, exacerbating the inflammatory response of the brain during metastasis, and ultimately worsening the outcome of metastatic brain cancers. Abrogating this leaky BBB-mediated inflammation via stem cell therapy represents a paradigm-shifting approach to treating brain cancer. This review article discusses the pros and cons of cell therapy for melanoma brain metastases.

  12. Cyclooxygenase-2 expression in primary and metastatic Merkel cell carcinoma.

    PubMed

    Joachims, Zohar; Feinmesser, Raphael; Purim, Ofer; Halpern, Marisa; Brenner, Baruch; Fenig, Eyal; Roizman, Pepi; Sulkes, Jaqueline; Feinmesser, Meora

    2008-10-01

    Cyclooxygenase-2 (COX-2) is involved in the development and progression of many tumors, and its inhibition has been shown to block tumor growth. This study examined COX-2 expression in primary and metastatic Merkel cell carcinoma (MCC). Formalin-fixed paraffin-embedded tissues from 26 primary MCCs and 7 lymph node metastases were stained immunohistochemically with a monoclonal antibody directed against COX-2, and the percentage and intensity of staining were analyzed semiquantitatively. Immunopositivity for COX-2 was found in 20 primary tumors (77%), and was diffuse in 16 of them (80%). Staining intensity was strong in 5 tumors (19%), moderate in 6 (23%), and weak in 9 (35%). Five metastases (71%) showed similar staining. Prominent mitotic activity was associated with more diffuse COX-2 immunopositivity. No association was found between COX-2 expression and outcome. This study confirms that most MCCs express COX-2 and shows that COX-2 expression is related to one parameter of aggressive behavior--a high mitotic rate--but not to any others. The possibility of treating MCC with COX-2 inhibitors should be considered.

  13. Systemic Therapies for Metastatic Renal Cell Carcinoma in Older Adults

    PubMed Central

    Pal, Sumanta K.; Vanderwalde, Ari; Hurria, Arti; Figlin, Robert A.

    2016-01-01

    The introduction of targeted therapies has radically changed the treatment paradigm for metastatic renal cell carcinoma (mRCC). However, multiple clinical dilemmas have emerged. For instance, limited data are available to juxtapose the safety and efficacy profile of targeted therapies between older and younger adults. Herein, pivotal trials of vascular endothelial growth factor (VEGF)- and mammalian target of rapamycin (mTOR)-directed therapies are assessed in the context of their implications in treating older adults with mRCC. In general, subset analyses from these pivotal studies suggest similar efficacy of targeted therapies amongst older adults. Aging is accompanied by a multitude of physiological changes, as well as an increased prevalence of co-morbidities. The age-related toxicity profiles of targeted agents for mRCC are detailed to provide a framework for the risks and benefits of these therapies in older adults. Ultimately, tools such as the Comprehensive Geriatric Assessment (CGA) that account for physiological (as opposed to chronological) age may prove useful in the evaluation and treatment of older adults with mRCC. PMID:21812499

  14. Exosomes secreted from human colon cancer cells influence the adhesion of neighboring metastatic cells: Role of microRNA-210

    PubMed Central

    Bigagli, Elisabetta; Luceri, Cristina; Guasti, Daniele; Cinci, Lorenzo

    2016-01-01

    ABSTRACT Cancer-secreted exosomes influence tumor microenvironment and support cancer growth and metastasis. MiR-210 is frequently up-regulated in colorectal cancer tissues and correlates with metastatic disease. We investigated whether exosomes are actively released by HCT-8 colon cancer cells, the role of exosomal miR-210 in the cross-talk between primary cancer cells and neighboring metastatic cells and its contribution in regulating epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET). After 7 d of culture, a subpopulation of viable HCT-8 cells detached the monolayer and started to grow in suspension, suggesting anoikis resistance and a metastatic potential. The expression of key proteins of EMT revealed that these cells were E-cadherin negative and vimentin positive further confirming their metastatic phenotype and the acquisition of anoikis resistance. Metastatic cells, in the presence of adherently growing HCT-8, continued to grow in suspension whereas only if seeded in cell-free wells, were able to adhere again and to form E-cadherin positive and vimentin negative new colonies, suggesting the occurrence of MET. The chemosensitivity to 5 fluorouracil and to FOLFOX-like treatment of metastatic cells was significantly diminished compared to adherent HCT-8 cells. Of note, adherent new colonies undergoing MET, were insensitive to both chemotherapeutic strategies. Electron microscopy analysis demonstrated that adherently growing HCT-8, actually secreted exosomes and that exosomes in turn were taken up by metastatic cells. When exosomes secreted by adherently growing HCT-8 were administered to metastatic cells, MET was significantly inhibited. miR-210 was significantly upregulated in exosomes compared to its intracellular levels in adherently growing HCT-8 cells and correlated to anoikis resistance and EMT markers. Exosomes containing miR-210 might be considered as EMT promoting signals that preserve the local cancer

  15. Cell cycle progression score predicts metastatic progression of clear cell renal cell carcinoma after resection.

    PubMed

    Askeland, Eric J; Chehval, Vincent A; Askeland, Ryan W; Fosso, Placede G; Sangale, Zaina; Xu, Nafei; Rajamani, Saradha; Stone, Steven; Brown, James A

    2015-01-01

    The outcome of surgically resected, apparently localized, clear cell renal carcinoma (ccRCC) is uncertain. To evaluate if cell cycle progression (CCP) gene expression can predict future metastasis. Pathologic T2a-T3b tumors at University of Iowa were reviewed. Patients with known or suspected metastasis, lymph node involvement or who received neoadjuvant or adjuvant radiation, chemotherapy or immunotherapy were excluded. Case and control cohorts were defined as those who did or did not develop metastatic disease within 5 years. Measured levels of 31 cell cycle genes and 15 control genes from the tumor were calculated as a CCP score. Additionally, gene expression data for a separate ccRCC cohort was downloaded from The Cancer Genome Atlas (TCGA). Univariate analysis of 26 cases and 38 controls revealed that the CCP score predicted progression to metastasis (OR 2.65, p = 0.0091). In multivariate logistic regression modeling, CCP expression remained a significant independent predictor for progression (p = 0.026). The CCP score was also significantly associated with distant metastasis in the TCGA renal cancer cohort in both univariate (p = 1.0 × 10-9) and multivariate (p = 5.6 × 10-3) analysis. The CCP score has prognostic value in predicting metastatic progression after resection of organ-confined ccRCC.

  16. Characterization of the metastatic phenotype of a panel of established osteosarcoma cells.

    PubMed

    Ren, Ling; Mendoza, Arnulfo; Zhu, Jack; Briggs, Joseph W; Halsey, Charles; Hong, Ellen S; Burkett, Sandra S; Morrow, James; Lizardo, Michael M; Osborne, Tanasa; Li, Samuel Q; Luu, Hue H; Meltzer, Paul; Khanna, Chand

    2015-10-06

    Osteosarcoma (OS) is the most common bone tumor in pediatric patients. Metastasis is a major cause of mortality and morbidity. The rarity of this disease coupled with the challenges of drug development for metastatic cancers have slowed the delivery of improvements in long-term outcomes for these patients. In this study, we collected 18 OS cell lines, confirmed their expression of bone markers and complex karyotypes, and characterized their in vivo tumorgenicity and metastatic potential. Since prior reports included conflicting descriptions of the metastatic and in vivo phenotypes of these models, there was a need for a comparative assessment of metastatic phenotypes using identical procedures in the hands of a single investigative group. We expect that this single characterization will accelerate the study of this metastatic cancer. Using these models we evaluated the expression of six previously reported metastasis-related OS genes. Ezrin was the only gene consistently differentially expressed in all the pairs of high/low metastatic OS cells. We then used a subtractive gene expression approach of the high and low human metastatic cells to identify novel genes that may be involved in OS metastasis. PHLDA1 (pleckstrin homology-like domain, family A) was identified as one of the genes more highly expressed in the high metastatic compared to low metastatic cells. Knocking down PHLDA1 with siRNA or shRNA resulted in down regulation of the activities of MAPKs (ERK1/2), c-Jun N-terminal kinases (JNK), and p38 mitogen-activated protein kinases (MAPKs). Reducing the expression of PHLDA1 also delayed OS metastasis progression in mouse xenograft models.

  17. Sunitinib in the treatment of metastatic renal cell carcinoma

    PubMed Central

    Schmid, Thomas A.; Gore, Martin E.

    2016-01-01

    Sunitinib is an oral multi-targeted tyrosine kinase inhibitor (TKI) that targets various receptors, including vascular endothelial growth factor receptors (VEGFRs). Sunitinib received approval in 2006 and became a standard treatment option in the first-line treatment of metastatic renal cell cancer (mRCC) after a phase III trial showed superiority compared with interferon alpha (IFN-α). Sunitinib has also shown activity in second-line treatment in several trials. Most of the combination trials with sunitinib with various agents have led to considerable toxicity without improving efficacy. Sunitinib alone causes significant side effects and has a distinct profile with diarrhoea, hypertension, skin effects hypothyroidism, fatigue and nausea of special interest. The recommended dose of sunitinib in mRCC is 50 mg orally daily for 4 weeks, followed by 2 weeks off treatment (4/2 schedule). An alternative 2 weeks on, 1 week off schedule (2/1 schedule) seems to be of similar efficacy and better tolerability and could be more widely used in the future. An intermittent treatment strategy with a stop in remission and re-induction after progression showed efficacy in smaller trials and is currently being evaluated in a phase III trial. Direct comparison of sunitinib with pazopanib in first-line treatment showed a similar efficacy for both TKIs with a distinct toxicity profile. Data from two phase II trials showed that sunitinib has also activity in non-clear cell cancer and is an option due to a lack of better alternatives. Currently, after immune checkpoint inhibitors have shown very promising results in the second-line treatment of RCC, they are being tested in a number of phase III trials in the first-line setting. The future will show the position of sunitinib in the first-line treatment of RCC in the era of the immune checkpoint inhibitors. PMID:27904651

  18. Modulation of the Metastatic Activity of Melanoma Cells by Laminin and Fibronectin

    NASA Astrophysics Data System (ADS)

    Terranova, Victor P.; Williams, Jeannette E.; Liotta, Lance A.; Martin, George R.

    1984-11-01

    Metastatic mouse melanoma cells have a high affinity for the basement membrane and the ability to degrade it; these properties may allow tumor cells to invade the membrane and disseminate. In this study it was found that the metastatic potential of mouse melanoma cells varied when the cells were exposed in culture to fibronectin or laminin. After removal of fibronectin or exposure to laminin, the cells had an increased affinity for basement membrane collagen, were more invasive of basement membranes in vitro, and produced more lung colonies in vivo. These changes are correlated with and may be due to an increase in the laminin-binding capacity of the tumor cell surface.

  19. A Distinct Macrophage Population Mediates Metastatic Breast Cancer Cell Extravasation, Establishment and Growth

    PubMed Central

    Qian, Binzhi; Deng, Yan; Im, Jae Hong; Muschel, Ruth J.; Zou, Yiyu; Li, Jiufeng; Lang, Richard A.; Pollard, Jeffrey W.

    2009-01-01

    Background The stromal microenvironment and particularly the macrophage component of primary tumors influence their malignant potential. However, at the metastatic site the role of these cells and their mechanism of actions for establishment and growth of metastases remain largely unknown. Methodology/Principal Findings Using animal models of breast cancer metastasis, we show that a population of host macrophages displaying a distinct phenotype is recruited to extravasating pulmonary metastatic cells regardless of species of origin. Ablation of this macrophage population through three independent means (genetic and chemical) showed that these macrophages are required for efficient metastatic seeding and growth. Importantly, even after metastatic growth is established, ablation of this macrophage population inhibited subsequent growth. Furthermore, imaging of intact lungs revealed that macrophages are required for efficient tumor cell extravasation. Conclusion/Significance These data indicate a direct enhancement of metastatic growth by macrophages through their effects on tumor cell extravasation, survival and subsequent growth and identifies these cells as a new therapeutic target for treatment of metastatic disease. PMID:19668347

  20. Inhibition of Metastatic Outgrowth From Single Dormant Tumor Cells by Targeting the Cytoskeleton

    PubMed Central

    Barkan, Dalit; Kleinman, Hynda; Simmons, Justin L.; Asmussen, Holly; Kamaraju, Anil K.; Hoenorhoff, Mark J.; Liu, Zi-yao; Costes, Sylvain V.; Cho, Edward H.; Lockett, Stephen; Khanna, Chand; Chambers, Ann F.; Green, Jeffrey E.

    2008-01-01

    Metastatic breast cancer may emerge from latent tumor cells that remain dormant at disseminated sites for many years. Identifying mechanisms regulating the switch from dormancy to proliferative metastatic growth has been elusive due to the lack of experimental models of tumor cell dormancy. We characterized the in vitro growth characteristics of cells that exhibit either dormant (D2OR, MCF7, K7M2-AS.46) or proliferative (D2.A1, MDA-MB-231, K7M2) metastatic behavior in vivo. Although these cells proliferate readily in 2D culture, we demonstrate that when grown in 3D matrix, distinct growth properties of the cells were revealed that correlate to their dormant or proliferative behavior at metastatic sites in vivo. In 3D culture, cells with dormant behavior in vivo remained cell cycle arrested with elevated nuclear expression of p16 and p27. The transition from quiescence to proliferation of D2A1 cells was dependent upon fibronectin production and signaling through integrin β1, leading to cytoskeletal reorganization with f-actin stress fiber formation. We demonstrate that phosphorylation of myosin light chain by MLC kinase (MLCK) through integrin 1 is required for actin stress fiber formation and proliferative growth. Inhibition of integrin β1 or MLCK prevents transition from a quiescent to proliferative state in vitro. Iinhibition of MLCK significantly reduces metastatic outgrowth in vivo. These studies demonstrate that the switch from dormancy to metastatic growth may be regulated, in part, through epigenetic signaling from the microenvironment leading to changes in the cytoskeletal architecture of dormant cells. Targeting this process may provide therapeutic strategies for inhibition of the dormant-to-proliferative metastatic switch. PMID:18676848

  1. Stimulation of Hepatoma Cell Invasiveness and Metastatic Potential by Proteins Secreted From Irradiated Nonparenchymal Cells

    SciTech Connect

    Zhou Leyuan; Wang Zhiming; Gao Yabo; Wang Lingyan; Zeng Zhaochong

    2012-11-01

    Purpose: To determine whether factors secreted by irradiated liver nonparenchymal cells (NPCs) may influence invasiveness and/or metastatic potential of hepatocellular carcinoma (HCC) cells and to elucidate a possible mechanism for such effect. Methods and Materials: Primary rat NPCs were cultured and divided into irradiated (10-Gy X-ray) and nonirradiated groups. Forty-eight hours after irradiation, conditioned medium from irradiated (SR) or nonirradiated (SnonR) cultures were collected and added to sublethally irradiated cultures of the hepatoma McA-RH7777 cell line. Then, hepatoma cells were continuously passaged for eight generations (RH10Gy-SR and RH10Gy-SnonR). The invasiveness and metastatic potential of McA-RH7777, RH10Gy-SnonR, and RH10Gy-SR cells were evaluated using an in vitro gelatinous protein (Matrigel) invasion and an in vivo metastasis assay. In addition, SR and SnonR were tested using rat cytokine antibody arrays and enzyme-linked immunosorbent assay (ELISA). Results: In vitro gelatinous protein invasion assay indicated that the numbers of invading cells was significantly higher in RH10Gy-SR (40 {+-} 4.74) than in RH10Gy-SnonR (30.6 {+-} 3.85) cells, and lowest in McA-RH7777 (11.4 {+-} 3.56) cells. The same pattern was observed in vivo in a lung metastasis assay, as evaluated by number of metastatic lung nodules seen with RH10Gy-SR (28.83 {+-} 5.38), RH10Gy-SnonR (22.17 {+-} 4.26), and McA-RH7777 (8.3 {+-} 3.8) cells. Rat cytokine antibody arrays and ELISA demonstrated that metastasis-promoting cytokines (tumor necrosis factor-{alpha} and interleukin-6), circulating growth factors (vascular endothelial growth factor and epidermal growth factor), and metalloproteinases (MMP-2 and MMP-9) were upregulated in SR compared with SnonR. Conclusions: Radiation can increase invasiveness and metastatic potential of sublethally irradiated hepatoma cells, and soluble mediators released from irradiated NPCs promote this potential. Increased secretion of

  2. Quantitative proteomics of extracellular vesicles derived from human primary and metastatic colorectal cancer cells.

    PubMed

    Choi, Dong-Sic; Choi, Do-Young; Hong, Bok Sil; Jang, Su Chul; Kim, Dae-Kyum; Lee, Jaewook; Kim, Yoon-Keun; Kim, Kwang Pyo; Gho, Yong Song

    2012-01-01

    Cancer cells actively release extracellular vesicles (EVs), including exosomes and microvesicles, into surrounding tissues. These EVs play pleiotropic roles in cancer progression and metastasis, including invasion, angiogenesis, and immune modulation. However, the proteomic differences between primary and metastatic cancer cell-derived EVs remain unclear. Here, we conducted comparative proteomic analysis between EVs derived from human primary colorectal cancer cells (SW480) and their metastatic derivatives (SW620). Using label-free quantitation, we identified 803 and 787 proteins in SW480 EVs and SW620 EVs, respectively. Based on comparison between the estimated abundance of EV proteins, we identified 368 SW480 EV-enriched and 359 SW620 EV-enriched proteins. SW480 EV-enriched proteins played a role in cell adhesion, but SW620 EV-enriched proteins were associated with cancer progression and functioned as diagnostic indicators of metastatic cancer; they were overexpressed in metastatic colorectal cancer and played roles in multidrug resistance. As the first proteomic analysis comparing primary and metastatic cancer-derived EVs, this study increases our understanding of the pathological function of EVs in the metastatic process and provides useful biomarkers for cancer metastasis.

  3. Methyl Sulfone Blocked Multiple Hypoxia- and Non-Hypoxia-Induced Metastatic Targets in Breast Cancer Cells and Melanoma Cells

    PubMed Central

    Caron, Joan McIntyre; Caron, Jane McIntyre

    2015-01-01

    Metastatic cancer causes 90% of cancer deaths. Unlike many primary tumors, metastatic tumors cannot be cured by surgery alone. Metastatic cancer requires chemotherapy. However, metastatic cells are not easily killed by chemotherapy. These problems with chemotherapy are caused in part by the metastatic cell niche: hypoxia. Here we show that the molecule, methyl sulfone, normalized metastatic metabolism of hypoxic breast cancer and melanoma cells by altering several metabolic functions of the cells. Under hypoxia, methyl sulfone decreased expression of the master regulator of hypoxia, HIF-1α, and reduced levels of the glycolytic enzymes, PKM2, LDHA, GLUT1, the pro-angiogenic protein, VEGF, and the iron-sulfur metabolism molecules, miR-210 and transferrin, all of which promote metastasis. Conversely, methyl sulfone increased levels of ISCU1/2 and ferroportin, proteins associated with iron-sulfur cluster biogenesis and iron homeostasis in normal cells. These data identify methyl sulfone as a multi-targeting molecule that blocks the survival/proliferative effect of hypoxia on metastatic cells and brings normality back to cellular metabolism. PMID:26536104

  4. An animal model for colon cancer metastatic cell line with enhanced metastasizing ability. Establishment and characterization.

    PubMed

    Lin, J C; Cheng, J Y; Tzeng, C C; Yeh, M Y; Meng, C L

    1991-06-01

    We have developed an animal model for colon cancer metastasis and produced a metastasizing tumor after using a microinjection technique to inject SW480 cells into the cecal wall of athymic nude mice during "minilaparotomy." After the metastatic foci formed in murine lung, an in vitro primary culture was performed and a new metastatic cancer cell line, which was designated as CC-ML3, was established. The studies included: 1) the comparison between SW 480 and CC-ML3 in morphology, growth kinetics, seeding and plating efficiency, and karyotype; and 2) carcino-embryonic antigen determination, origination, and metastatic ability of CC-ML3. The results showed that CC-ML3 was significantly different from SW480 in vitro and possessed a high metastatic potential in vivo. This newly developed animal model may thus be useful for studying the biology and pathogenesis of metastasis of human colonic cancer.

  5. Metastatic transitional cell carcinoma presenting with skin metastasis.

    PubMed

    Açıkgöz, Onur; Ölçücüoğlu, Erkan; Kasap, Yusuf; Yığman, Metin; Güneş, Zeki Ender; Gazel, Eymen

    2015-01-01

    Transitional cell carcinomas (TCC) of upper urinary system account for 5% of all TCCs. The incidence of such metastases ranges from 0.18% to 2%. Experimental studies reported a general unsatisfactory survival time following skin metastasis. We report in this paper a case of metastatic urinary system TCC, which had become evident with a skin lesion in the right hypogastric region. A 60-year-old female patient with a history of being operated upon due to renal pelvic TCC was admitted to our outpatient clinic with complaints of red skin lesion in the near vicinity of the operational incision scar for 3 months. Her medical history revealed nothing but nephroureterectomy operation on the upper urinary system; moreover, it was learned that she had been ignoring what was recommended to her for routine controls. Thoraco-abdominal computed tomographic (CT) examination performed on the basis of aforementioned findings depicted a mass lesion of 24*20 mm dimension with high contrast uptake detected within the subcutaneous fat tissue in the right abdominal wall. The skin lesion depicted in CT was surgically excised. The pathological examination of the excised material was reported to be compatible with TCC. The patient was referred due to abdominal lesion to medical oncology after the operation. Followed up under chemotherapy protocol, the patient died 3 months after the metastasectomy operation. Skin metastasis of upper urinary system TCCs, especially renal pelvic TCCs, are quite rare conditions. Among the likely skin sites of metastasis for genitourinary system TCCs are head, face, extremities, suprapubic region and abdomen. Taking into consideration the low survival rates, the importance of early diagnosis of recurrences and/or distant metastases should be better appreciated. These patients die soon after the skin metastasis even with the administration of aggressive therapy. Similarly, our patient died 90 days after the diagnosis of skin metastasis despite the oncologic

  6. Metastatic transitional cell carcinoma presenting with skin metastasis

    PubMed Central

    Açıkgöz, Onur; Ölçücüoğlu, Erkan; Kasap, Yusuf; Yığman, Metin; Güneş, Zeki Ender; Gazel, Eymen

    2015-01-01

    Transitional cell carcinomas (TCC) of upper urinary system account for 5% of all TCCs. The incidence of such metastases ranges from 0.18% to 2%. Experimental studies reported a general unsatisfactory survival time following skin metastasis. We report in this paper a case of metastatic urinary system TCC, which had become evident with a skin lesion in the right hypogastric region. A 60-year-old female patient with a history of being operated upon due to renal pelvic TCC was admitted to our outpatient clinic with complaints of red skin lesion in the near vicinity of the operational incision scar for 3 months. Her medical history revealed nothing but nephroureterectomy operation on the upper urinary system; moreover, it was learned that she had been ignoring what was recommended to her for routine controls. Thoraco-abdominal computed tomographic (CT) examination performed on the basis of aforementioned findings depicted a mass lesion of 24*20 mm dimension with high contrast uptake detected within the subcutaneous fat tissue in the right abdominal wall. The skin lesion depicted in CT was surgically excised. The pathological examination of the excised material was reported to be compatible with TCC. The patient was referred due to abdominal lesion to medical oncology after the operation. Followed up under chemotherapy protocol, the patient died 3 months after the metastasectomy operation. Skin metastasis of upper urinary system TCCs, especially renal pelvic TCCs, are quite rare conditions. Among the likely skin sites of metastasis for genitourinary system TCCs are head, face, extremities, suprapubic region and abdomen. Taking into consideration the low survival rates, the importance of early diagnosis of recurrences and/or distant metastases should be better appreciated. These patients die soon after the skin metastasis even with the administration of aggressive therapy. Similarly, our patient died 90 days after the diagnosis of skin metastasis despite the oncologic

  7. Benefit of on nephrectomy for treating metastatic renal cell carcinoma.

    PubMed

    González-Ruiz de León, C; Pellejero-Pérez, P; Quintás-Blanco, A; García-Rodríguez, J; Álvarez-Fernández, C; Fernández-Gómez, J M

    2017-06-01

    Systemic treatment for metastatic renal cell carcinoma (mRCC) has changed with the new therapies, and it is not clear if nephrectomy (NEP) has a survival benefit in this kind of patients. To investigate if NEP associated to systemic treatment improves overall survival (OS) and progression-free survival (PFS). A retrospective, observational, descriptive study of 45 patients with diagnosis of mRCC between 2006-2014. Advanced cases with only palliative care were excluded, also patients with solitary metastasis who were managed with surgical resection. Finally 34 patients were treated with systemic treatment. Twenty-six also with surgery associated. Seventy percent were intermediate/low risk at the Motzer classification and>80% Karnofsky performance status. PFS was 7m. NEP improves PFS (10 vs. 4m). High risk Motzer decreased PFS (P<.001). The OS was 11.5m. Patients with Karnofsky performance status>80, intermediate or low risk Motzer treated with NEP and mTOR as second line treatment, increased the OS (14 vs. 3m, P=.0001; 14 vs. 6m, P=.001; and 9 vs. 5m, P=.003, respectively). In the multivariate analysis only NEP (P=0,006; HR 4.5) and intermediate/low risk at the Motzer classification(P=.020; HR 8.9) demonstrated significant improvement in OS. Patients treated with NEP associated to systemic treatment and with an intermediate/low risk in the Motzer classification had a better PFS and OS. The OS also improves in patients treated with mTOR in second line, and Karnofsky performance status>80%in the univariate study, but not in the multivariable one. Copyright © 2016 AEU. Publicado por Elsevier España, S.L.U. All rights reserved.

  8. Advanced new strategies for metastatic cancer treatment by therapeutic stem cells and oncolytic virotherapy

    PubMed Central

    Park, Geon-Tae; Choi, Kyung-Chul

    2016-01-01

    The field of therapeutic stem cell and oncolytic virotherapy for cancer treatment has rapidly expanded over the past decade. Oncolytic viruses constitute a promising new class of anticancer agent because of their ability to selectively infect and destroy tumor cells. Engineering of viruses to express anticancer genes and specific cancer targeting molecules has led to the use of these systems as a novel platform of metastatic cancer therapy. In addition, stem cells have a cancer specific migratory capacity, which is available for metastatic cancer targeting. Prodrug activating enzyme or anticancer cytokine expressing stem cells successfully inhibited the proliferation of cancer cells. Preclinical models have clearly demonstrated anticancer activity of these two platforms against a number of different cancer types and metastatic cancer. Several systems using therapeutic stem cells or oncolytic virus have entered clinical trials, and promising results have led to late stage clinical development. Consequently, metastatic cancer therapies using stem cells and oncolytic viruses are extremely promising. The following review will focus on the metastatic cancer targeting mechanism of therapeutic stem cells and oncolytic viruses, and potential challenges ahead for advancing the field. PMID:27494901

  9. Heterogeneity of isozyme expression in tumor cells does not correlate with metastatic potential.

    PubMed

    Aukerman, S L; Siciliano, M J; Fidler, I J

    1986-01-01

    The major purpose of these studies was to determine whether the expression of isozymes by tumor cells was heterogeneous among tumor cell subpopulations within a neoplasm and whether expression of one or another isozyme correlated with metastatic potential of tumor cells. The expression levels of 40 isozymes were determined in 56 cell lines, many of them clonal, from nine different murine and human tumors. The enzymes chosen for study are involved in nucleotide, carbohydrate and pentose phosphate metabolism, and as such are indicators of the general metabolic and differentiational status of the cell. The tumors studied included two murine and two human malignant melanomas, four murine fibrosarcomas, and one human prostatic adenocarcinoma. The lines isolated from these tumors consisted of cells that are tumorigenic non-metastatic, tumorigenic low metastatic and tumorigenic highly metastatic. Clonally derived cell lines from a given tumor differed in their expression of a number of different isozymes, including adenosine deaminase, creatine phosphokinase-B and lactate dehydrogenase. Different patterns of isozyme expression were observed among different tumor types as well as between tumors of the same type; however, there were no differences in isozyme expression for any enzyme tested that correlated with metastatic ability of tumor cells.

  10. Advanced new strategies for metastatic cancer treatment by therapeutic stem cells and oncolytic virotherapy.

    PubMed

    Park, Geon-Tae; Choi, Kyung-Chul

    2016-09-06

    The field of therapeutic stem cell and oncolytic virotherapy for cancer treatment has rapidly expanded over the past decade. Oncolytic viruses constitute a promising new class of anticancer agent because of their ability to selectively infect and destroy tumor cells. Engineering of viruses to express anticancer genes and specific cancer targeting molecules has led to the use of these systems as a novel platform of metastatic cancer therapy. In addition, stem cells have a cancer specific migratory capacity, which is available for metastatic cancer targeting. Prodrug activating enzyme or anticancer cytokine expressing stem cells successfully inhibited the proliferation of cancer cells. Preclinical models have clearly demonstrated anticancer activity of these two platforms against a number of different cancer types and metastatic cancer. Several systems using therapeutic stem cells or oncolytic virus have entered clinical trials, and promising results have led to late stage clinical development. Consequently, metastatic cancer therapies using stem cells and oncolytic viruses are extremely promising. The following review will focus on the metastatic cancer targeting mechanism of therapeutic stem cells and oncolytic viruses, and potential challenges ahead for advancing the field.

  11. Proteome profiling of exosomes derived from human primary and metastatic colorectal cancer cells reveal differential expression of key metastatic factors and signal transduction components.

    PubMed

    Ji, Hong; Greening, David W; Barnes, Thomas W; Lim, Justin W; Tauro, Bow J; Rai, Alin; Xu, Rong; Adda, Christopher; Mathivanan, Suresh; Zhao, Wei; Xue, Yanhong; Xu, Tao; Zhu, Hong-Jian; Simpson, Richard J

    2013-05-01

    Exosomes are small extracellular 40-100 nm diameter membrane vesicles of late endosomal origin that can mediate intercellular transfer of RNAs and proteins to assist premetastatic niche formation. Using primary (SW480) and metastatic (SW620) human isogenic colorectal cancer cell lines we compared exosome protein profiles to yield valuable insights into metastatic factors and signaling molecules fundamental to tumor progression. Exosomes purified using OptiPrep™ density gradient fractionation were 40-100 nm in diameter, were of a buoyant density ~1.09 g/mL, and displayed stereotypic exosomal markers TSG101, Alix, and CD63. A major finding was the selective enrichment of metastatic factors (MET, S100A8, S100A9, TNC), signal transduction molecules (EFNB2, JAG1, SRC, TNIK), and lipid raft and lipid raft-associated components (CAV1, FLOT1, FLOT2, PROM1) in exosomes derived from metastatic SW620 cells. Additionally, using cryo-electron microscopy, ultrastructural components in exosomes were identified. A key finding of this study was the detection and colocalization of protein complexes EPCAM-CLDN7 and TNIK-RAP2A in colorectal cancer cell exosomes. The selective enrichment of metastatic factors and signaling pathway components in metastatic colon cancer cell-derived exosomes contributes to our understanding of the cross-talk between tumor and stromal cells in the tumor microenvironment.

  12. Synthesis and shedding of hyaluronan from plasma membranes of human fibroblasts and metastatic and non-metastatic melanoma cells.

    PubMed Central

    Lüke, H J; Prehm, P

    1999-01-01

    The regulation of hyaluronan synthesis and shedding was analysed in human fibroblasts and in two melanoma cells that differed in the metastatic potential and proteolysis of the hyaluronan receptor CD44. Dissociation of nascent hyaluronan from plasma membranes isolated from fibroblasts by high salt concentrations led to activation of hyaluronan synthase. Hyaluronan synthesis was also enhanced in plasma membranes from fibroblasts that had been treated with hyaluronidase or trypsin. Hyaluronan oligosaccharides stimulated hyaluronan production in fibroblast cultures. These results indicated that nascent high-molecular-mass hyaluronan inhibited its own chain elongation, if it was retained in the vicinity of the synthase by cell-surface receptors. The results also indicated that increased hyaluronan synthesis and shedding correlated with proteolysis of CD44 on the melanoma cell lines, which has been observed by others. PMID:10493913

  13. Characterization of the metastatic phenotype of a panel of established osteosarcoma cells

    PubMed Central

    Ren, Ling; Mendoza, Arnulfo; Zhu, Jack; Briggs, Joseph W.; Halsey, Charles; Hong, Ellen S.; Burkett, Sandra S.; Morrow, James J.; Lizardo, Michael M.; Osborne, Tanasa; Li, Samuel Q.; Luu, Hue H.; Meltzer, Paul; Khanna, Chand

    2015-01-01

    Osteosarcoma (OS) is the most common bone tumor in pediatric patients. Metastasis is a major cause of mortality and morbidity. The rarity of this disease coupled with the challenges of drug development for metastatic cancers have slowed the delivery of improvements in long-term outcomes for these patients. In this study, we collected 18 OS cell lines, confirmed their expression of bone markers and complex karyotypes, and characterized their in vivo tumorgenicity and metastatic potential. Since prior reports included conflicting descriptions of the metastatic and in vivo phenotypes of these models, there was a need for a comparative assessment of metastatic phenotypes using identical procedures in the hands of a single investigative group. We expect that this single characterization will accelerate the study of this metastatic cancer. Using these models we evaluated the expression of six previously reported metastasis-related OS genes. Ezrin was the only gene consistently differentially expressed in all the pairs of high/low metatstatic OS cells. We then used a subtractive gene expression approach of the high and low human metastatic cells to identify novel genes that may be involved in OS metastasis. PHLDA1 (pleckstrin homology-like domain, family A) was identified as one of the genes more highly expressed in the high metastatic compared to low metastatic cells. Knocking down PHLDA1 with siRNA or shRNA resulted in down regulation of the activities of MAPKs (ERK1/2), c-Jun N-terminal kinases (JNK), and p38 mitogen-activated protein kinases (MAPKs). Reducing the expression of PHLDA1 also delayed OS metastasis progression in mouse xenograft models. PMID:26320182

  14. Induction of trismus by sunitinib and pazopanib in metastatic renal cell carcinoma

    PubMed Central

    Iyer, Ridhima; Montgomery, Bruce; Pandha, Hardev S.

    2017-01-01

    Tyrosine kinase inhibitors sunitinib and pazopanib are used as first-line agents in the treatment of metastatic renal cell carcinoma. Treatment-related toxicities have been described with both these drugs. This report describes a patient with metastatic renal carcinoma who developed trismus while being treated with these agents and is, to the best of our knowledge, the first such case to be reported. PMID:28197036

  15. Vismodegib: a guide to its use in locally advanced or metastatic basal cell carcinoma.

    PubMed

    Lyseng-Williamson, Katherine A; Keating, Gillian M

    2013-02-01

    Vismodegib is the first Hedgehog pathway inhibitor to be approved in the USA, where it is indicated for the treatment of adults with metastatic basal cell carcinoma (BCC), or with locally advanced BCC that has recurred following surgery or who are not candidates for surgery, and who are not candidates for radiation. In an ongoing, noncomparative, phase II trial, oral vismodegib was effective in and had an acceptable tolerability profile in the treatment of patients with locally advanced or metastatic BCC.

  16. Establishment and characterization of a novel human cholangiocarcinoma cell line with high metastatic activity.

    PubMed

    Uthaisar, Kwuntida; Vaeteewoottacharn, Kulthida; Seubwai, Wunchana; Talabnin, Chutima; Sawanyawisuth, Kanlayanee; Obchoei, Sumalee; Kraiklang, Ratthaphol; Okada, Seiji; Wongkham, Sopit

    2016-09-01

    Cholangiocarcinoma (CCA) is a highly metastatic tumor, and the lung is a common site of metastasis. A greater understanding of the biology of metastases is needed to improve treatment outcomes. Herein, a highly metastatic human CCA subline, KKU-213L5 from an original cell line, KKU-213 that has marginally metastatic ability, was established and characterized. KKU-213L5 was selected in vivo through the fifth serial passage of pulmonary metastasized tissues via tail-vein injection in NOD/scid/Jak3 mice. The metastatic abilities of the KKU-213L5 cells were compared with the parental line in vitro and in vivo. The expression profile of this metastatic cell line was determined using real-time PCR. KKU-213L5 cells were found to possess higher metastatic phenotypes, i.e., growth rates, stem cell surface markers (CD133), migration and invasion characteristics when compared with the parental cells. Compared to the KKU-213 cells, KKU-213L5 cells formed larger tumors in subcutaneous xenografted mice and had a >10-fold increase in lung metastases in the tail-vein injected metastatic mouse model. Mice injected intravenously with KKU-213L5 cells had a significantly shorter survival. Analysis of the expressed genes related to progression of cancer revealed significant upregulation of anterior gradient protein-2 (AGR2) and suppression of KiSS-1 in the KKU-213L5 cells. The association of these two genes with metastasis was affirmed in CCA patient tissues since increased AGR2 expression and decreased KiSS-1 expression were found in higher stage patient tumors. In conclusion, a highly metastatic human CCA cell line was established and characterized. It is plausible that the differential expression between the parental KKU-213 and highly metastatic KKU-213L5 cells may be beneficial to classify novel genes associated with metastasis. The KKU-213L5 cell line should serve as a valued device for discovering the molecular mechanisms of CCA metastasis and enabling the search for an

  17. Metastatic Renal Cell Carcinoma Masquerading as Jugular Foramen Paraganglioma: A Role for Novel Magnetic Resonance Imaging.

    PubMed

    Thomas, Andrew J; Wiggins, Richard H; Gurgel, Richard K

    2017-08-01

    To describe a case of metastatic renal cell carcinoma (RCC) masquerading as a jugular foramen paraganglioma (JP). To compare imaging findings between skull base metastatic RCC and histologically proven paraganglioma. A case of unexpected metastatic skull base RCC is reviewed. Computed tomography (CT) and magnetic resonance imaging (MRI) were compared between 3 confirmed cases of JP and our case of metastatic RCC. Diffusion-weighted MRI (DW-MRI) sequences and computed apparent diffusion coefficient (ADC) values were compared between these entities. A 55-year-old man presents with what appears clinically and radiographically to be JP. The tumor was resected, then discovered on postoperative pathology to be metastatic RCC. Imaging was retrospectively compared between 3 histologically confirmed cases of JP and our case of skull base RCC. The RCC metastasis was indistinguishable from JP on CT and traditional MRI but distinct by ADC values calculated from DW-MRI. Metastatic RCC at the skull base may mimic the clinical presentation and radiographic appearance of JP. The MRI finding of flow voids is seen in both paraganglioma and metastatic RCC. Diffusion-weighted MRI is able to distinguish these entities, highlighting its potential utility in distinguishing skull base lesions.

  18. Comparative metabolic and lipidomic profiling of human breast cancer cells with different metastatic potentials

    PubMed Central

    Kim, So-Hyun; Kwon, Yeo-Jung; Chun, Young-Jin; Choi, Hyung-Kyoon

    2016-01-01

    This study conducted comprehensive and comparative metabolic and lipidomic profiling of a human epithelial breast cell line (MCF-10A), a slightly metastatic (MCF-7), and a highly metastatic (MDA-MB-231) breast cancer cell line using gas chromatography mass spectrometry (GC-MS) and direct infusion mass spectrometry (DI-MS). Among 39 metabolites identified by GC-MS analysis, xanthine, glucose-6-phosphate, mannose-6-phosphate, guanine, and adenine were selected as prognostic markers of breast cancer metastasis. Major metabolic pathways involved in differentiation of the cell lines were alanine, aspartate, and glutamate metabolism, purine metabolism and glycine, serine, and threonine metabolism. Among 44 intact lipid species identified by DI-MS analysis, the levels of most phospholipids were higher in both metastatic groups than in normal cells. Specifically, the levels of phosphatidylserine (PS) 18:0/20:4, phosphatidylinositol (PI) 18:0/20:4, and phosphatidylcholine (PC) 18:0/20:4 were markedly higher while those of phosphatidylethanolamine (PE) 18:1/18:1 and PI 18:0/18:1 were lower in MDA-MB-231 cells than in MCF-7 cells. A partial-least-squares regression model was developed and validated for predicting the metastatic potential of breast cancer cells. The information obtained in this study will be useful when developing diagnostic tools and for identifying potential therapeutic targets for metastatic breast cancer. PMID:27564096

  19. Analytical cell adhesion chromatography reveals impaired persistence of metastatic cell rolling adhesion to P-selectin

    PubMed Central

    Oh, Jaeho; Edwards, Erin E.; McClatchey, P. Mason; Thomas, Susan N.

    2015-01-01

    ABSTRACT Selectins facilitate the recruitment of circulating cells from the bloodstream by mediating rolling adhesion, which initiates the cell–cell signaling that directs extravasation into surrounding tissues. To measure the relative efficiency of cell adhesion in shear flow for in vitro drug screening, we designed and implemented a microfluidic-based analytical cell adhesion chromatography system. The juxtaposition of instantaneous rolling velocities with elution times revealed that human metastatic cancer cells, but not human leukocytes, had a reduced capacity to sustain rolling adhesion with P-selectin. We define a new parameter, termed adhesion persistence, which is conceptually similar to migration persistence in the context of chemotaxis, but instead describes the capacity of cells to resist the influence of shear flow and sustain rolling interactions with an adhesive substrate that might modulate the probability of extravasation. Among cell types assayed, adhesion persistence to P-selectin was specifically reduced in metastatic but not leukocyte-like cells in response to a low dose of heparin. In conclusion, we demonstrate this as an effective methodology to identify selectin adhesion antagonist doses that modulate homing cell adhesion and engraftment in a cell-subtype-selective manner. PMID:26349809

  20. GAD1 Upregulation Programs Aggressive Features of Cancer Cell Metabolism in the Brain Metastatic Microenvironment.

    PubMed

    Schnepp, Patricia M; Lee, Dennis D; Guldner, Ian H; O'Tighearnaigh, Treasa K; Howe, Erin N; Palakurthi, Bhavana; Eckert, Kaitlyn E; Toni, Tiffany A; Ashfeld, Brandon L; Zhang, Siyuan

    2017-04-11

    The impact of altered amino acid metabolism on cancer progression is not fully understood. We hypothesized that a metabolic transcriptome shift during metastatic evolution is crucial for brain metastasis. Here we report a powerful impact in this setting caused by epigenetic upregulation of glutamate decarboxylase 1 (GAD1), a regulator of the GABA neurotransmitter metabolic pathway. In cell-based culture and brain metastasis models, we found that downegulation of the DNA methyltransferase DNMT1 induced by the brain microenvironment-derived clusterin resulted in decreased GAD1 promoter methylation and subsequent upregulation of GAD1 expression in brain metastatic tumor cells. In a system to dynamically visualize cellular metabolic responses mediated by GAD1, we monitored the cytosolic NADH:NAD+ equilibrium in tumor cells. Reducing GAD1 in metastatic cells by primary glia cell co-culture abolished the capacity of metastatic cells to utilize extracellular glutamine, leading to cytosolic accumulation of NADH and increased oxidative status. Similarly, genetic or pharmacological disruption of the GABA metabolic pathway decreased the incidence of brain metastasis in vivo. Taken together, our results show how epigenetic changes in GAD1 expression alter local glutamate metabolism in the brain metastatic microenvironment, contributing to a metabolic adaption that facilitates metastasis outgrowth in that setting.

  1. Dendritic cell vaccination of patients with metastatic colorectal cancer.

    PubMed

    Burgdorf, Stefan K

    2010-09-01

    Colorectal cancer is with more than 4000 new cases every year the third most common cancer in Denmark. Metastases are most often found in the liver, and 20-25% of the patients have synchronous metastases to the liver at time of primary diagnosis. Other frequent sites for metastases are lungs and lymph nodes. Without treatment the median survival for patients with metastatic colorectal cancer is 7-9 months. Patients receiving systemic or regional chemotherapy now have a median survival of approximately 20 months. Up to 40% of the patients undergoing intended curative surgery subsequently relapse with local or distant disease, and approximately 80% of the relapses appear within the first 3 years. If the cancer metastasises, and the chances of radical surgery are eliminated, the prognosis is poor. The aim of the present study was to evaluate the clinical and immunological effects of treating patients with disseminated colorectal cancer with a dendritic cell based cancer vaccine (MelCancerVac). The vaccine consisted of dendritic cells generated from autologous mononuclear cells pulsed with an allogeneic tumor cell lysate, selected for its high expression of cancer associated antigens. A clinical phase I study evaluating tolerability and toxicity of the treatment was established. Six patients with progressive disease were included and the analysis revealed that the treatment was well tolerated and not associated with toxicity. A subsequent clinical phase II study evaluating the activity of the treatment with CT-scan based measurements of tumors (RECIST), self reported quality of life (SF-36), and clinical evaluation was established. Out of twenty included patients with progressive disease, seventeen received intervention with the vaccine. Stable disease was achieved in four patients and two of these remained stable throughout the entire study period. Quality of life remained for most parameters included in the evaluation high and stable. The immunological consequences

  2. Methyl Sulfone Induces Loss of Metastatic Properties and Reemergence of Normal Phenotypes in a Metastatic Cloudman S-91 (M3) Murine Melanoma Cell Line

    PubMed Central

    Caron, Joan McIntyre; Bannon, Marissa; Rosshirt, Lindsay; Luis, Jessica; Monteagudo, Luke; Caron, John M.; Sternstein, Gerson Marc

    2010-01-01

    Background The most deadly form of cancer is not lung or colon, breast or prostate; it is any cancer that has become metastatic. Mortality due to metastatic melanoma, one of the most aggressive and deadly cancers, has increased steadily over the last several decades. Unfortunately, the arsenal of chemotherapeutic agents available today is most often unsuccessful at extending and improving the life expectancy of afflicted individuals. We sought to identify an effective and nontoxic agent against metastatic melanoma. Methodology/Principal Findings We chose to study Cloudman S-91 mouse melanoma cells (sub-clone M3, CCL53.1) because these cells are highly aggressive and metastatic, representing one of the deadliest types of cancer. Melanoma cells also had an experimental advantage because their morphology, which is easily monitored, relates to the physiology of metastatic cells and normal melanocytes. We chose to test methyl sulfone as a chemotherapeutic agent for two reasons. Because of its chemical structure, we speculated a potential anti-cancer activity by targeting microtubules. Equally important, methyl sulfone has a well-established safety profile in humans. Surprisingly, we found that malignant melanoma cells exposed to methyl sulfone demonstrated the loss of phenotypes characteristic of malignant cells, and the reemergence of phenotypes characteristic of healthy melanocytes. Briefly, over time methyl sulfone induced contact inhibition, loss of ability to migrate through an extracellular matrix, loss of anchorage-independent growth, proper wound healing followed by contact inhibition, irreversible senescence followed by arborization with melanosomes in arbors as seen in normal melanocytes. Conclusions/Significance Methyl sulfone may have clinical potential as a non-toxic agent effective against metastatic melanoma. Additionally, methyl sulfone has promise as a tool to explore molecular mechanisms of metastatic transformation as well as fundamental processes

  3. Proton NMR characterization of intact primary and metastatic melanoma cells in 2D & 3D cultures.

    PubMed

    Ramachandran, Gokula Krishnan; Yeow, Chen Hua

    2017-03-16

    To characterize the differences between the primary and metastatic melanoma cell lines grown in 2D cultures and 3D cultures. Primary melanoma cells (WM115) and metastatic melanoma cells (WM266) extracted from a single donor was cultured in 2D as well as 3D cultures. These cells were characterized using proton NMR spectrometry, and the qualitative chemical shifts markers were identified and discussed. In monolayer culture (2D), we observed one qualitative chemical shift marker for primary melanoma cells. In spheroid cultures (3D), we observed nine significant chemical shifts, of which eight markers were specific for primary melanoma spheroids, whereas the other one marker was specific to metastatic melanoma spheroids. This study suggests that the glucose accumulation and phospholipid composition vary significantly between the primary and metastatic cells lines that are obtained from a single donor and also with the cell culturing methods. 14 qualitative chemical shift markers were obtained in the comparison between monolayer culture and spheroids cultures irrespective of the differences in the cell lines. Among which 4 were unique to monolayer cultures whereas 10 chemical shifts were unique to the spheroid cultures. This study also shows that the method of cell culture would drastically affect the phospholipid composition of the cells and also depicts that the cells in spheroid culture closely resembles the cells in vivo. This study shows the high specificity of proton NMR spectrometry in characterizing cancer cell lines and also shows the variations in the glucose accumulation and phospholipid composition between the primary and metastatic melanoma cell lines from the same donor. Differences in the cell culture method does plays an important role in phospholipid composition of the cells.

  4. New metastatic model of human small-cell lung cancer by orthotopic transplantation in mice.

    PubMed

    Sakamoto, Shuichi; Inoue, Hiroyuki; Ohba, Shunichi; Kohda, Yasuko; Usami, Ihomi; Masuda, Tohru; Kawada, Manabu; Nomoto, Akio

    2015-04-01

    Small-cell lung cancer (SCLC) is an aggressive cancer with high metastatic ability and novel strategies against the metastasis are urgently needed to improve SCLC treatment. However, the mechanism of metastasis of SCLC remains largely to be elucidated. For further studies of SCLC metastasis, we developed a new orthotopic transplantation model in mice. We established a GFP-labeled subline from the human SCLC cell line DMS273 and transplanted them orthotopically into the lung of nude mice with Matrigel. The GFP-labeled cells showed significant metastatic activity and formed metastatic foci in distant tissues such as bone, kidney, and brain, as observed in SCLC patients. From a bone metastasis focus of the mouse, we isolated another subline, termed G3H, with enhanced metastatic potential and higher hepatocyte growth factor (HGF) expression than the parental line. Further studies indicated that the HGF/MET signaling pathway was involved in in vitro motility and invasion activities of the G3H cells and treatments with MET inhibitors decreased formation of distant metastases in our orthotopic model using G3H cells. These data indicated that our model mimics the clinical aspect of SCLC such as metastatic tropism and autocrine of HGF/MET signaling. Compared with other orthotopic SCLC models, our model has a superior ability to form distant metastases. Therefore, our model will provide a valuable tool for the study of SCLC metastasis. © 2015 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.

  5. 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.

  6. FRIZZLED7 Is Required for Tumor Inititation and Metastatic Growth of Melanoma Cells

    PubMed Central

    Tiwary, Shweta; Xu, Lei

    2016-01-01

    Metastases are thought to arise from cancer stem cells and their tumor initiating abilities are required for the establishment of metastases. Nevertheless, in metastatic melanoma, the nature of cancer stem cells is under debate and their contribution to metastasis formation remains unknown. Using an experimental metastasis model, we discovered that high levels of the WNT receptor, FZD7, correlated with enhanced metastatic potentials of melanoma cell lines. Knocking down of FZD7 in a panel of four melanoma cell lines led to a significant reduction in lung metastases in animal models, arguing that FZD7 plays a causal role during metastasis formation. Notably, limiting dilution analyses revealed that FZD7 is essential for the tumor initiation of melanoma cells and FZD7 knockdown impeded the early expansion of metastatic melanoma cells shortly after seeding, in accordance with the view that tumor initiating ability of cancer cells is required for metastasis formation. FZD7 activated JNK in melanoma cell lines in vitro and the expression of a dominant negative JNK suppressed metastasis formation in vivo, suggesting that FZD7 may promote metastatic growth of melanoma cells via activation of JNK. Taken together, our findings uncovered a signaling pathway that regulates the tumor initiation of melanoma cells and contributes to metastasis formation in melanoma. PMID:26808375

  7. Fourier analysis of cell motility: correlation of motility with metastatic potential.

    PubMed Central

    Partin, A W; Schoeniger, J S; Mohler, J L; Coffey, D S

    1989-01-01

    We report the development of a computerized, mathematical system for quantitating the various types of cell motility. This Fourier analysis method simultaneously quantifies for individual cells (i) temporal changes in cell shape represented by cell ruffling, undulation, and pseudopodal extension, (ii) cell translation, and (iii) average cell size and shape. This spatial-temporal Fourier analysis was tested on a series of well-characterized animal tumor cell lines of rat prostatic cancer to study in a quantitative manner the correlation of cell motility with increasing in vivo metastatic potential. Fourier motility coefficients measuring pseudopodal extension correlated best with metastatic potential in the cell lines studied. This study demonstrated that Fourier analysis provides quantitative measurement of cell motility that may be applied to the study of biological processes. This analysis should aid in the study of the motility of individual cells in various areas of cellular and tumor biology. Images PMID:2919174

  8. Treatment Algorithms for Patients with Metastatic Non-Small Cell, Non-Squamous Lung Cancer

    PubMed Central

    Melosky, Barbara

    2014-01-01

    A number of developments have altered the treatment paradigm for metastatic non-small cell, non-squamous lung cancer. These include increasing knowledge of molecular signal pathways, as well as the outcomes of several large-scale trials. As a result, treatments are becoming more efficacious and more personalized, and are changing the management and prognosis of non-small cell lung cancer patients. This is resulting in increased survival in select patient groups. In this paper, a simplified algorithm for treating patients with metastatic non-small cell, non-squamous lung cancer is presented. PMID:25325013

  9. Immunotherapy with dendritic cells in an animal model of early pulmonary metastatic squamous cell carcinoma.

    PubMed

    Moon, Jeong Hwan; Chung, Man Ki; Son, Young-Ik

    2012-11-01

    Distant metastases is becoming a more frequently recognized pattern of treatment failure in patients with squamous cell carcinoma of the head and neck (SCCHN). In this study, we evaluated the effect of a dendritic cell (DC)-based vaccine in an early pulmonary metastatic murine model with the aim of providing an effective treatment for SCCHN patients presenting with occult pulmonary metastasis. In vivo animal experiments were conducted in C3H/He immunocompetent mice using the SCCVII syngeneic squamous carcinoma cell line. SCCVII cells were injected through the tail vein to establish early pulmonary metastases. Bone marrow-derived DCs were cultured and educated with ultraviolet B-irradiated apoptotic SCCVII cells before adoptive transfer into the inguinal area. Control groups were vaccinated with normal saline, naïve DCs, or apoptotic tumor cells. In the apoptotic SCCVII-pulsed DC group, the number of pulmonary tumor nodules was reduced, extirpated lung weight was less, and survival was longer than in control groups. Differences were statistically significant (P < .0001). Specific antitumor immunity was established only in the pulsed DC group, which was confirmed by an interferon-γ enzyme-linked immunosorbent assay. In an early pulmonary metastatic SCC murine model, systemic antitumor responses can be elicited by adoptive transfers of DCs, which were primed with apoptotic tumor cells. We hope this study will help improve overall survival of patients with SCCHN, especially when they have early or occult pulmonary metastasis. Copyright © 2012 The American Laryngological, Rhinological, and Otological Society, Inc.

  10. Increased expression of melanoma stem cell marker CD271 in metastatic melanoma to the brain

    PubMed Central

    Guo, Ruifeng; Fierro-Fine, Amelia; Goddard, Lindsey; Russell, Madison; Chen, Jie; Liu, Cheng Z; Fung, Kar-Ming; Hassell, Lewis A

    2014-01-01

    Human melanoma contains multipotent stem cells that express the neural crest stem cell marker CD271. CD271-expressing melanoma cells in murine xenografts give rise to metastatic tumor. However, a comprehensive clinical investigation of its role in different stages of melanomagenesis has not been well studied. We studied CD271 expression with immunohistochemistry in 11 cases of banal melanocytic nevus, 9 cases of primary cutaneous melanoma, 10 cases of primary mucosal melanoma, 5 cases of metastatic melanoma in regional lymph nodes, and 11 cases of metastatic melanoma in the brain. In addition, 9 cases of metastatic, high-grade adenocarcinomas from breast and lung to the brain were studied as controls. The staining was scored based on the number of positive cells and analyzed by student t-test. All banal melanocytic nevi showed negative to equivocal staining. Primary cutaneous melanomas showed variable patterns, mucosal melanomas were mostly negative, and metastases to lymph nodes ranged from negative to moderate positivity. In contrast, all 11 cases of metastatic melanoma to the brain showed moderate (4 cases) to strong positivity (7 cases). Metastases from lung and breast origin were used as controls and showed negative to weakly positive staining in all but one case. Statistically, CD271 has significantly increased expression in metastatic melanoma to the brain when compared to the other groups studied (P < 0.05). The findings suggest that CD271 expression is specifically increased in metastatic melanoma to the brain. Further prospective study for the role of CD271 in prediction of melanoma brain metastasis as well as prognosis assessment will be of great clinical significance. PMID:25674270

  11. Increased expression of melanoma stem cell marker CD271 in metastatic melanoma to the brain.

    PubMed

    Guo, Ruifeng; Fierro-Fine, Amelia; Goddard, Lindsey; Russell, Madison; Chen, Jie; Liu, Cheng Z; Fung, Kar-Ming; Hassell, Lewis A

    2014-01-01

    Human melanoma contains multipotent stem cells that express the neural crest stem cell marker CD271. CD271-expressing melanoma cells in murine xenografts give rise to metastatic tumor. However, a comprehensive clinical investigation of its role in different stages of melanomagenesis has not been well studied. We studied CD271 expression with immunohistochemistry in 11 cases of banal melanocytic nevus, 9 cases of primary cutaneous melanoma, 10 cases of primary mucosal melanoma, 5 cases of metastatic melanoma in regional lymph nodes, and 11 cases of metastatic melanoma in the brain. In addition, 9 cases of metastatic, high-grade adenocarcinomas from breast and lung to the brain were studied as controls. The staining was scored based on the number of positive cells and analyzed by student t-test. All banal melanocytic nevi showed negative to equivocal staining. Primary cutaneous melanomas showed variable patterns, mucosal melanomas were mostly negative, and metastases to lymph nodes ranged from negative to moderate positivity. In contrast, all 11 cases of metastatic melanoma to the brain showed moderate (4 cases) to strong positivity (7 cases). Metastases from lung and breast origin were used as controls and showed negative to weakly positive staining in all but one case. Statistically, CD271 has significantly increased expression in metastatic melanoma to the brain when compared to the other groups studied (P < 0.05). The findings suggest that CD271 expression is specifically increased in metastatic melanoma to the brain. Further prospective study for the role of CD271 in prediction of melanoma brain metastasis as well as prognosis assessment will be of great clinical significance.

  12. Mesenchymal Cancer Cell-Stroma Crosstalk Promotes Niche Activation, Epithelial Reversion, and Metastatic Colonization

    PubMed Central

    del Pozo Martin, Yaiza; Park, Danielle; Ramachandran, Anassuya; Ombrato, Luigi; Calvo, Fernando; Chakravarty, Probir; Spencer-Dene, Bradley; Derzsi, Stefanie; Hill, Caroline S.; Sahai, Erik; Malanchi, Ilaria

    2015-01-01

    Summary During metastatic colonization, tumor cells must establish a favorable microenvironment or niche that will sustain their growth. However, both the temporal and molecular details of this process remain poorly understood. Here, we found that metastatic initiating cells (MICs) exhibit a high capacity for lung fibroblast activation as a result of Thrombospondin 2 (THBS2) expression. Importantly, inhibiting the mesenchymal phenotype of MICs by blocking the epithelial-to-mesenchymal transition (EMT)-associated kinase AXL reduces THBS2 secretion, niche-activating ability, and, consequently, metastatic competence. Subsequently, disseminated metastatic cells revert to an AXL-negative, more epithelial phenotype to proliferate and decrease the phosphorylation levels of TGF-β-dependent SMAD2-3 in favor of BMP/SMAD1-5 signaling. Remarkably, newly activated fibroblasts promote this transition. In summary, our data reveal a crosstalk between cancer cells and their microenvironment whereby the EMT status initially triggers and then is regulated by niche activation during metastatic colonization. PMID:26670048

  13. Trafficking of Metastatic Breast Cancer Cells in Bone

    DTIC Science & Technology

    2005-08-01

    at 4wk showing two large metastatic foci, one at each end of the femur . The distal end shows an iatrogenic fracture presumable due to weakness caused...protein (MDA-MB 231 ) were inoculated intracardiacly into athymic mice.; femurs harvested from 1 hr to 6 wk later and analyzed by fluorescence...modifying the bone microenvironment, are needed to improve treatment of osteolytic bone metastases. 15. SUBJECT TERMS Breast cancer, bone, metastasis

  14. Radiation therapy in the treatment of metastatic renal cell carcinoma

    SciTech Connect

    Onufrey, V.; Mohiuddin, M.

    1985-11-01

    Adenocarcinoma of the kidney is an unusual tumor, both in its biological behavior and in its response to radiation treatment. Historically, these tumors have been considered to be radioresistant, and the role of radiation therapy remains questionable in the primary management of this disease. However, radiation treatment is routinely used in the palliation of metastatic lesions for relief of symptoms. Therefore, we have undertaken a review of our experience in the treatment of this disease to determine the effectiveness of radiation in its palliation. From 1956 to 1981, 125 patients with metastatic lesions from hypernephroma have been treated in the Department of Radiation Therapy at Thomas Jefferson University Hospital. Most patients were referred for relief of bone pain (86), brain metastasis (12), spinal cord compression (9), and soft tissue masses (18). Total doses varied from 2000 rad to a maximum of 6000 rad. Response to treatment was evaluated on the basis of relief of symptoms, either complete, partial or no change. Our results indicate a significantly higher response rate of 65% for total doses equal to or greater than a TDF of 70, as compared to 25% for doses lower than a TDF of 70. No difference in response was observed either for bone or soft tissue metastasis or visceral disease. This leads us to believe that metastatic lesions from adenocarcinomas of the kidney should be treated to higher doses to obtain maximum response rates. Analysis of these results are presented in detail.

  15. Effective activity of cytokine-induced killer cells against autologous metastatic melanoma including cells with stemness features.

    PubMed

    Gammaitoni, Loretta; Giraudo, Lidia; Leuci, Valeria; Todorovic, Maja; Mesiano, Giulia; Picciotto, Franco; Pisacane, Alberto; Zaccagna, Alessandro; Volpe, Maria Giuseppa; Gallo, Susanna; Caravelli, Daniela; Giacone, Elena; Venesio, Tiziana; Balsamo, Antonella; Pignochino, Ymera; Grignani, Giovanni; Carnevale-Schianca, Fabrizio; Aglietta, Massimo; Sangiolo, Dario

    2013-08-15

    We investigate the unknown tumor-killing activity of cytokine-induced killer (CIK) cells against autologous metastatic melanoma and the elusive subset of putative cancer stem cells (mCSC). We developed a preclinical autologous model using same patient-generated CIK cells and tumor targets to consider the unique biology of each patient/tumor pairing. In primary tumor cell cultures, we visualized and immunophenotypically defined a putative mCSC subset using a novel gene transfer strategy that exploited their exclusive ability to activate the promoter of stemness gene Oct4. The CIK cells from 10 patients with metastatic melanoma were successfully expanded (median, 23-fold; range, 11-117). Primary tumor cell cultures established and characterized from the same patients were used as autologous targets. Patient-derived CIK cells efficiently killed autologous metastatic melanoma [up to 71% specific killing (n = 26)]. CIK cells were active in vivo against autologous melanoma, resulting in delayed tumor growth, increased necrotic areas, and lymphocyte infiltration at tumor sites. The metastatic melanoma cultures presented an average of 11.5% ± 2.5% putative mCSCs, which was assessed by Oct4 promoter activity and stemness marker expression (Oct4, ABCG2, ALDH, MITF). Expression was confirmed on mCSC target molecules recognized by CIK cells (MIC A/B; ULBPs). CIK tumor killing activity against mCSCs was intense (up to 71%, n = 4) and comparable with results reported against differentiated metastatic melanoma cells (P = 0.8). For the first time, the intense killing activity of CIK cells against autologous metastatic melanoma, including mCSCs, has been shown. These findings move clinical investigation of a new immunotherapy for metastatic melanoma, including mCSCs, closer. ©2013 AACR.

  16. Metastatic Colonization

    PubMed Central

    Massagué, Joan; Obenauf, Anna C.

    2016-01-01

    Metastasis is the main cause of death from cancer. To colonize distant organs, circulating cancer cells must overcome many obstacles through mechanisms that we are starting to understand. Infiltrating distant tissue, evading immune defences, adapting to supportive niches, surviving as latent tumour-initiating seeds, and eventually breaking out to replace the host tissue, are key steps for metastatic colonization. These obstacles make metastasis a highly inefficient process, but once metastases are established current treatments frequently fail to provide durable responses. A better understanding of the mechanistic determinants of metastatic colonization is needed to better prevent and treat metastatic cancer. PMID:26791720

  17. The BMP Inhibitor Coco Reactivates Breast Cancer Cells at Lung Metastatic sites

    PubMed Central

    Gao, Hua; Chakraborty, Goutam; Lee-Lim, Ai Ping; Mo, Qianxing; Decker, Markus; Vonica, Alin; Shen, Ronglai; Brogi, Edi; Brivanlou, Ali H.; Giancotti, Filippo G.

    2012-01-01

    SUMMARY The mechanistic underpinnings of metastatic dormancy and reactivation are poorly understood. A gain-of-function cDNA screen reveals that Coco, a secreted antagonist of TGF-β ligands, induces dormant breast cancer cells to undergo reactivation in the lung. Mechanistic studies indicate that Coco exerts this effect by blocking lung-derived BMP ligands. Whereas Coco enhances the manifestation of traits associated with cancer stem cells, BMP signaling suppresses it. Coco induces a discrete gene expression signature, which is strongly associated with metastatic relapse to the lung but not to the bone or brain in patients. Experiments in mouse models suggest that these latter organs contain niches devoid of bioactive BMP. These findings reveal that metastasis-initiating cells need to overcome organ-specific anti-metastatic signals in order to undergo reactivation. PMID:22901808

  18. Photoacoustic detection of metastatic melanoma cells in the human circulatory system.

    PubMed

    Weight, Ryan M; Viator, John A; Dale, Paul S; Caldwell, Charles W; Lisle, Allison E

    2006-10-15

    Detection of disseminating tumor cells among patients suffering from various types and stages of cancer can function as an early warning system, alerting the physician of the metastatic spread or recurrence of the disease. Early detection of such cells can result in preventative treatment of the disease, while late stage detection can serve as an indicator of the effectiveness of chemotherapeutics. The prognostic value of exposing disseminating tumor cells poses an urgent need for an efficient, accurate screening method for metastatic cells. We propose a system for the detection of metastatic circulating tumor cells based on the thermoelastic properties of melanoma. The method employs photoacoustic excitation coupled with a detection system capable of determining the presence of disseminating cells within the circulatory system in vitro. Detection trials consisting of tissue phantoms and a human melanoma cell line resulted in a detection threshold of the order of ten individual cells, thus validating the effectiveness of the proposed mechanism. Results imply the potential to assay simple blood draws, from healthy and metastatic patients, for the presence of cancerous melanoma providing an unprecedented method for routine cancer screening.

  19. Targeted Therapies: Bevacizumab and interferon-alpha in metastatic renal-cell carcinoma.

    PubMed

    Bukowski, Ronald M

    2009-05-01

    Rini and colleagues provide additional data on bevacizumab and interferon-alpha in clear-cell carcinoma of the kidney; a comparison of these results with the findings from contemporary trials suggests that bevacizumab and interferon-alpha is another clinically useful treatment option for patients with metastatic renal-cell carcinoma.

  20. Photoacoustic detection of metastatic melanoma cells in the human circulatory system

    NASA Astrophysics Data System (ADS)

    Weight, Ryan M.; Viator, John A.; Dale, Paul S.; Caldwell, Charles W.; Lisle, Allison E.

    2006-10-01

    Detection of disseminating tumor cells among patients suffering from various types and stages of cancer can function as an early warning system, alerting the physician of the metastatic spread or recurrence of the disease. Early detection of such cells can result in preventative treatment of the disease, while late stage detection can serve as an indicator of the effectiveness of chemotherapeutics. The prognostic value of exposing disseminating tumor cells poses an urgent need for an efficient, accurate screening method for metastatic cells. We propose a system for the detection of metastatic circulating tumor cells based on the thermoelastic properties of melanoma. The method employs photoacoustic excitation coupled with a detection system capable of determining the presence of disseminating cells within the circulatory system in vitro. Detection trials consisting of tissue phantoms and a human melanoma cell line resulted in a detection threshold of the order of ten individual cells, thus validating the effectiveness of the proposed mechanism. Results imply the potential to assay simple blood draws, from healthy and metastatic patients, for the presence of cancerous melanoma providing an unprecedented method for routine cancer screening.

  1. Tracking sub-clonal TP53 mutated tumor cells in human metastatic renal cell carcinoma

    PubMed Central

    Bousquet, Guilhem; Bouchtaoui, Morad El; Leboeuf, Christophe; Battistella, Maxime; Varna, Mariana; Ferreira, Irmine; Plassa, Louis-François; Hamdan, Diaddin; Bertheau, Philippe; Feugeas, Jean-Paul; Damotte, Diane; Janin, Anne

    2015-01-01

    Renal Cell Carcinomas (RCCs) are heterogeneous tumors with late acquisition of TP53 abnormalities during their evolution. They harbor TP53 abnormalities in their metastases. We aimed to study TP53 gene alterations in tissue samples from primary and metastatic RCCs in 36 patients followed up over a median of 4.2 years, and in xenografted issued from primary RCCs. In 36 primary RCCs systematically xenografted in mice, and in biopsies of metastases performed whenever possible during patient follow-up, we studied p53-expressing tumor cells and TP53 gene abnormalities. We identified TP53 gene alterations in primary tumors, metastases and xenografts. Quantification of tumors cells with TP53 gene alterations showed a significant increase in the metastases compared to the primary RCCs, and, strikingly, the xenografts were similar to the metastases and not to the primary RCCs from which they were derived. Using laser-microdissection of p53-expressing tumor cells, we identified TP53-mutated tumor cells in the xenografts derived from the primary RCC, and in a lung metastasis later developed in one patient. The mutation enabled us to track back their origin to a minority sub-clone in the primary heterogeneous RCC. Combining in situ and molecular analyses, we demonstrated a clonal expansion in a living patient with metastatic RCC. PMID:26002555

  2. Tracking sub-clonal TP53 mutated tumor cells in human metastatic renal cell carcinoma.

    PubMed

    Bousquet, Guilhem; El Bouchtaoui, Morad; Leboeuf, Christophe; Battistella, Maxime; Varna, Mariana; Ferreira, Irmine; Plassa, Louis-François; Hamdan, Diaddin; Bertheau, Philippe; Feugeas, Jean-Paul; Damotte, Diane; Janin, Anne

    2015-08-07

    Renal Cell Carcinomas (RCCs) are heterogeneous tumors with late acquisition of TP53 abnormalities during their evolution. They harbor TP53 abnormalities in their metastases. We aimed to study TP53 gene alterations in tissue samples from primary and metastatic RCCs in 36 patients followed up over a median of 4.2 years, and in xenografted issued from primary RCCs. In 36 primary RCCs systematically xenografted in mice, and in biopsies of metastases performed whenever possible during patient follow-up, we studied p53-expressing tumor cells and TP53 gene abnormalities.We identified TP53 gene alterations in primary tumors, metastases and xenografts. Quantification of tumors cells with TP53 gene alterations showed a significant increase in the metastases compared to the primary RCCs, and, strikingly, the xenografts were similar to the metastases and not to the primary RCCs from which they were derived.Using laser-microdissection of p53-expressing tumor cells, we identified TP53-mutated tumor cells in the xenografts derived from the primary RCC, and in a lung metastasis later developed in one patient. The mutation enabled us to track back their origin to a minority sub-clone in the primary heterogeneous RCC. Combining in situ and molecular analyses, we demonstrated a clonal expansion in a living patient with metastatic RCC.

  3. 4-methylcatechol-Induced Oxidative Stress Induces Intrinsic Apoptotic Pathway in Metastatic Melanoma Cells

    PubMed Central

    Payton, Florastina; Bose, Rumu; Alworth, William L; Kumar, Addanki P; Ghosh, Rita

    2011-01-01

    There has been a steady rise in fatalities associated with thick melanomas (>4mm). Although understanding of the biology of the disease has improved, effective treatment strategies for patients with advanced metastatic melanoma remain elusive. Therefore, more intensive testing of agents with therapeutic potential are needed to improve survival of patients with metastatic malignant melanoma. We have tested the ability of 4-methylcatechol, a metabolite of quercetin; a naturally occurring compound that is commonly found in a variety of fruits for its potential as an anti-melanoma agent. Our results show that 4-methylcatechol inhibits proliferation of melanoma cells in culture while not affecting the growth of normal human epidermal melanocytes. Further, the ability of metastatic melanoma cells to form colonies on soft agar was also inhibited. 4-methylcatechol caused the accumulation of cells in G2/M phase of the cell cycle and induced apoptosis. There was an increase in reactive oxygen species following treatment with 4-methylcatechol that led to apoptosis through the intrinsic mitochondrial pathway. Treatment also inhibited cell survival mediated by Akt, a key player in melanoma cell survival. Taken together our results suggest that 4-methylcatechol exhibits cytotoxicity towards metastatic malignant melanoma cells while sparing normal melanocytes and should be tested further as a potential drug candidate for malignant melanoma. PMID:21419106

  4. Comparative Gene Expression Profiling of Primary and Metastatic Renal Cell Carcinoma Stem Cell-Like Cancer Cells.

    PubMed

    Khan, Mohammed I; Czarnecka, Anna M; Lewicki, Sławomir; Helbrecht, Igor; Brodaczewska, Klaudia; Koch, Irena; Zdanowski, Robert; Król, Magdalena; Szczylik, Cezary

    2016-01-01

    Recent advancement in cancer research has shown that tumors are highly heterogeneous, and multiple phenotypically different cell populations are found in a single tumor. Cancer development and tumor growth are driven by specific types of cells-stem cell-like cancer cells (SCLCCs)-which are also responsible for metastatic spread and drug resistance. This research was designed to verify the presence of SCLCCs in renal cell cancer cell lines. Subsequently, we aimed to characterize phenotype and cell biology of CD105+ cells, defined previously as renal cell carcinoma tumor-initiating cells. The main goal of the project was to describe the gene-expression profile of stem cell-like cancer cells of primary tumor and metastatic origin. Real-time PCR analysis of stemness genes (Oct-4, Nanog and Ncam) and soft agar colony formation assay were conducted to check the stemness properties of renal cell carcinoma (RCC) cell lines. FACS analysis of CD105+ and CD133+ cells was performed on RCC cells. Isolated CD105+ cells were verified for expression of mesenchymal markers-CD24, CD146, CD90, CD73, CD44, CD11b, CD19, CD34, CD45, HLA-DR and alkaline phosphatase. Hanging drop assay was used to investigate CD105+ cell-cell cohesion. Analysis of free-floating 3D spheres formed by isolated CD105+ was verified, as spheres have been hypothesized to contain undifferentiated multipotent progenitor cells. Finally, CD105+ cells were sorted from primary (Caki-2) and metastatic (ACHN) renal cell cancer cell lines. Gene-expression profiling of sorted CD105+ cells was performed with Agilent's human GE 4x44K v2 microarrays. Differentially expressed genes were further categorized into canonical pathways. Network analysis and downstream analysis were performed with Ingenuity Pathway Analysis. Metastatic RCC cell lines (ACHN and Caki-1) demonstrated higher colony-forming ability in comparison to primary RCC cell lines. Metastatic RCC cell lines harbor numerous CD105+ cell subpopulations and have

  5. Targeted therapies in metastatic renal cell carcinoma: overview of the past year.

    PubMed

    Gross-Goupil, Marine; Massard, Christophe; Ravaud, Alain

    2012-02-01

    During the past half-decade, clinical trials have permitted major progress in treatment of metastatic renal cell carcinoma with the first generation of targeted therapies (bevacizumab, sunitinib, sorafenib, everolimus, and temsirolimus). New targeted agents such as axitinib, tivozanib, and dovitinib, all of which are tyrosine kinase inhibitors, have been developed in treatment of metastatic renal cell carcinoma. In the same time, more information regarding mechanism of disease and drug resistance shed light on new targets and new potent agents. We report an overview of the more relevant data published over the past year, which may modify the therapeutic landscape of kidney cancer in the near future.

  6. Trials with TALL-1O4 Cells for Treatment of Metastatic Breast Cancer

    DTIC Science & Technology

    1999-10-01

    AD Award Number: DAMD17-97-C- 7056 TITLE: Phase I Trial~with TALL-104 Cells for Treatment of Metastatic Breast Cancer PRINCIPAL INVESTIGATOR: Daniela...Metastatic Breast Cancer DAMD17-97-C- 7056 It AU1ITDI(SI Da~iela Sa~mol, Ph.D. 7. PERFORMING ORGANIZATION NAMEM(S N0 A•ESS . PERFORMING ORGANIZATIONREPORT...a commercial PCR kit (ATCC, Rockville, MD). Three times a week, cells were harvested by centrifugation in 250 ml conical tubes ( Corning , New York, NY

  7. Current Treatment Algorithms for Patients with Metastatic Non-Small Cell, Non-Squamous Lung Cancer

    PubMed Central

    Melosky, Barbara

    2017-01-01

    The treatment paradigm for metastatic non-small cell, non-squamous lung cancer is continuously evolving due to new treatment options and our increasing knowledge of molecular signal pathways. As a result of treatments becoming more efficacious and more personalized, survival for selected groups of non-small cell lung cancer (NSCLC) patients is increasing. In this paper, three algorithms will be presented for treating patients with metastatic non-squamous, NSCLC. These include treatment algorithms for NSCLC patients whose tumors have EGFR mutations, ALK rearrangements, or wild-type/wild-type tumors. As the world of immunotherapy continues to evolve quickly, a future algorithm will also be presented. PMID:28373963

  8. Stevens-Johnson syndrome induced by sorafenib for metastatic renal cell carcinoma.

    PubMed

    Ikeda, Masaomi; Fujita, Tetsuo; Amoh, Yasuyuki; Mii, Sumiyuki; Matsumoto, Kazumasa; Iwamura, Masatsugu

    2013-01-01

    Sorafenib is an orally administered active multikinase inhibitor for metastatic renal cell carcinoma that is now considered a standard agent. Skin toxicity, such as hand-foot skin reaction, is one of the frequent adverse effects of sorafenib. On the other hand, sorafenib-induced erythema multiforme is very rare, and Stevens-Johnson syndrome and toxic epidermal necrolysis induced by sorafenib have not been reported. We report the first case of Stevens-Johnson syndrome caused by sorafenib for metastatic renal cell carcinoma. © 2013 S. Karger AG, Basel.

  9. Comparative Gene Expression Profiling of Primary and Metastatic Renal Cell Carcinoma Stem Cell-Like Cancer Cells

    PubMed Central

    Czarnecka, Anna M.; Lewicki, Sławomir; Helbrecht, Igor; Brodaczewska, Klaudia; Koch, Irena; Zdanowski, Robert; Król, Magdalena; Szczylik, Cezary

    2016-01-01

    Background Recent advancement in cancer research has shown that tumors are highly heterogeneous, and multiple phenotypically different cell populations are found in a single tumor. Cancer development and tumor growth are driven by specific types of cells—stem cell-like cancer cells (SCLCCs)—which are also responsible for metastatic spread and drug resistance. This research was designed to verify the presence of SCLCCs in renal cell cancer cell lines. Subsequently, we aimed to characterize phenotype and cell biology of CD105+ cells, defined previously as renal cell carcinoma tumor-initiating cells. The main goal of the project was to describe the gene-expression profile of stem cell-like cancer cells of primary tumor and metastatic origin. Materials and Methods Real-time PCR analysis of stemness genes (Oct-4, Nanog and Ncam) and soft agar colony formation assay were conducted to check the stemness properties of renal cell carcinoma (RCC) cell lines. FACS analysis of CD105+ and CD133+ cells was performed on RCC cells. Isolated CD105+ cells were verified for expression of mesenchymal markers—CD24, CD146, CD90, CD73, CD44, CD11b, CD19, CD34, CD45, HLA-DR and alkaline phosphatase. Hanging drop assay was used to investigate CD105+ cell-cell cohesion. Analysis of free-floating 3D spheres formed by isolated CD105+ was verified, as spheres have been hypothesized to contain undifferentiated multipotent progenitor cells. Finally, CD105+ cells were sorted from primary (Caki-2) and metastatic (ACHN) renal cell cancer cell lines. Gene-expression profiling of sorted CD105+ cells was performed with Agilent’s human GE 4x44K v2 microarrays. Differentially expressed genes were further categorized into canonical pathways. Network analysis and downstream analysis were performed with Ingenuity Pathway Analysis. Results Metastatic RCC cell lines (ACHN and Caki-1) demonstrated higher colony-forming ability in comparison to primary RCC cell lines. Metastatic RCC cell lines harbor

  10. Non-linear optical imaging and quantitative analysis of the pathological changes in normal and carcinomatous human colorectal muscularis.

    PubMed

    Xia, Guowei; Zhi, Weijia; Zou, Yong; Wang, Lifeng; Wang, Changzhen; Peng, Ruiyun; Hu, Xiangjun

    2017-10-01

    Non-linear optical (NLO) imaging based on two-photon excitation (2PE) and second harmonic generation (SHG) has been widely used to image microstructures of biomedical specimens over the last two decades. We employed NLO imaging technology to investigate the histology of normal and carcinomatous human colorectal muscularis in transverse and longitudinal views. Results show there are different patterns of pathological changes of muscularis in tissue structure and cell morphology from both views. The NLO imaging provides identical histological information as the H&E images but requires neither stain nor tissue processing. Our study indicates that NLO imaging technology shows more detailed microstructure, which is a critical complementary tool in pathological diagnosis of colorectal tumours. It suggests that NLO imaging could be a very important diagnostic tool to help pathologists realise the real time early detection of human colorectal tumours in the foreseeable future. Copyright © 2017. Published by Elsevier B.V.

  11. An optofluidic constriction chip for monitoring metastatic potential and drug response of cancer cells.

    PubMed

    Martinez Vazquez, R; Nava, G; Veglione, M; Yang, T; Bragheri, F; Minzioni, P; Bianchi, E; Di Tano, M; Chiodi, I; Osellame, R; Mondello, C; Cristiani, I

    2015-04-01

    Cellular mechanical properties constitute good markers to characterize tumor cells, to study cell population heterogeneity and to highlight the effect of drug treatments. In this work, we describe the fabrication and validation of an integrated optofluidic chip capable of analyzing cellular deformability on the basis of the pressure gradient needed to push a cell through a narrow constriction. We demonstrate the ability of the chip to discriminate between tumorigenic and metastatic breast cancer cells (MCF7 and MDA-MB231) and between human melanoma cells with different metastatic potential (A375P and A375MC2). Moreover, we show that this chip allows highlighting the effect of drugs interfering with microtubule organization (paclitaxel, combretastatin A-4 and nocodazole) on cancer cells, which leads to changes in the pressure-gradient required to push cells through the constriction. Our single-cell microfluidic device for mechanical evaluation is compact and easy to use, allowing for an extensive use in different laboratory environments.

  12. Role of stromal cell-derived factor 1α pathway in bone metastatic prostate cancer

    PubMed Central

    Gupta, Nisha; Duda, Dan G.

    2016-01-01

    Abstract Metastatic prostate cancer is one of the leading causes of cancer-related death in men. The primary site of metastasis from prostate cancers is the bone. During the last decade, multiple studies have pointed to the role of the stromal cell-derived factor 1 alpha (SDF1α)/CXCR4 axis in the metastatic spread of the disease, but the mechanisms that underlie this effect are still incompletely understood. In this review, we summarize the current understanding of the role of the SDF1α/CXCR4 pathway in bone metastatic prostate cancer. We also discuss the therapeutic potential of disrupting the interaction between prostate tumor cells and bone environment with focus on the SDF1α pathway. PMID:27533927

  13. High glucose levels boost the aggressiveness of highly metastatic cholangiocarcinoma cells via O-GlcNAcylation

    PubMed Central

    Phoomak, Chatchai; Vaeteewoottacharn, Kulthida; Silsirivanit, Atit; Saengboonmee, Charupong; Seubwai, Wunchana; Sawanyawisuth, Kanlayanee; Wongkham, Chaisiri; Wongkham, Sopit

    2017-01-01

    Increased glucose utilization is a feature of cancer cells to support cell survival, proliferation, and metastasis. An association between diabetes mellitus and cancer progression was previously demonstrated in cancers including cholangiocarcinoma (CCA). This study was aimed to determine the effects of high glucose on protein O-GlcNAcylation and metastatic potentials of CCA cells. Two pairs each of the parental low metastatic and highly metastatic CCA sublines were cultured in normal (5.6 mM) or high (25 mM) glucose media. The migration and invasion abilities were determined and underlying mechanisms were explored. Results revealed that high glucose promoted migration and invasion of CCA cells that were more pronounced in the highly metastatic sublines. Concomitantly, high glucose increased global O-GlcNAcylated proteins, the expressions of vimentin, hexokinase, glucosamine-fructose-6-phosphate amidotransferase (GFAT) and O-GlcNAc transferase of CCA cells. The glucose level that promoted migration/invasion was shown to be potentiated by the induction of GFAT, O-GlcNAcylation and an increase of O-GlcNAcylated vimentin and vimentin expression. Treatment with a GFAT inhibitor reduced global O-GlcNAcylated proteins, vimentin expression, and alleviated cell migration. Altogether, these results suggested the role of high glucose enhanced CCA metastasis via modulation of O-GlcNAcylation, through the expressions of GFAT and vimentin. PMID:28262738

  14. CD44 integrates signaling in normal stem cell, cancer stem cell and (pre)metastatic niches.

    PubMed

    Williams, Karin; Motiani, Karan; Giridhar, Premkumar Vummidi; Kasper, Susan

    2013-03-01

    The stem cell niche provides a regulatory microenvironment for cells as diverse as totipotent embryonic stem cells to cancer stem cells (CSCs) which exhibit stem cell-like characteristics and have the capability of regenerating the bulk of tumor cells while maintaining self-renewal potential. The transmembrane glycoprotein CD44 is a common component of the stem cell niche and exists as a standard isoform (CD44s) and a range of variant isoforms (CD44v) generated though alternative splicing. CD44 modulates signal transduction through post-translational modifications as well as interactions with hyaluronan, extracellular matrix molecules and growth factors and their cognate receptor tyrosine kinases. While the function of CD44 in hematopoietic stem cells has been studied in considerable detail, our knowledge of CD44 function in tissue-derived stem cell niches remains limited. Here we review CD44s and CD44v in both hematopoietic and tissue-derived stem cell niches, focusing on their roles in regulating stem cell behavior including self-renewal and differentiation in addition to cell-matrix interactions and signal transduction during cell migration and tumor progression. Determining the role of CD44 and CD44v in normal stem cell, CSC and (pre)metastatic niches and elucidating their unique functions could provide tools and therapeutic strategies for treating diseases as diverse as fibrosis during injury repair to cancer progression.

  15. Metastatic Mantle Cell Lymphoma to the Pituitary Gland: Case Report and Literature Review.

    PubMed

    Wang, Arthur; Carberry, Nathan; Solli, Elena; Kleinman, George; Tandon, Adesh

    2016-01-01

    We present an unusual case of a metastatic mantle cell lymphoma (MCL) to the pituitary gland. The patient had a known history of MCL for which she previously received chemotherapy. She presented with new-onset diplopia and confusion, and reported a history of progressive vision blurriness associated with headache, nausea, and vomiting. MRI of the brain showed an enhancing lesion within the sella turcica involving the cavernous sinuses bilaterally, extending into Meckel's cave on the left, and abutting the optic nerves bilaterally. Following surgical excision, histopathology revealed the tumor to be a MCL. Metastatic pituitary tumors are rare and have been estimated to make up 1% of tumors discovered in the sellar region. The two most common secondary metastatic lesions to the sella are breast and lung carcinoma followed by prostate, renal cell, and gastrointestinal carcinoma. Metastatic lymphoma to the pituitary gland is especially rare and is estimated to constitute 0.5% of all metastatic tumors to the sella turcica. To our knowledge, this is the first reported case of MCL metastasizing to the pituitary gland.

  16. Platelet factors induce chemotactic migration of murine mammary adenocarcinoma cells with different metastatic capabilities.

    PubMed Central

    Sarach, M. A.; Rovasio, R. A.; Eynard, A. R.

    1993-01-01

    The chemotactic response of neoplastic cells (NC) induced by soluble platelet factors was investigated. NC suspensions isolated from murine mammary gland adenocarcinomas having different metastatic capabilities were incubated in Boyden's chambers and challenged with (1) 'Early Platelet Factors' (EP), obtained from the soluble fraction of recently collagen-activated human platelets, and (2) 'Late Platelet Factors' (LP), isolated after 24 hours incubation of the platelet aggregates. Chemotaxis was expressed as the distance travelled by NC through nitrocellulose filters. NC isolated from M3, the tumour line having the stronger metastatic potential, showed a significant chemotactic response towards LP factors, whereas NC from the M2 line exhibiting the lower metastatic behaviour, showed a chemotactic response towards EP factors. Both tumour cell lines lacked motion capability towards the well known chemoattractant peptide N-f-Met-Leu-Phe-Phe as well as to serum, plasma, collagen type I or culture medium. The different chemotactic response of both tumour lines when they were challenged by concentration gradients of factors released by early or late collagen-activated human platelets, confirm a relationship between platelet activity and metastatic capabilities and suggests that platelet chemoattractants might play a role in the metastatic dissemination of these mammary gland adenocarcinomas. Images Figure 1 PMID:8217786

  17. Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET

    PubMed Central

    Peinado, Héctor; Alečković, Maša; Lavotshkin, Simon; Matei, Irina; Costa-Silva, Bruno; Moreno-Bueno, Gema; Hergueta-Redondo, Marta; Williams, Caitlin; García-Santos, Guillermo; Nitadori-Hoshino, Ayuko; Hoffman, Caitlin; Badal, Karen; Garcia, Benjamin A.; Callahan, Margaret K.; Yuan, Jianda; Martins, Vilma R.; Skog, Johan; Kaplan, Rosandra N.; Brady, Mary S.; Wolchok, Jedd D.; Chapman, Paul B.; Kang, Yibin; Bromberg, Jacqueline; Lyden, David

    2013-01-01

    Tumor-derived exosomes are emerging mediators of tumorigenesis with tissue-specific addresses and messages. We explored the function of melanoma-derived exosomes in the formation of primary tumor and metastases in mouse and human subjects. Exosomes from highly metastatic melanoma increased the metastatic behavior of primary tumors by permanently “educating” bone marrow (BM) progenitors via the MET receptor. Melanoma-derived exosomes also induced vascular leakiness at pre-metastatic sites, and reprogrammed BM progenitors towards a c-Kit+Tie2+Met+ pro-vasculogenic phenotype. Reducing Met expression in exosomes diminished the pro-metastatic behavior of BM cells. Importantly, MET expression was elevated in circulating CD45−C-KITlow/+TIE2+ BM progenitors from metastatic melanoma subjects. RAB1a, RAB5b, RAB7, and RAB27a were highly expressed in melanoma cells and Rab27a RNA interference decreased exosome production, preventing BM education, tumor growth and metastasis. Finally, we identified an exosome-specific “melanoma signature” with prognostic and therapeutic potential, comprised of TYRP2, VLA-4, HSP70, an HSP90 isoform and the MET oncoprotein. PMID:22635005

  18. Metastatic Mantle Cell Lymphoma to the Pituitary Gland: Case Report and Literature Review

    PubMed Central

    Wang, Arthur; Carberry, Nathan; Solli, Elena; Kleinman, George; Tandon, Adesh

    2016-01-01

    We present an unusual case of a metastatic mantle cell lymphoma (MCL) to the pituitary gland. The patient had a known history of MCL for which she previously received chemotherapy. She presented with new-onset diplopia and confusion, and reported a history of progressive vision blurriness associated with headache, nausea, and vomiting. MRI of the brain showed an enhancing lesion within the sella turcica involving the cavernous sinuses bilaterally, extending into Meckel's cave on the left, and abutting the optic nerves bilaterally. Following surgical excision, histopathology revealed the tumor to be a MCL. Metastatic pituitary tumors are rare and have been estimated to make up 1% of tumors discovered in the sellar region. The two most common secondary metastatic lesions to the sella are breast and lung carcinoma followed by prostate, renal cell, and gastrointestinal carcinoma. Metastatic lymphoma to the pituitary gland is especially rare and is estimated to constitute 0.5% of all metastatic tumors to the sella turcica. To our knowledge, this is the first reported case of MCL metastasizing to the pituitary gland. PMID:26933415

  19. Metastatic model of HPV+ oropharyngeal squamous cell carcinoma demonstrates heterogeneity in tumor metastasis

    PubMed Central

    Vermeer, Daniel W.; Coppock, Joseph D.; Zeng, Erliang; Lee, Kimberly M.; Spanos, William C.; Onken, Michael D.; Uppaluri, Ravindra; Lee, John H.; Vermeer, Paola D.

    2016-01-01

    Human papillomavirus induced (HPV+) cancer incidence is rapidly rising, comprising 60–80% of oropharyngeal squamous cell carcinomas (OPSCCs); while rare, recurrent/metastatic disease accounts for nearly all related deaths. An in vivo pre-clinical model for these invasive cancers is necessary for testing new therapies. We characterize an immune competent recurrent/metastatic HPV+ murine model of OPSSC which consists of four lung metastatic (MLM) cell lines isolated from an animal with HPV+ OPSCC that failed cisplatin/radiation treatment. These individual metastatic clonal cell lines were tested to verify their origin (parental transgene expression and define their physiological properties: proliferation, metastatic potential, heterogeneity and sensitivity/resistance to cisplatin and radiation. All MLMs retain expression of parental HPV16 E6 and E7 and degrade P53 yet are heterogeneous from one another and from the parental cell line as defined by Illumina expression microarray. Consistent with this, reverse phase protein array defines differences in protein expression/activation between MLMs as well as the parental line. While in vitro growth rates of MLMs are slower than the parental line, in vivo growth of MLM clones is greatly enhanced. Moreover, in vivo resistance to standard therapies is dramatically increased in 3 of the 4 MLMs. Lymphatic and/or lung metastasis occurs 100% of the time in one MLM line. This recurrent/metastatic model of HPV+ OPSCC retains the characteristics evident in refractory human disease (heterogeneity, resistance to therapy, metastasis in lymph nodes/lungs) thus serving as an ideal translational system to test novel therapeutics. Moreover, this system may provide insights into the molecular mechanisms of metastasis. PMID:27013584

  20. Enhanced OXPHOS, glutaminolysis and β-oxidation constitute the metastatic phenotype of melanoma cells.

    PubMed

    Rodrigues, Mariana F; Obre, Emilie; de Melo, Fabiana H M; Santos, Gilson C; Galina, Antonio; Jasiulionis, Miriam G; Rossignol, Rodrigue; Rumjanek, Franklin D; Amoêdo, Nivea D

    2016-03-15

    Tumours display different cell populations with distinct metabolic phenotypes. Thus, subpopulations can adjust to different environments, particularly with regard to oxygen and nutrient availability. Our results indicate that progression to metastasis requires mitochondrial function. Our research, centered on cell lines that display increasing degrees of malignancy, focused on metabolic events, especially those involving mitochondria, which could reveal which stages are mechanistically associated with metastasis. Melanocytes were subjected to several cycles of adhesion impairment, producing stable cell lines exhibiting phenotypes representing a progression from non-tumorigenic to metastatic cells. Metastatic cells (4C11+) released the highest amounts of lactate, part of which was derived from glutamine catabolism. The 4C11+ cells also displayed an increased oxidative metabolism, accompanied by enhanced rates of oxygen consumption coupled to ATP synthesis. Enhanced mitochondrial function could not be explained by an increase in mitochondrial content or mitochondrial biogenesis. Furthermore, 4C11+ cells had a higher ATP content, and increased succinate oxidation (complex II activity) and fatty acid oxidation. In addition, 4C11+ cells exhibited a 2-fold increase in mitochondrial membrane potential (ΔΨmit). Consistently, functional assays showed that the migration of cells depended on glutaminase activity. Metabolomic analysis revealed that 4C11+ cells could be grouped as a subpopulation with a profile that was quite distinct from the other cells investigated in the present study. The results presented here have centred on how the multiple metabolic inputs of tumour cells may converge to compose the so-called metastatic phenotype.

  1. ErbB2 and bone sialoprotein as markers for metastatic osteosarcoma cells

    PubMed Central

    Valabrega, G; Fagioli, F; Corso, S; Madon, E; Brach del Prever, A; Biasin, E; Linari, A; Aglietta, M; Giordano, S

    2003-01-01

    Osteosarcoma is the most common malignant bone neoplasia occurring in young patients in the first two decades of life, and represents 20% of all primitive malignant bone tumours. At present, treatment of metastatic osteosarcoma is unsatisfactory. High-dose chemotherapy followed by CD34+ leukapheresis rescue may improve these poor results. Neoplastic cells contaminating the apheresis may, however, contribute to relapse. To identify markers suitable for detecting osteosarcoma cells in aphereses we analysed the expression of bone-specific genes (Bone Sialoprotein (BSP) and Osteocalcin) and oncogenes (Met and ErbB2) in 22 patients with metastatic osteosarcoma and six healthy stem cell donors. The expression of these genes in aphereses of patients affected by metastatic osteosarcoma was assessed by RT–PCR and Southern blot analysis. Met and Osteocalcin proved to be not useful markers since they are positive in aphereses of both patients with metastatic osteosarcoma and healthy stem cell donors. On the contrary, BSP was expressed at significant levels in 85% of patients. Moreover, 18% of patients showed a strong and significantly positive (seven to 16 times higher than healthy stem cell donors) ErbB2 expression. In all positive cases, neoplastic tissue also expressed ErbB2. Our data show that ErbB2 can be a useful marker for tumour contamination in aphereses of patients affected by ErbB2-expressing osteosarcomas and that analysis of Bone Sialoprotein expression can be an alternative useful marker. PMID:12569382

  2. Critical appraisal of pazopanib as treatment for patients with advanced metastatic renal cell carcinoma.

    PubMed

    Bukowski, Ronald M

    2011-01-01

    The management of renal cell carcinoma (RCC) has undergone significant changes during the past 10 years, with the treatment of metastatic RCC undergoing the most radical changes. These developments reflect an enhanced understanding of this tumor's underlying biology, which was then translated into the development of a new treatment paradigm. Current therapeutic approaches for the management of patients with metastatic RCC utilize knowledge of histology, molecular abnormalities, clinical prognostic factors, the natural history of this malignancy, and the treatment efficacy and toxicity of available agents. The treatment options available for patients with metastatic RCC have changed dramatically over the past 6 years. Interferon-α and interleukin-2 were the previous mainstays of therapy, but since December 2005, six new agents have been approved in the US for the treatment of advanced RCC. Three are multi-targeted tyrosine kinase inhibitors (TKI) including sunitinib, sorafenib, and pazopanib, two target the mammalian target of rapamycin (temsirolimus and everolimus), and one is a humanized monoclonal antibody (bevacizumab in combination with interferon-α). The current review focuses on the newest TKI available to treat patients with metastatic RCC, pazopanib. The development of this agent both preclinically and clinically is reviewed. The efficacy and safety data from the pivotal clinical trials are discussed, and the potential role of pazopanib in the treatment of patients with metastatic RCC in comparison to other treatment alternatives is critically appraised. This agent has a favorable overall risk benefit, and the available data demonstrate efficacy in patients with metastatic RCC who are either treatment-naïve or cytokine refractory. It therefore represents another alternative for treatment of metastatic RCC patients.

  3. Critical appraisal of pazopanib as treatment for patients with advanced metastatic renal cell carcinoma

    PubMed Central

    Bukowski, Ronald M

    2011-01-01

    The management of renal cell carcinoma (RCC) has undergone significant changes during the past 10 years, with the treatment of metastatic RCC undergoing the most radical changes. These developments reflect an enhanced understanding of this tumor’s underlying biology, which was then translated into the development of a new treatment paradigm. Current therapeutic approaches for the management of patients with metastatic RCC utilize knowledge of histology, molecular abnormalities, clinical prognostic factors, the natural history of this malignancy, and the treatment efficacy and toxicity of available agents. The treatment options available for patients with metastatic RCC have changed dramatically over the past 6 years. Interferon-α and interleukin-2 were the previous mainstays of therapy, but since December 2005, six new agents have been approved in the US for the treatment of advanced RCC. Three are multi-targeted tyrosine kinase inhibitors (TKI) including sunitinib, sorafenib, and pazopanib, two target the mammalian target of rapamycin (temsirolimus and everolimus), and one is a humanized monoclonal antibody (bevacizumab in combination with interferon-α). The current review focuses on the newest TKI available to treat patients with metastatic RCC, pazopanib. The development of this agent both preclinically and clinically is reviewed. The efficacy and safety data from the pivotal clinical trials are discussed, and the potential role of pazopanib in the treatment of patients with metastatic RCC in comparison to other treatment alternatives is critically appraised. This agent has a favorable overall risk benefit, and the available data demonstrate efficacy in patients with metastatic RCC who are either treatment-naïve or cytokine refractory. It therefore represents another alternative for treatment of metastatic RCC patients. PMID:21931501

  4. Metastatic Squamous Cell Carcinoma of the Pleura: A Rare Complication of Hidradenitis Suppurativa

    PubMed Central

    Joglekar, Kiran; Jackson, Christopher; Kadaria, Dipen; Sodhi, Amik

    2016-01-01

    Patient: Male, 46 Final Diagnosis: Metastatic squamous cell carcinoma Symptoms: Short of breath Medication: — Clinical Procedure: Pleural biopsy Specialty: Oncology Objective: Rare disease Background: Squamous cell carcinoma (SCC), also known as Marjolin ulcer, is a rare complication of hidradenitis suppurativa (HS). Metastatic SCC from HS typically involves the axial skeleton or abdominopelvic viscera. Metastatic disease to the lungs is a rare phenomenon with only three reported cases of lung parenchyma. We present a biopsy proven case of metastatic SCC to the pleura from gluteal HS. Case Report: A 46-year-old male with a history of recently diagnosed Marjolin ulcer secondary to gluteal HS was transferred to our intensive care unit for acute hypoxemic respiratory failure secondary to recurrent pleural effusion. On examination, patient was febrile (38.3°C), normotensive (blood pressure 98/65 mm Hg), tachycardic (116 beats/minute) and tachypneic (40 breaths/minute) with oxygen saturation of 93% on room air. He was in moderate distress requiring endotracheal intubation and mechanical ventilation. Chest examination revealed decreased breath sounds bilaterally and skin examination was significant for 18 cm wide sacral lesion. CT thorax showed bilateral pleural effusions, pleural thickening, and scattered nodular densities within both lungs concerning for metastatic disease. Thoracentesis showed lymphocyte predominant exudate with negative cytology for malignant cells. A video-assisted thoracoscopic surgery (VATS) illustrated thickened pleural rind with histopathology and positive p40 stain consistent with invasive well-to-moderately differentiated keratinizing SCC. Conclusions: SCC arising from HS is rare and metastatic disease to the pleura has not been reported previously. Strong clinical suspicion for malignancy is warranted in patients with advanced HS and evolving pulmonary symptoms despite negative cytology. PMID:28028308

  5. Protein Profiles Associated with Anoikis Resistance of Metastatic MDA-MB-231 Breast Cancer Cells.

    PubMed

    Akekawatchai, Chareeporn; Roytrakul, Sittiruk; Kittisenachai, Suthathip; Isarankura-Na-Ayudhya, Patcharee; Jitrapakdee, Sarawut

    2016-01-01

    Resistance to anoikis, a cell-detachment induced apoptosis, is one of the malignant phenotypes which support tumor metastasis. Molecular mechanisms underlying the establishment of this phenotype require further investigation. This study aimed at exploring protein expression profiles associated with anoikis resistance of a metastatic breast cancer cell. Cell survival of suspension cultures of non-metastatic MCF-7 and metastatic MDA-MB-231 cells were compared with their adherent cultures. Trypan blue exclusion assays demonstrated a significantly higher percentage of viable cells in MDA-MB-231 than MCF-7 cell cultures, consistent with analysis of annexin V-7-AAD stained cells indicating that MDA-MB-231 possess anti-apoptotic ability 1.7 fold higher than MCF-7 cells. GeLC-MS/MS analysis of protein lysates of MDA-MB-231 and MCF-7 cells grown under both culture conditions identified 925 proteins which are differentially expressed, 54 of which were expressed only in suspended and adherent MDA-MB-231 but not in MCF-7 cells. These proteins have been implicated in various cellular processes, including DNA replication and repair, transcription, translation, protein modification, cytoskeleton, transport and cell signaling. Analysis based on the STITCH database predicted the interaction of phospholipases, PLC and PLD, and 14-3-3 beta/alpha, YWHAB, with the intrinsic and extrinsic apoptotic signaling network, suggesting putative roles in controlling anti-anoikis ability. MDA-MB-231 cells grown in the presence of inhibitors of phospholipase C, U73122, and phospholipase D, FIPI, demonstrated reduced ability to survive in suspension culture, indicating functional roles of PLC and PLD in the process of anti-anoikis. Our study identified intracellular mediators potentially associated with establishment of anoikis resistance of metastatic cells. These proteins require further clarification as prognostic and therapeutic targets for advanced breast cancer.

  6. Non-lethal heat treatment of cells results in reduction of tumor initiation and metastatic potential

    SciTech Connect

    Kim, Yoo-Shin; Lee, Tae Hoon; O'Neill, Brian E.

    2015-08-14

    Non-lethal hyperthermia is used clinically as adjuvant treatment to radiation, with mixed results. Denaturation of protein during hyperthermia treatment is expected to synergize with radiation damage to cause cell cycle arrest and apoptosis. Alternatively, hyperthermia is known to cause tissue level changes in blood flow, increasing the oxygenation and radiosensitivity of often hypoxic tumors. In this study, we elucidate a third possibility, that hyperthermia alters cellular adhesion and mechanotransduction, with particular impact on the cancer stem cell population. We demonstrate that cell heating results in a robust but temporary loss of cancer cell aggressiveness and metastatic potential in mouse models. In vitro, this heating results in a temporary loss in cell mobility, adhesion, and proliferation. Our hypothesis is that the loss of cellular adhesion results in suppression of cancer stem cells and loss of tumor virulence and metastatic potential. Our study suggests that the metastatic potential of cancer is particularly reduced by the effects of heat on cellular adhesion and mechanotransduction. If true, this could help explain both the successes and failures of clinical hyperthermia, and suggest ways to target treatments to those who would most benefit. - Highlights: • Non-lethal hyperthermia treatment of cancer cells is shown to cause a reduction in rates of tumor initiation and metastasis. • Dynamic imaging of cells during heat treatment shows temporary changes in cell shape, cell migration, and cell proliferation. • Loss of adhesion may lead to the observed effect, which may disproportionately impact the tumor initiating cell fraction. • Loss or suppression of the tumor initiating cell fraction results in the observed loss of metastatic potential in vivo. • This result may lead to new approaches to synergizing hyperthermia with surgery, radiation, and chemotherapy.

  7. HDAC6 activity is not required for basal autophagic flux in metastatic prostate cancer cells

    PubMed Central

    Watson, Gregory W; Wickramasekara, Samanthi; Fang, Yufeng; Maier, Claudia S; Williams, David E; Dashwood, Roderick H; Perez, Viviana I

    2015-01-01

    Histone deacetylase 6 is a multifunctional lysine deacetylase that is recently emerging as a central facilitator of response to stress and may play an important role in cancer cell proliferation. The histone deacetylase 6-inhibitor tubacin has been shown to slow the growth of metastatic prostate cancer cells and sensitize cancer cells to chemotherapeutic agents. However, the proteins histone deacetylase 6 interacts with, and thus its role in cancer cells, remains poorly characterized. Histone deacetylase 6 deacetylase activity has recently been shown to be required for efficient basal autophagic flux. Autophagy is often dysregulated in cancer cells and may confer stress resistance and allow for cell maintenance and a high proliferation rate. Tubacin may therefore slow cancer cell proliferation by decreasing autophagic flux. We characterized the histone deacetylase 6-interacting proteins in LNCaP metastatic prostate cancer cells and found that histone deacetylase 6 interacts with proteins involved in several cellular processes, including autophagy. Based on our interaction screen, we assessed the impact of the histone deacetylase 6-inhibitor tubacin on autophagic flux in two metastatic prostate cancer cell lines and found that tubacin does not influence autophagic flux. Histone deacetylase 6 therefore influences cell proliferation through an autophagy-independent mechanism. PMID:26643866

  8. Golden bullet-denosumab: early rapid response of metastatic giant cell tumor of the bone.

    PubMed

    Demirsoy, Ugur; Karadogan, Meriban; Selek, Özgür; Anik, Yonca; Aksu, Görkem; Müezzinoglu, Bahar; Corapcioglu, Funda

    2014-03-01

    Giant cell tumor of the bone (GCTB) is usually a benign, locally aggressive tumor with metastatic potential. Histogenesis of GCTB is unknown and a correlation has not been found between histologic and clinical course. For this reason, many authors consider its prognosis unpredictable. Lung metastasis after GCTB treatment is well known and generally has unfavorable outcome, despite varied chemotherapy regimens. Denosumab, which inhibits RANK-RANKL interaction, is a new, promising actor among targeted therapeutic agents for GCTB. In this report, we emphasize on early rapid response to denosumab in metastatic GCTB.

  9. Review of the treatment of metastatic non small cell lung carcinoma: A practical approach

    PubMed Central

    Hirsh, Vera

    2011-01-01

    In recent years, as we have a better knowledge and understanding of the biology of non small cell lung carcinoma (NSCLC), which leads us to targeting biomarkers driving the NSCLC carcinogenesis and metastatic potential, we now have an increased number of options to offer our patients with NSCLC. We also realize the importance of distinguishing squamous and non squamous histology to guide our treatment decisions of NSCLC. The palliative care concomitant with therapies from the very start of the treatment also showed an impact on survival. This review examines the treatment options in all lines of therapy for metastatic NSCLC that have been approved in Canada, the United States, or Europe. PMID:21773076

  10. Metastatic patterns of myxoid/round cell liposarcoma: a review of a 25-year experience.

    PubMed

    Asano, Naofumi; Susa, Michiro; Hosaka, Seiichi; Nakayama, Robert; Kobayashi, Eisuke; Takeuchi, Katsuhito; Horiuchi, Keisuke; Suzuki, Yoshihisa; Anazawa, Ukei; Mukai, Makio; Toyama, Yoshiaki; Yabe, Hiroo; Morioka, Hideo

    2012-01-01

    Myxoid/round cell liposarcoma (MRCL), unlike other soft tissue sarcomas, has been associated with unusual pattern of metastasis to extrapulmonary sites. In an attempt to elucidate the clinical features of MRCL with metastatic lesions, 58 cases, from the medical database of Keio University Hospital were used for the evaluation. 47 patients (81%) had no metastases, whereas 11 patients (11%) had metastases during their clinical course. Among the 11 patients with metastatic lesions, 8 patients (73%) had extrapulmonary metastases and 3 patients (27%) had pulmonary metastases. Patients were further divided into three groups; without metastasis, with extrapulmonary metastasis, and with pulmonary metastasis. When the metastatic patterns were stratified according to tumor size, there was statistical significance between the three groups (P = 0.028). The 8 cases with extrapulmonary metastases were all larger than 10 cm. Similarly, histological grading had a significant impact on metastatic patterns (P = 0.027). 3 cases with pulmonary metastatic lesions were all diagnosed as high grade. In conclusion, large size and low histological grade were significantly associated with extrapulmonary metastasis.

  11. Metastin is not involved in metastatic potential of non-small cell lung cancer.

    PubMed

    Karapanagiotou, Eleni M; Dilana, Kalliopi D; Gkiozos, Ioannis; Gratsias, Ioannis; Tsimpoukis, Sotirios; Polyzos, Aris; Syrigos, Kostas N

    2011-06-01

    Metastin, the product of the KISS-1 gene, seems to represent a strong suppressant of metastasis for some types of cancer. The aim of this study is to explore whether circulating levels of metastin could be used as a marker for the metastatic potential of non-small cell lung cancer (NSCLC) as well as a diagnostic marker in NSCLC patients. The possible correlation between metastin and leptin circulating levels was also evaluated. Fasting serum levels of metastin and leptin were determined in 96 NSCLC patients at diagnosis (76 with metastatic disease and 21 with locally advanced disease) and 49 healthy volunteers using commercial available ELISA. Serum metastin levels presented no differences between NSCLC patients and healthy volunteers (1.18 ± 0.98 vs. 1.17 ± 0.39 ng/ml, P = 0.979) as well as between patients with metastatic and locally advanced disease (1.17 ± 1.05 vs. 1.21 ± 0.64 ng/ml, P = 0.872). There was no statistically significant correlation between circulating metastin and leptin levels in NSCLC patients and patients with locally advanced and metastatic disease. This study shows a lack of direct involvement of metastin in the diagnosis and metastatic potential of NSCLC.

  12. Management of an invasive and metastatic Sertoli cell tumor with associated myelotoxicosis in a dog.

    PubMed

    Withers, Sita S; Lawson, Corinne M; Burton, Andrew G; Rebhun, Robert B; Steffey, Michele A

    2016-03-01

    We describe the surgical and post-operative management of a large, invasive, and metastatic functional Sertoli cell tumor in a 9-year-old cryptorchid male Labrador retriever dog. Despite residual disease after surgery, bone marrow recovery occurred without administration of bone marrow stimulants and serum estradiol accurately predicted tumor recurrence.

  13. Management of an invasive and metastatic Sertoli cell tumor with associated myelotoxicosis in a dog

    PubMed Central

    Withers, Sita S.; Lawson, Corinne M.; Burton, Andrew G.; Rebhun, Robert B.; Steffey, Michele A.

    2016-01-01

    We describe the surgical and post-operative management of a large, invasive, and metastatic functional Sertoli cell tumor in a 9-year-old cryptorchid male Labrador retriever dog. Despite residual disease after surgery, bone marrow recovery occurred without administration of bone marrow stimulants and serum estradiol accurately predicted tumor recurrence. PMID:26933269

  14. Anti-tumor Properties of cis-Resveratrol Methylated Analogues in Metastatic Mouse Melanoma Cells

    PubMed Central

    Morris, Valery L.; Toseef, Tayyaba; Nazumudeen, Fathima B.; Rivoira, Christian; Spatafora, Carmela; Tringali, Corrado; Rotenberg, Susan A.

    2015-01-01

    Resveratrol (E-3,5,4’-trihydroxystilbene) is a polyphenol found in red wine that has been shown to have multiple anti-cancer properties. Although cis (Z) and trans (E) isomers of resveratrol occur in nature, the cis form is not biologically active. However, methylation at key positions of the cis form results in more potent anti-cancer properties. This study determined that synthetic cis-polymethoxystilbenes (methylated analogues of cis-resveratrol) inhibited cancer-related phenotypes of metastatic B16 F10 and non-metastatic B16 F1 mouse melanoma cells. In contrast with cis or trans-resveratrol and trans-polymethoxystilbene which were ineffective at 10 μM, cis-polymethoxystilbenes inhibited motility and proliferation of melanoma cells with low micromolar specificity (IC50 <10 μM). Inhibitory effects by cis-polymethoxystilbenes were significantly stronger with B16 F10 cells and were accompanied by decreased expression of β-tubulin and pleckstrin homology domain-interacting protein, a marker of metastatic B16 cells. Thus, cis-polymethoxystilbenes have potential as chemotherapeutic agents for metastatic melanoma. PMID:25567208

  15. Paranuclear blue inclusions in metastatic undifferentiated small cell carcinoma in the bone marrow.

    PubMed

    Wittchow, R; Laszewski, M; Walker, W; Dick, F

    1992-09-01

    Paranuclear blue inclusions (PBIs) are frequently identified within metastatic undifferentiated small cell carcinoma (SCC) cells on air-dried bone marrow aspirates stained with Wright's stain. To determine the sensitivity and specificity of this finding, 116 bone marrow aspirates containing metastatic neoplasms were evaluated for the presence and frequency of PBIs. Bone marrow specimens included 47 cases of metastatic SCC of the lung, 13 cases of large cell lymphoma, 19 cases of neuroblastoma, five cases of small, noncleaved cell lymphoma, seven cases of rhabdomyosarcoma, three cases of Ewing's sarcoma, three cases of other sarcomas, and 19 cases of non-small cell carcinoma (adenocarcinoma). PBIs were identified in 40 of 47 (85%) cases of SCC and their frequency varied from 0 to 24% of tumor cells among different cases. In approximately half the cases of SCC, PBIs were identified in 1 to 4% tumor cells; and in eight cases, PBIs were present in 5% or more of tumor cells. PBIs were also identified in two of seven (29%) cases of rhabdomyosarcoma and one case of malignant peripheral nerve sheath tumor, but they were not seen in Ewing's sarcoma, small non-cleaved cell lymphoma, large cell lymphoma, neuroblastoma, or non-small cell carcinoma. In addition, PBIs were not seen in alcohol-fixed, Papanicolaou-stained cytology specimens containing SCC. Ultrastructurally, PBIs may represent phagocytized nuclear/cellular material. PBIs are a feature of small cell carcinoma on air-dried, cytologic material stained with Romanowsky type stains. Their presence may provide diagnostic information with regard to the differential diagnosis of metastatic SCC in the bone marrow. Future studies evaluating non-bone marrow Wright's stained fine-needle aspiration specimens are needed to determine if PBIs are useful in distinguishing SCC from other poorly differentiated tumors in the cytology laboratory.

  16. Metastatic squamous cell carcinoma of the anus to the lung confirmed with allelotyping.

    PubMed

    Roth, Rachel; Moffatt-Bruce, Susan; Leon, Marino E

    2014-01-01

    Histopathologic techniques are insufficient for distinguishing primary squamous cell carcinoma (SCC) from metastatic SCC, which is clinically important. A patient with SCC of the anus was found to also have SCC of the lung, and the question of metastatic versus synchronous primary diseases was raised. Immunohistochemical and hematoxylin and eosin (H&E) staining on sections of tissue could not discriminate between the two entities. Immunostain for p16 and chromogenic in situ hybridization for human papillomavirus (HPV) type 16 were positive in both tumors. Additionally, allelotyping for loss of heterozygosity displayed similar findings and confirmed the histopathological impression of anal SCC metastasis to the lung. The patient was treated with palliative chemotherapy instead of additional surgical treatment. When multiple tumors are present, determining metastatic versus synchronous primary tumors is necessary for appropriate treatment. Identification can be achieved using allelotyping for loss of heterozygosity.

  17. Dose fractionation effects in primary and metastatic human uveal melanoma cell lines.

    PubMed

    van den Aardweg, Gerard J M J; Kiliç, Emine; de Klein, Annelies; Luyten, Gregorius P M

    2003-11-01

    To investigate the effects of split-dose irradiation on primary and metastatic uveal melanoma cell lines, with a clonogenic survival assay. Appropriate cell concentrations of four primary and four metastatic human uveal melanoma cell lines were cultured for irradiation with single doses and with two equal fractions separated by 5 hours. After irradiation, colony formation was allowed for 7 to 21 days. Two cutaneous melanomas were also tested for comparison. All survival curves were analyzed using the linear quadratic (LQ) model. Specific parameters for the intrinsic radiosensitivity (alpha-component, SF2), for the capacity of repair of DNA damage (beta-component), as well as the alpha/beta ratio were calculated. After single-dose irradiation a wide range in the values of the alpha- and beta-component was obtained for both primary and metastatic uveal melanomas, which resulted in a wide range of alpha/beta ratios. In contrast, calculations based on split-dose data, with which the beta-component could be estimated independent of the alpha-component, indicated that estimates for the capacity of sublethal DNA damage repair was very similar in all cell lines. This indicated that intrinsic factors dominated the radiosensitivity of these cell lines. Split-dose irradiation had little influence on the intrinsic radiosensitivity (alpha-component), but cell survival increased for all cell lines. For the two cutaneous melanomas comparable split-dose results were obtained. For both primary and metastatic uveal melanoma cell lines, data from single and fractionated doses indicate large variations in radiosensitivity, which are mainly dominated by the intrinsic radiosensitivities. Doses of approximately 8 Gy in five fractions would be sufficient to eradicate 10(9) cells (approximately 1 cm3) of the most radioresistant tumor cell lines, but this schedule is an overkill for the radiosensitive tumor cell lines. Based on specific morphologic and histologic tumor markers, more

  18. Visualization of immediate immune responses to pioneer metastatic cells in the lung.

    PubMed

    Headley, Mark B; Bins, Adriaan; Nip, Alyssa; Roberts, Edward W; Looney, Mark R; Gerard, Audrey; Krummel, Matthew F

    2016-03-24

    Lung metastasis is the lethal determinant in many cancers and a number of lines of evidence point to monocytes and macrophages having key roles in its development. Yet little is known about the immediate fate of incoming tumour cells as they colonize this tissue, and even less known about how they make first contact with the immune system. Primary tumours liberate circulating tumour cells (CTCs) into the blood and we have developed a stable intravital two-photon lung imaging model in mice for direct observation of the arrival of CTCs and subsequent host interaction. Here we show dynamic generation of tumour microparticles in shear flow in the capillaries within minutes of CTC entry. Rather than dispersing under flow, many of these microparticles remain attached to the lung vasculature or independently migrate along the inner walls of vessels. Using fluorescent lineage reporters and flow cytometry, we observed 'waves' of distinct myeloid cell subsets that load differentially and sequentially with this CTC-derived material. Many of these tumour-ingesting myeloid cells collectively accumulated in the lung interstitium along with the successful metastatic cells and, as previously understood, promote the development of successful metastases from surviving tumour cells. Although the numbers of these cells rise globally in the lung with metastatic exposure and ingesting myeloid cells undergo phenotypic changes associated with microparticle ingestion, a consistently sparse population of resident conventional dendritic cells, among the last cells to interact with CTCs, confer anti-metastatic protection. This work reveals that CTC fragmentation generates immune-interacting intermediates, and defines a competitive relationship between phagocyte populations for tumour loading during metastatic cell seeding.

  19. Cetuximab strongly enhances immune cell infiltration into liver metastatic sites in colorectal cancer.

    PubMed

    Inoue, Yuka; Hazama, Shoichi; Suzuki, Nobuaki; Tokumitsu, Yukio; Kanekiyo, Shinsuke; Tomochika, Shinobu; Tsunedomi, Ryouichi; Tokuhisa, Yoshihiro; Iida, Michihisa; Sakamoto, Kazuhiko; Takeda, Shigeru; Ueno, Tomio; Yoshino, Shigefumi; Nagano, Hiroaki

    2017-03-01

    Cetuximab has activity against colorectal cancers. Recent studies demonstrated that cetuximab induces antibody-dependent cell-mediated cytotoxicity via immune cells, and a new immune-related mechanism of inducing immunogenic cell death. This study aimed to evaluate the immune responses induced by cetuximab in tumor microenvironments at liver metastasis sites of metastatic colorectal cancer patients. We assessed immune cell infiltration in the liver metastatic sites of 53 colorectal cancer patients. These patients were divided into three groups according to the treatment before operation: chemotherapy with cetuximab, chemotherapy without cetuximab, and no chemotherapy. The inflammatory cells in the liver metastatic sites were assessed by hematoxylin-eosin staining, focusing on the invasive margin. The overall inflammatory reaction and number of lymphoid cells were assessed with a four-point scoring system. We then assessed immune cell infiltration (CD3, CD8 and CD56) in 15 liver metastatic sites. Hematoxylin-eosin staining demonstrated more inflammatory cells in the chemotherapy with cetuximab group than in the other groups (P < 0.001). Of note, inflammatory cells were found in intratumoral areas, and the destruction of cancer cell foci was observed in the chemotherapy with cetuximab group. Moreover, a higher infiltration of CD3+ (P = 0.003), CD8+ (P = 0.003) and CD56+ (P = 0.001) cells was observed in the chemotherapy with cetuximab group than in the other groups. These results suggest that cetuximab might have an immune-enhancing effect. As such, the immune-related mechanism of action of cetuximab may enhance the efficacy of combination therapy, such as chemotherapy and immunotherapy using therapeutic peptides.

  20. Tumour endothelial cells in high metastatic tumours promote metastasis via epigenetic dysregulation of biglycan

    PubMed Central

    Maishi, Nako; Ohba, Yusuke; Akiyama, Kosuke; Ohga, Noritaka; Hamada, Jun-ichi; Nagao-Kitamoto, Hiroko; Alam, Mohammad Towfik; Yamamoto, Kazuyuki; Kawamoto, Taisuke; Inoue, Nobuo; Taketomi, Akinobu; Shindoh, Masanobu; Hida, Yasuhiro; Hida, Kyoko

    2016-01-01

    Tumour blood vessels are gateways for distant metastasis. Recent studies have revealed that tumour endothelial cells (TECs) demonstrate distinct phenotypes from their normal counterparts. We have demonstrated that features of TECs are different depending on tumour malignancy, suggesting that TECs communicate with surrounding tumour cells. However, the contribution of TECs to metastasis has not been elucidated. Here, we show that TECs actively promote tumour metastasis through a bidirectional interaction between tumour cells and TECs. Co-implantation of TECs isolated from highly metastatic tumours accelerated lung metastases of low metastatic tumours. Biglycan, a small leucine-rich repeat proteoglycan secreted from TECs, activated tumour cell migration via nuclear factor-κB and extracellular signal–regulated kinase 1/2. Biglycan expression was upregulated by DNA demethylation in TECs. Collectively, our results demonstrate that TECs are altered in their microenvironment and, in turn, instigate tumour cells to metastasize, which is a novel mechanism for tumour metastasis. PMID:27295191

  1. Cytoskeletal stiffness, friction, and fluidity of cancer cell lines with different metastatic potential.

    PubMed

    Coughlin, Mark F; Bielenberg, Diane R; Lenormand, Guillaume; Marinkovic, Marina; Waghorne, Carol G; Zetter, Bruce R; Fredberg, Jeffrey J

    2013-03-01

    We quantified mechanical properties of cancer cells differing in metastatic potential. These cells included normal and H-ras-transformed NIH3T3 fibroblast cells, normal and oncoprotein-overexpressing MCF10A breast cancer cells, and weakly and strongly metastatic cancer cell line pairs originating from human cancers of the skin (A375P and A375SM cells), kidney (SN12C and SN12PM6 cells), prostate (PC3M and PC3MLN4 cells), and bladder (253J and 253JB5 cells). Using magnetic twisting cytometry, cytoskeletal stiffness (g') and internal friction (g″) were measured over a wide frequency range. The dependencies of g' and g″ upon frequency were used to determine the power law exponent x which is a direct measure of cytoskeletal fluidity and quantifies where the cytoskeleton resides along the spectrum of solid-like (x = 1) to fluid-like (x = 2) states. Cytoskeletal fluidity x increased following transformation by H-ras oncogene expression in NIH3T3 cells, overexpression of ErbB2 and 14-3-3-ζ in MCF10A cells, and implantation and growth of PC3M and 253J cells in the prostate and bladder, respectively. Each of these perturbations that had previously been shown to enhance cancer cell motility and invasion are shown here to shift the cytoskeleton towards a more fluid-like state. In contrast, strongly metastatic A375SM and SN12PM6 cells that disseminate by lodging in the microcirculation of peripheral organs had smaller x than did their weakly metastatic cell line pairs A375P and SN12C, respectively. Thus, enhanced hematological dissemination was associated with decreased x and a shift towards a more solid-like cytoskeleton. Taken together, these results are consistent with the notion that adaptations known to enhance metastatic ability in cancer cell lines define a spectrum of fluid-like versus solid-like states, and the position of the cancer cell within this spectrum may be a determinant of cancer progression.

  2. Transfusion of sickle cells may be a therapeutic option for patients suffering metastatic disease.

    PubMed

    Goldberg, Joel S

    2010-04-01

    Red blood cells from patients with sickle cell disease will sickle under conditions of hypoxemia and acidosis which is a similar milieu found in malignant tumors. While control of tumor angiogenesis has long been a goal of cancer therapy, selective occlusion of tumor blood supply may be achieved by transfusion of sickle cells into patients who suffer metastatic cancer. Although this potential therapy has not been previously reported in the medical literature, the concept may have been elusive to medical mainstream thinking because it requires transfusion of diseased cells. For this therapy to be effective, other environmental factors may need to be manipulated such inducing mild hypoxemia or hypercarbia (respiratory acidosis) to induce red cell sickling. Preliminary evidence supportive of this therapeutic approach to cancer treatment is provided by case evidence that sickle cell occlusion of a malignant brain tumor (glioma) produced tumor necrosis. Also sickle cells have been successfully transfused into primates. Furthermore, donor blood is crossmatched and transfused into patients suffering from sickle cell disease regularly in clinics and this procedure is associated with acceptable morbidity. Most importantly, animal models of sickle cell disease and cancer currently exist, and this theory could be tried with available technologies including ultrasound detection of vaso-occlusion. While the proposed therapy may not cure metastatic cancer, this treatment could prove useful for decreasing the size and perhaps the pain from metastatic tumor burden. Therefore, it is hypothesized that ABO Rh compatible crossmatched sickle cells transfused into patients who suffer metastatic cancer under controlled conditions of blood oxygenation and pH will selectively produce vaso-occlusive infarcts in malignant tumors and be a useful therapy. The author hopes for further investigations.

  3. Enhanced detection of metastatic prostate cancer cells in human plasma with lipid bodies staining.

    PubMed

    Mitra, Ranjana; Goodman, Oscar B; Le, Thuc T

    2014-02-15

    Reprogramming of energy metabolism of malignant cancer cells confers competitive advantage in growth environments with limited resources. However, not every process of cancer development is associated with competition for resources. During hematogenous transport, cancer cells are exposed to high levels of oxygen and nutrients. Does energy metabolism of cancer cells change as a function of exposure to the bloodstream? Could such changes be exploited to improve the detection of circulating tumor cells (CTC)? These questions have clinical significance, but have not yet been sufficiently examined. The energy metabolism was examined as a function of incubation in nutrient-rich plasma in prostate metastatic cancer cells LNCaP and non-transformed prostate epithelial cells RWPE1. Uptake kinetics of a fluorescent glucose analog (2-NBD) and lipophilic dyes (DiD & Bodipy) were measured in both cell lines, as well as in peripheral blood mononuclear cells (PBMC). LNCaP cells exhibited hyper-acetylation of low molecular weight proteins compared to RWPE1 cells. Following plasma incubation, protein lysine acetylation profile was unchanged for LNCaP cells while significantly altered for RWPE1 cells. O-linked glycosylated protein profiles were different between LNCaP and RWPE1 cells and varied in both cell lines with plasma incubation. Maximal respiration or glycolytic capacities was unchanged in LNCaP cells and impaired in RWPE1 cells following plasma incubation. However, the uptake rates of 2-NBD and DiD were insufficient for discrimination of LNCaP, or RWPE1 cells from PBMC. On the other hand, both RWPE1 and LNCaP cells exhibited intracellular lipid bodies following plasma incubation; whereas, PBMC did not. The presence of lipid bodies in LNCaP cells permitted retention of Bodipy dye and allowed discrimination of LNCaP cells from PBMC with flow cytometry. Despite clear differences in energy metabolism, metastatic prostate cancer cells could not be efficiently distinguished from

  4. Novel near-diploid ovarian cancer cell line derived from a highly aneuploid metastatic ovarian tumor

    PubMed Central

    Rozenblum, Ester; Sotelo-Silveira, Jose R.; Kim, Gina Y.; Zhu, Jack Y.; Lau, Christopher C.; McNeil, Nicole; Korolevich, Susana; Liao, Hongling; Cherry, James M.; Munroe, David J.; Ried, Thomas; Meltzer, Paul S.; Kuehl, Walter M.

    2017-01-01

    A new ovarian near-diploid cell line, OVDM1, was derived from a highly aneuploid serous ovarian metastatic adenocarcinoma. A metastatic tumor was obtained from a 47-year-old Ashkenazi Jewish patient three years after the first surgery removed the primary tumor, both ovaries, and the remaining reproductive organs. OVDM1 was characterized by cell morphology, genotyping, tumorigenic assay, mycoplasma testing, spectral karyotyping (SKY), and molecular profiling of the whole genome by aCGH and gene expression microarray. Targeted sequencing of a panel of cancer-related genes was also performed. Hierarchical clustering of gene expression data clearly confirmed the ovarian origin of the cell line. OVDM1 has a near-diploid karyotype with a low-level aneuploidy, but samples of the original metastatic tumor were grossly aneuploid. A number of single nucleotide variations (SNVs)/mutations were detected in OVDM1 and the metastatic tumor samples. Some of them were cancer-related according to COSMIC and HGMD databases (no founder mutations in BRCA1 and BRCA2 have been found). A large number of focal copy number alterations (FCNAs) were detected, including homozygous deletions (HDs) targeting WWOX and GATA4. Progression of OVDM1 from early to late passages was accompanied by preservation of the near-diploid status, acquisition of only few additional large chromosomal rearrangements and more than 100 new small FCNAs. Most of newly acquired FCNAs seem to be related to localized but massive DNA fragmentation (chromothripsis-like rearrangements). Newly developed near-diploid OVDM1 cell line offers an opportunity to evaluate tumorigenesis pathways/events in a minor clone of metastatic ovarian adenocarcinoma as well as mechanisms of chromothripsis. PMID:28787462

  5. Suppression of MAGE-A10 alters the metastatic phenotype of tongue squamous cell carcinoma cells.

    PubMed

    Mendonça, Bruna Dos Santos; Agostini, Michelle; Aquino, Iara Gonçalves; Dias, Wagner Barbosa; Bastos, Débora Campanella; Rumjanek, Franklin D

    2017-07-01

    MAGE-A10 is a member of the MAGE protein family (melanoma associated antigen) which is overexpressed in cancer cells. Although MAGE-A10 has been characterized for some time and is generally associated to metastasis its function remains unknown. Here we describe experiments using as models oral squamous cell carcinoma (OSCC) cell lines displaying increasing metastatic potential (LN1 and LN2). These cell lines were transduced with lentivirus particles coding for short hairpin against MAGE-A10 mRNA. Repression of MAGE-A10 expression in LN2 cells altered their morphology and impaired growth of LN1 and LN2 cell lines. Furthermore, repression of MAGE-A10 expression increased cell-cell and cell matrix adhesion. Furthermore shMAGEA10 cells were shown to assemble aberrantly on a 3D culture system (microspheroids) when compared to cells transduced with the control scrambled construct. Cell migration was inhibited in knocked down cells as revealed by two different migration assays, wound healing and a phagokinetic track motility assay. In vitro invasion assay using a leiomyoma tissue derived matrix (myogel) showed that shMAGEA10 LN1 and shMAGEA10 LN2 cells displayed a significantly diminished ability to penetrate the matrices. Concomitantly, the expression of E-cadherin, N-cadherin and vimentin genes was analyzed. shMAGEA10 activated the expression of E-cadherin and repression N-cadherin and vimentin transcription. Taken together the results indicate that MAGE-A10 exerts its effects at the level of the epithelial-mesenchymal transition (EMT) presumably by regulating the expression of adhesion molecules.

  6. Metastatic renal cell carcinoma in a supraclavicular lymph node with no known primary: a case report.

    PubMed

    Choi, Young-Rak; Han, Hye-Suk; Lee, Ok-Jun; Lim, Sung-Nam; Kim, Mi-Jin; Yeon, Myeong-Ho; Jeon, Hyun-Jung; Lee, Ki Hyeong; Kim, Seung Taik

    2012-09-01

    Although metastasis is relatively frequent in cases of renal cell carcinoma (RCC), metastasis in the cervical or supraclavicular lymph node (LN) is relatively rare. Moreover, cases of metastatic RCC with a non-identifiable kidney mass are extremely rare. Here, the authors report a case of metastatic RCC in a supraclavicular LN without a primary kidney lesion. A 69-year-old man presented with a progressively enlarging right supraclavicular mass. Incisional biopsy of the affected supraclavicular LN was performed, and histological examination revealed metastatic RCC. However, no tumor was found in either kidney, despite various examinations. The patient was treated with radiotherapy followed by sunitinib. After three months on sunitinib, a follow-up computed tomography scan revealed that the supraclavicular LN had markedly decreased, and after 20 months, the disease had not progressed. This case suggests that, even when there is no primary kidney lesion, clinicians must consider the possibility of metastatic RCC when evaluating patients with clear cell carcinoma with an unknown primary site.

  7. Metastatic potential of cloned murine melanoma cells transfected with activated c-Ha-ras.

    PubMed

    Price, J E; Aukerman, S L; Ananthaswamy, H N; McIntyre, B W; Schackert, G; Schackert, H K; Fidler, I J

    1989-08-01

    We sought to determine whether the transfection of tumorigenic but not metastatic cells with the activated c-Ha-ras oncogene was invariably associated with acquisition of the metastatic phenotype. Three clonally derived lines of the K-1735 murine melanoma, characterized as nonmetastatic or poorly metastatic, were transfected with plasmids containing the 6.6-kilobase BamHI fragment of the mutant human c-Ha-ras gene and the neo gene, that confers resistance to neomycin (pSV2neoEJ). Cells transfected with pSV2neo, a plasmid containing the neo gene, served as controls for the procedure of Polybrene-mediated transfection. All cell lines were injected into syngeneic C3H/HeN and into athymic mice, and the results were compared with those produced by highly metastatic K-1735 M-2 cells. Although the pSV2neoEJ-transfected cells produced more rapidly growing s.c. tumors than the control cell lines did, the incidence of spontaneous metastasis was not increased. Following i.v. inoculation, the c-Ha-ras transfectants were retained in lung vasculature in greater proportions than pSV2neo counterpart transfectants were. The c-Ha-ras transfectants also produced significantly more lung tumor colonies, which grew faster than the few lung tumor colonies in mice given injections of control melanoma cells. We concluded that transfection of the activated c-Ha-ras oncogene into nonmetastatic K-1735 melanoma cells leads to accelerated tumor growth in vivo and can confer the ability to form lung colonies after i.v. injection but not the ability to metastasize from a primary s.c. tumor.

  8. Metastatic renal cell carcinoma avid for 82Rb but not 18F-FDG.

    PubMed

    Murthy, Venkatesh L; Brown, Richard K J; Corbett, James R

    2014-10-01

    Renal cell carcinoma has a variable uptake of F-FDG resulting in poor sensitivity and limited clinical application. There is intense interest in improved molecular imaging of this condition. We present a case of a 64-year-old man with known metastatic renal cell carcinoma found to have intense uptake of Rb but not F-FDG in multiple thoracic metastases seen on imaging performed to assess myocardial hibernation.

  9. Metastatic Insulinoma Following Resection of Nonsecreting Pancreatic Islet Cell Tumor

    PubMed Central

    Gordon, Ilyssa O.; Van Ha, Thuong G.; Kaplan, Edwin L.; Philipson, Louis H.

    2013-01-01

    A 56-year-old woman presented to our clinic for recurrent hypoglycemia after undergoing resection of an incidentally discovered nonfunctional pancreatic endocrine tumor 6 years ago. She underwent a distal pancreatectomy and splenectomy, after which she developed diabetes and was placed on an insulin pump. Pathology showed a pancreatic endocrine neoplasm with negative islet hormone immunostains. Two years later, computed tomography scan of the abdomen showed multiple liver lesions. Biopsy of a liver lesion showed a well-differentiated neuroendocrine neoplasm, consistent with pancreatic origin. Six years later, she presented to clinic with 1.5 years of recurrent hypoglycemia. Laboratory results showed elevated proinsulin, insulin levels, and c-peptide levels during a hypoglycemic episode. Computed tomography scan of the abdomen redemonstrated multiple liver lesions. Repeated transarterial catheter chemoembolization and microwave thermal ablation controlled hypoglycemia. The unusual features of interest of this case include the transformation of nonfunctioning pancreatic endocrine tumor to a metastatic insulinoma and the occurrence of atrial flutter after octreotide for treatment. PMID:26425568

  10. Recognition and capture of metastatic hepatocellular carcinoma cells using aptamer-conjugated quantum dots and magnetic particles.

    PubMed

    Wang, Fu-Bing; Rong, Yuan; Fang, Min; Yuan, Jing-Ping; Peng, Chun-Wei; Liu, Shao-Ping; Li, Yan

    2013-05-01

    Metastatic recurrence is the most important biological behavior of hepatocellular carcinoma (HCC) and the main cause of treatment failure. Early prediction of metastasis is currently impossible due to the lack of specific molecular probes to recognize metastatic HCC cells. Aptamers have recently emerged as promising potential molecular probes for biomedical applications. Two well-matched HCC cell lines including HCCLM9 with high metastatic potential and MHCC97-L with low metastatic potential, were used to select aptamers for HCC metastasis. With a whole-cell-SELEX strategy, in which HCCLM9 cells were used as target cells and MHCC97-L cells as subtractive cell, 6 potential aptamers had been generated. Detailed study on selected aptamer LY-1 revealed that it could bind metastatic HCC cells with high affinity and specificity, not only in cells culture and animal models of HCC metastasis, but also in clinical HCC specimens. Moreover, the aptamer LY-1 and magnetic particles conjugates could efficiently capture the HCC cells from complex mixture whole blood. These studies demonstrated that this HCC specific aptamer LY-1 could be a promising molecular probe to recognize metastatic HCC cells.

  11. Increased autophagic response in a population of metastatic breast cancer cells.

    PubMed

    Li, Y I; Libby, Emily Falk; Lewis, Monica J; Liu, Jianzhong; Shacka, John J; Hurst, Douglas R

    2016-07-01

    Breast cancer cells are heterogeneous in their ability to invade and fully metastasize, and thus also in their capacity to survive the numerous stresses encountered throughout the multiple steps of the metastatic cascade. Considering the role of autophagy as a survival response to stress, the present study hypothesized that distinct populations of breast cancer cells may possess an altered autophagic capacity that influences their metastatic potential. It was observed that a metastatic breast cancer cell line, MDA-MB-231, that was sensitive to autophagic induction additionally possessed the ability to proliferate following nutrient deprivation. Furthermore, a selected subpopulation of these cells that survived multiple exposures to starvation conditions demonstrated a heightened response to autophagic induction compared to their parent cells. Although this subpopulation maintained a more grape-like pattern in three-dimensional culture compared to the extended spikes of the parent population, autophagic induction in this subpopulation elicited an invasive phenotype with extended spikes. Taken together, these results suggest that autophagic induction may contribute to the ability of distinct breast cancer cell populations to survive and invade.

  12. Ketone supplementation decreases tumor cell viability and prolongs survival of mice with metastatic cancer.

    PubMed

    Poff, A M; Ari, C; Arnold, P; Seyfried, T N; D'Agostino, D P

    2014-10-01

    Cancer cells express an abnormal metabolism characterized by increased glucose consumption owing to genetic mutations and mitochondrial dysfunction. Previous studies indicate that unlike healthy tissues, cancer cells are unable to effectively use ketone bodies for energy. Furthermore, ketones inhibit the proliferation and viability of cultured tumor cells. As the Warburg effect is especially prominent in metastatic cells, we hypothesized that dietary ketone supplementation would inhibit metastatic cancer progression in vivo. Proliferation and viability were measured in the highly metastatic VM-M3 cells cultured in the presence and absence of β-hydroxybutyrate (βHB). Adult male inbred VM mice were implanted subcutaneously with firefly luciferase-tagged syngeneic VM-M3 cells. Mice were fed a standard diet supplemented with either 1,3-butanediol (BD) or a ketone ester (KE), which are metabolized to the ketone bodies βHB and acetoacetate. Tumor growth was monitored by in vivo bioluminescent imaging. Survival time, tumor growth rate, blood glucose, blood βHB and body weight were measured throughout the survival study. Ketone supplementation decreased proliferation and viability of the VM-M3 cells grown in vitro, even in the presence of high glucose. Dietary ketone supplementation with BD and KE prolonged survival in VM-M3 mice with systemic metastatic cancer by 51 and 69%, respectively (p < 0.05). Ketone administration elicited anticancer effects in vitro and in vivo independent of glucose levels or calorie restriction. The use of supplemental ketone precursors as a cancer treatment should be further investigated in animal models to determine potential for future clinical use.

  13. Ketone supplementation decreases tumor cell viability and prolongs survival of mice with metastatic cancer

    PubMed Central

    Poff, AM; Ari, C; Arnold, P; Seyfried, TN; D’Agostino, DP

    2014-01-01

    Cancer cells express an abnormal metabolism characterized by increased glucose consumption owing to genetic mutations and mitochondrial dysfunction. Previous studies indicate that unlike healthy tissues, cancer cells are unable to effectively use ketone bodies for energy. Furthermore, ketones inhibit the proliferation and viability of cultured tumor cells. As the Warburg effect is especially prominent in metastatic cells, we hypothesized that dietary ketone supplementation would inhibit metastatic cancer progression in vivo. Proliferation and viability were measured in the highly metastatic VM-M3 cells cultured in the presence and absence of β-hydroxybutyrate (βHB). Adult male inbred VM mice were implanted subcutaneously with firefly luciferase-tagged syngeneic VM-M3 cells. Mice were fed a standard diet supplemented with either 1,3-butanediol (BD) or a ketone ester (KE), which are metabolized to the ketone bodies βHB and acetoacetate. Tumor growth was monitored by in vivo bioluminescent imaging. Survival time, tumor growth rate, blood glucose, blood βHB and body weight were measured throughout the survival study. Ketone supplementation decreased proliferation and viability of the VM-M3 cells grown in vitro, even in the presence of high glucose. Dietary ketone supplementation with BD and KE prolonged survival in VM-M3 mice with systemic metastatic cancer by 51 and 69%, respectively (p < 0.05). Ketone administration elicited anticancer effects in vitro and in vivo independent of glucose levels or calorie restriction. The use of supplemental ketone precursors as a cancer treatment should be further investigated in animal models to determine potential for future clinical use. PMID:24615175

  14. A physical sciences network characterization of non-tumorigenic and metastatic cells

    PubMed Central

    Agus, David B.; Alexander, Jenolyn F.; Arap, Wadih; Ashili, Shashanka; Aslan, Joseph E.; Austin, Robert H.; Backman, Vadim; Bethel, Kelly J.; Bonneau, Richard; Chen, Wei-Chiang; Chen-Tanyolac, Chira; Choi, Nathan C.; Curley, Steven A.; Dallas, Matthew; Damania, Dhwanil; Davies, Paul C. W.; Decuzzi, Paolo; Dickinson, Laura; Estevez-Salmeron, Luis; Estrella, Veronica; Ferrari, Mauro; Fischbach, Claudia; Foo, Jasmine; Fraley, Stephanie I.; Frantz, Christian; Fuhrmann, Alexander; Gascard, Philippe; Gatenby, Robert A.; Geng, Yue; Gerecht, Sharon; Gillies, Robert J.; Godin, Biana; Grady, William M.; Greenfield, Alex; Hemphill, Courtney; Hempstead, Barbara L.; Hielscher, Abigail; Hillis, W. Daniel; Holland, Eric C.; Ibrahim-Hashim, Arig; Jacks, Tyler; Johnson, Roger H.; Joo, Ahyoung; Katz, Jonathan E.; Kelbauskas, Laimonas; Kesselman, Carl; King, Michael R.; Konstantopoulos, Konstantinos; Kraning-Rush, Casey M.; Kuhn, Peter; Kung, Kevin; Kwee, Brian; Lakins, Johnathon N.; Lambert, Guillaume; Liao, David; Licht, Jonathan D.; Liphardt, Jan T.; Liu, Liyu; Lloyd, Mark C.; Lyubimova, Anna; Mallick, Parag; Marko, John; McCarty, Owen J. T.; Meldrum, Deirdre R.; Michor, Franziska; Mumenthaler, Shannon M.; Nandakumar, Vivek; O’Halloran, Thomas V.; Oh, Steve; Pasqualini, Renata; Paszek, Matthew J.; Philips, Kevin G.; Poultney, Christopher S.; Rana, Kuldeepsinh; Reinhart-King, Cynthia A.; Ros, Robert; Semenza, Gregg L.; Senechal, Patti; Shuler, Michael L.; Srinivasan, Srimeenakshi; Staunton, Jack R.; Stypula, Yolanda; Subramanian, Hariharan; Tlsty, Thea D.; Tormoen, Garth W.; Tseng, Yiider; van Oudenaarden, Alexander; Verbridge, Scott S.; Wan, Jenny C.; Weaver, Valerie M.; Widom, Jonathan; Will, Christine; Wirtz, Denis; Wojtkowiak, Jonathan; Wu, Pei-Hsun

    2013-01-01

    To investigate the transition from non-cancerous to metastatic from a physical sciences perspective, the Physical Sciences–Oncology Centers (PS-OC) Network performed molecular and biophysical comparative studies of the non-tumorigenic MCF-10A and metastatic MDA-MB-231 breast epithelial cell lines, commonly used as models of cancer metastasis. Experiments were performed in 20 laboratories from 12 PS-OCs. Each laboratory was supplied with identical aliquots and common reagents and culture protocols. Analyses of these measurements revealed dramatic differences in their mechanics, migration, adhesion, oxygen response, and proteomic profiles. Model-based multi-omics approaches identified key differences between these cells' regulatory networks involved in morphology and survival. These results provide a multifaceted description of cellular parameters of two widely used cell lines and demonstrate the value of the PS-OC Network approach for integration of diverse experimental observations to elucidate the phenotypes associated with cancer metastasis. PMID:23618955

  15. The BMP inhibitor Coco reactivates breast cancer cells at lung metastatic sites.

    PubMed

    Gao, Hua; Chakraborty, Goutam; Lee-Lim, Ai Ping; Mo, Qianxing; Decker, Markus; Vonica, Alin; Shen, Ronglai; Brogi, Edi; Brivanlou, Ali H; Giancotti, Filippo G

    2012-08-17

    The mechanistic underpinnings of metastatic dormancy and reactivation are poorly understood. A gain-of-function cDNA screen reveals that Coco, a secreted antagonist of TGF-β ligands, induces dormant breast cancer cells to undergo reactivation in the lung. Mechanistic studies indicate that Coco exerts this effect by blocking lung-derived BMP ligands. Whereas Coco enhances the manifestation of traits associated with cancer stem cells, BMP signaling suppresses it. Coco induces a discrete gene expression signature, which is strongly associated with metastatic relapse to the lung, but not to the bone or brain in patients. Experiments in mouse models suggest that these latter organs contain niches devoid of bioactive BMP. These findings reveal that metastasis-initiating cells need to overcome organ-specific antimetastatic signals in order to undergo reactivation.

  16. Fusions of Breast Carcinoma and Dendritic Cells as a Vaccine for the Treatment of Metastatic Breast Cancer

    DTIC Science & Technology

    2005-07-01

    regulate the development of anti-tumor immune responses . Importantly, our results show that, compared to unfused DC and tumor cells, the DC/ breast tumor...AD Award Number: DAMD17-03-1-0487 TITLE: Fusions of Breast Carcinoma and Dendritic Cells as a Vaccine for the Treatment of Metastatic Breast Cancer ...4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Fusions of Breast Carcinoma and Dendritic Cells as a Vaccine for the Treatment of Metastatic Breast Cancer

  17. Metastatic giant basal cell carcinoma: a case report

    PubMed Central

    Bellahammou, Khadija; Lakhdissi, Asmaa; Akkar, Othman; Rais, Fadoua; Naoual, Benhmidou; Elghissassi, Ibrahim; M’rabti, Hind; Errihani, Hassan

    2016-01-01

    Basal cell carcinoma is the most common skin cancer, characterised by a slow growing behavior, metastasis are extremely rare, and it occurs in less than 0, 1% of all cases. Giant basal cell carcinoma is a rare form of basal cell carcinoma, more aggressive and defined as a tumor measuring more than 5 cm at its largest diameter. Only 1% of all basal cell carcinoma develops to a giant basal cell carcinoma, resulting of patient's negligence. Giant basal cell carcinoma is associated with higher potential of metastasis and even death, compared to ordinary basal cell carcinoma. We report a case of giant basal cell carcinoma metastaticin lung occurring in a 79 years old male patient, with a fatal evolution after one course of systemic chemotherapy. Giant basal cell carcinoma is a very rare entity, early detection of these tumors could prevent metastasis occurrence and improve the prognosis of this malignancy. PMID:27795755

  18. Metastatic giant basal cell carcinoma: a case report.

    PubMed

    Bellahammou, Khadija; Lakhdissi, Asmaa; Akkar, Othman; Rais, Fadoua; Naoual, Benhmidou; Elghissassi, Ibrahim; M'rabti, Hind; Errihani, Hassan

    2016-01-01

    Basal cell carcinoma is the most common skin cancer, characterised by a slow growing behavior, metastasis are extremely rare, and it occurs in less than 0, 1% of all cases. Giant basal cell carcinoma is a rare form of basal cell carcinoma, more aggressive and defined as a tumor measuring more than 5 cm at its largest diameter. Only 1% of all basal cell carcinoma develops to a giant basal cell carcinoma, resulting of patient's negligence. Giant basal cell carcinoma is associated with higher potential of metastasis and even death, compared to ordinary basal cell carcinoma. We report a case of giant basal cell carcinoma metastaticin lung occurring in a 79 years old male patient, with a fatal evolution after one course of systemic chemotherapy. Giant basal cell carcinoma is a very rare entity, early detection of these tumors could prevent metastasis occurrence and improve the prognosis of this malignancy.

  19. Uncovering cancer cell behavioral phenotype in 3-D in vitro metastatic landscapes

    NASA Astrophysics Data System (ADS)

    Liu, Liyu; Sun, Bo; Duclos, Guillaume; Kam, Yoonseok; Gatenby, Robert; Stone, Howard; Austin, Robert

    2012-02-01

    One well-known fact is that cancer cell genetics determines cell metastatic potentials. However, from a physics point of view, genetics as cell properties cannot directly act on metastasis. An agent is needed to unscramble the genetics first before generating dynamics for metastasis. Exactly this agent is cell behavioral phenotype, which is rarely studied due to the difficulties of real-time cell tracking in in vivo tissue. Here we have successfully constructed a micro in vitro environment with collagen based Extracellular Matrix (ECM) structures for cell 3-D metastasis. With stable nutrition (glucose) gradient inside, breast cancer cell MDA-MB-231 is able to invade inside the collagen from the nutrition poor site towards the nutrition rich site. Continuous confocal microscopy captures images of the cells every 12 hours and tracks their positions in 3-D space. The micro fluorescent beads pre-mixed inside the ECM demonstrate that invasive cells have altered the structures through mechanics. With the observation and the analysis of cell collective behaviors, we argue that game theory may exist between the pioneering cells and their followers in the metastatic cell group. The cell collaboration may explain the high efficiency of metastasis.

  20. Monocytic and granulocytic myeloid derived suppressor cells differentially regulate spatiotemporal tumour plasticity during metastatic cascade

    PubMed Central

    Ouzounova, Maria; Lee, Eunmi; Piranlioglu, Raziye; El Andaloussi, Abdeljabar; Kolhe, Ravindra; Demirci, Mehmet F.; Marasco, Daniela; Asm, Iskander; Chadli, Ahmed; Hassan, Khaled A.; Thangaraju, Muthusamy; Zhou, Gang; Arbab, Ali S.; Cowell, John K.; Korkaya, Hasan

    2017-01-01

    It is widely accepted that dynamic and reversible tumour cell plasticity is required for metastasis, however, in vivo steps and molecular mechanisms are poorly elucidated. We demonstrate here that monocytic (mMDSC) and granulocytic (gMDSC) subsets of myeloid-derived suppressor cells infiltrate in the primary tumour and distant organs with different time kinetics and regulate spatiotemporal tumour plasticity. Using co-culture experiments and mouse transcriptome analyses in syngeneic mouse models, we provide evidence that tumour-infiltrated mMDSCs facilitate tumour cell dissemination from the primary site by inducing EMT/CSC phenotype. In contrast, pulmonary gMDSC infiltrates support the metastatic growth by reverting EMT/CSC phenotype and promoting tumour cell proliferation. Furthermore, lung-derived gMDSCs isolated from tumour-bearing animals enhance metastatic growth of already disseminated tumour cells. MDSC-induced ‘metastatic gene signature' derived from murine syngeneic model predicts poor patient survival in the majority of human solid tumours. Thus spatiotemporal MDSC infiltration may have clinical implications in tumour progression. PMID:28382931

  1. Altered expression of glycosaminoglycans in metastatic 13762NF rat mammary adenocarcinoma cells

    SciTech Connect

    Steck, P.A.; Cheong, P.H.; Nakajima, M.; Yung, W.K.A.; Moser, R.P.; Nicolson, G.L.

    1987-02-24

    A difference in the expression and metabolism of (/sup 35/S)sulfated glycosaminoglycans between rat mammary tumor cells derived from a primary tumor and those from its metastatic lesions has been observed. Cells from the primary tumor possessed about equal quantities of chondroitin sulfate and heparan sulfate on their cell surfaces but released fourfold more chondroitin sulfate than heparan sulfate into their medium. In contrast, cells from distal metastatic lesions expressed approximately 5 times more heparan sulfate than chondroitin sulfate in both medium and cell surface fractions. This was observed to be the result of differential synthesis of the glycosaminoglycans and not of major structural alterations of the individual glycosaminoglycans. The degree of sulfation and size of heparan sulfate were similar for all cells examined. However, chondroitin sulfate, observed to be only chondroitin 4-sulfate, from the metastases-derived cells had a smaller average molecular weight on gel filtration chromatography and showed a decreased quantity of sulfated disaccharides upon degradation with chondroitin ABC lyase compared to the primary tumor derived cells. Major qualitative or quantitative alterations were not observed for hyaluronic acid among the various 13762NF cells. The metabolism of newly synthesized sulfated glycosaminoglycans was also different between cells from primary tumor and metastases. A pulse-chase kinetics study demonstrated that both heparan sulfate and chondroitin sulfate were degraded by the metastases-derived cells, whereas the primary tumor derived cells degraded only heparan sulfate and degraded it at a slower rate. These results suggested that altered glycosaminoglycan expression and metabolism may be associated with the metastatic process in 13762NF rat mammary tumor cells.

  2. Maraviroc decreases CCL8-mediated migration of CCR5(+) regulatory T cells and reduces metastatic tumor growth in the lungs.

    PubMed

    Halvorsen, E C; Hamilton, M J; Young, A; Wadsworth, B J; LePard, N E; Lee, H N; Firmino, N; Collier, J L; Bennewith, K L

    2016-06-01

    Regulatory T cells (Tregs) play a crucial physiological role in the regulation of immune homeostasis, although recent data suggest Tregs can contribute to primary tumor growth by suppressing antitumor immune responses. Tregs may also influence the development of tumor metastases, although there is a paucity of information regarding the phenotype and function of Tregs in metastatic target organs. Herein, we demonstrate that orthotopically implanted metastatic mammary tumors induce significant Treg accumulation in the lungs, which is a site of mammary tumor metastasis. Tregs in the primary tumor and metastatic lungs express high levels of C-C chemokine receptor type 5 (CCR5) relative to Tregs in the mammary fat pad and lungs of tumor-free mice, and Tregs in the metastatic lungs are enriched for CCR5 expression in comparison to other immune cell populations. We also identify that C-C chemokine ligand 8 (CCL8), an endogenous ligand of CCR5, is produced by F4/80(+) macrophages in the lungs of mice with metastatic primary tumors. Migration of Tregs toward CCL8 ex vivo is reduced in the presence of the CCR5 inhibitor Maraviroc. Importantly, treatment of mice with Maraviroc (MVC) reduces the level of CCR5(+) Tregs and metastatic tumor burden in the lungs. This work provides evidence of a CCL8/CCR5 signaling axis driving Treg recruitment to the lungs of mice bearing metastatic primary tumors, representing a potential therapeutic target to decrease Treg accumulation and metastatic tumor growth.

  3. Maraviroc decreases CCL8-mediated migration of CCR5+ regulatory T cells and reduces metastatic tumor growth in the lungs

    PubMed Central

    Halvorsen, E. C.; Hamilton, M. J.; Young, A.; Wadsworth, B. J.; LePard, N. E.; Lee, H. N.; Firmino, N.; Collier, J. L.; Bennewith, K. L.

    2016-01-01

    ABSTRACT Regulatory T cells (Tregs) play a crucial physiological role in the regulation of immune homeostasis, although recent data suggest Tregs can contribute to primary tumor growth by suppressing antitumor immune responses. Tregs may also influence the development of tumor metastases, although there is a paucity of information regarding the phenotype and function of Tregs in metastatic target organs. Herein, we demonstrate that orthotopically implanted metastatic mammary tumors induce significant Treg accumulation in the lungs, which is a site of mammary tumor metastasis. Tregs in the primary tumor and metastatic lungs express high levels of C–C chemokine receptor type 5 (CCR5) relative to Tregs in the mammary fat pad and lungs of tumor-free mice, and Tregs in the metastatic lungs are enriched for CCR5 expression in comparison to other immune cell populations. We also identify that C–C chemokine ligand 8 (CCL8), an endogenous ligand of CCR5, is produced by F4/80+ macrophages in the lungs of mice with metastatic primary tumors. Migration of Tregs toward CCL8 ex vivo is reduced in the presence of the CCR5 inhibitor Maraviroc. Importantly, treatment of mice with Maraviroc (MVC) reduces the level of CCR5+ Tregs and metastatic tumor burden in the lungs. This work provides evidence of a CCL8/CCR5 signaling axis driving Treg recruitment to the lungs of mice bearing metastatic primary tumors, representing a potential therapeutic target to decrease Treg accumulation and metastatic tumor growth. PMID:27471618

  4. Astrocytes from the brain microenvironment alter migration and morphology of metastatic breast cancer cells.

    PubMed

    Shumakovich, Marina A; Mencio, Caitlin P; Siglin, Jonathan S; Moriarty, Rebecca A; Geller, Herbert M; Stroka, Kimberly M

    2017-08-09

    Tumor cell metastasis to the brain involves cell migration through biochemically and physically complex microenvironments at the blood-brain barrier (BBB). The current understanding of tumor cell migration across the BBB is limited. We hypothesize that an interplay between biochemical cues and physical cues at the BBB affects the mechanisms of brain metastasis. We found that astrocyte conditioned medium (ACM) applied directly to tumor cells increased tumor cell velocity, induced elongation, and promoted actin stress fiber organization. Notably, treatment of the extracellular matrix with ACM led to even more significant increases in tumor cell velocity in comparison with ACM treatment of cells directly. Furthermore, inhibiting matrix metalloproteinases in ACM reversed ACM's effect on tumor cells. The effects of ACM on tumor cell morphology and migration also depended on astrocytes' activation state. Finally, using a microfluidic device, we found that the effects of ACM were abrogated in confinement. Overall, our work demonstrates that astrocyte-secreted factors alter migration and morphology of metastatic breast tumor cells, and this effect depends on the cells' mechanical microenvironment.-Shumakovich, M. A., Mencio, C. P., Siglin, J. S., Moriarty, R. A., Geller, H. M., Stroka, K. M. Astrocytes from the brain microenvironment alter migration and morphology of metastatic breast cancer cells. © FASEB.

  5. Differentiation of highly metastatic nasopharyngeal carcinoma cells using multiphoton microscopy

    NASA Astrophysics Data System (ADS)

    Zhan, Zhenlin; Sun, Zhenzhen; Li, Jingwen; Ye, Qing; Zhuo, Shuangmu; Xie, Shusen

    2016-10-01

    The primary hypothesis tested in the study was that nasopharyngeal carcinoma (NPC) cells at different stage of invasion and metastasis can be differentiated using multiphoton microscopy (MPM). CNE1 and CNE2Z cells were cultured and used in this study. The activity of cell migration and invasion was measured using Transwell assays. At the same time, the morphologic features were quantified from the multiphoton images. The measurements of Transwell migration and invasion showed that the invasion and migration of CNE2Z cells were significantly enhanced when compared with that of CNE1 cells. Also, statistically significant differences in the morphologic features were found between two kinds of cancer cells. In conclusion, it is feasible to use MPM to differentiate cancer cells with different stage of invasion and metastasis.

  6. Establishment of a highly metastatic buccal squamous cell carcinoma cell line from a Sprague-Dawley Rat.

    PubMed

    Qin, Xing; Yan, Ming; Zhang, Jianjun; Xu, Qin; Lv, Zhongjing; Chen, Wantao

    2016-02-01

    The incidence of buccal squamous cell carcinoma (buccal SCC) is considered to be the second highest out of all oral cancers, but the unsatisfactory in vivo tumorigenicity and metastatic potential of the widely used cell lines have greatly delayed studies on the mechanisms of tumor progression. This study aimed to establish a highly metastatic buccal SCC cell line, which may serve a useful tool in buccal SCC research. Buccal SCC was induced by 4-nitroquinoline-1-oxide (4NQO) in Sprague-Dawley rats. The cancer samples were collected, and the tumor cells were purified in vitro. A highly aggressive cell line termed "Rca-B" was established by an invasion assay. Its proliferative ability, cell cycle distribution, baseline level of apoptosis, carcinogenicity and metastatic behavior in nude mice were investigated. To date, Rca-B cells have been stably cultured in vitro for more than 180 passages. These cells were polygonal or spindle-shaped, grew adhesively, and exhibited a stable epithelial phenotype as characterized by positive expression of cytokeratin. The population doubling time was 25.09 h. Cells in S-phase of the cell cycle accounted for 31.17% of the total number of cells, and the baseline level of apoptosis was 8.52%. The in vitro migration and invasion assays revealed highly aggressive features of Rca-B cells. In addition, the rate of xenograft formation was 100%, and the incidence of experimental lung metastasis was 81.8% in immunodeficient nude mice. The Rca-B cell line was established as a highly metastatic rat buccal SCC cell line, and its in-depth characterization, which includes malignant behaviors, allows for a wealth of functional studies on the molecular mechanisms of buccal SCC progression and targeted therapy. Copyright © 2015 Elsevier Ltd. All rights reserved.

  7. Exome Sequencing of Cell-Free DNA from Metastatic Cancer Patients Identifies Clinically Actionable Mutations Distinct from Primary Disease

    PubMed Central

    Butler, Timothy M.; Johnson-Camacho, Katherine; Peto, Myron; Wang, Nicholas J.; Macey, Tara A.; Korkola, James E.; Koppie, Theresa M.; Corless, Christopher L.; Gray, Joe W.; Spellman, Paul T.

    2015-01-01

    The identification of the molecular drivers of cancer by sequencing is the backbone of precision medicine and the basis of personalized therapy; however, biopsies of primary tumors provide only a snapshot of the evolution of the disease and may miss potential therapeutic targets, especially in the metastatic setting. A liquid biopsy, in the form of cell-free DNA (cfDNA) sequencing, has the potential to capture the inter- and intra-tumoral heterogeneity present in metastatic disease, and, through serial blood draws, track the evolution of the tumor genome. In order to determine the clinical utility of cfDNA sequencing we performed whole-exome sequencing on cfDNA and tumor DNA from two patients with metastatic disease; only minor modifications to our sequencing and analysis pipelines were required for sequencing and mutation calling of cfDNA. The first patient had metastatic sarcoma and 47 of 48 mutations present in the primary tumor were also found in the cell-free DNA. The second patient had metastatic breast cancer and sequencing identified an ESR1 mutation in the cfDNA and metastatic site, but not in the primary tumor. This likely explains tumor progression on Anastrozole. Significant heterogeneity between the primary and metastatic tumors, with cfDNA reflecting the metastases, suggested separation from the primary lesion early in tumor evolution. This is best illustrated by an activating PIK3CA mutation (H1047R) which was clonal in the primary tumor, but completely absent from either the metastasis or cfDNA. Here we show that cfDNA sequencing supplies clinically actionable information with minimal risks compared to metastatic biopsies. This study demonstrates the utility of whole-exome sequencing of cell-free DNA from patients with metastatic disease. cfDNA sequencing identified an ESR1 mutation, potentially explaining a patient’s resistance to aromatase inhibition, and gave insight into how metastatic lesions differ from the primary tumor. PMID:26317216

  8. Reoxygenation using a novel CO2 therapy decreases the metastatic potential of osteosarcoma cells.

    PubMed

    Harada, Risa; Kawamoto, Teruya; Ueha, Takeshi; Minoda, Masaya; Toda, Mitsunori; Onishi, Yasuo; Fukase, Naomasa; Hara, Hitomi; Sakai, Yoshitada; Miwa, Masahiko; Kuroda, Ryosuke; Kurosaka, Masahiro; Akisue, Toshihiro

    2013-08-01

    Osteosarcoma is the most common primary solid malignant bone tumor. Despite substantial improvements in surgery and chemotherapy, metastasis remains a major cause of fatal outcomes, and the molecular mechanisms of metastasis are still poorly understood. Hypoxia, which is common in malignant tumors including osteosarcoma, increases expressions of hypoxia inducible factor (HIF)-1α, matrix metalloproteinase (MMP)-2 and MMP-9, and can induce invasiveness. As we previously showed a novel transcutaneous CO2 application to decrease HIF-1α expression and induce apoptosis in malignant fibrous histiocytoma, we hypothesize that transcutaneous CO2 application could suppress metastatic potential of osteosarcoma by improving hypoxic conditions. Here, we examined the effects of transcutaneous CO2 application on apoptosis, and development of pulmonary metastasis using a highly metastatic osteosarcoma cell line, LM8. Transcutaneous CO2 application significantly decreased tumor growth and pulmonary metastasis in LM8 cells. Apoptotic activity increased, and intratumoral hypoxia was improved with decreased expressions of HIF-1α, MMP-2 and MMP-9, significantly, in the CO2-treated tumors. In conclusion, we found that transcutaneous CO2 application can induce tumor cell apoptosis and might suppress pulmonary metastasis by improvement of hypoxic conditions with decreased expressions of HIF-1α and MMPs in highly metastatic osteosarcoma cell. These findings strongly indicate that this novel transcutaneous CO2 therapy could be a therapeutic breakthrough for osteosarcoma patients. Copyright © 2013 Elsevier Inc. All rights reserved.

  9. Additive enhancement of apoptosis by TRAIL and fenretinide in metastatic breast cancer cells in vitro.

    PubMed

    Ulukaya, Engin; Sarimahmut, Mehmet; Cevatemre, Buse; Ari, Ferda; Yerlikaya, Azmi; Dimas, Konstantinos

    2014-05-01

    Successful management of metastatic breast cancer still needs better chemotherapeutic approaches. The combination of fenretinide (4-HPR), a synthetic retinoid inducing apoptosis by ROS generation, and TRAIL, a cell death ligand inducing caspase-dependent apoptosis, might result in more powerful cytotoxic activity. We therefore investigated the cytotoxic activity and resulting cell death mode of this combination in MDA-MB-231 cell line as a representative of metastatic state. Cytotoxicity was assessed by the ATP viability assay while the mode of cell death was determined both morphologically using fluorescence microscopy and biochemically using Western blotting and ELISA. The combination resulted in an additive cytotoxic effect at the doses used. Fragmented and/or pyknotic nuclei, which is a feature of apoptosis, were observed after treatment with fenretinide or TRAIL. However, the combinatorial treatment further increased apoptotic figures. Confirming apoptosis, active caspase-3 and cleaved PARP were increased by fenretinide or TRAIL in both western blotting and ELISA. Again, apoptosis was further increased by the combination. The combination warrants further studies due to its superior cytotoxic activity in the metastatic setting of breast cancer. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  10. Nitric Oxide Inhibits Hetero-adhesion of Cancer Cells to Endothelial Cells: Restraining Circulating Tumor Cells from Initiating Metastatic Cascade

    NASA Astrophysics Data System (ADS)

    Lu, Yusheng; Yu, Ting; Liang, Haiyan; Wang, Jichuang; Xie, Jingjing; Shao, Jingwei; Gao, Yu; Yu, Suhong; Chen, Shuming; Wang, Lie; Jia, Lee

    2014-03-01

    Adhesion of circulating tumor cells (CTCs) to vascular endothelial bed becomes a crucial starting point in metastatic cascade. We hypothesized that nitric oxide (NO) may prevent cancer metastasis from happening by its direct vasodilation and inhibition of cell adhesion molecules (CAMs). Here we show that S-nitrosocaptopril (CAP-NO, a typical NO donor) produced direct vasorelaxation that can be antagonized by typical NO scavenger hemoglobin and guanylate cyclase inhibitor. Cytokines significantly stimulated production of typical CAMs by the highly-purified human umbilical vein endothelial cells (HUVECs). CAP-NO inhibited expression of the stimulated CAMs (particularly VCAM-1) and the resultant hetero-adhesion of human colorectal cancer cells HT-29 to the HUVECs in a concentration-dependent manner. The same concentration of CAP-NO, however, did not significantly affect cell viability, cell cycle and mitochondrial membrane potential of HT-29, thus excluding the possibility that inhibition of the hetero-adhesion was caused by cytotoxicity by CAP-NO on HT-29. Hemoglobin reversed the inhibition of CAP-NO on both the hetero-adhesion between HT-29 and HUVECs and VCAM-1 expression. These data demonstrate that CAP-NO, by directly releasing NO, produces vasorelaxation and interferes with hetero-adhesion of cancer cells to vascular endothelium via down-regulating expression of CAMs. The study highlights the importance of NO in cancer metastatic prevention.

  11. [Successful Management by Immunoglobulin for Sunitinib-Induced Thrombocytopenia in a Patient with Advanced Metastatic Renal Cell Carcinoma].

    PubMed

    Okazaki, Satoshi; Hori, Jun-ichi; Watanabe, Masaki; Hashizume, Kazumi; Kobayashi, Shin; Azumi, Makoto; Kita, Masafumi; Iwata, Tatsuya; Matsumoto, Seiji; Kakizaki, Hidehiro

    2016-02-01

    An 81-year-old man was referred to our hospital because of a right renal tumor with vena cava thrombus and multiple lung metastases that were detected by computed tomography (CT) scan during evaluation of respiratory discomfort. We started medical treatment with sunitinib at a dose of 50 mg daily in a 2-week-on, 1-week-off schedule after confirming clear cell renal cell carcinoma by tumor biopsy. After 2-week sunitinib treatment, thrombocytopenia continued and platelet count decreased to 1.8×10(9)/l at day 11 after stopping sunitinib. We needed to administer a total of 60 units platelet transfusion because of persistent thrombocytopenia. Bone marrow aspiration did not reveal myelosuppression or carcinoma invasion to bone marrow. Under the clinical diagnosis of drug-induced thrombocytopenia secondary to sunitinib, we started immunoglobulin therapy at day 23 after stopping sunitinib. Platelet count returned to normal 10 days after starting immunoglobulin. The patient developed exacerbating lung metastasis and carcinomatous lymphangiosis during subsequent course and died of renal cell carcinoma 79 days after starting sunitinib. Thrombocytopenia after sunitinib therapy is often encountered but prolonged thrombocytopenia is rare after stopping sunitinib. This case suggests that immunoglobulin therapy is effective for drug-induced prolonged thrombocytopenia through immunological mechanism.

  12. Nanoroughened adhesion-based capture of circulating tumor cells with heterogeneous expression and metastatic characteristics.

    PubMed

    Chen, Weiqiang; Allen, Steven G; Reka, Ajaya Kumar; Qian, Weiyi; Han, Shuo; Zhao, Jianing; Bao, Liwei; Keshamouni, Venkateshwar G; Merajver, Sofia D; Fu, Jianping

    2016-08-08

    Circulating tumor cells (CTCs) have shown prognostic relevance in many cancer types. However, the majority of current CTC capture methods rely on positive selection techniques that require a priori knowledge about the surface protein expression of disseminated CTCs, which are known to be a dynamic population. We developed a microfluidic CTC capture chip that incorporated a nanoroughened glass substrate for capturing CTCs from blood samples. Our CTC capture chip utilized the differential adhesion preference of cancer cells to nanoroughened etched glass surfaces as compared to normal blood cells and thus did not depend on the physical size or surface protein expression of CTCs. The microfluidic CTC capture chip was able to achieve a superior capture yield for both epithelial cell adhesion molecule positive (EpCAM+) and EpCAM- cancer cells in blood samples. Additionally, the microfluidic CTC chip captured CTCs undergoing transforming growth factor beta-induced epithelial-to-mesenchymal transition (TGF-β-induced EMT) with dynamically down-regulated EpCAM expression. In a mouse model of human breast cancer using EpCAM positive and negative cell lines, the number of CTCs captured correlated positively with the size of the primary tumor and was independent of their EpCAM expression. Furthermore, in a syngeneic mouse model of lung cancer using cell lines with differential metastasis capability, CTCs were captured from all mice with detectable primary tumors independent of the cell lines' metastatic ability. The microfluidic CTC capture chip using a novel nanoroughened glass substrate is broadly applicable to capturing heterogeneous CTC populations of clinical interest independent of their surface marker expression and metastatic propensity. We were able to capture CTCs from a non-metastatic lung cancer model, demonstrating the potential of the chip to collect the entirety of CTC populations including subgroups of distinct biological and phenotypical properties. Further

  13. N-acetylglucosaminyltransferase IVa regulates metastatic potential of mouse hepatocarcinoma cells through glycosylation of CD147.

    PubMed

    Fan, Jianhui; Wang, Shujing; Yu, Shengjin; He, Jingna; Zheng, Weilong; Zhang, Jianing

    2012-08-01

    N-acetylglucosaminyltransferase (GnT)-IV a is a key enzyme that catalyzes the formation of the GlcNAC β1-4 branch on the core structure of complex N-Glycans, which is the common substrate for other N-acetylglucosaminyltransferases, such as GnT-III and GnT-V. Our recent study indicates that the expression of GnT-IVa in Hca-F cells was much higher than that in Hepa1-6 cells, these two mouse hepatocarcinoma cell lines have high and no metastatic potential in lymph nodes respectively. To investigate the effects of GnT-IVa on the metastasis of hepatocarcinoma, exogenous GnT-IVa was introduced into Hepa1-6 cells, and on the other hand, the expression of GnT-IVa was down-regulated in Hca-F cells. The engineered overexpression of GnT-IVa in Hepa1-6 cells increased the antennary branches of complex N-glycans and reduced bisecting branches in vitro and in vivo, which leads to the increase in migration and metastatic capability of hepatocarcinoma cells. Conversely, down-regulated expression of GnT-IVa in Hca-F cells showed reduced tetra-antennary branches of N-Glycans, and significantly decreased the migration and metastatic capability. Furthermore, we found that the regulated GnT-IVa converts the heterogeneous N-glycosylated forms of CD147 in Hepa1-6 and Hca-F cells, and significantly changed the antennary oligosaccharide structures on CD147. These results suggest that GnT-IVa could be acting as a key role in migration and metastasis of mouse hepatocarcinoma cells through altering the glycosylation of CD147. These findings should be valuable in delineating the important function of GnT-IVa during the process of hepatocarcinoma growth and metastasis.

  14. Comprehensive Genomic Profiling of Metastatic Squamous Cell Carcinoma of the Anal Canal.

    PubMed

    Morris, Van; Rao, Xiayu; Pickering, Curtis; Foo, Wai Chin; Rashid, Asif; Eterovic, Karina; Kim, Taebeom; Chen, Ken; Wang, Jing; Shaw, Kenna; Eng, Cathy

    2017-08-07

    Squamous cell carcinoma of the anal canal (SCCA) is a rare gastrointestinal malignancy with an increasing annual incidence globally. The majority of cases are linked to prior infection with the human papillomavirus (HPV). For patients with metastatic SCCA, no consensus standard treatment exists. Identification of relevant targeted agents as novel therapeutic approaches for metastatic SCCA has been limited by a lack of comprehensive molecular profiling. We performed whole-exome sequencing on tumor-normal pairs from 24 patients with metastatic SCCA. Tumor tissue from 17 additional patients was analyzed using a 263-gene panel as a validation cohort. Gene expression profiling was performed on available frozen tissue to assess for differential expression patterns. Based on these findings, patient-derived xenograft (PDX) models of SCCA were generated to test targeted therapies against PI3K and EGFR. Despite a low mutation burden, mutations in PIK3CA, MLL2, and MLL3 were among the most commonly mutated genes. An association between TP53 mutations and HPV-negative SCCA tumors was observed. Gene expression analysis suggested distinct tumor subpopulations harboring PIK3CA mutations and for which HPV had integrated into the host genome. In vivo studies demonstrated improvement with anti-EGFR treatment. Gene mutation frequencies, tumor mutation burden, and gene expression patterns for metastatic SCCA appear similar to other HPV-associated malignancies.Implications: This first comprehensive genomic characterization for patients with metastatic SCCA provides further rationale for the integration of SCCA into the development of novel targeted therapies across HPV-related cancers. Mol Cancer Res; 1-9. ©2017 AACR. ©2017 American Association for Cancer Research.

  15. Oncogenic LINE-1 Retroelements Sustain Prostate Tumor Cells and Promote Metastatic Progression

    DTIC Science & Technology

    2015-10-01

    RNA -sequencing data that we are part way through processing, but suggests so far significant activation of non-coding RNA sequences derived from RNA ...metastasis tumor tissues in the UTHSCSA tissue bank, however the RNA was not considered of sufficient quality to submit for RNA sequencing. We did RNA ...sequencing of LNCaP cell line RNA as this is derived from a prostate cancer lymph node metastatic deposit, although the bioinformatics analysis has

  16. A rare cause in etiology of left atrial mass: metastatic testicular germ cell tumor

    PubMed Central

    Huseyin, Serhat; Okyay, Ahmet; Hacıbekiroğlu, İlhan; Tastekin, Ebru; Yılmaztepe, Mustafa; Taylan, Gökay; Canbaz, Suat; Çiçin, İrfan

    2016-01-01

    Although intracardiac metastasis of germ cell tumors is rare, it can be localized in the right or left heart by disseminating spread and give their cardiac symptoms depending on the location of metastatic mass. We present a 38-year-old male patient with a preliminary diagnosis of testicular tumor who was followed by the medical oncology clinic with cerebrovascular event and heart failure symptoms. PMID:27212979

  17. Prognostic factors for survival in metastatic renal cell carcinoma: update 2008.

    PubMed

    Bukowski, Ronald M

    2009-05-15

    A variety of prognostic factor models to predict survival in patients with metastatic renal cell carcinoma have been developed. Diverse populations of patients with variable treatments have been used for these analyses. A variety of clinical, pathologic, and molecular factors have been studied, but current models use predominantly easily obtained clinical factors. These approaches are reviewed, and current approaches to further refine and develop these techniques are reviewed.

  18. Proteinuria with first-line therapy of metastatic renal cell cancer.

    PubMed

    Land, Josiah D; Chen, Adrienne H; Atkinson, Bradley J; Cauley, Diana H; Tannir, Nizar M

    2016-04-01

    Vascular endothelial growth factor receptor inhibitors, mammalian target of rapamycin inhibitors, and tyrosine kinase inhibitors are approved for metastatic renal cell cancer. Proteinuria can occur, but there is limited data regarding the incidence, monitoring, and management in metastatic renal cell cancer patients. Our primary objective was to describe the incidence and severity of proteinuria in metastatic renal cell cancer patients treated in the first-line setting with pazopanib, bevacizumab, or everolimus. We conducted a retrospective review of patients with metastatic renal cell cancer enrolled from January 2011-April 2013 in a phase II trial. Baseline and toxicity data were extracted from the electronic medical record. Descriptive statistics were used. In all, 129 patients were eligible for analysis. The overall incidence of proteinuria was 81%, with most events being Grade 1 or 2. The incidence of proteinuria was 80% (n = 35) for pazopanib, 64% (n = 25) for bevacizumab, and 96% (n = 44) for everolimus. At peak proteinuria, 80% (n = 28), 64% (n = 16), and 80% (n = 35) of patients on pazopanib, bevacizumab, and everolimus, respectively, were managed with continued monitoring at the same dose. The overall incidence of Grades 3 and 4 events was 24% (n = 6) and found in the bevacizumab group. A high incidence of proteinuria with minor severity within each class was demonstrated. It may be reasonable to continue therapy at the same dose for Grade 1 or 2 proteinuria. Treatment modification or discontinuation of therapy may be warranted with Grade 3 or 4 proteinuria. © The Author(s) 2014.

  19. Metastatic renal cell carcinoma of the buccal mucosa masquerading as a salivary gland neoplasm

    PubMed Central

    Kudva, Ranjini; Nayal, Bhavna; Kantipudi, Swarna; Ray, Satadru

    2016-01-01

    Metastasis to the oral cavity is a rare occurrence with renal cell carcinoma (RCC) being the third most common tumor to metastasize to this location. Buccal mucosa is rarely involved and in the absence of a known primary, such lesions pose a diagnostic challenge to the pathologist. The histomorphological features may mimic a primary salivary gland neoplasm adding to the dilemma. We present one such case of metastatic RCC of the buccal mucosa. PMID:27721630

  20. Ixabepilone in Treating Patients With Metastatic or Recurrent Squamous Cell Cancer of the Head and Neck

    ClinicalTrials.gov

    2013-02-26

    Metastatic Squamous Neck Cancer With Occult Primary Squamous Cell Carcinoma; Recurrent Metastatic Squamous Neck Cancer With Occult Primary; Recurrent Salivary Gland Cancer; Recurrent Squamous Cell Carcinoma of the Hypopharynx; Recurrent Squamous Cell Carcinoma of the Larynx; Recurrent Squamous Cell Carcinoma of the Lip and Oral Cavity; Recurrent Squamous Cell Carcinoma of the Oropharynx; Recurrent Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Recurrent Verrucous Carcinoma of the Larynx; Recurrent Verrucous Carcinoma of the Oral Cavity; Salivary Gland Squamous Cell Carcinoma; Stage IV Squamous Cell Carcinoma of the Hypopharynx; Stage IVA Salivary Gland Cancer; Stage IVA Squamous Cell Carcinoma of the Larynx; Stage IVA Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IVA Squamous Cell Carcinoma of the Oropharynx; Stage IVA Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Stage IVA Verrucous Carcinoma of the Larynx; Stage IVA Verrucous Carcinoma of the Oral Cavity; Stage IVB Salivary Gland Cancer; Stage IVB Squamous Cell Carcinoma of the Larynx; Stage IVB Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IVB Squamous Cell Carcinoma of the Oropharynx; Stage IVB Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Stage IVB Verrucous Carcinoma of the Larynx; Stage IVB Verrucous Carcinoma of the Oral Cavity; Stage IVC Salivary Gland Cancer; Stage IVC Squamous Cell Carcinoma of the Larynx; Stage IVC Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IVC Squamous Cell Carcinoma of the Oropharynx; Stage IVC Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Stage IVC Verrucous Carcinoma of the Larynx; Stage IVC Verrucous Carcinoma of the Oral Cavity; Tongue Cancer

  1. Green tea extract selectively targets nanomechanics of live metastatic cancer cells

    NASA Astrophysics Data System (ADS)

    Cross, Sarah E.; Jin, Yu-Sheng; Lu, Qing-Yi; Rao, JianYu; Gimzewski, James K.

    2011-05-01

    Green tea extract (GTE) is known to be a potential anticancer agent (Yang et al 2009 Nat. Rev. Cancer 9 429-39) with various biological activities (Lu et al 2005 Clin. Cancer Res. 11 1675-83 Yang et al 1998 Carcinogenesis 19 611-6) yet the precise mechanism of action is still unclear. The biomechanical response of GTE treated cells taken directly from patient's body samples was measured using atomic force microscopy (AFM) (Binnig et al 1986 Phys. Rev. Lett. 56 930). We found significant increase in stiffness of GTE treated metastatic tumor cells, with a resulting value similar to untreated normal mesothelial cells, whereas mesothelial cell stiffness after GTE treatment is unchanged. Immunofluorescence analysis showed an increase in cytoskeletal-F-actin in GTE treated tumor cells, suggesting GTE treated tumor cells display mechanical, structural and morphological features similar to normal cells, which appears to be mediated by annexin-I expression, as determined by siRNA analysis of an in vitro cell line model. Our data indicates that GTE selectively targets human metastatic cancer cells but not normal mesothelial cells, a finding that is significantly advantageous compared to conventional chemotherapy agents.

  2. Metapristone (RU486 derivative) inhibits cell proliferation and migration as melanoma metastatic chemopreventive agent.

    PubMed

    Zheng, Ning; Chen, Jiahang; Liu, Weiqun; Wang, Jichuang; Liu, Jian; Jia, Lee

    2017-04-01

    Uncontrolled cell proliferation and metastasis are the two well-known manifestations of melanoma. We hypothesized that metapristone, a potential cancer metastatic chemopreventive agent derived from mifepristone (RU486), had a dual function to fight cancer. In the present study, our findings clearly demonstrated that metapristone had modest cytostatic effect in melanoma cells. Metapristone inhibited cell viability and induced both early and late apoptosis in B16F10 and A375 cells in a time- and concentrate-dependent manner. Metapristone-treatment caused the cell arrest at the G0/G1 stage, and the inhibition of colony formation in B16F10 cells. Western blot analysis further revealed that metapristone treatment elicited a decline of Akt and ERK phosphorylation and Bcl-2, and facilitated expression of total P53 and Bax in A375 cells. In addition, cell migration and invasion were significantly suppressed by metapristone through down-regulating the expression of MMP-2, MMP-9, N-cadherin and vimentin, whereas up-regulating E-cadherin expression. Notably, metapristone exhibited anti-metastatic activity in melanoma B16F10 cells in vivo. Our results reveal metapristone, having the dual function of anti-proliferation and anti-migration for melanoma cell lines, may be a useful chemopreventive agent to reduce the risk of melanoma cancer metastasis.

  3. Development of a highly metastatic model that reveals a crucial role of fibronectin in lung cancer cell migration and invasion

    PubMed Central

    2010-01-01

    Background The formation of metastasis is the most common cause of death in patients with lung cancer. A major implement to understand the molecular mechanisms involved in lung cancer metastasis has been the lack of suitable models to address it. In this study, we aimed at establishing a highly metastatic model of human lung cancer and characterizing its metastatic properties and underlying mechanisms. Methods The human lung adeno-carcinoma SPC-A-1 cell line was used as parental cells for developing of highly metastatic cells by in vivo selection in NOD/SCID mice. After three rounds of selection, a new SPC-A-1sci cell line was established from pulmonary metastatic lesions. Subsequently, the metastatic properties of this cell line were analyzed, including optical imaging of in vivo metastasis, immunofluorescence and immunohistochemical analysis of several epithelial mesenchymal transition (EMT) makers and trans-well migration and invasion assays. Finally, the functional roles of fibronectin in the invasive and metastatic potentials of SPC-A-1sci cells were determined by shRNA analysis. Results A spontaneously pulmonary metastatic model of human lung adeno-carcinoma was established in NOD/SCID mice, from which a new lung cancer cell line, designated SPC-A-1sci, was isolated. Initially, the highly metastatic behavior of this cell line was validated by optical imaging in mice models. Further analyses showed that this cell line exhibit phenotypic and molecular alterations consistent with EMT. Compared with its parent cell line SPC-A-1, SPC-A-1sci was more aggressive in vitro, including increased potentials for cell spreading, migration and invasion. Importantly, fibronectin, a mesenchymal maker of EMT, was found to be highly expressed in SPC-A-1sci cells and down-regulation of it can decrease the in vitro and in vivo metastatic abilities of this cell line. Conclusions We have successfully established a new human lung cancer cell line with highly metastatic potentials

  4. Stem cell-like transcriptional reprogramming mediates metastatic resistance to mTOR inhibition

    PubMed Central

    Mateo, F; Arenas, E J; Aguilar, H; Serra-Musach, J; de Garibay, G Ruiz; Boni, J; Maicas, M; Du, S; Iorio, F; Herranz-Ors, C; Islam, A; Prado, X; Llorente, A; Petit, A; Vidal, A; Català, I; Soler, T; Venturas, G; Rojo-Sebastian, A; Serra, H; Cuadras, D; Blanco, I; Lozano, J; Canals, F; Sieuwerts, A M; de Weerd, V; Look, M P; Puertas, S; García, N; Perkins, A S; Bonifaci, N; Skowron, M; Gómez-Baldó, L; Hernández, V; Martínez-Aranda, A; Martínez-Iniesta, M; Serrat, X; Cerón, J; Brunet, J; Barretina, M P; Gil, M; Falo, C; Fernández, A; Morilla, I; Pernas, S; Plà, M J; Andreu, X; Seguí, M A; Ballester, R; Castellà, E; Nellist, M; Morales, S; Valls, J; Velasco, A; Matias-Guiu, X; Figueras, A; Sánchez-Mut, J V; Sánchez-Céspedes, M; Cordero, A; Gómez-Miragaya, J; Palomero, L; Gómez, A; Gajewski, T F; Cohen, E E W; Jesiotr, M; Bodnar, L; Quintela-Fandino, M; López-Bigas, N; Valdés-Mas, R; Puente, X S; Viñals, F; Casanovas, O; Graupera, M; Hernández-Losa, J; Ramón y Cajal, S; García-Alonso, L; Saez-Rodriguez, J; Esteller, M; Sierra, A; Martín-Martín, N; Matheu, A; Carracedo, A; González-Suárez, E; Nanjundan, M; Cortés, J; Lázaro, C; Odero, M D; Martens, J W M; Moreno-Bueno, G; Barcellos-Hoff, M H; Villanueva, A; Gomis, R R; Pujana, M A

    2017-01-01

    Inhibitors of the mechanistic target of rapamycin (mTOR) are currently used to treat advanced metastatic breast cancer. However, whether an aggressive phenotype is sustained through adaptation or resistance to mTOR inhibition remains unknown. Here, complementary studies in human tumors, cancer models and cell lines reveal transcriptional reprogramming that supports metastasis in response to mTOR inhibition. This cancer feature is driven by EVI1 and SOX9. EVI1 functionally cooperates with and positively regulates SOX9, and promotes the transcriptional upregulation of key mTOR pathway components (REHB and RAPTOR) and of lung metastasis mediators (FSCN1 and SPARC). The expression of EVI1 and SOX9 is associated with stem cell-like and metastasis signatures, and their depletion impairs the metastatic potential of breast cancer cells. These results establish the mechanistic link between resistance to mTOR inhibition and cancer metastatic potential, thus enhancing our understanding of mTOR targeting failure. PMID:27991928

  5. Tumor Mutational Load and Immune Parameters across Metastatic Renal Cell Carcinoma Risk Groups.

    PubMed

    de Velasco, Guillermo; Miao, Diana; Voss, Martin H; Hakimi, A Ari; Hsieh, James J; Tannir, Nizar M; Tamboli, Pheroze; Appleman, Leonard J; Rathmell, W Kimryn; Van Allen, Eliezer M; Choueiri, Toni K

    2016-10-01

    Patients with metastatic renal cell carcinoma (mRCC) have better overall survival when treated with nivolumab, a cancer immunotherapy that targets the immune checkpoint inhibitor programmed cell death 1 (PD-1), rather than everolimus (a chemical inhibitor of mTOR and immunosuppressant). Poor-risk mRCC patients treated with nivolumab seemed to experience the greatest overall survival benefit, compared with patients with favorable or intermediate risk, in an analysis of the CheckMate-025 trial subgroup of the Memorial Sloan Kettering Cancer Center (MSKCC) prognostic risk groups. Here, we explore whether tumor mutational load and RNA expression of specific immune parameters could be segregated by prognostic MSKCC risk strata and explain the survival seen in the poor-risk group. We queried whole-exome transcriptome data in renal cell carcinoma patients (n = 54) included in The Cancer Genome Atlas who ultimately developed metastatic disease or were diagnosed with metastatic disease at presentation and did not receive immune checkpoint inhibitors. Nonsynonymous mutational load did not differ significantly by the MSKCC risk group, nor was the expression of cytolytic genes-granzyme A and perforin-or selected immune checkpoint molecules different across MSKCC risk groups. In conclusion, this analysis revealed that mutational load and expression of markers of an active tumor microenvironment did not correlate with MSKCC risk prognostic classification in mRCC. Cancer Immunol Res; 4(10); 820-2. ©2016 AACR.

  6. Activity of outpatient intravenous interleukin-2 and famotidine in metastatic clear cell kidney cancer.

    PubMed

    Quan, Walter D Y; Quan, Francine Marie

    2014-03-01

    Outpatient daily intravenous infusions of interleukin-2 (IL-2) have been developed to maintain anticancer activity and decrease toxicity of this agent against kidney cancer. Lymphokine activated killer cell (LAK) numbers are increased with these IL-2 schedules. Famotidine may enhance the LAK activity by increasing IL-2 internalization by the IL-2 receptor on lymphocytes. Fifteen patients with metastatic clear cell kidney cancer received IL-2 18 million IU/M² intravenously over 15-30 minutes preceded by famotidine 20 mg IV daily for 3 days for 6 consecutive weeks as outpatients. Cycles were repeated every 8 weeks. Patient characteristics were seven males/eight females, median age 59 (range: 28-70), median Eastern Cooperative Oncology Group (ECOG) performance status-1; common metastatic sites were lungs (14), lymph nodes (9), liver (4), bone (4), and pancreas (4). Prior systemic therapies were oral tyrosine kinase inhibitor (8), IL-2 (6), and mTor inhibitor (2). Most common toxicities were rigors, arthralgia/myalgia, nausea/emesis, fever, and hypotension. All episodes of hypotension were reversible with intravenous fluid. No patients required hospitalization due to toxicity. One complete response (7%) and four partial responses (26%) were seen (total response rate=33%; 95% confidence interval: 15%-59%). Responses occurred in the lungs, liver, lymph nodes, and bone. Outpatient intravenous IL-2 with famotidine has activity in metastatic clear cell kidney cancer.

  7. Elective neck management for squamous cell carcinoma metastatic to the parotid area lymph nodes.

    PubMed

    Herman, Michael P; Amdur, Robert J; Werning, John W; Dziegielewski, Peter; Morris, Christopher G; Mendenhall, William M

    2016-11-01

    The objective of this study is to determine if radiotherapy (RT) alone to the cervical lymphatics is a suitable alternative to elective neck dissection (END) in patients who undergo parotidectomy and postoperative RT for squamous cell carcinoma metastatic to the parotid area lymph nodes (PALN). We retrospectively reviewed the medical records of 107 patients consecutively treated from November 1969 to March 2012 for cutaneous squamous cell carcinoma metastatic to the PALN with a clinically node-negative neck. Primary therapy consisted of parotidectomy in all cases. We compared regional (cervical) control in two subgroups: 42 patients treated with END and RT and 65 patients treated with elective neck irradiation (ENI) alone. The median time of follow-up was 5.5 years (range 0.3-30 years) for all patients and 11 years for living patients (range 1.8-26 years). There was 1 neck recurrence in each subgroup: END and RT, 1/42 (2 %); and ENI alone, 1/65 (1.5 %). No patient experienced a complication related to neck RT. ENI to a dose of approximately 50-60 Gy is a suitable alternative to END and postoperative RT in patients with squamous cell carcinoma metastatic to the PALN.

  8. Stem cell-like transcriptional reprogramming mediates metastatic resistance to mTOR inhibition.

    PubMed

    Mateo, F; Arenas, E J; Aguilar, H; Serra-Musach, J; de Garibay, G Ruiz; Boni, J; Maicas, M; Du, S; Iorio, F; Herranz-Ors, C; Islam, A; Prado, X; Llorente, A; Petit, A; Vidal, A; Català, I; Soler, T; Venturas, G; Rojo-Sebastian, A; Serra, H; Cuadras, D; Blanco, I; Lozano, J; Canals, F; Sieuwerts, A M; de Weerd, V; Look, M P; Puertas, S; García, N; Perkins, A S; Bonifaci, N; Skowron, M; Gómez-Baldó, L; Hernández, V; Martínez-Aranda, A; Martínez-Iniesta, M; Serrat, X; Cerón, J; Brunet, J; Barretina, M P; Gil, M; Falo, C; Fernández, A; Morilla, I; Pernas, S; Plà, M J; Andreu, X; Seguí, M A; Ballester, R; Castellà, E; Nellist, M; Morales, S; Valls, J; Velasco, A; Matias-Guiu, X; Figueras, A; Sánchez-Mut, J V; Sánchez-Céspedes, M; Cordero, A; Gómez-Miragaya, J; Palomero, L; Gómez, A; Gajewski, T F; Cohen, E E W; Jesiotr, M; Bodnar, L; Quintela-Fandino, M; López-Bigas, N; Valdés-Mas, R; Puente, X S; Viñals, F; Casanovas, O; Graupera, M; Hernández-Losa, J; Ramón Y Cajal, S; García-Alonso, L; Saez-Rodriguez, J; Esteller, M; Sierra, A; Martín-Martín, N; Matheu, A; Carracedo, A; González-Suárez, E; Nanjundan, M; Cortés, J; Lázaro, C; Odero, M D; Martens, J W M; Moreno-Bueno, G; Barcellos-Hoff, M H; Villanueva, A; Gomis, R R; Pujana, M A

    2016-12-19

    Inhibitors of the mechanistic target of rapamycin (mTOR) are currently used to treat advanced metastatic breast cancer. However, whether an aggressive phenotype is sustained through adaptation or resistance to mTOR inhibition remains unknown. Here, complementary studies in human tumors, cancer models and cell lines reveal transcriptional reprogramming that supports metastasis in response to mTOR inhibition. This cancer feature is driven by EVI1 and SOX9. EVI1 functionally cooperates with and positively regulates SOX9, and promotes the transcriptional upregulation of key mTOR pathway components (REHB and RAPTOR) and of lung metastasis mediators (FSCN1 and SPARC). The expression of EVI1 and SOX9 is associated with stem cell-like and metastasis signatures, and their depletion impairs the metastatic potential of breast cancer cells. These results establish the mechanistic link between resistance to mTOR inhibition and cancer metastatic potential, thus enhancing our understanding of mTOR targeting failure.Oncogene advance online publication, 19 December 2016; doi:10.1038/onc.2016.427.

  9. Squamous cell carcinoma of cervix metastatic to ileal loop

    SciTech Connect

    Hulecki, S.J.; Klein, F.A.; Davis, J.E.

    1985-12-01

    A case is presented of squamous cell carcinoma of the cervix with an isolated metastasis to an ileal loop six years after diversion and seven years after definitive treatment of the primary lesion with irradiation.

  10. The Metastatic Potential and Chemoresistance of Human Pancreatic Cancer Stem Cells.

    PubMed

    Bhagwandin, Vikash J; Bishop, J Michael; Wright, Woodring E; Shay, Jerry W

    2016-01-01

    Cancer stem cells (CSCs) typically have the capacity to evade chemotherapy and may be the principal source of metastases. CSCs for human pancreatic ductal carcinoma (PDAC) have been identified, but neither the metastatic potential nor the chemoresistance of these cells has been adequately evaluated. We have addressed these issues by examining side-population (SP) cells isolated from the Panc-1 and BxPC3 lines of human PDAC cells, the oncogenotypes of which differ. SP cells could be isolated from monolayers of Panc-1, but only from spheroids of BxPC3. Using orthotopic xenografts into the severely immunocompromised NSG mouse, we found that SP cells isolated from both cell lines produced tumors that were highly metastatic, in contrast to previous experience with PDAC cell lines. SP cells derived from both cell lines expressed the ABCG2 transporter, which was demonstrably responsible for the SP phenotype. SP cells gave rise to non-SP (NSP) cells in vitro and in vivo, a transition that was apparently due to posttranslational inhibition of the ABCG2 transporter. Twenty-two other lines of PDAC cells also expressed ABCG2. The sensitivity of PDAC SP cells to the vinca alkaloid vincristine could be greatly increased by verapamil, a general inhibitor of transporters. In contrast, verapamil had no effect on the killing of PDAC cells by gemcitabine, the current first-line therapeutic for PDAC. We conclude that the isolation of SP cells can be a convenient and effective tool for the study of PDAC CSCs; that CSCs may be the principal progenitors of metastasis by human PDAC; that the ABCG2 transporter is responsible for the SP phenotype in human PDAC cells, and may be a ubiquitous source of drug-resistance in PDAC, but does not confer resistance to gemcitabine; and that inhibition of ABCG2 might offer a useful adjunct in a therapeutic attack on the CSCs of PDAC.

  11. The Metastatic Potential and Chemoresistance of Human Pancreatic Cancer Stem Cells

    PubMed Central

    Bhagwandin, Vikash J.; Bishop, J. Michael; Wright, Woodring E.; Shay, Jerry W.

    2016-01-01

    Cancer stem cells (CSCs) typically have the capacity to evade chemotherapy and may be the principal source of metastases. CSCs for human pancreatic ductal carcinoma (PDAC) have been identified, but neither the metastatic potential nor the chemoresistance of these cells has been adequately evaluated. We have addressed these issues by examining side-population (SP) cells isolated from the Panc-1 and BxPC3 lines of human PDAC cells, the oncogenotypes of which differ. SP cells could be isolated from monolayers of Panc-1, but only from spheroids of BxPC3. Using orthotopic xenografts into the severely immunocompromised NSG mouse, we found that SP cells isolated from both cell lines produced tumors that were highly metastatic, in contrast to previous experience with PDAC cell lines. SP cells derived from both cell lines expressed the ABCG2 transporter, which was demonstrably responsible for the SP phenotype. SP cells gave rise to non-SP (NSP) cells in vitro and in vivo, a transition that was apparently due to posttranslational inhibition of the ABCG2 transporter. Twenty-two other lines of PDAC cells also expressed ABCG2. The sensitivity of PDAC SP cells to the vinca alkaloid vincristine could be greatly increased by verapamil, a general inhibitor of transporters. In contrast, verapamil had no effect on the killing of PDAC cells by gemcitabine, the current first-line therapeutic for PDAC. We conclude that the isolation of SP cells can be a convenient and effective tool for the study of PDAC CSCs; that CSCs may be the principal progenitors of metastasis by human PDAC; that the ABCG2 transporter is responsible for the SP phenotype in human PDAC cells, and may be a ubiquitous source of drug-resistance in PDAC, but does not confer resistance to gemcitabine; and that inhibition of ABCG2 might offer a useful adjunct in a therapeutic attack on the CSCs of PDAC. PMID:26859746

  12. Impact of Hypoxia on the Metastatic Potential of Human Prostate Cancer Cells

    SciTech Connect

    Dai Yao; Bae, Kyungmi; Siemann, Dietmar W.

    2011-10-01

    Purpose: Intratumoral hypoxia is known to be associated with radioresistance and metastasis. The present study examined the effect of acute and chronic hypoxia on the metastatic potential of prostate cancer PC-3, DU145, and LNCaP cells. Methods and Materials: Cell proliferation and clonogenicity were tested by MTT assay and colony formation assay, respectively. 'Wound-healing' and Matrigel-based chamber assays were used to monitor cell motility and invasion. Hypoxia-inducible factor 1 alpha (HIF-1{alpha}) expression was tested by Western blot, and HIF-1-target gene expression was detected by real-time polymerase chain reaction. Secretion of matrix metalloproteinases (MMPs) was determined by gelatin zymography. Results: When PC-3 cells were exposed to 1% oxygen (hypoxia) for various periods of time, chronic hypoxia ({>=}24 h) decreased cell proliferation and induced cell death. In contrast, prostate cancer cells exposed to acute hypoxia ({<=}6 h) displayed increased motility, clonogenic survival, and invasive capacity. At the molecular level, both hypoxia and anoxia transiently stabilized HIF-1{alpha}. Exposure to hypoxia also induced the early expression of MMP-2, an invasiveness-related gene. Treatment with the HIF-1 inhibitor YC-1 attenuated the acute hypoxia-induced migration, invasion, and MMP-2 activity. Conclusions: The length of oxygen deprivation strongly affected the functional behavior of all three prostate cancer cell lines. Acute hypoxia in particular was found to promote a more aggressive metastatic phenotype.

  13. Implications of occult metastatic cells for systemic cancer treatment in patients with breast or gastrointestinal cancer.

    PubMed

    Braun, S; Rosenberg, R; Thorban, S; Harbeck, N

    2001-06-01

    The early and clinically occult spread of viable tumour cells to the organism is becoming acknowledged as a hallmark in cancer progression, since abundant clinical and experimental data suggest that these cells are precursors of subsequent distant relapse. Using monoclonal antibodies against epithelial cytokeratins or tumour-associated cell membrane glycoproteins, individual carcinoma cells can be detected in cytological bone marrow preparations at frequencies of 10(-5) to 10(-6). Prospective clinical studies have shown that the presence of such immunostained cells in bone marrow is prognostically relevant with regard to relapse-free and overall survival, even in malignancies that do not preferentially metastasise to bone. As current treatment strategies have resulted in a substantial improvement of cancer mortality rates, it is noteworthy to consider the intriguing options of immunocytochemical screening of bone marrow aspirates for occult metastatic cells. Besides improved tumour staging, such screening offers opportunities for guiding patient stratification for adjuvant therapy trials, monitoring response to adjuvant therapies (which, at present, can only be assessed retrospectively after an extended period of clinical follow-up), and specifically targeting tumour-biological therapies against disseminated tumour cells. The present review summarises the current data on the clinical significance of occult metastatic cancer cells in bone marrow.

  14. Cofilin drives cell-invasive and metastatic responses to TGF-β in prostate cancer.

    PubMed

    Collazo, Joanne; Zhu, Beibei; Larkin, Spencer; Martin, Sarah K; Pu, Hong; Horbinski, Craig; Koochekpour, Shahriar; Kyprianou, Natasha

    2014-04-15

    Cofilin (CFL) is an F-actin-severing protein required for the cytoskeleton reorganization and filopodia formation, which drives cell migration. CFL binding and severing of F-actin is controlled by Ser3 phosphorylation, but the contributions of this step to cell migration during invasion and metastasis of cancer cells are unclear. In this study, we addressed the question in prostate cancer cells, including the response to TGF-β, a critical regulator of migration. In cells expressing wild-type CFL, TGF-β treatment increased LIMK-2 activity and cofilin phosphorylation, decreasing filopodia formation. Conversely, constitutively active CFL (SerAla) promoted filipodia formation and cell migration mediated by TGF-β. Notably, in cocultures of prostate cancer epithelial cells and cancer-associated fibroblasts, active CFL promoted invasive migration in response to TGF-β in the microenvironment. Further, constitutively active CFL elevated the metastatic ability of prostate cancer cells in vivo. We found that levels of active CFL correlated with metastasis in a mouse model of prostate tumor and that in human prostate cancer, CFL expression was increased significantly in metastatic tumors. Our findings show that the actin-severing protein CFL coordinates responses to TGF-β that are needed for invasive cancer migration and metastasis.

  15. Anti-metastatic effect of Smilax china L. extract on MDA-MB-231 cells.

    PubMed

    Nho, Kyoung Jin; Chun, Jin Mi; Kim, Ho Kyoung

    2015-01-01

    Cancer metastases are not always cured by chemotherapy. Conventional and alternative drugs, including Chinese herbal remedies, have been developed to target metastatic cancer cells. Smilax china L. (SCL), a member of the Smilacaceae family, exerts anti-inflammatory, detoxification and anti-cancer effects. However, the effect of SCL on breast cancer cell metastasis and the underlying mechanisms are yet to be elucidated. The aim of this study was to investigate the effect of a SCL ethanol extract (SCLE) on the proliferation and migration of MDA-MB-231 human breast cancer cells, as well as the expression of urokinase plasminogen activator (uPA), uPA receptor (uPAR) and tissue inhibitors of metalloproteinases (TIMPs). Cell proliferation was assessed using the Cell Counting Kit‑8 and cell migration was determined by wound healing assay. Quantitative polymerase chain reaction was performed to quantify the mRNA levels of uPA, uPAR and TIMPs. SCLE markedly inhibited the proliferation and migration of MDA-MB-231 cells, and reduced the mRNA levels of the extracellular matrix (ECM) degradation-associated molecules uPA, uPAR. By contrast, SCLE significantly increased the mRNA levels of TIMP1 and TIMP2. These findings show that SCLE exerts an anti-metastatic effect on human breast cancer cells, which may involve the modulation of ECM degradation.

  16. PAX-2 is a helpful marker for diagnosing metastatic renal cell carcinoma: comparison with the renal cell carcinoma marker antigen and kidney-specific cadherin.

    PubMed

    Ozcan, Ayhan; Zhai, Qihui; Javed, Rehana; Shen, Steven S; Coffey, Donna; Krishnan, Bhuvaneswari; Truong, Luan D

    2010-08-01

    The diagnosis of metastatic renal cell carcinoma (RCC) remains problematic. To evaluate the role of PAX-2, a renal tubular cell transcription factor, in the diagnosis of metastatic RCC. PAX-2 expression in metastatic RCC was compared with that of the renal cell carcinoma marker antigen (RCCM) and kidney-specific cadherin (KSC), which are 2 known markers for RCC. Immunostaining for PAX-2, RCCM, and KSC was performed on consecutive tissue sections of 95 metastatic RCCs (77 clear cell, 8 papillary, 5 sarcomatoid, and 5 collecting duct) and 183 metastatic tumors other than RCC. For PAX-2, positive immunoreactivity was detected in 77% clear cell, 75% papillary, 100% collecting duct, and 0% sarcomatoid metastatic RCCs. For RCCM, positive immunoreactivity was detected in 49% clear cell, 75% papillary, 0% collecting duct, and 0% sarcomatoid metastatic RCCs. For KSC, only 2 metastatic clear cell RCCs (3%) were positive. In combination, all markers were positive in 0% of cases; all markers were negative in 23% of cases (17 clear cell, 1 papillary, and for all 5 sarcomatoid); and at least 1 marker was positive in 76% of cases (PAX-2 only in 28% of cases [21 clear cell, 1 papillary, and 5 collecting duct] and RCCM only in 3% of cases [2 clear, 1 papillary]). Of 183 metastatic tumors other than RCC, 14 were positive for PAX-2 (nodal metastasis of carcinoma of colon [1], breast [1], endometrium [1], and ovary [1]; and omental metastasis of carcinoma of uterus or ovary [10]). PAX-2 is a sensitive and specific marker for metastatic RCC. The diagnostic yield would be marginally increased by adding RCCM, but not KSC, as an immunomarker.

  17. The in vitro invasiveness and interactions with laminin of K-1735 melanoma cells. Evidence for different laminin-binding affinities in high and low metastatic variants.

    PubMed

    Albini, A; Aukerman, S L; Ogle, R C; Noonan, D M; Fridman, R; Martin, G R; Fidler, I J

    1989-01-01

    The invasive and metastatic characteristics of cloned cells derived from the K-1735 murine melanoma were investigated. Cell lines which are highly metastatic in mice were found to be invasive in vitro, and to show an enhanced attachment to, spreading on and migration toward laminin. As attachment, spreading and directional migration are thought to be receptor-mediated events, the binding of laminin to these cells was studied. Biotinylated laminin was used to evaluate receptor binding by fluorescence activated cell sorting (FACS) and this method was compared with that in which the binding of radioactive laminin is measured. Both studies revealed that metastatic K-1735 cells (a) have more receptors for laminin compared with non-metastatic cells and (b) exhibit a second population of low-affinity binding sites not present on the non-metastatic cells. The differences in receptor number and type may account for the greater interaction of metastatic cells with laminin and their invasive phenotype.

  18. Hypoxia-induced lysyl oxidase is a critical mediator of bone marrow cell recruitment to form the pre-metastatic niche

    PubMed Central

    Erler, Janine T.; Bennewith, Kevin L.; Cox, Thomas R.; Lang, Georgina; Bird, Demelza; Koong, Albert; Le, Quynh-Thu; Giaccia, Amato J.

    2010-01-01

    Summary Tumor cell metastasis is facilitated by “pre-metastatic niches” formed in destination organs by invading bone marrow-derived cells (BMDCs). Lysyl oxidase (LOX) is critical for pre-metastatic niche formation. LOX secreted by hypoxic breast tumor cells accumulates at pre-metastatic sites, cross-links collagen-IV in the basement membrane, and is essential for CD11b+ myeloid cell recruitment. CD11b+ cells adhere to cross-linked collagen-IV and produce matrix metalloproteinase-2 which cleaves collagen, enhancing the invasion and recruitment of BMDCs and metastasizing tumor cells. LOX inhibition prevents CD11b+ cell recruitment and metastatic growth. CD11b+ cells and LOX also co-localize in biopsies of human metastases. Our findings demonstrate a critical role for LOX in pre-metastatic niche formation and support targeting LOX for the treatment and prevention of metastatic disease. PMID:19111879

  19. A logistic model for the detection of circulating tumour cells in human metastatic colorectal cancer

    PubMed Central

    Barbazán, Jorge; Vieito, María; Abalo, Alicia; Alonso-Alconada, Lorena; Muinelo-Romay, Laura; Alonso-Nocelo, Marta; León, Luís; Candamio, Sonia; Gallardo, Elena; Anido, Urbano; Doll, Andreas; los Ángeles Casares, María; Gómez-Tato, Antonio; Abal, Miguel; López-López, Rafael

    2012-01-01

    The accuracy in the diagnosis of metastatic colorectal cancer (mCRC) represents one of the challenges in the clinical management of patients. The detection of circulating tumour cells (CTC) is becoming a promising alternative to current detection techniques, as it focuses on one of the players of the metastatic disease and it should provide with more specific and sensitive detection rates. Here, we describe an improved method of detection of CTC from mCRC patients by combining immune-enrichment, optimal purification of RNA from very low cell numbers, and the selection of accurate PCR probes. As a result, we obtained a logistic model that combines GAPDH and VIL1 normalized to CD45 rendering powerful results in the detection of CTC from mCRC patients (AUROC value 0.8599). We further demonstrated the utility of this model at the clinical setting, as a reliable prognosis tool to determine progression-free survival in mCRC patients. Overall, we developed a strategy that ameliorates the specificity and sensitivity in the detection of CTC, resulting in a robust and promising logistic model for the clinical management of metastatic colorectal cancer patients. PMID:22304365

  20. Signet ring cell carcinoma of resectable metastatic colorectal cancer has rare surgical value.

    PubMed

    Fu, Jianfei; Wu, Lunpo; Jiang, Mengjie; Tan, Yinuo; Li, Dan; Chen, Fei; Jiang, Ting; Du, Jinlin

    2016-12-01

    Signet ring cell carcinoma (SRCC) is a uniquely separated subgroup in metastatic colorectal cancer (mCRC). The aims are to investigate the value of resection in patients with resectable metastatic signet ring cell colorectal cancer. Patients with mCRC who underwent resection in Surveillance, Epidemiology, and End Results database during 1998-2010 were retrospectively analyzed. Kaplan-Meier and COX models were used to analyze the differences in the survival. Logistic regression models were used to evaluate the relationship between SRCC and other clinicopathological factors. Among the 3,568 patients, 94 (2.63%) patients had SRCC. The median survival time of patients with SRCC and non-SRCC were 17 and 29 months, respectively (P < 0.001). Multivariate analysis indicated that SRCC was an independent prognostic factor for poor overall survival. Logistic regression model based on variables identified by univariate analysis indicated that younger age (≤50 years old) (P = 0.005), female (P < 0.001), location in colon (P = 0.012), and N positive status (P = 0.003) were independent variables correlated with the SRCC subgroup. SRCC had a dramatically higher invalid surgical outcome rate than non-SRCC (P = 0.001). SRCC patients might benefit little from the resection of primary and metastatic lesions with a high rate of undergoing invalid operations. J. Surg. Oncol. 2016;114:1004-1008. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  1. Metastatic transitional cell carcinoma in proximal humerus of a dog

    PubMed Central

    Malek, Sarah; Murphy, Kimberly A.; Nykamp, Stephanie G.; Allavena, Rachel

    2011-01-01

    Transitional cell carcinoma (TCC) was diagnosed in the proximal humerus of a dog that was presented with persistent right forelimb lameness with no clinical signs of urinary tract involvement. A diagnosis of TCC was made from surgical biopsy of the humeral lesion with subsequent necropsy revealing the prostatic urethra as the primary site of the tumor. PMID:22379204

  2. [Successful therapy of metastatic basal cell carcinoma with vismodegib].

    PubMed

    Zutt, M; Mazur, F; Bergmann, M; Lemke, A J; Kaune, K M

    2014-11-01

    A 71-year-old man presented with giant basal cell carcinoma on the abdomen which had metastasized. He was treated with oral vismodegib. Both the primary ulcerated tumor on the abdomen and the metastases responded. Vismodegib was well tolerated without significant side effects. The tumor recurred promptly after vismodegib was discontinued, and then was resistant to therapy when vismodegib was re-administered.

  3. Diagnosis of metastatic renal cell carcinoma on fine-needle aspiration cytology.

    PubMed

    Lew, Madelyn; Foo, Wen-Chi; Roh, Michael H

    2014-10-01

    Fine-needle aspiration has assumed an increasingly important role in the diagnosis and management of patients with advanced stage cancer. Given its predilection for metastases to distant sites and organs at the time of presentation, metastatic renal cell carcinoma (RCC) is not infrequently encountered in the setting of fine-needle aspiration for initial diagnosis. In some instances, fine-needle aspiration may be the only opportunity to obtain diagnostic tissue to diagnose and subclassify RCC. Therefore, cytopathologists and cytotechnologists should be familiar with and recognize the cytomorphology of RCC and the ancillary studies that can be used to confirm and subclassify RCC. Herein, we describe a case of metastatic RCC initially diagnosed on fine-needle aspiration, discuss the cytomorphologic features of RCC subtypes, and review pertinent ancillary immunohistochemical and cytogenetic adjuncts.

  4. Targeted therapies used sequentially in metastatic renal cell cancer: overall results from a large experience.

    PubMed

    Procopio, Giuseppe; Verzoni, Elena; Iacovelli, Roberto; Guadalupi, Valentina; Gelsomino, Francesco; Buzzoni, Roberto

    2011-11-01

    Targeted therapies have improved survival in patients with metastatic renal cell cancer (RCC); however, expert opinion on the optimal therapeutic strategy is divided. This retrospective study evaluates different sequential schemes of targeted therapies in 310 patients with advanced/metastatic RCC who received different systemic agents - sorafenib, sunitinib, bevacizumab, everolimus, temsirolimus and axitinib - alone or in different sequences, until disease progression or intolerable toxicity (median follow-up: 37 months). The median overall survival (OS) was 22 months and the 5-year OS was 23.4%; differential therapeutic schemes were not associated with differences in OS. A worse performance status, no nephrectomy and a poor-risk classification according to the Motzer criteria was associated with a shorter OS. These findings support the use of targeted therapies in the treatment of RCC, even in a large unselected population from a single institution, and suggest that treatment should be tailored to meet individual circumstances and needs.

  5. Passive Entrapment of Tumor Cells Determines Metastatic Dissemination to Spinal Bone and Other Osseous Tissues.

    PubMed

    Broggini, Thomas; Piffko, Andras; Hoffmann, Christian J; Harms, Christoph; Vajkoczy, Peter; Czabanka, Marcus

    2016-01-01

    During the metastatic process tumor cells circulate in the blood stream and are carried to various organs. In order to spread to different organs tumor cell-endothelial cell interactions are crucial for extravasation mechanisms. It remains unclear if tumor cell dissemination to the spinal bone occurs by passive entrapment of circulating tumor cells or by active cellular mechanisms mediated by cell surface molecules or secreted factors. We investigated the seeding of three different tumor cell lines (melanoma, lung and prostate carcinoma) to the microvasculature of different organs. Their dissemination was compared to biologically passive microbeads. The spine and other organs were resected three hours after intraarterial injection of tumor cells or microbeads. Ex vivo homogenization and fluorescence analysis allowed quantification of tumor cells or microbeads in different organs. Interestingly, tumor cell distribution to the spinal bone was comparable to dissemination of microbeads independent of the tumor cell type (melanoma: 5.646% ± 7.614%, lung: 6.007% ± 1.785%, prostate: 3.469% ± 0.602%, 7 μm beads: 9.884% ± 7.379%, 16 μm beads: 7.23% ± 1.488%). Tumor cell seeding differed significantly between tumor cells and microbeads in all soft tissue organs. Moreover, there were significant differences between the different tumor cell lines in their dissemination behaviour to soft tissue organs only. These findings demonstrate that metastatic dissemination of tumor cells to spinal bone and other osseous organs is mediated by passive entrapment of tumor cells similar to passive plugging of microvasculature observed after intraarterial microbeads injection.

  6. Matrix Metalloproteinase-10 Is Required for Lung Cancer Stem Cell Maintenance, Tumor Initiation and Metastatic Potential

    PubMed Central

    Tseng, I-Chu; Walsh, Michael P.; Batra, Jyotica; Radisky, Evette S.; Murray, Nicole R.; Fields, Alan P.

    2012-01-01

    Matrix metalloproteinases (Mmps) stimulate tumor invasion and metastasis by degrading the extracellular matrix. Here we reveal an unexpected role for Mmp10 (stromelysin 2) in the maintenance and tumorigenicity of mouse lung cancer stem-like cells (CSC). Mmp10 is highly expressed in oncosphere cultures enriched in CSCs and RNAi-mediated knockdown of Mmp10 leads to a loss of stem cell marker gene expression and inhibition of oncosphere growth, clonal expansion, and transformed growth in vitro. Interestingly, clonal expansion of Mmp10 deficient oncospheres can be restored by addition of exogenous Mmp10 protein to the culture medium, demonstrating a direct role for Mmp10 in the proliferation of these cells. Oncospheres exhibit enhanced tumor-initiating and metastatic activity when injected orthotopically into syngeneic mice, whereas Mmp10-deficient cultures show a severe defect in tumor initiation. Conversely, oncospheres implanted into syngeneic non-transgenic or Mmp10−/− mice show no significant difference in tumor initiation, growth or metastasis, demonstrating the importance of Mmp10 produced by cancer cells rather than the tumor microenvironment in lung tumor initiation and maintenance. Analysis of gene expression data from human cancers reveals a strong positive correlation between tumor Mmp10 expression and metastatic behavior in many human tumor types. Thus, Mmp10 is required for maintenance of a highly tumorigenic, cancer-initiating, metastatic stem-like cell population in lung cancer. Our data demonstrate for the first time that Mmp10 is a critical lung cancer stem cell gene and novel therapeutic target for lung cancer stem cells. PMID:22545096

  7. Epigenetic impacts of ascorbate on human metastatic melanoma cells.

    PubMed

    Venturelli, Sascha; Sinnberg, Tobias W; Berger, Alexander; Noor, Seema; Levesque, Mitchell Paul; Böcker, Alexander; Niessner, Heike; Lauer, Ulrich M; Bitzer, Michael; Garbe, Claus; Busch, Christian

    2014-01-01

    In recent years, increasing evidence has emerged demonstrating that high-dose ascorbate bears cytotoxic effects on cancer cells in vitro and in vivo, making ascorbate a pro-oxidative drug that catalyzes hydrogen peroxide production in tissues instead of acting as a radical scavenger. This anticancer effect of ascorbate is hypoxia-inducible factor-1α- and O2-dependent. However, whether the intracellular mechanisms governing this effect are modulated by epigenetic phenomena remains unknown. We treated human melanoma cells with physiological (200 μM) or pharmacological (8 mM) ascorbate for 1 h to record the impact on DNA methyltransferase (DNMT)-activity, histone deacetylases (HDACs), and microRNA (miRNA) expression after 12 h. The results were analyzed with the MIRUMIR online tool that estimates the power of miRNA to serve as potential biomarkers to predict survival of cancer patients. FACS cell-cycle analyses showed that 8 mM ascorbate shifted BLM melanoma cells toward the sub-G1 fraction starting at 12 h after an initial primary G2/M arrest, indicative for secondary apoptosis induction. In pharmacological doses, ascorbate inhibited the DNMT activity in nuclear extracts of MeWo and BLM melanoma cells, but did not inhibit human HDAC enzymes of classes I, II, and IV. The expression of 151 miRNAs was altered 12 h after ascorbate treatment of BLM cells in physiological or pharmacological doses. Pharmacological doses up-regulated 32 miRNAs (≥4-fold) mainly involved in tumor suppression and drug resistance in our preliminary miRNA screening array. The most prominently up-regulated miRNAs correlated with a significantly increased overall survival of breast cancer or nasopharyngeal carcinoma patients of the MIRUMIR database with high expression of the respective miRNA. Our results suggest a possible epigenetic signature of pharmacological doses of ascorbate in human melanoma cells and support further pre-clinical and possibly even clinical evaluation of

  8. Lymphangioleiomyomatosis Biomarkers Linked to Lung Metastatic Potential and Cell Stemness

    PubMed Central

    Ruiz de Garibay, Gorka; Herranz, Carmen; Llorente, Alicia; Boni, Jacopo; Serra-Musach, Jordi; Mateo, Francesca; Aguilar, Helena; Gómez-Baldó, Laia; Petit, Anna; Vidal, August; Climent, Fina; Hernández-Losa, Javier; Cordero, Álex; González-Suárez, Eva; Sánchez-Mut, José Vicente; Esteller, Manel; Llatjós, Roger; Varela, Mar; López, José Ignacio; García, Nadia; Extremera, Ana I.; Gumà, Anna; Ortega, Raúl; Plà, María Jesús; Fernández, Adela; Pernas, Sònia; Falo, Catalina; Morilla, Idoia; Campos, Miriam; Gil, Miguel; Román, Antonio; Molina-Molina, María; Ussetti, Piedad; Laporta, Rosalía; Valenzuela, Claudia; Ancochea, Julio; Xaubet, Antoni; Casanova, Álvaro; Pujana, Miguel Angel

    2015-01-01

    Lymphangioleiomyomatosis (LAM) is a rare lung-metastasizing neoplasm caused by the proliferation of smooth muscle-like cells that commonly carry loss-of-function mutations in either the tuberous sclerosis complex 1 or 2 (TSC1 or TSC2) genes. While allosteric inhibition of the mechanistic target of rapamycin (mTOR) has shown substantial clinical benefit, complementary therapies are required to improve response and/or to treat specific patients. However, there is a lack of LAM biomarkers that could potentially be used to monitor the disease and to develop other targeted therapies. We hypothesized that the mediators of cancer metastasis to lung, particularly in breast cancer, also play a relevant role in LAM. Analyses across independent breast cancer datasets revealed associations between low TSC1/2 expression, altered mTOR complex 1 (mTORC1) pathway signaling, and metastasis to lung. Subsequently, immunohistochemical analyses of 23 LAM lesions revealed positivity in all cases for the lung metastasis mediators fascin 1 (FSCN1) and inhibitor of DNA binding 1 (ID1). Moreover, assessment of breast cancer stem or luminal progenitor cell biomarkers showed positivity in most LAM tissue for the aldehyde dehydrogenase 1 (ALDH1), integrin-ß3 (ITGB3/CD61), and/or the sex-determining region Y-box 9 (SOX9) proteins. The immunohistochemical analyses also provided evidence of heterogeneity between and within LAM cases. The analysis of Tsc2-deficient cells revealed relative over-expression of FSCN1 and ID1; however, Tsc2-deficient cells did not show higher sensitivity to ID1-based cancer inhibitors. Collectively, the results of this study reveal novel LAM biomarkers linked to breast cancer metastasis to lung and to cell stemness, which in turn might guide the assessment of additional or complementary therapeutic opportunities for LAM. PMID:26167915

  9. Apoptotic circulating tumor cells in early and metastatic breast cancer patients.

    PubMed

    Kallergi, Galatea; Konstantinidis, Georgios; Markomanolaki, Harris; Papadaki, Maria A; Mavroudis, Dimitris; Stournaras, Christos; Georgoulias, Vassilis; Agelaki, Sofia

    2013-09-01

    The detection of circulating tumor cells (CTC) in breast cancer is strongly associated with disease relapse. Since it is unclear whether all CTCs are capable of generating metastasis, we investigated their apoptotic and proliferative status in 56 CTC-positive (29 early and 27 metastatic) patients with breast cancer. Double-staining immunofluorescence experiments were carried out in peripheral blood mononuclear cells (PBMC) cytospins, using the pancytokeratin A45-B/B3 antibody and either M30 (apoptotic marker) or Ki67 (proliferation marker) antibodies. Apoptosis was also evaluated using a polycaspase detection kit. Patients with metastatic disease had significantly lower numbers of apoptotic CTCs compared with patients with early breast cancer (polycaspase kit: 8.1% vs. 47.4% of the total CTC number; P = 0.0001; M30-antibody: 32.1% vs. 76.63%; P = 0.002). The median percentage of apoptotic CTCs per patient was also lower in patients with advanced compared with those with early disease (polycaspase kit: 0% vs. 53.6%; M30-antibody: 15% vs. 80%). Ki67-positive CTCs were identified in 51.7% and 44% of patients with early and metastatic disease, respectively. Adjuvant chemotherapy reduced both the number of CTCs per patient and the number of proliferating CTCs (63.9% vs. 30%). In conclusion, apoptotic CTCs could be detected in patients with breast cancer irrespective of their clinical status, though the incidence of detection is higher in early compared with metastatic patients. The detection of CTCs that survive despite adjuvant therapy implies that CTC elimination should be attempted using agents targeting their distinctive molecular characteristics.

  10. Emergence of chemoresistance in a metastatic basal cell carcinoma patient after complete response to hedgehog pathway inhibitor vismodegib (GDC-0449).

    PubMed

    Meani, Rowena E; Lim, Shueh-Wen; Chang, Anne Lynn S; Kelly, John W

    2014-08-01

    Vismodegib (GDC-0449, Genentech, USA), a small molecule inhibitor of the Hedgehog signalling pathway, has potent anti-tumour activity in advanced basal cell carcinoma (BCC). We report a case of a 67-year-old Australian man with metastatic BCC including pulmonary disease with malignant effusion who showed a dramatic complete response to vismodegib but subsequently experienced a recurrence of pulmonary disease, indicative of chemoresistance to vismodegib. This case is the first to illustrate chemoresistance in a patient with metastatic BCC, and demonstrates the need for closely monitoring metastatic BCC patients even after an apparently complete response.

  11. Spontaneous dormancy of metastatic breast cancer cells in an all human liver microphysiologic system.

    PubMed

    Wheeler, S E; Clark, A M; Taylor, D P; Young, C L; Pillai, V C; Stolz, D B; Venkataramanan, R; Lauffenburger, D; Griffith, L; Wells, A

    2014-12-09

    Metastatic outgrowth in breast cancer can occur years after a seeming cure. Existing model systems of dormancy are limited as they do not recapitulate human metastatic dormancy without exogenous manipulations and are unable to query early events of micrometastases. Here, we describe a human ex vivo hepatic microphysiologic system. The system is established with fresh human hepatocytes and non-parenchymal cells (NPCs) creating a microenvironment into which breast cancer cells (MCF7 and MDA-MB-231) are added. The hepatic tissue maintains function through 15 days as verified by liver-specific protein production and drug metabolism assays. The NPCs form an integral part of the hepatic niche, demonstrated within the system through their participation in differential signalling cascades and cancer cell outcomes. Breast cancer cells intercalate into the hepatic niche without interfering with hepatocyte function. Examination of cancer cells demonstrated that a significant subset enter a quiescent state of dormancy as shown by lack of cell cycling (EdU(-) or Ki67(-)). The presence of NPCs altered the cancer cell fraction entering quiescence, and lead to differential cytokine profiles in the microenvironment effluent. These findings establish the liver microphysiologic system as a relevant model for the study of breast cancer metastases and entry into dormancy.

  12. Molecular features of a human rhabdomyosarcoma cell line with spontaneous metastatic progression

    PubMed Central

    Scholl, F A; Betts, D R; Niggli, F K; Schäfer, B W

    2000-01-01

    A novel human cell line was established from a primary botryoid rhabdomyosarcoma. Reverse transcription polymerase chain reaction investigations of this cell line, called RUCH-2, demonstrated expression of the regulatory factors PAX3, Myf3 and Myf5. After 3.5 months in culture, cells underwent a crisis after which Myf3 and Myf5 could no longer be detected, whereas PAX3 expression remained constant over the entire period. Karyotype analysis revealed breakpoints in regions similar to previously described alterations in primary rhabdomyosarcoma tumour samples. Interestingly, cells progressed to a metastatic phenotype, as observed by enhanced invasiveness in vitro and tumour growth in nude mice in vivo. On the molecular level, microarray analysis before and after progression identified extensive changes in the composition of the extracellular matrix. As expected, down-regulation of tissue inhibitors of metalloproteinases and up-regulation of matrix metalloproteinases were observed. Extensive down-regulation of several death receptors of the tumour necrosis factor family suggests that these cells might have an altered response to appropriate apoptotic stimuli. The RUCH-2 cell line represents a cellular model to study multistep tumorigenesis in human rhabdomyosarcoma, allowing molecular comparison of tumorigenic versus metastatic cancer cells. © 2000 Cancer Research Campaign PMID:10735512

  13. Identification of a Human Airway Epithelial Cell Subpopulation with Altered Biophysical, Molecular, and Metastatic Properties.

    PubMed

    Pagano, Paul C; Tran, Linh M; Bendris, Nawal; O'Byrne, Sean; Tse, Henry T; Sharma, Shivani; Hoech, Jonathan W; Park, Stacy J; Liclican, Elvira L; Jing, Zhe; Li, Rui; Krysan, Kostyantyn; Paul, Manash K; Fontebasso, Yari; Larsen, Jill E; Hakimi, Shaina; Seki, Atsuko; Fishbein, Michael C; Gimzewski, James K; Carlo, Dino Di; Minna, John D; Walser, Tonya C; Dubinett, Steven M

    2017-09-01

    Lung cancers are documented to have remarkable intratumoral genetic heterogeneity. However, little is known about the heterogeneity of biophysical properties, such as cell motility, and its relationship to early disease pathogenesis and micrometastatic dissemination. In this study, we identified and selected a subpopulation of highly migratory premalignant airway epithelial cells that were observed to migrate through microscale constrictions at up to 100-fold the rate of the unselected immortalized epithelial cell lines. This enhanced migratory capacity was found to be Rac1-dependent and heritable, as evidenced by maintenance of the phenotype through multiple cell divisions continuing more than 8 weeks after selection. The morphology of this lung epithelial subpopulation was characterized by increased cell protrusion intensity. In a murine model of micrometastatic seeding and pulmonary colonization, the motility-selected premalignant cells exhibit both enhanced survival in short-term assays and enhanced outgrowth of premalignant lesions in longer-term assays, thus overcoming important aspects of "metastatic inefficiency." Overall, our findings indicate that among immortalized premalignant airway epithelial cell lines, subpopulations with heritable motility-related biophysical properties exist, and these may explain micrometastatic seeding occurring early in the pathogenesis of lung cancer. Understanding, targeting, and preventing these critical biophysical traits and their underlying molecular mechanisms may provide a new approach to prevent metastatic behavior. Cancer Prev Res; 10(9); 514-24. ©2017 AACRSee related editorial by Hynds and Janes, p. 491. ©2017 American Association for Cancer Research.

  14. Spontaneous dormancy of metastatic breast cancer cells in an all human liver microphysiologic system

    PubMed Central

    Wheeler, S E; Clark, A M; Taylor, D P; Young, C L; Pillai, V C; Stolz, D B; Venkataramanan, R; Lauffenburger, D; Griffith, L; Wells, A

    2014-01-01

    Background: Metastatic outgrowth in breast cancer can occur years after a seeming cure. Existing model systems of dormancy are limited as they do not recapitulate human metastatic dormancy without exogenous manipulations and are unable to query early events of micrometastases. Methods: Here, we describe a human ex vivo hepatic microphysiologic system. The system is established with fresh human hepatocytes and non-parenchymal cells (NPCs) creating a microenvironment into which breast cancer cells (MCF7 and MDA-MB-231) are added. Results: The hepatic tissue maintains function through 15 days as verified by liver-specific protein production and drug metabolism assays. The NPCs form an integral part of the hepatic niche, demonstrated within the system through their participation in differential signalling cascades and cancer cell outcomes. Breast cancer cells intercalate into the hepatic niche without interfering with hepatocyte function. Examination of cancer cells demonstrated that a significant subset enter a quiescent state of dormancy as shown by lack of cell cycling (EdU− or Ki67−). The presence of NPCs altered the cancer cell fraction entering quiescence, and lead to differential cytokine profiles in the microenvironment effluent. Conclusions: These findings establish the liver microphysiologic system as a relevant model for the study of breast cancer metastases and entry into dormancy. PMID:25314052

  15. Characterization of the platelet-aggregating activity of cancer cells with different metastatic potential.

    PubMed

    Grignani, G; Pacchiarini, L; Almasio, P; Pagliarino, M; Gamba, G; Rizzo, S C; Ascari, E

    1986-08-15

    We studied the mechanisms of platelet activation by sublines exhibiting different metastatic potential of two murine experimental tumors: sublines M4 and M9 of the benzopyrene-induced mFS6 sarcoma and sublines B77-AA6 and B77-3T3 of RSV-transformed BALB/c 3T3 fibroblasts. The neoplastic cells of both models induced platelet aggregation, secretion and prostaglandin biosynthesis. In the first model but not in the second, all these processes correlated with the in vivo malignancy of cells. Pretreatment of B77-AA6 and B77-3T3 cells with apyrase significantly decreased platelet aggregation, while pretreatment of M4 cells was ineffective. However, pretreatment with trypsin or neuraminidase was effective in reducing platelet aggregation induced by M4 cells, but not that induced by any of the others; furthermore, phospholipase A2 reduced the platelet response by all sublines. Finally, platelet-activating activity was also found in the pellets obtained following centrifugation of culture media. These results suggest that platelets are stimulated by cancer cells through different mechanisms; platelet activation by a sialo-lipo-protein complex of the cellular membrane was found to be characteristic of the model in which the platelet-aggregating activity of neoplastic cells correlated with their in vivo metastatic behavior.

  16. Passive Entrapment of Tumor Cells Determines Metastatic Dissemination to Spinal Bone and Other Osseous Tissues

    PubMed Central

    Piffko, Andras; Hoffmann, Christian J.; Harms, Christoph; Vajkoczy, Peter; Czabanka, Marcus

    2016-01-01

    During the metastatic process tumor cells circulate in the blood stream and are carried to various organs. In order to spread to different organs tumor cell—endothelial cell interactions are crucial for extravasation mechanisms. It remains unclear if tumor cell dissemination to the spinal bone occurs by passive entrapment of circulating tumor cells or by active cellular mechanisms mediated by cell surface molecules or secreted factors. We investigated the seeding of three different tumor cell lines (melanoma, lung and prostate carcinoma) to the microvasculature of different organs. Their dissemination was compared to biologically passive microbeads. The spine and other organs were resected three hours after intraarterial injection of tumor cells or microbeads. Ex vivo homogenization and fluorescence analysis allowed quantification of tumor cells or microbeads in different organs. Interestingly, tumor cell distribution to the spinal bone was comparable to dissemination of microbeads independent of the tumor cell type (melanoma: 5.646% ± 7.614%, lung: 6.007% ± 1.785%, prostate: 3.469% ± 0.602%, 7 μm beads: 9.884% ± 7.379%, 16 μm beads: 7.23% ± 1.488%). Tumor cell seeding differed significantly between tumor cells and microbeads in all soft tissue organs. Moreover, there were significant differences between the different tumor cell lines in their dissemination behaviour to soft tissue organs only. These findings demonstrate that metastatic dissemination of tumor cells to spinal bone and other osseous organs is mediated by passive entrapment of tumor cells similar to passive plugging of microvasculature observed after intraarterial microbeads injection. PMID:27603673

  17. Tissue engineering a surrogate niche for metastatic cancer cells.

    PubMed

    Seib, F Philipp; Berry, Janice E; Shiozawa, Yusuke; Taichman, Russell S; Kaplan, David L

    2015-05-01

    In breast and prostate cancer patients, the bone marrow is a preferred site of metastasis. We hypothesized that we could use tissue-engineering strategies to lure metastasizing cancer cells to tissue-engineered bone marrow. First, we generated highly porous 3D silk scaffolds that were biocompatible and amenable to bone morphogenetic protein 2 functionalization. Control and functionalized silk scaffolds were subcutaneously implanted in mice and bone marrow development was followed. Only functionalized scaffolds developed cancellous bone and red bone marrow, which appeared as early as two weeks post-implantation and further developed over the 16-week study period. This tissue-engineered bone marrow microenvironment could be readily manipulated in situ to understand the biology of bone metastasis. To test the ability of functionalized scaffolds to serve as a surrogate niche for metastasis, human breast cancer cells were injected into the mammary fat pads of mice. The treatment of animals with scaffolds had no significant effect on primary tumor growth. However, extensive metastasis was observed in functionalized scaffolds, and the highest levels for scaffolds that were in situ manipulated with receptor activator of nuclear factor kappa-B ligand (RANKL). We also applied this tissue-engineered bone marrow model in a prostate cancer and experimental metastasis setting. In summary, we were able to use tissue-engineered bone marrow to serve as a target or "trap" for metastasizing cancer cells.

  18. Improved detection of circulating tumor cells in non-metastatic high-risk prostate cancer patients

    PubMed Central

    Kuske, Andra; Gorges, Tobias M.; Tennstedt, Pierre; Tiebel, Anne-Kathrin; Pompe, Raisa; Preißer, Felix; Prues, Sandra; Mazel, Martine; Markou, Athina; Lianidou, Evi; Peine, Sven; Alix-Panabières, Catherine; Riethdorf, Sabine; Beyer, Burkhard; Schlomm, Thorsten; Pantel, Klaus

    2016-01-01

    The relevance of blood-based assays to monitor minimal residual disease (MRD) in non-metastatic prostate cancer (PCa) remains unclear. Proving that clinically relevant circulating tumor cells (CTCs) can be detected with available technologies could address this. This study aimed to improve CTC detection in non-metastatic PCa patients by combining three independent CTC assays: the CellSearch system, an in vivo CellCollector and the EPISPOT. Peripheral blood samples from high-risk PCa patients were screened for CTCs before and three months after radical prostatectomy (RP). Combining the results of both time points, CTCs were detected in 37%, 54.9% and 58.7% of patients using CellSearch, CellCollector and EPISPOT, respectively. The cumulative positivity rate of the three CTC assays was 81.3% (87/107) with 21.5% (23/107) of patients harboring ≥5 CTCs/7.5 ml blood. Matched pair analysis of 30 blood samples taken before and after surgery indicated a significant decrease in CTCs captured by the CellCollector from 66% before RP to 34% after therapy (p = 0.031). CTC detection by EPISPOT before RP significantly correlated with PSA serum values (p < 0.0001) and clinical tumor stage (p = 0.04), while the other assays showed no significant correlations. In conclusion, CTC-based liquid biopsies have the potential to monitor MRD in patients with non-metastatic prostate cancer. PMID:28000772

  19. Primary adrenal sarcomatoid carcinoma metastatic to the lung: Case report and review of the literature

    PubMed Central

    ZHU, CHUANGZHI; ZHENG, AIPING; MAO, XIANGMING; SHI, BENTAO; LI, XIANXIN

    2016-01-01

    Adrenal sarcomatoid carcinoma is a rare adrenal carcinoma. To the best of our knowledge, only 11 cases have been reported since 1987. Adrenal sarcomatoid carcinoma presents a diagnostic challenge due to its atypical symptoms and histological patterns. At the time of diagnosis, a large percentage of patients are already at the metastatic stage and succumb within a few months. The present study reports a case of a 59-year-old man presenting with asthenia and weight loss with adrenal sarcomatoid carcinoma metastatic to the lung. A computed tomography (CT) scan and ultrasonography of the patient's abdomen suggested a large homogeneous mass in the right adrenal gland, and a CT scan of his chest suggested lung metastasis. Right adrenalectomy was performed. Histological examination revealed that the tumor was composed of sarcomatous and carcinomatous differentiation elements. Immunohistochemical examination revealed tumor cell positivity for vimentin and cytokeratin. At the 6-month follow-up the patient exhibited no disease progression and refused further proposed treatment. The patient was alive at the time of writing the current report. The present case report additionally reviews the literature, for the purpose of raising awareness of these rare lesions and assisting in achieving accurate diagnoses and effective treatment. PMID:27123074

  20. Targeted therapy for cytokine-refractory metastatic renal cell carcinoma, and treatment in the community.

    PubMed

    Bukowski, Ronald M

    2006-05-01

    This report of a case of cytokine-refractory metastatic, clear-cell renal cell carcinoma (RCC) presents some current issues related to use of targeted therapy in the community. Due to the different mechanisms of cytostatic vs. cytotoxic agents, traditional response assessments may not always apply in deciding when to either continue or stop treatment. While community physicians may increasingly focus more on duration of response, symptom relief, and how well patients tolerate treatment, there is a clear need for validated surrogate markers of biologic activity and response, as well as randomized trials that directly compare some of the targeted therapies being applied in advanced RCC.

  1. Metastatic progression and gene expression between breast cancer cell lines from African American and Caucasian women

    PubMed Central

    Yancy, Haile F; Mason, Jacquline A; Peters, Sharla; Thompson, Charles E; Littleton, George K; Jett, Marti; Day, Agnes A

    2007-01-01

    African American (AA) women have a lower overall incidence of breast cancer than do Caucasian (CAU) women, but a higher overall mortality. Little is known as to why the incidence of breast cancer is lower yet mortality is higher in AA women. Many studies speculate that this is only a socio-economical problem. This investigation suggests the possibility that molecular mechanisms contribute to the increased mortality of AA women with breast cancer. This study investigates the expression of 14 genes which have been shown to play a role in cancer metastasis. Cell lines derived from AA and CAU patients were analyzed to demonstrate alterations in the transcription of genes known to be involved in cancer and the metastatic process. Total RNA was isolated from cell lines and analyzed by RT-PCR analysis. Differential expression of the 14 targeted genes between a spectrum model (6 breast cancer cell lines and 2 non-cancer breast cell lines) and a metastasis model (12 metastatic breast cancer cell lines) were demonstrated. Additionally, an in vitro comparison of the expression established differences in 5 of the 14 biomarker genes between African American and Caucasian breast cell lines. Results from this study indicates that altered expression of the genes Atp1b1, CARD 10, KLF4, Spint2, and Acly may play a role in the aggressive phenotype seen in breast cancer in African American women. PMID:17472751

  2. The utility of PAX-2 in distinguishing metastatic clear cell renal cell carcinoma from its morphologic mimics: an immunohistochemical study with comparison to renal cell carcinoma marker.

    PubMed

    Gokden, Neriman; Gokden, Murat; Phan, Dan C; McKenney, Jesse K

    2008-10-01

    PAX-2 is a homeogene expressed during kidney development. Although immunohistochemical expression of PAX-2 has been described in a variety of primary renal cell carcinoma (RCC) subtypes and in metastatic RCC, its specificity as a marker of renal lineage in a metastatic setting has not been fully evaluated. In addition, its utility has not been directly compared with the most widely used antibody in this setting, renal cell carcinoma marker (RCCma). We studied PAX-2 expression in metastatic clear cell renal cell carcinoma (CC-RCC) and in a variety of nonrenal neoplasms with clear cytoplasm that may potentially mimic CC-RCC. Archival material from 27 CC-RCCs metastatic to various organs and 50 close morphologic mimics of CC-RCC were retrieved. Immunohistochemistry with PAX-2 and RCCmapi antibodies was performed on each case. Nuclear staining (PAX-2) or membranous staining (RCCma) was scored semiquantitatively. Twenty-three of 27 (85%) metastatic CC-RCCs showed nuclear immunoreactivity for PAX-2, whereas RCCma reactivity was found in 19 of 27 (70%). The immunoprofiles of the metastatic CC-RCC were PAX-2+/RCCma+: 19 of 27 (70%), PAX-2+/RCCma-: 5 of 27 (19%), PAX-2-/RCCma+: 2 of 27 (7%), and PAX-2-/RCCma-: 1 of 27 (4%). Five of the 50 mimics of CC-RCC (10%) had at least focal nuclear reactivity with PAX-2, including 1 of 3 parathyroid carcinomas (33%), 3 of 7 clear cell carcinomas of the ovary (43%), and the 1 clear cell papillary cystadenoma of the epididymis. Membranous RCCma reactivity was identified in 26 of the 50 mimics (52%). We conclude that PAX-2 is a useful marker for distinguishing metastatic CC-RCC from its potential morphologic mimics, but caution must be used in certain differential diagnostic settings where nonrenal tumors such as parathyroid carcinoma, ovarian clear cell carcinoma, and clear cell papillary cystadenoma of the epididymis were shown to express both PAX-2 and RCCma.

  3. Prophylactic Dendritic Cell-Based Vaccines Efficiently Inhibit Metastases in Murine Metastatic Melanoma

    PubMed Central

    Sennikov, Sergey V.; Vlassov, Valentin V.; Zenkova, Marina A.

    2015-01-01

    Recent data on the application of dendritic cells (DCs) as anti-tumor vaccines has shown their great potential in therapy and prophylaxis of cancer. Here we report on a comparison of two treatment schemes with DCs that display the models of prophylactic and therapeutic vaccination using three different experimental tumor models: namely, Krebs-2 adenocarcinoma (primary tumor), melanoma (B16, metastatic tumor without a primary node) and Lewis lung carcinoma (LLC, metastatic tumor with a primary node). Dendritic cells generated from bone marrow-derived DC precursors and loaded with lysate of tumor cells or transfected with the complexes of total tumor RNA with cationic liposomes were used for vaccination. Lipofectamine 2000 and liposomes consisting of helper lipid DOPE (1,2-dioleoyl-sn-glycero-3-phosphoethanolamine) and cationic lipid 2D3 (1,26-Bis(1,2-de-O-tetradecyl-rac-glycerol)-7,11,16,20-tetraazahexacosan tetrahydrocloride) were used for RNA transfection. It was shown that DCs loaded with tumor lysate were ineffective in contrast to tumor-derived RNA. Therapeutic vaccination with DCs loaded by lipoplexes RNA/Lipofectamine 2000 was the most efficient for treatment of non-metastatic Krebs-2, where a 1.9-fold tumor growth retardation was observed. Single prophylactic vaccination with DCs loaded by lipoplexes RNA/2D3 was the most efficient to treat highly aggressive metastatic tumors LLC and B16, where 4.7- and 10-fold suppression of the number of lung metastases was observed, respectively. Antimetastatic effect of single prophylactic DC vaccination in metastatic melanoma model was accompanied by the reductions in the levels of Th2-specific cytokines however the change of the levels of Th1/Th2/Th17 master regulators was not found. Failure of double prophylactic vaccination is explained by Th17-response polarization associated with autoimmune and pro-inflammatory reactions. In the case of therapeutic DC vaccine the polarization of Th1-response was found nevertheless

  4. Prophylactic Dendritic Cell-Based Vaccines Efficiently Inhibit Metastases in Murine Metastatic Melanoma.

    PubMed

    Markov, Oleg V; Mironova, Nadezhda L; Sennikov, Sergey V; Vlassov, Valentin V; Zenkova, Marina A

    2015-01-01

    Recent data on the application of dendritic cells (DCs) as anti-tumor vaccines has shown their great potential in therapy and prophylaxis of cancer. Here we report on a comparison of two treatment schemes with DCs that display the models of prophylactic and therapeutic vaccination using three different experimental tumor models: namely, Krebs-2 adenocarcinoma (primary tumor), melanoma (B16, metastatic tumor without a primary node) and Lewis lung carcinoma (LLC, metastatic tumor with a primary node). Dendritic cells generated from bone marrow-derived DC precursors and loaded with lysate of tumor cells or transfected with the complexes of total tumor RNA with cationic liposomes were used for vaccination. Lipofectamine 2000 and liposomes consisting of helper lipid DOPE (1,2-dioleoyl-sn-glycero-3-phosphoethanolamine) and cationic lipid 2D3 (1,26-Bis(1,2-de-O-tetradecyl-rac-glycerol)-7,11,16,20-tetraazahexacosan tetrahydrocloride) were used for RNA transfection. It was shown that DCs loaded with tumor lysate were ineffective in contrast to tumor-derived RNA. Therapeutic vaccination with DCs loaded by lipoplexes RNA/Lipofectamine 2000 was the most efficient for treatment of non-metastatic Krebs-2, where a 1.9-fold tumor growth retardation was observed. Single prophylactic vaccination with DCs loaded by lipoplexes RNA/2D3 was the most efficient to treat highly aggressive metastatic tumors LLC and B16, where 4.7- and 10-fold suppression of the number of lung metastases was observed, respectively. Antimetastatic effect of single prophylactic DC vaccination in metastatic melanoma model was accompanied by the reductions in the levels of Th2-specific cytokines however the change of the levels of Th1/Th2/Th17 master regulators was not found. Failure of double prophylactic vaccination is explained by Th17-response polarization associated with autoimmune and pro-inflammatory reactions. In the case of therapeutic DC vaccine the polarization of Th1-response was found nevertheless

  5. Targeting Neuronal-like Metabolism of Metastatic Tumor Cells as a Novel Therapy for Breast Cancer Brain Metastasis

    DTIC Science & Technology

    2016-03-01

    intravital imaging and whole tissue clearing based imaging to dissect the interaction between tumor cell and its brain metastatic microenvironment. We...have successfully expanded GFAP-GFP mouse line (brain astrocyte specific) and performed preliminary testing on the intravital imaging capability. In...breast cancer driver genes. 2. Keywords……………………………………………………………. Breast cancer, brain metastasis, metastatic outgrowth, brain intravital imaging

  6. Periaortic lymph node involvement by metastatic angiosarcoma and benign sinus mesothelial cells.

    PubMed

    Isotalo, P A; Jabit, M; Wenckebach, G F

    2001-05-01

    Hyperplastic mesothelial cells involving lymph node sinuses have only been recently described. Most nodal mesothelial cells are thought to originate from mesothelial surfaces disrupted by serosal effusions. Dislodged mesothelial cells likely gain access to submesothelial lymphatics via mesothelial stomata and disseminate to draining lymph nodes. Unusual lymph node architectural patterns result when benign sinus mesothelial cells occur concurrently with a neoplastic nodal process. We describe a young man who developed diffuse metastases from a primary cardiac angiosarcoma. His periaortic lymph nodes contained metastatic angiosarcoma and hyperplastic mesothelial cells with a sinus distribution. The patient had a clinical history of progressive haemoperitoneum, exacerbated by thrombocytopaenia and disseminated intravascular coagulation. Massive haemoperitoneum of 5000 ml was confirmed at autopsy. This is the first report to suggest that multiple episodes of intraperitoneal haemorrhage and ascites may both act in the same manner to cause dislodgment and dissemination of mesothelial cells to draining lymph node sinuses.

  7. Differential targets of CpG island hypermethylation in primary and metastatic head and neck squamous cell carcinoma (HNSCC)

    PubMed Central

    Smiraglia, D; Smith, L; Lang, J; Rush, L; Dai, Z; Schuller, D; Plass, C

    2003-01-01

    Head and neck squamous cell carcinomas (HNSCC) often metastasise to the cervical lymph nodes. It is known for HNSCC as well as other cancers that progression from normal tissue to primary tumour and finally to metastatic tumour is characterised by an accumulation of genetic mutations. DNA methylation, an epigenetic modification, can result in loss of gene function in cancer, similar to genetic mutations such as deletions and point mutations. We have investigated the DNA methylation phenotypes of both primary HNSCC and metastatic tumours from 13 patients using restriction landmark genomic scanning (RLGS). With this technique, we were able to assess the methylation status of an average of nearly 1300 CpG islands for each tumour. We observed that the number of CpG islands hypermethylated in metastatic tumours is significantly greater than what is found in the primary tumours overall, but not in every patient. Interestingly, the data also clearly show that many loci methylated in a patient's primary tumour are no longer methylated in the metastatic tumour of the same patient. Thus, even though metastatic HNSCC methylate a greater proportion of CpG islands than do the primary tumours, they do so at different subsets of loci. These data show an unanticipated variability in the methylation state of loci in primary and metastatic HNSCCs within the same patient. We discuss two possible explanations for how different epigenetic events might arise between the primary tumour and the metastatic tumour of a person. PMID:12525538

  8. Role of partial nephrectomy as cytoreduction in the management of metastatic renal cell carcinoma.

    PubMed

    Karam, J A; Babaian, K N; Tannir, N M; Matin, S F; Wood, C G

    2015-06-01

    In this review, we describe the role, feasibility and safety of partial nephrectomy in the setting of metastatic renal cell carcinoma. Partial nephrectomy is currently the preferred therapeutic modality in patients with localized renal tumors, while radical cytoreductive nephrectomy is the standard of care for appropriately selected patients with metastatic disease. Several studies have shown the prognostic value of percentage tumor removed when cytoreductive nephrectomy is done. This concept of percentage tumor removal and the associated benefit should also be applied when considering patients for cytoreductive partial nephrectomy; however, the potential adverse events after partial nephrectomy should be kept in mind, as these, when they occur, could delay time to starting systemic therapy. Several small retrospective studies have shown the feasibility of this approach in carefully selected patient groups. In well-selected patients with metastatic disease and primary tumors that are amenable to nephron sparing approaches, partial nephrectomy could offer an alternative to radical nephrectomy, with manageable adverse events, and good renal functional outcomes. Preserving renal function in this population could allow these patients to participate in clinical trial that they otherwise might not qualify for.

  9. Melatonin and IL-25 modulate apoptosis and angiogenesis mediators in metastatic (CF-41) and non-metastatic (CMT-U229) canine mammary tumour cells.

    PubMed

    Gelaleti, G B; Borin, T F; Maschio-Signorini, L B; Moschetta, M G; Hellmén, E; Viloria-Petit, A M; Zuccari, D A P C

    2017-03-20

    Melatonin has oncostatic actions and IL-25 is active in inflammatory processes that induce apoptosis in tumor cells AIM: The aim of this study was to evaluate melatonin and IL-25 in metastatic (CF-41) and non-metastatic (CMT-U229) canine mammary tumor cells cultured as monolayers and tridimensional structures. The cells were treated with melatonin, IL-25 and IL-17B silencing gene and performed cell viability, gene and protein expression of caspase-3 and VEGFA (Vascular endothelial growth factor A) and an apoptosis membrane protein array. Treatment with 1 mM of melatonin reduced cell viability of both tumor cell lines, all treatments alone and combined significantly increased caspase-3 cleaved and proteins involved in the apoptotic pathway and reduced pro-angiogenic VEGFA, confirming the effectiveness of these potential promising treatments. This is the first study evaluating the potential use of these strategies in CF-41 and CMT-U229 cell lines and together encourages subsequent in vitro and in vivo studies for further exploration of clinical applications. © 2017 John Wiley & Sons Ltd.

  10. Interleukin-4 promoter polymorphisms: a genetic prognostic factor for survival in metastatic renal cell carcinoma.

    PubMed

    Kleinrath, Thomas; Gassner, Christoph; Lackner, Peter; Thurnher, Martin; Ramoner, Reinhold

    2007-03-01

    Renal cell carcinoma (RCC) is considered a cytokine-responsive tumor. The clinical course of a patient may thus be influenced by the patient's capacity to produce distinct cytokines. Therefore, cytokine gene polymorphisms in RCC patients were analyzed to determine haplotype combinations with prognostic significance. A selection of 21 single nucleotide polymorphisms within the promoter regions of 13 cytokine genes were analyzed in a cross-sectional single-center study of 80 metastatic RCC patients. Univariate and multivariate analyses and the Cox forward-stepwise regression model were chosen to assess genetic risk factors. Multivariate Cox regression analysis confirmed by a bootstrap technique identified the heterozygous IL4 genotype -589T-33T/-589C-33C as an independent prognostic risk factor (risk ratio, 3.1; P < .01; 95% CI, 1.4 to 6.9; adjusted for age, sex, and nuclear grading) in metastatic RCC patients. IL4 haplotype -589T-33T and -589C-33C were found with a frequency of 0.069 and 0.925, respectively, which represents a two-fold decrease of IL4 haplotype -589T-33T (P < .01) and an increase of IL4 haplotype -589C-33C frequency (P < .05) in metastatic RCC compared with other white reference study populations. The median overall survival was decreased 3.5-fold (P < .05) in heterozygote patients carrying IL4 haplotype -589T-33T and -589C-33C (3.78 months) compared with patients homozygote for IL4 haplotype -589C-33C (13.44 months). In addition, a linkage disequilibrium between the IL4 gene and the KIF3A gene was detected. Our findings indicate that IL4 promoter variants influence prognosis in patients with metastatic RCC and suggest that genetically determined interleukin-4 (IL-4) production affects the clinical course of the disease possibly through regulation of immune surveillance.

  11. Lactate Formation in Primary and Metastatic Colon Cancer Cells at Hypoxia and Normoxia.

    PubMed

    Graboń, Wojciech; Otto-Ślusarczyk, Dagmara; Chrzanowska, Alicja; Mielczarek-Puta, Magdalena; Joniec-Maciejak, Ilona; Słabik, Krzysztof; Barańczyk-Kuźma, Anna

    2016-10-01

    High glucose consumption and lactate synthesis in aerobic glycolysis are a hallmark of cancer cells. They can form lactate also in glutaminolysis, but it is not clear how oxygen availability affects this process. We studied lactate synthesis at various oxygen levels in human primary (SW480) and metastatic (SW620) colon cancer cells cultured with L-Ser and/or L-Asp. Glucose and lactate levels were determined colorimetrically, amino acids by HPLC, expression of AST1-mRNA and AST2-mRNA by RT-PCR. In both lines glucose consumption and lactate synthesis were higher at 10% than at 1% oxygen, and lactate/glucose ratio was increased above 2.0 by L-Asp. AST1-mRNA expression was independent on oxygen and cell line, but AST2-mRNA was lower at hypoxia in SW480. We conclude that, in both cell lines at 1% hypoxia, lactate is formed mainly from glucose but at 10% normoxia also from L-Asp. At 10% normoxia, lactate synthesis is more pronounced in primary than metastatic colon cancer cells. Copyright © 2016 John Wiley & Sons, Ltd.

  12. Analysis of autophagic flux in response to sulforaphane in metastatic prostate cancer cells

    PubMed Central

    Watson, Gregory W; Wickramasekara, Samanthi; Fang, Yufeng; Palomera-Sanchez, Zoraya; Maier, Claudia S; Williams, David E; Dashwood, Roderick H; Perez, Viviana I; Ho, Emily

    2015-01-01

    Scope The phytochemical sulforaphane has been shown to decrease prostate cancer metastases in a genetic mouse model of prostate carcinogenesis, though the mechanism of action is not fully known. Sulforaphane has been reported to stimulate autophagy, and modulation of autophagy has been proposed to influence sulforaphane cytotoxicity; however, no conclusions about autophagy can be drawn without assessing autophagic flux, which has not been characterized in prostate cancer cells following sulforaphane treatment. Methods and Results We conducted an investigation to assess the impact of sulforaphane on autophagic flux in two metastatic prostate cancer cell lines at a concentration shown to decrease metastasis in vivo. Autophagic flux was assessed by multiple autophagy related proteins and substrates. We found that sulforaphane can stimulate autophagic flux and cell death only at high concentrations, above what has been observed in vivo. Conclusion These results suggest that sulforaphane does not directly stimulate autophagy or cell death in metastatic prostate cancer cells under physiologically relevant conditions, but instead supports the involvement of in vivo factors as important effectors of sulforaphane- mediated prostate cancer suppression. PMID:26108801

  13. Elimination of metastatic melanoma using gold nanoshell-enabled photothermal therapy and adoptive T cell transfer.

    PubMed

    Bear, Adham S; Kennedy, Laura C; Young, Joseph K; Perna, Serena K; Mattos Almeida, Joao Paulo; Lin, Adam Y; Eckels, Phillip C; Drezek, Rebekah A; Foster, Aaron E

    2013-01-01

    Ablative treatments such as photothermal therapy (PTT) are attractive anticancer strategies because they debulk accessible tumor sites while simultaneously priming antitumor immune responses. However, the immune response following thermal ablation is often insufficient to treat metastatic disease. Here we demonstrate that PTT induces the expression of proinflammatory cytokines and chemokines and promotes the maturation of dendritic cells within tumor-draining lymph nodes, thereby priming antitumor T cell responses. Unexpectedly, however, these immunomodulatory effects were not beneficial to overall antitumor immunity. We found that PTT promoted the infiltration of secondary tumor sites by CD11b(+)Ly-6G/C(+) myeloid-derived suppressor cells, consequently failing to slow the growth of poorly immunogenic B16-F10 tumors and enhancing the growth of distant lung metastases. To exploit the beneficial effects of PTT activity against local tumors and on antitumor immunity whilst avoiding the adverse consequences, we adoptively transferred gp100-specific pmel T cells following PTT. The combination of local control by PTT and systemic antitumor immune reactivity provided by adoptively transferred T cells prevented primary tumor recurrence post-ablation, inhibited tumor growth at distant sites, and abrogated the outgrowth of lung metastases. Hence, the combination of PTT and systemic immunotherapy prevented the adverse effects of PTT on metastatic tumor growth and optimized overall tumor control.

  14. Alterations of p53 in tumorigenic human bronchial epithelial cells correlate with metastatic potential

    NASA Technical Reports Server (NTRS)

    Piao, C. Q.; Willey, J. C.; Hei, T. K.; Hall, E. J. (Principal Investigator)

    1999-01-01

    The cellular and molecular mechanisms of radiation-induced lung cancer are not known. In the present study, alterations of p53 in tumorigenic human papillomavirus-immortalized human bronchial epithelial (BEP2D) cells induced by a single low dose of either alpha-particles or 1 GeV/nucleon (56)Fe were analyzed by PCR-single-stranded conformation polymorphism (SSCP) coupled with sequencing analysis and immunoprecipitation assay. A total of nine primary and four secondary tumor cell lines, three of which were metastatic, together with the parental BEP2D and primary human bronchial epithelial (NHBE) cells were studied. The immunoprecipitation assay showed overexpression of mutant p53 proteins in all the tumor lines but not in NHBE and BEP2D cells. PCR-SSCP and sequencing analysis found band shifts and gene mutations in all four of the secondary tumors. A G-->T transversion in codon 139 in exon 5 that replaced Lys with Asn was detected in two tumor lines. One mutation each, involving a G-->T transversion in codon 215 in exon 6 (Ser-->lle) and a G-->A transition in codon 373 in exon 8 (Arg-->His), was identified in the remaining two secondary tumors. These results suggest that p53 alterations correlate with tumorigenesis in the BEP2D cell model and that mutations in the p53 gene may be indicative of metastatic potential.

  15. Modulation of Cell Signaling Networks after CTLA4 Blockade in Patients with Metastatic Melanoma

    PubMed Central

    Comin-Anduix, Begoña; Sazegar, Hooman; Chodon, Thinle; Matsunaga, Douglas; Jalil, Jason; von Euw, Erika; Escuin-Ordinas, Helena; Balderas, Robert; Chmielowski, Bartosz; Gomez-Navarro, Jesus; Koya, Richard C.; Ribas, Antoni

    2010-01-01

    Background The effects on cell signalling networks upon blockade of cytotoxic T lymphocyte-associated antigen-4 (CTLA4) using the monoclonal antibody tremelimumab were studied in peripheral blood mononuclear cell (PBMC) samples from patients with metastatic melanoma. Methodology/Principal Findings Intracellular flow cytometry was used to detect phosphorylated (p) signaling molecules downstream of the T cell receptor (TCR) and cytokine receptors. PBMC from tremelimumab-treated patients were characterized by increase in pp38, pSTAT1 and pSTAT3, and decrease in pLck, pERK1/2 and pSTAT5 levels. These changes were noted in CD4 and CD8 T lymphocytes but also in CD14 monocytes. A divergent pattern of phosphorylation of Zap70, LAT, Akt and STAT6 was noted in patients with or without an objective tumor response. Conclusions/Significance The administration of the CTLA4-blocking antibody tremelimumab to patients with metastatic melanoma influences signaling networks downstream of the TCR and cytokine receptors both in T cells and monocytes. The strong modulation of signaling networks in monocytes suggests that this cell subset may be involved in clinical responses to CTLA4 blockade. Clinical Trial Registration clinicaltrials.gov; Registration numbers NCT00090896 and NCT00471887 PMID:20856802

  16. Anti-metastatic activity of fangchinoline in human gastric cancer AGS cells

    PubMed Central

    Chen, Zhengrong; He, Tengfei; Zhao, Kui; Xing, Chungen

    2017-01-01

    Fangchinoline (FCL) is an active component isolated from the traditional medicinal plant Stephania tetrandra S. Moore, and has been reported to possess anti-cancer functions in several types of cancers; however, the effect of FCL on gastric cancer metastasis and its underlying molecular mechanisms remain unknown. The current study aimed to investigate the effect of FCL on the cell migration and invasion of human metastatic gastric cancer AGS cells and its mechanisms. Our study demonstrates that FCL dosage dependently suppressed the adhesion, migration and invasion capacities of human gastric cancer AGS cells without obvious cytotoxic effects. Reverse transcription-polymerase chain reaction and western blot assays demonstrated that FCL greatly inhibited the expression of matrix metalloproteinase (MMP)-2 and MMP-9 at both the mRNA and protein levels, while it significantly increased the expression of tissue inhibitor of metalloproteinase (TIMP) 1 and TIMP2 messenger RNAs. Our results also indicated that FCL repressed the phosphorylation of AKT in gastric cancer AGS cells. In summary, FCL may exert its anti-metastatic property in human gastric cancer cells in vitro by suppression of MMP-2 and MMP-9, increase of TIMP1 and TIMP2 genes, and inhibition of AKT phosphorylation. FCL may be a drug candidate for the treatment of gastric cancer metastasis.

  17. Alterations of p53 in tumorigenic human bronchial epithelial cells correlate with metastatic potential

    NASA Technical Reports Server (NTRS)

    Piao, C. Q.; Willey, J. C.; Hei, T. K.; Hall, E. J. (Principal Investigator)

    1999-01-01

    The cellular and molecular mechanisms of radiation-induced lung cancer are not known. In the present study, alterations of p53 in tumorigenic human papillomavirus-immortalized human bronchial epithelial (BEP2D) cells induced by a single low dose of either alpha-particles or 1 GeV/nucleon (56)Fe were analyzed by PCR-single-stranded conformation polymorphism (SSCP) coupled with sequencing analysis and immunoprecipitation assay. A total of nine primary and four secondary tumor cell lines, three of which were metastatic, together with the parental BEP2D and primary human bronchial epithelial (NHBE) cells were studied. The immunoprecipitation assay showed overexpression of mutant p53 proteins in all the tumor lines but not in NHBE and BEP2D cells. PCR-SSCP and sequencing analysis found band shifts and gene mutations in all four of the secondary tumors. A G-->T transversion in codon 139 in exon 5 that replaced Lys with Asn was detected in two tumor lines. One mutation each, involving a G-->T transversion in codon 215 in exon 6 (Ser-->lle) and a G-->A transition in codon 373 in exon 8 (Arg-->His), was identified in the remaining two secondary tumors. These results suggest that p53 alterations correlate with tumorigenesis in the BEP2D cell model and that mutations in the p53 gene may be indicative of metastatic potential.

  18. Treatment Selection for Patients With Metastatic Renal Cell Carcinoma

    PubMed Central

    Atkins, Michael B.; Choueiri, Toni K.; Cho, Daniel; Regan, Meredith; Signoretti, Sabina

    2009-01-01

    The availability of approved agents with distinct mechanisms of action has encouraged investigations to identify optimal treatment strategies for specific patients and specific tumor features. Study of tumors from patients treated with interleukin 2 (IL-2) has suggested that response was unlikely in patients with tumors with papillary features or low carbonic anhydrase IX (CAIX) expression. A model combining histologic features and CAIX expression separated patients into 2 groups of roughly equal size, with 96% of the responding patients being in the favorable prognostic group. Additional studies have begun to identify molecular features that might predict response IL-2 therapy. In contrast, clinical trial data suggest that temsirolimus was relatively more active than interferon in patients with tumors containing non-clear cell features. Furthermore, pathologic examination showed no correlation of response with CAIX expression but an apparent association with high expression of either phospho-AKT or phospho-S6, proteins either upstream or downstream of mTOR. Preliminary investigations of tumor specimens from patients receiving VEGF-targeted therapy suggested that high hypoxia inducible factor expression might predict for response. In addition, response appeared more likely in tumors with mutated or methylated VHL genes; however, substantial antitumor activity was still seen in patients with VHL wild-type tumors, particularly in patients treated with either sunitinib or axitinib, rather than bevacizumab or sorafenib. Although these data provide some guidance in treatment selection, considerably more research is needed to identify and validate selection models for particular treatment approaches and enable rational and optimal utilization of the available treatment options. PMID:19402069

  19. Elevated Na(+)/H(+) exchanger-1 expression enhances the metastatic collective migration of head and neck squamous cell carcinoma cells.

    PubMed

    Kaminota, Teppei; Yano, Hajime; Shiota, Kohei; Nomura, Noriko; Yaguchi, Haruna; Kirino, Yui; Ohara, Kentaro; Tetsumura, Issei; Sanada, Tomoyoshi; Ugumori, Toru; Tanaka, Junya; Hato, Naohito

    2017-04-22

    Cancer cells can migrate as collectives during invasion and/or metastasis; however, the precise molecular mechanisms of this form of migration are less clear compared with single cell migration following epithelial-mesenchymal transition. Elevated Na(+)/H(+) exchanger1 (NHE1) expression has been suggested to have malignant roles in a number of cancer cell lines and in vivo tumor models. Furthermore, a metastatic human head and neck squamous cell carcinoma (HNSCC) cell line (SASL1m) that was isolated based on its increased metastatic potential also exhibited higher NHE1 expression than its parental line SAS. Time-lapse video recordings indicated that both cell lines migrate as collectives, although with different features, e.g., SASL1m was much more active and changed the direction of migration more frequently than SAS cells, whereas locomotive activities were comparable. SASL1m cells also exhibited higher invasive activity than SAS in Matrigel invasion assays. shRNA-mediated NHE1 knockdown in SASL1m led to reduced locomotive and invasive activities, suggesting a critical role for NHE1 in the collective migration of SASL1m cells. SASL1m cells also exhibited a higher metastatic rate than SAS cells in a mouse lymph node metastasis model, while NHE1 knockdown suppressed in vivo SASL1m metastasis. Finally, elevated NHE1 expression was observed in human HNSCC tissue, and Cariporide, a specific NHE1 inhibitor, reduced the invasive activity of SASL1m cells, implying NHE1 could be a target for anti-invasion/metastasis therapy. Copyright © 2017 Elsevier Inc. All rights reserved.

  20. Preventing postoperative metastatic disease by inhibiting surgery-induced dysfunction in natural killer cells.

    PubMed

    Tai, Lee-Hwa; de Souza, Christiano Tanese; Bélanger, Simon; Ly, Lundi; Alkayyal, Almohanad A; Zhang, Jiqing; Rintoul, Julia L; Ananth, Abhirami A; Lam, Tiffany; Breitbach, Caroline J; Falls, Theresa J; Kirn, David H; Bell, John C; Makrigiannis, Andrew P; Auer, Rebecca A

    2013-01-01

    Natural killer (NK) cell clearance of tumor cell emboli following surgery is thought to be vital in preventing postoperative metastases. Using a mouse model of surgical stress, we transferred surgically stressed NK cells into NK-deficient mice and observed enhanced lung metastases in tumor-bearing mice as compared with mice that received untreated NK cells. These results establish that NK cells play a crucial role in mediating tumor clearance following surgery. Surgery markedly reduced NK cell total numbers in the spleen and affected NK cell migration. Ex vivo and in vivo tumor cell killing by NK cells were significantly reduced in surgically stressed mice. Furthermore, secreted tissue signals and myeloid-derived suppressor cell populations were altered in surgically stressed mice. Significantly, perioperative administration of oncolytic parapoxvirus ovis (ORFV) and vaccinia virus can reverse NK cell suppression, which correlates with a reduction in the postoperative formation of metastases. In human studies, postoperative cancer surgery patients had reduced NK cell cytotoxicity, and we show for the first time that oncolytic vaccinia virus markedly increases NK cell activity in patients with cancer. These data provide direct in vivo evidence that surgical stress impairs global NK cell function. Perioperative therapies aimed at enhancing NK cell function will reduce metastatic recurrence and improve survival in surgical cancer patients.

  1. Anti-metastatic activity of biologically synthesized gold nanoparticles on human fibrosarcoma cell line HT-1080.

    PubMed

    Karuppaiya, Palaniyandi; Satheeshkumar, Elumalai; Chao, Wei-Ting; Kao, Lin-Yi; Chen, Emily Chin-Fun; Tsay, Hsin-Sheng

    2013-10-01

    Plants are exploited as a potential source for the large-scale production of noble gold nanoparticles in the recent years owing to their various potential applications in nanobiotechnology and nanomedicine. The present work describes green biosynthetic procedures for the production of gold nanoparticles for the first time by using an aqueous extract of the Dysosma pleiantha rhizome. The biosynthesized gold nanoparticles were confirmed and characterized by ultraviolet-visible spectroscopy, Fourier transform infrared spectroscopy, transmission electron microscopy, and scanning electron microscopy equipped with energy dispersive spectroscopy. The results revealed that aqueous extract of D. pleiantha rhizome has potential to reduce chloroauric ions into gold nanoparticles and the synthesized gold nanoparticles were showed spherical in shape with an average of 127nm. Further, we investigated the anti-metastatic activity of biosynthesized gold nanoparticles against human fibrosarcoma cancer cell line HT-1080. The results showed that the biosynthesized gold nanoparticles were non-toxic to cell proliferation and, also it can inhibit the chemo-attractant cell migration of human fibrosarcoma cancer cell line HT-1080 by interfering the actin polymerization pathway. Thus, the usage of gold nanoparticles biosynthesized from D. pleiantha rhizome can be used as a potential candidate in the drug and gene delivery to metastatic cancer.

  2. Metastatic Renal Cell Carcinoma Presenting as a Paranasal Sinus Mass: The Importance of Differential Diagnosis

    PubMed Central

    Altissimi, Giancarlo; Turchetta, Rosaria; Rigante, Mario

    2017-01-01

    Metastases in the paranasal sinuses are rare; renal cell carcinoma is the most common cancer that metastasizes to this region. We present the case of a patient with a 4-month history of a rapidly growing mass of the nasal pyramid following a nasal trauma, associated with spontaneous epistaxis and multiple episodes of hematuria. Cranial CT scan and MRI showed an ethmoid mass extending to the choanal region, the right orbit, and the right frontal sinus with an initial intracranial extension. Patient underwent surgery with a trans-sinusal frontal approach using a bicoronal incision combined with an anterior midfacial degloving; histological exam was compatible with a metastasis of clear cell renal cell carcinoma. Following histological findings, a total body CT scan showed a solitary 6 cm mass in the upper posterior pole of the left kidney identified as the primary tumor. Although rare, metastatic renal cell carcinoma should always be suspected in patients with nasal or paranasal masses, especially if associated with symptoms suggestive of a systemic involvement such as hematuria. A correct early-stage diagnosis of metastatic RCC can considerably improve survival rate in these patients; preoperative differential diagnosis with contrast-enhanced imaging is fundamental for the correct treatment and follow-up strategy. PMID:28168075

  3. Matrix Rigidity Induces Osteolytic Gene Expression of Metastatic Breast Cancer Cells

    PubMed Central

    Ruppender, Nazanin S.; Merkel, Alyssa R.; Martin, T. John; Sterling, Julie A.; Guelcher, Scott A.

    2010-01-01

    Nearly 70% of breast cancer patients with advanced disease will develop bone metastases. Once established in bone, tumor cells produce factors that cause changes in normal bone remodeling, such as parathyroid hormone-related protein (PTHrP). While enhanced expression of PTHrP is known to stimulate osteoclasts to resorb bone, the environmental factors driving tumor cells to express PTHrP in the early stages of development of metastatic bone disease are unknown. In this study, we have shown that tumor cells known to metastasize to bone respond to 2D substrates with rigidities comparable to that of the bone microenvironment by increasing expression and production of PTHrP. The cellular response is regulated by Rho-dependent actomyosin contractility mediated by TGF-ß signaling. Inhibition of Rho-associated kinase (ROCK) using both pharmacological and genetic approaches decreased PTHrP expression. Furthermore, cells expressing a dominant negative form of the TGF-ß receptor did not respond to substrate rigidity, and inhibition of ROCK decreased PTHrP expression induced by exogenous TGF-ß. These observations suggest a role for the differential rigidity of the mineralized bone microenvironment in early stages of tumor-induced osteolysis, which is especially important in metastatic cancer since many cancers (such as those of the breast and lung) preferentially metastasize to bone. PMID:21085597

  4. Two Canine Papillomaviruses Associated With Metastatic Squamous Cell Carcinoma in Two Related Basenji Dogs.

    PubMed

    Luff, J; Rowland, P; Mader, M; Orr, C; Yuan, H

    2016-11-01

    Papillomaviruses (PV) are associated with benign mucosal and cutaneous epithelial proliferations. In dogs, PV-associated pigmented plaques and papillomas can undergo malignant transformation, but this is rare, and most cases of canine squamous cell carcinoma do not arise from PV-induced precursor lesions. We describe herein the progression of pigmented plaques to invasive and metastatic squamous cell carcinoma associated with 2 canine papillomaviruses (CPV) in 2 related Basenji dogs. Immunohistochemistry for PV antigen revealed strong nuclear immunoreactivity within keratinocytes from pigmented plaques from both dogs, consistent with a productive viral infection. Polymerase chain reaction (PCR) using degenerate primers for the L1 gene revealed PV DNA sequences from 2 different CPVs. In situ hybridization for CPV revealed strong hybridization signals within the pigmented plaques and neoplastic squamous epithelial cells from both dogs. We report here progression of PV-associated pigmented plaques to metastatic squamous cell carcinoma within 2 Basenji dogs associated with 2 different CPVs. © The Author(s) 2016.

  5. Registered report: Interactions between cancer stem cells and their niche govern metastatic colonization

    PubMed Central

    Incardona, Francesca; Doroudchi, M Mehdi; Ismail, Nawfal; Carreno, Alberto; Griner, Erin; Anna Lim, Minyoung; Iorns, Elizabeth

    2015-01-01

    The Reproducibility Project: Cancer Biology seeks to address growing concerns about reproducibility in scientific research by replicating selected results from a substantial number of high-profile papers in the field of cancer biology published between 2010 and 2012. This Registered report describes the proposed replication plan of key experiments from ‘Interactions between cancer stem cells and their niche govern metastatic colonization’ by Malanchi and colleagues, published in Nature in 2012 (Malanchi et al., 2012). The key experiments that will be replicated are those reported in Figures 2H, 3A, 3B, and S13. In these experiments, Malanchi and colleagues analyze messenger RNA levels of periostin (POSTN) in pulmonary fibroblasts, endothelial cells, and immune cells isolated from mice with micrometastases to determine which cell type is producing POSTN in the metastatic niche (Figure 2H; Malanchi et al., 2012). Additionally, they examine MMTV-PyMT control or POSTN null mice to test the effect of POSTN on primary tumor growth and metastasis (Figures 3A, 3B, and S13; Malanchi et al., 2012). The Reproducibility Project: Cancer Biology is a collaboration between the Center for Open Science and Science Exchange, and the results of the replications will be published in eLife. DOI: http://dx.doi.org/10.7554/eLife.06938.001 PMID:26086719

  6. Single-nucleotide polymorphisms associated with outcome in metastatic renal cell carcinoma treated with sunitinib

    PubMed Central

    Beuselinck, B; Karadimou, A; Lambrechts, D; Claes, B; Wolter, P; Couchy, G; Berkers, J; Paridaens, R; Schöffski, P; Méjean, A; Verkarre, V; Lerut, E; de la Taille, A; Tourani, J-M; Bigot, P; Linassier, C; Négrier, S; Berger, J; Patard, J-J; Zucman-Rossi, J; Oudard, S

    2013-01-01

    Background: There are no validated markers that predict response in metastatic renal cell cancer (RCC) patients treated with sunitinib. We aim to study the impact of single-nucleotide polymorphisms (SNPs) that have recently been proposed as predictors of outcome to anti-VEGF-targeted therapy in metastatic RCC in an independent cohort of patients. Methods: We genotyped 16 key SNPs in 10 genes involved in sunitinib pharmacokinetics, pharmacodynamics and VEGF-independent angiogenesis in patients with metastatic clear-cell RCC treated with sunitinib as the first-line targeted therapy. Association between SNPs, progression-free survival (PFS) and overall survival (OS) were studied by multivariate Cox regression using relevant clinical factors associated with PFS and OS as covariates. Results: In a series of 88 patients, both PFS and OS were associated significantly with SNP rs1128503 in ABCB1 (P=0.027 and P=0.025), rs4073054 in NR1/3 (P=0.025 and P=0.035) and rs307821 in VEGFR3 (P=0.032 and P=0.011). Progression-free survival alone was associated with rs2981582 in FGFR2 (P=0.031) and rs2276707 in NR1/2 (P=0.047), whereas OS alone was associated with rs2307424 in NR1/3 (P=0.048) and rs307826 in VEGFR3 (P=0.013). Conclusion: Our results confirm former communications regarding the association between SNPs in ABCB1, NR1/2, NR1/3 and VEGFR3 and sunitinib outcome in clear-cell RCC. Prospective validation of these SNPs is now required. PMID:23462807

  7. Comparison of MMP2 and MMP9 expression levels between primary and metastatic regions of oral squamous cell carcinoma.

    PubMed

    Nishio, Kensuke; Motozawa, Keiko; Omagari, Daisuke; Gojoubori, Takahiro; Ikeda, Takayuki; Asano, Masatake; Gionhaku, Nobuhito

    2016-01-01

    Matrix metalloproteinases (MMPs) and tumor-associated macrophages (TAMs) play important roles in tumor growth. The present study investigated the expression levels of MMP2 and MMP9 in relation to the distribution of TAMs in the primary and metastatic regions of oral squamous cell carcinoma. Twenty-nine cases of oral squamous cell carcinoma (OSCC) with regional lymph node metastasis were selected from available documents in the archives of the Department of Pathology, Nihon University School of Dentistry. Four-micrometer-thick sections were prepared from the primary and metastatic regions. Each section was subjected to immunohistochemical staining using anti-MMP2, anti-MMP9, and anti-CD68 antibodies. The distribution and localization of MMPs and TAMs were compared between primary and metastatic regions. The expression levels of both MMPs were higher in the metastatic regions of lingual and gingival cancers. Statistically significant differences were observed in both T1 and T2 cases. In contrast to the higher expression of MMPs in metastatic regions, a higher number of TAMs were distributed in the primary regions. From these results, MMP expression levels and the numbers of TAMs were expected to have an inverse relationship between the primary and metastatic regions of OSCC. (J Oral Sci 58, 59-65, 2016).

  8. [Effect of Aloe emodin on invasion and metastasis of high metastatic breast cancer MDA-MB-231 cells].

    PubMed

    He, Zhen-Hui; Huang, Yue-Qun; Weng, Shan-Fan; Tan, Yao-Rong; He, Tai-Ping; Qin, Yan-Mei; Liang, Nian-Ci

    2013-09-01

    To investigate the effect of Aloe emodin (AE) on the invasive and metastatic abilities of human high metastatic breast cancer MDA-MB-231 cells. MTT assay was used to evaluate the viability of MDA-MB-231 cells after treated with AE for 6 h and 24 h. The adhesive potential of MDA-MB-231 cells to FN and LN was tested by cell-matrix adhesion assay. The effect of AE on invasion of MDA-MB-231 cells was measured by Transwell chamber assay. Scratch wound healing assay was applied to determine the effect on migration of MDA-MB-231 cells. The effect of AE on MDA-MB-231 lung metastasis was determined on an experimental metastatic model. 80 micromol/L AE significantly inhibited the invasion, adhesion to FN, LN of MDA-MB-231 cells in vitro, the inhibitory rates were (52.98 +/- 5.46)%, (34.99 +/- 2.63)%, (28.73 +/- 7.00)%, respectively. After 24 h treatment, AE significantly inhibited the migration of MDA-MB-231 cells. The number and volume of lung metastatic nodules formed by MDA-MB-231 cells after 80 micromol/L AE 24 h treatment were decreased compared with control group. AE can suppress the metastasis of MDA-MB-231 cells. Their mechanisms may be related to the inhibition of the capabilities of invasion and migration of MDA-MB-231 cells.

  9. Lactoferrin selectively triggers apoptosis in highly metastatic breast cancer cells through inhibition of plasmalemmal V-H+-ATPase

    PubMed Central

    Pereira, Cátia S.; Guedes, Joana P.; Gonçalves, Marília; Loureiro, Luís; Castro, Lisandra; Gerós, Hernâni; Rodrigues, Lígia R.; Côrte-Real, Manuela

    2016-01-01

    Breast cancer is the most common type of cancer affecting women. Despite the good prognosis when detected early, significant challenges remain in the treatment of metastatic breast cancer. The recruitment of the vacuolar H+-ATPase (V-H+-ATPase) to the plasma membrane, where it mediates the acidification of the tumor microenvironment (TME), is a recognized feature involved in the acquisition of a metastatic phenotype in breast cancer. Therefore, inhibitors of this pump have emerged as promising anticancer drugs. Lactoferrin (Lf) is a natural pro-apoptotic iron-binding glycoprotein with strong anticancer activity whose mechanism of action is not fully understood. Here, we show that bovine Lf (bLf) preferentially induces apoptosis in the highly metastatic breast cancer cell lines Hs 578T and MDA-MB-231, which display a prominent localisation of V-H+-ATPase at the plasma membrane, but not in the lowly metastatic T-47D or in the non-tumorigenic MCF-10-2A cell lines. We also demonstrate that bLf decreases the extracellular acidification rate and causes intracellular acidification in metastatic breast cancer cells and, much like the well-known proton pump inhibitors concanamycin A and bafilomycin A1, inhibits V-H+-ATPase in sub-cellular fractions. These data further support that bLf targets V-H+-ATPase and explain the selectivity of bLf for cancer cells, especially for highly metastatic breast cancer cells. Altogether, our results pave the way for more rational in vivo studies aiming to explore this natural non-toxic compound for metastatic breast cancer therapy. PMID:27556694

  10. Interleukin-4 Expressed By Neoplastic Cells Provokes an Anti-Metastatic Myeloid Immune Response

    PubMed Central

    Zhang, Connie S.; Kim, Hyeyeon; Mullins, Graeme; Tyryshkin, Kathrin; LeBrun, David P.; Elliott, Bruce E.; Greer, Peter A.

    2016-01-01

    Objective Interleukin-4 (IL-4) can induce macrophages to undergo alternative activation and polarize toward an M2-like or wound healing phenotype. Tumor associated macrophages (TAMs) are thought to assume M2-like properties, and it has been suggested they promote tumor growth and metastasis through effects on the tumor stroma, including extracelluar matrix remodeling and angiogenesis. IL-4 also promotes macrophage survival and formation of multinucleated giant cells, which have enhanced phagocytic behavior. This study was designed to explore the effect of cancer cell derived IL-4 on the tumor immune stroma and metastasis. Methods The metastatic mouse mammary carcinoma cell line AC2M2 was transduced with control or IL-4 encoding retroviruses and employed in orthotopic engraftment models. Tumor growth and metastasis were assessed. The cellular composition and biomarker expression of tumors were examined by immunohistochemical staining and flow cytometry; the transcriptome of the immune stroma was analyzed by nanoString based transcript quantitation; and in vivo and in vitro interactions between cancer cells and macrophages were assessed by flow cytometry and co-culture with video-time lapse microscopy, respectively. Results Unexpectedly, tumors from IL-4 expressing AC2M2 engrafted cells grew at reduced rates, and most surprising, they lost all metastatic potential relative to tumors from control AC2M2 cells. Myeloid cell numbers were not increased in IL-4 expressing tumors, but their expression of the M2 marker arginase I was elevated. Transcriptome analysis revealed an immune signature consistent with IL-4 induced M2 polarization of the tumor microenvironment and a generalized increase in myeloid involvement in the tumor stroma. Flow cytometry analysis indicated enhanced cancer cell phagocytosis by TAMs from IL-4 expressing tumors, and co-culture studies showed that IL-4 expressing cancer cells supported the survival and promoted the in vitro phagocytic behavior of

  11. Grape seed proanthocyanidins induce apoptosis and inhibit metastasis of highly metastatic breast carcinoma cells.

    PubMed

    Mantena, Sudheer K; Baliga, Manjeshwar S; Katiyar, Santosh K

    2006-08-01

    The strategies available for the treatment of metastatic breast cancer are limited. Dietary botanicals may have a better protective effect on this disease. We therefore investigated the effects of grape seed proanthocyanidins (GSPs) on a highly metastatic mouse mammary carcinoma cell line. In vitro treatment of breast cancer cells, 4T1, MCF-7 and MDA-MB-468, with GSPs resulted in significant inhibition of cellular proliferation and viability, and induction of apoptosis in 4T1 cells in a time- and dose-dependent manner. Further analysis indicated an alteration in the ratio of Bax/Bcl-2 proteins in favor of apoptosis, and the knockdown of Bax using Bax siRNA transfection of 4T1 cells resulted in blocking of GSPs-induced apoptosis. Induction of apoptosis was associated with the release of cytochrome c, increased expression of Apaf-1 and activation of caspase 3 and poly (ADP-ribose) polymerase. Treatment with the pan-caspase inhibitor (Z-VAD-FMK) resulted in partial but significant inhibition of apoptosis in 4T1 cells suggesting the involvement of both caspase activation-dependent and activation-independent pathways in the apoptosis of 4T1 cells induced by GSPs. The effects of dietary GSPs were then examined using an in vivo model in which 4T1 cells were implanted subcutaneously in Balb/c mice. Dietary GSPs (0.2 and 0.5%, w/w) significantly inhibited the growth of the implanted 4T1 tumor cells and increased the ratio of Bax:Bcl-2 proteins, cytochrome c release, induction of Apaf-1 and activation of caspase 3 in the tumor microenvironment. Notably, the metastasis of tumor cells to the lungs was inhibited significantly and the survival of the mice enhanced. These data suggest that GSPs possess chemotherapeutic efficacy against breast cancer including inhibition of metastasis.

  12. Paraneoplastic pityriasis rubra pilaris as the presenting manifestation of metastatic squamous cell carcinoma.

    PubMed

    Remedios, Isabel M; Jensen, J Daniel; Beckum, Kathleen; McKay, Kristopher; Kissel, Rebecca

    2014-05-01

    Pityriasis rubra pilaris (PRP) is a rare idiopathic papulosquamous eruption. Few cases of PRP have been reported in association with malignancies. We report a case of an 83-year-old Caucasian male who presented with recalcitrant paraneoplastic PRP as the presenting manifestation of metastatic squamous cell carcinoma with unknown primary. Treatment with chemotherapy and radiation led to temporary radiologic and symptomatic regression of the cancer as well as resolution of cutaneous findings. This suggests a direct relationship between the PRP and the underlying malignancy in this patient. This case highlights a rare, but important phenomenon in which PRP may act as a harbinger for underlying malignancy.

  13. Bilateral Asynchronous Renal Cell Carcinoma with Metastatic Involvement of the Tongue

    PubMed Central

    Ghazali, Naseem; Davis, Charlotte; Barrett, A. W.; Tighe, John V.

    2012-01-01

    Renal cell carcinoma (RCC) has a propensity for distant organ metastasis and late recurrence, involving not only the ipsilateral but also contralateral kidney. Lingual metastasis by RCC is rare. We present an unusual case of bilateral asynchronous RCC. Involvement of the right kidney was discovered only after a metastatic tongue lesion was diagnosed. The original RCC had been treated by left nephrectomy 14 years previously. Due to end-stage primary pulmonary malignancy, and poor function of the remaining kidney, immunotherapy was unsuitable. Palliative local resection of the lingual metastasis alleviated functional difficulties and was preventative against airway obstruction, but the patient died five months later. PMID:23008792

  14. Bilateral asynchronous renal cell carcinoma with metastatic involvement of the tongue.

    PubMed

    Ghazali, Naseem; Davis, Charlotte; Barrett, A W; Tighe, John V

    2012-01-01

    Renal cell carcinoma (RCC) has a propensity for distant organ metastasis and late recurrence, involving not only the ipsilateral but also contralateral kidney. Lingual metastasis by RCC is rare. We present an unusual case of bilateral asynchronous RCC. Involvement of the right kidney was discovered only after a metastatic tongue lesion was diagnosed. The original RCC had been treated by left nephrectomy 14 years previously. Due to end-stage primary pulmonary malignancy, and poor function of the remaining kidney, immunotherapy was unsuitable. Palliative local resection of the lingual metastasis alleviated functional difficulties and was preventative against airway obstruction, but the patient died five months later.

  15. Novel therapeutic options for second-line therapy in metastatic renal cell carcinoma

    PubMed Central

    VON KLOT, CHRISTOPH-A. J.; MERSEBURGER, AXEL S.; KUCZYK, MARKUS A.

    2016-01-01

    Metastatic renal cell carcinoma (mRCC) has gained a variety of therapeutic options since the introduction of targeted therapy, starting in 2007. The basic molecular mechanisms included predominantly the targeting of vascular endothelial growth factor or the inhibition of the mammalian target of rapamycin. Recently, results from two randomized controlled trials, the CheckMate-25 and the METEOR trial, regarding therapy for RCC in the second-line setting have been published. In the present review, the current status of second-line therapy in mRCC is discussed, together with results from the two newly introduced substances, nivolumab and cabozantinib. PMID:27313856

  16. Disseminated metastatic penile squamous cell carcinoma detected by fluorodeoxyglucose PET/computerized tomography

    PubMed Central

    Kaya, Zubeyde Rana; Sager, Sait; Halac, Metin; Sonmezoglu, Kerim

    2012-01-01

    Penile cancer is an uncommon malignancy which of the management depends on the clinical stage and location of the lesion. Positron emission tomography/computerized tomography (PET/CT) is a promising method for detection of distant metastatic lesions and therapeutic strategy planning. Here, we report a case of penile squamous cell carcinoma of 57-year-old male patient, was referred to PET/CT department for investigation of metastases. There were significantly increased fluoro-18 fluorodeoxyglucose activities in supradiaphragmatic and infradiaphragmatic lymphatic stations. PMID:23919076

  17. Radiation Therapy and MK-3475 for Patients With Recurrent/Metastatic Head and Neck Cancer, Renal Cell Cancer, Melanoma, and Lung Cancer

    ClinicalTrials.gov

    2016-10-18

    Head and Neck Squamous Cell Carcinoma; Metastatic Renal Cell Cancer; Recurrent Head and Neck Carcinoma; Recurrent Lung Carcinoma; Recurrent Renal Cell Carcinoma; Recurrent Skin Carcinoma; Stage III Renal Cell Cancer; Stage IV Lung Cancer; Stage IV Skin Melanoma

  18. Phagocytosis and solubilization of fixed cells by metastatic hamster embryo fibroblasts, Nil2C2

    SciTech Connect

    Sakiyama, H.; Nishino, Y.; Nishimura, K.; Noda, Y.; Otsu, H.

    1984-05-01

    When Nil2C2, a metastatic clone derived from hamster embryo fibroblasts (Nil), was inoculated over (/sup 3/H)leucine-labeled fixed cells, Nil2C2 cells solubilized and phagocytosed fixed cells, and the radioactivity was released into the culture medium as trichloroacetic acid-soluble fragments. The solubilization of fixed cells was dependent on both the time of incubation of living cells with fixed cells and the number of living cells inoculated. Nil2C2 cells were shown by autoradiographic and electron microscopic studies to peel off fixed cells and ingest them as large fragments. The solubilization of fixed cells was significantly decreased when plasminogen was depleted from the culture medium. Protease inhibitors such as leupeptin, epsilon-aminocaproic acid, and soybean trypsin inhibitor partially inhibited the proteolysis and phagocytosis of Nil2C2 cells. Mouse peritoneal macrophages activated by Salmonella typhimurium solubilized fixed cells after the addition of 12-O-tetradecanoylphorbol-13-acetate. However, they did not phagocytose fixed cells as large fragments.

  19. The adoptive transfer of cultured T cells for patients with metastatic melanoma.

    PubMed

    Yang, James C

    2013-01-01

    T cells have been shown to be capable of rejecting a patient's tumor. Weak responses to current vaccines and the toxicity of exogenously administered cytokines limit the intensity of the T-cell response that can be actively generated in vivo. Adoptive T-cell transfer enhances an intrinsically weak immune response to cancer by activating and expanding tumor reactive T cells in vitro and manipulating the environment of the host at the time of transfer. One can frequently find tumor-reactive T cells in metastatic lesions in patients with melanoma, and expand them in vitro for readministration. When successful, this adoptive cellular immunotherapy has resulted in sustainable curative outcomes. Subsequently, the applicability of adoptive T-cell transfer has been greatly expanded by the development of methods to genetically engineer open-repertoire human T-cells to confer tumor reactivity. This re-direction of T-cell specificity can be achieved by introducing a variety of receptors that ligate tumor-associated antigens and then trigger the normal activation mechanism of T cells. Future T-cell engineering will add a new dimension by reprogramming T-cell functions for optimal tumor rejection. The antigens recognized by T cells, the techniques to procure and grow tumor reactive T cells, the conditioning of the recipient to optimize efficacy, and the results of clinical protocols are reviewed herein.

  20. Tocilizumab unmasks a stage-dependent interleukin-6 component in statin-induced apoptosis of metastatic melanoma cells

    PubMed Central

    Minichsdorfer, Christoph; Wasinger, Christine; Sieczkowski, Evelyn; Atil, Bihter

    2015-01-01

    The interleukin (IL)-6 inhibits the growth of early-stage melanoma cells, but not metastatic cells. Metastatic melanoma cells are susceptible to statin-induced apoptosis, but this is not clear for early-stage melanoma cells. This study aimed to investigate the IL-6 susceptibility of melanoma cells from different stages in the presence of simvastatin to overcome loss of growth arrest. ELISA was used to detect secreted IL-6 in human melanoma cells. The effects of IL-6 were measured by western blots for STAT3 and Bcl-2 family proteins. Apoptosis and proliferation were measured by caspase 3 activity, Annexin V staining, cell cycle analysis, and a wound-healing assay. Human metastatic melanoma cells A375 and 518A2 secrete high amounts of IL-6, in contrast to early-stage WM35 cells. Canonical IL-6 signaling is intact in these cells, documented by transient phosphorylation of STAT3. Although WM35 cells are highly resistant to simvastatin-induced apoptosis, coadministration with IL-6 enhanced the susceptibility to undergo apoptosis. This proapoptotic effect of IL-6 might be explained by a downregulation of Bcl-XL, observed only in WM35 cells. Furthermore, the IL-6 receptor blocking antibody tocilizumab was coadministered and unmasked an IL-6-sensitive proportion in the simvastatin-induced caspase 3 activity of metastatic melanoma cells. These results confirm that simvastatin facilitates apoptosis in combination with IL-6. Although endogenous IL-6 secretion is sufficient in metastatic melanoma cells, exogenously added IL-6 is needed for WM35 cells. This effect may explain the failure of simvastatin to reduce melanoma incidence in clinical trials and meta-analyses. PMID:26020489

  1. Different deficiencies in the prevention of tumorigenic-low-metastatic murine K-1735b melanoma cells from producing metastases.

    PubMed

    Aukerman, S L; Price, J E; Fidler, I J

    1986-10-01

    To produce metastasis, malignant tumor cells must be able to complete a sequence of many steps that depend not only on tumor cell properties but also on ability of the tumor cells to interact effectively with host homeostatic mechanisms to avoid destruction. Therefore, it should be possible to isolate clonal populations non- or low metastatic. In a study of K-1735 clones introduced into normal syngeneic hosts, the reasons for the lack of or low ability of metastasis production did indeed differ among different clones. Some clones were identified that were low metastatic in syngeneic C3H/HeN mice because of antigenic characteristics. Others failed to give rise to metastases because they could not survive and grow once arrested in the lung parenchyma. These data suggested that the success of future studies dealing with genetic analysis of the metastatic phenotype could depend on the use of appropriate tumor cell populations.

  2. Translocation of BBAP from the cytoplasm to the nucleus reduces the metastatic ability of vemurafenib-resistant SKMEL28 cells.

    PubMed

    Thang, Nguyen Dinh; Minh, Nguyen Van; Huong, Pham Thu

    2017-01-01

    To the best of our knowledge, the present study is the first to demonstrate that treatment of vemurafenib-resistant SKMEL28 (SKMEL28-R) cells with paclitaxel leads to a shift in localization of the E3-ligase BBAP from the cytoplasm to the nucleus, consequently decreasing the metastatic ability of this cell line. The present study revealed that the movement of BBAP from the cytoplasm to nucleus initiated a change in cell morphology. In addition, the translocation of BBAP led to a decrease of metastatic characteristics in SKMEL28‑R cells, including migration and invasion via downregulation of the phosphorylated form of focal adhesion kinase and N‑cadherin, as well as an upregulation of p21 and E-cadherin. The results of the present study suggested that BBAP may not only be a novel biomarker for melanoma, but also a novel therapeutic target for treatment of metastatic melanoma.

  3. Haematuria as an uncommon initial presenting symptom of metastatic squamous cell carcinoma (SCC) to kidney

    PubMed Central

    Kawsar, Hameem I; Spiro, Timothy P; Daw, Hamed A

    2011-01-01

    A 47-year-old female presented with a 2-week history of painless haematuria. Urine dipstick showed moderate leucocytes. Blood and urine cultures were negative and cytology was negative for malignant cells. Flexible cystoscopy was negative for any bladder pathology. An ultrasonogram of the abdomen showed a mass in the left kidney. CT showed a mass-like lesion within the left kidney suspicious for renal carcinoma, and cavitary lesions in both lungs. Biopsy of the lung showed clusters of atypical cells suspicious for squamous cell carcinoma (SCC), and left kidney lesion showed malignant cells derived from SCC. A whole body positron emission tomography/CT showed lesions in the lungs, left kidney and skeleton. Complete clinical examination, laboratory and imaging studies did not reveal any site of primary tumour in any part of the body. Haematuria is a very unusual initial presentation of metastatic tumour to kidney. PMID:22688475

  4. New treatment options for metastatic renal cell carcinoma with prior anti-angiogenesis therapy.

    PubMed

    Zarrabi, Kevin; Fang, Chunhui; Wu, Shenhong

    2017-02-02

    Angiogenesis is a critical process in the progression of advanced renal cell carcinoma. Agents targeting angiogenesis have played a primary role in the treatment of metastatic renal cell carcinoma. However, resistance to anti-angiogenesis therapy almost always occurs, and major progress has been made in understanding its underlying molecular mechanism. Axitinib and everolimus have been used extensively in patients whom have had disease progression after prior anti-angiogenesis therapy. Recently, several new agents have been shown to improve overall survival in comparison with everolimus. This review provides an in-depth summary of drugs employable in the clinical setting, the rationale to their use, and the studies conducted leading to their approval for use and provides perspective on the paradigm shift in the treatment of renal cell carcinoma. Highlighted are the newly approved agents cabozantinib, nivolumab, and lenvatinib for advanced renal cell carcinoma patients treated with prior anti-angiogenesis therapy.

  5. Anti-Metastatic Effect of Dehydrocorydaline on H1299 Non-Small Cell Lung Carcinoma Cells via Inhibition of Matrix Metalloproteinases and B Cell Lymphoma 2.

    PubMed

    Lee, Jihyun; Sohn, Eun Jung; Yoon, Sang Wook; Kim, Chang Geun; Lee, Sangil; Kim, Joe Young; Baek, Namin; Kim, Sung-Hoon

    2017-03-01

    Though Dehydrocorydaline, an alkaloid isolated from Corydalis turtschaninovii tuber, was known to have anti-coronary artery disease, anti-inflammatory, apoptotic, anti-allergic, anti-acetylcholinesterase, and antitumor effects, the underlying anti-metastatic mechanism of Dehydrocorydalin was never elucidated in lung cancer cells so far. Thus, in the present study, the anti-metastatic effect of Dehydrocorydaline was examined in non-small cell lung carcinoma (NSCLC) cells, mainly targeting matrix metalloproteinases (MMPs) and B cell lymphoma-2 (Bcl-2) signaling. Here, Dehydrocorydaline exerted weak cytotoxicity and attenuated the protein expression of Bcl-2 and activated Bax in a concentration-dependent manner in NSCLC cells, such as A549, H460, H1299, and H596 cells. Also, Dehydrocorydaline suppressed the migration of H1299 cells by wound healing assay and transwell migration assay. Consistently, Dehydrocorydaline attenuated mRNA and protein levels of MMP7 and MMP9 as metastasis biomarkers in H1299 cells by quantitative reverse transcription polymerase chain reaction. Of note, Bcl-2 overexpression reduced the cytotoxic and anti-metastatic effects of Dehydrocorydaline on pCDNA-Bcl-2 transfected H1299 cells. Overall, our findings provide scientific evidence that Dehydrocorydaline exerts anti-metastatic potential via suppression of MMPs and Bcl-2 signaling in NSCLC cells. Copyright © 2017 John Wiley & Sons, Ltd.

  6. High OCT4A levels drive tumorigenicity and metastatic potential of medulloblastoma cells.

    PubMed

    da Silva, Patrícia Benites Gonçalves; Teixeira Dos Santos, Márcia Cristina; Rodini, Carolina Oliveira; Kaid, Carolini; Pereira, Márcia Cristina Leite; Furukawa, Gabriela; da Cruz, Daniel Sanzio Gimenes; Goldfeder, Mauricio Barbugiani; Rocha, Clarissa Ribeiro Reily; Rosenberg, Carla; Okamoto, Oswaldo Keith

    2017-03-21

    Medulloblastoma is a highly aggressive pediatric brain tumor, in which sporadic expression of the pluripotency factor OCT4 has been recently correlated with poor patient survival. However the contribution of specific OCT4 isoforms to tumor aggressiveness is still poorly understood. Here, we report that medulloblastoma cells stably overexpressing the OCT4A isoform displayed enhanced clonogenic, tumorsphere generation, and invasion capabilities. Moreover, in an orthotopic metastatic model of medulloblastoma, OCT4A overexpressing cells generated more developed, aggressive and infiltrative tumors, with tumor-bearing mice attaining advanced metastatic disease and shorter survival rates. Pro-oncogenic OCT4A effects were expression-level dependent and accompanied by distinct chromosomal aberrations. OCT4A overexpression in medulloblastoma cells also induced a marked differential expression of non-coding RNAs, including poorly characterized long non-coding RNAs and small nucleolar RNAs. Altogether, our findings support the relevance of pluripotency-related factors in the aggravation of medulloblastoma traits classically associated with poor clinical outcome, and underscore the prognostic and therapeutic value of OCT4A in this challenging type of pediatric brain cancer.

  7. High OCT4A levels drive tumorigenicity and metastatic potential of medulloblastoma cells

    PubMed Central

    Gonçalves da Silva, Patrícia Benites; Teixeira dos Santos, Márcia Cristina; Rodini, Carolina Oliveira; Kaid, Carolini; Leite Pereira, Márcia Cristina; Furukawa, Gabriela; Gimenes da Cruz, Daniel Sanzio; Goldfeder, Mauricio Barbugiani; Reily Rocha, Clarissa Ribeiro; Rosenberg, Carla; Okamoto, Oswaldo Keith

    2017-01-01

    Medulloblastoma is a highly aggressive pediatric brain tumor, in which sporadic expression of the pluripotency factor OCT4 has been recently correlated with poor patient survival. However the contribution of specific OCT4 isoforms to tumor aggressiveness is still poorly understood. Here, we report that medulloblastoma cells stably overexpressing the OCT4A isoform displayed enhanced clonogenic, tumorsphere generation, and invasion capabilities. Moreover, in an orthotopic metastatic model of medulloblastoma, OCT4A overexpressing cells generated more developed, aggressive and infiltrative tumors, with tumor-bearing mice attaining advanced metastatic disease and shorter survival rates. Pro-oncogenic OCT4A effects were expression-level dependent and accompanied by distinct chromosomal aberrations. OCT4A overexpression in medulloblastoma cells also induced a marked differential expression of non-coding RNAs, including poorly characterized long non-coding RNAs and small nucleolar RNAs. Altogether, our findings support the relevance of pluripotency-related factors in the aggravation of medulloblastoma traits classically associated with poor clinical outcome, and underscore the prognostic and therapeutic value of OCT4A in this challenging type of pediatric brain cancer. PMID:28186969

  8. Adenovirus MART-1-engineered autologous dendritic cell vaccine for metastatic melanoma.

    PubMed

    Butterfield, Lisa H; Comin-Anduix, Begonya; Vujanovic, Lazar; Lee, Yohan; Dissette, Vivian B; Yang, Jin-Quan; Vu, Hong T; Seja, Elizabeth; Oseguera, Denise K; Potter, Douglas M; Glaspy, John A; Economou, James S; Ribas, Antoni

    2008-04-01

    We performed a phase 1/2 trial testing the safety, toxicity, and immune response of a vaccine consisting of autologous dendritic cells (DCs) transduced with a replication-defective adenovirus (AdV) encoding the full-length melanoma antigen MART-1/Melan-A (MART-1). This vaccine was designed to activate MART-1-specific CD+8 and CD4+ T cells. Metastatic melanoma patients received 3 injections of 10(6) or 10(7) DCs, delivered intradermally. Cell surface phenotype and cytokine production of the DCs used for the vaccines were tested, and indicated intermediate maturity. CD8+ T-cell responses to MART-1 27-35 were assessed by both major histocompatibility complex class I tetramer and interferon (IFN)-gamma enzyme-linked immunosorbent spot (ELISPOT) before, during, and after each vaccine and CD4+ T-cell responses to MART-1 51-73 were followed by IFN-gamma ELISPOT. We also measured antigen response breadth. Determinant spreading from the immunizing antigen MART-1 to other melanoma antigens [gp100, tyrosinase, human melanoma antigen-A3 (MAGE-A3)] was assessed by IFN-gamma ELISPOT. Twenty-three patients were enrolled and 14 patients received all 3 scheduled DC vaccines. Significant CD8+ and/or CD4+ MART-1-specific T-cell responses were observed in 6/11 and 2/4 patients evaluated, respectively, indicating that the E1-deleted adenovirus encoding the cDNA for MART-1/Melan-A (AdVMART1)/DC vaccine activated both helper and killer T cells in vivo. Responses in CD8+ and CD4+ T cells to additional antigens were noted in 2 patients. The AdVMART1-transduced DC vaccine was safe and immunogenic in patients with metastatic melanoma.

  9. Adenovirus MART-1–engineered Autologous Dendritic Cell Vaccine for Metastatic Melanoma

    PubMed Central

    Butterfield, Lisa H.; Comin-Anduix, Begonya; Vujanovic, Lazar; Lee, Yohan; Dissette, Vivian B.; Yang, Jin-Quan; Vu, Hong T.; Seja, Elizabeth; Oseguera, Denise K.; Potter, Douglas M.; Glaspy, John A.; Economou, James S.; Ribas, Antoni

    2013-01-01

    Summary We performed a phase 1/2 trial testing the safety, toxicity, and immune response of a vaccine consisting of autologous dendritic cells (DCs) transduced with a replication-defective adenovirus (AdV) encoding the full-length melanoma antigen MART-1/Melan-A (MART-1). This vaccine was designed to activate MART-1–specific CD8+ and CD4+ T cells. Metastatic melanoma patients received 3 injections of 106 or 107 DCs, delivered intradermally. Cell surface phenotype and cytokine production of the DCs used for the vaccines were tested, and indicated intermediate maturity. CD8+ T-cell responses to MART-127-35 were assessed by both major histocompatibility complex class I tetramer and interferon (IFN)-γ enzyme-linked immunosorbent spot (ELISPOT) before, during, and after each vaccine and CD4+ T-cell responses to MART-151-73 were followed by IFN-γ ELISPOT. We also measured antigen response breadth. Determinant spreading from the immunizing antigen MART-1 to other melanoma antigens [gp100, tyrosinase, human melanoma antigen-A3 (MAGE-A3)] was assessed by IFN-γ ELISPOT. Twenty-three patients were enrolled and 14 patients received all 3 scheduled DC vaccines. Significant CD8+ and/or CD4+ MART-1–specific T-cell responses were observed in 6/11 and 2/4 patients evaluated, respectively, indicating that the E1-deleted adeno-virus encoding the cDNA for MART-1/Melan-A (AdV-MART1)/DC vaccine activated both helper and killer T cells in vivo. Responses in CD8+ and CD4+ T cells to additional antigens were noted in 2 patients. The AdVMART1-transduced DC vaccine was safe and immunogenic in patients with metastatic melanoma. PMID:18317358

  10. Adenosine potentiates the therapeutic effects of neural stem cells expressing cytosine deaminase against metastatic brain tumors.

    PubMed

    Kang, Wonyoung; Seol, Ho Jun; Seong, Dong-Ho; Kim, Jandi; Kim, Yonghyun; Kim, Seung U; Nam, Do-Hyun; Joo, Kyeung Min

    2013-09-01

    Tumor-tropic properties of neural stem cells (NSCs) provide a novel approach with which to deliver targeting therapeutic genes to brain tumors. Previously, we developed a therapeutic strategy against metastatic brain tumors using a human NSC line (F3) expressing cytosine deaminase (F3.CD). F3.CD converts systemically administered 5-fluorocytosine (5-FC), a blood-brain barrier permeable nontoxic prodrug, into the anticancer agent 5-fluorouracil (5-FU). In this study, we potentiated a therapeutic strategy of treatment with nucleosides in order to chemically facilitate the endogenous conversion of 5-FU to its toxic metabolite 5-FU ribonucleoside (5-FUR). In vitro, 5-FUR showed superior cytotoxic activity against MDA-MB-435 cancer cells when compared to 5-FU. Although adenosine had little cytotoxic activity, the addition of adenosine significantly potentiated the in vitro cytotoxicity of 5-FU. When MDA-MB‑435 cells were co-cultured with F3.CD cells, F3.CD cells and 5-FC inhibited the growth of MDA-MB-435 cells more significantly in the presence of adenosine. Facilitated 5-FUR production by F3.CD was confirmed by an HPLC analysis of the conditioned media derived from F3.CD cells treated with 5-FC and adenosine. In vivo systemic adenosine treatment also significantly potentiated the therapeutic effects of F3.CD cells and 5-FC in an MDA-MB-435 metastatic brain tumor model. Simple adenosine addition improved the antitumor activity of the NSCs carrying the therapeutic gene. Our results demonstrated an increased therapeutic potential, and thereby, clinical applicability of NSC-based gene therapy.

  11. PAX-8 expression in primary and metastatic Merkel cell carcinoma: an immunohistochemical analysis.

    PubMed

    Sangoi, Ankur R; Cassarino, David S

    2013-06-01

    PAX-8, a nephric cell lineage transcription factor initially characterized in renal cell carcinomas, is also well recognized as a marker of Müllerian tract and thyroid tumors. From a previous tissue microarray study of nonrenal neoplasms including a variety of skin tumors, we identified PAX-8 staining in a small set of Merkel cell carcinomas, a finding not previously described. Herein, we explore PAX-8 immunoreactivity in 34 whole-section Merkel cell carcinomas (24 primary, 10 metastatic) using polyclonal PAX-8 (prediluted) and 2 varieties of monoclonal PAX-8 (prediluted clone MRQ-50 and 1:100 dilution clone BC12). Nuclear staining intensity and extent was semiquantitatively analyzed with a comparison of staining thresholds required for a "positive" result (≥ 2+ vs. 1+). Thirty-three of 34 (97%) cases showed positive Cell Marque polyclonal PAX-8 staining, whereas 31 of 34 (91%) cases showed positive Cell Marque monoclonal PAX-8 staining. There was no significant difference in staining between primary versus metastatic tumors. The Cell Marque polyclonal PAX-8 was superior to their monoclonal PAX-8, maintaining strong sensitivity using a ≥ 2+ versus 1+ staining cut point for positive results (79% vs. 18%, respectively), which may be important in cases with scant tissue or background staining. The Biocare monoclonal PAX-8 was negative in all cases. PAX-8 staining in Merkel cell carcinoma expands the spectrum of tumors showing immunoreactivity and may prove to be a useful addition to a diagnostic panel. Awareness of this immunoreactivity and recognition of the antibody source and clone are important to preclude diagnostic pitfalls with tumors in the differential diagnosis.

  12. Impact of Non-Pulmonary Visceral Metastases in the Prognosis and Practice of Metastatic Testicular Germ Cell Tumors

    PubMed Central

    Rossi, Lorena; Martignano, Filippo; Gallà, Valentina; Maugeri, Antonio; Schepisi, Giuseppe

    2016-01-01

    Non-pulmonary visceral metastases, in bones, brain and liver, represent nearly the 10% of metastatic sites of advanced germ cell tumors and are associated with poor prognosis. This review article summarizes major evidences on the impact of different visceral sites on the prognosis, treatment and clinical outcome of patients with germ cell tumors. The clinic-biological mechanisms by which these metastatic sites are associated with poor clinical outcome remain unclear. The multimodality treatment showed a potential better survival, in particular in patients with relapsed disease. Patients with advanced germ cell tumors with visceral metastases should be referred to centers with high expertise in the clinical management of such disease. PMID:27471579

  13. Blocking TNF-α inhibits angiogenesis and growth of IFIT2-depleted metastatic oral squamous cell carcinoma cells.

    PubMed

    Lai, Kuo-Chu; Liu, Chung-Ji; Lin, Tsung-Jen; Mar, Ai-Chung; Wang, Hsiu-Hua; Chen, Chi-Wei; Hong, Zi-Xuan; Lee, Te-Chang

    2016-01-28

    Our previous study demonstrated that the depletion of interferon-induced protein with tetratricopeptide repeats 2 (IFIT2) promoted metastasis and was associated with a poor prognosis in patients with oral squamous cell carcinoma (OSCC). Our current study explores the major downstream signaling involved in IFIT2 depletion-induced OSCC metastasis. To this end, we used two cell lines (designated sh-control-xeno and sh-IFIT2-xeno) derived from human OSCC xenografts expressing sh-control and sh-IFIT2, respectively, and one metastatic OSCC subline (sh-IFIT2-meta) from an IFIT2-depleted metastatic tumor. We found that the sh-IFIT2-meta cells proliferated more slowly than the sh-control-xeno cells but exhibited higher migration and chemoresistance. Using microarray technology and Ingenuity Pathway Analysis, we found that TNF-α was one of the major downstream targets in IFIT2-depleted OSCC cells. Quantitative real-time PCR, western blotting, and ELISA results confirmed that TNF-α was upregulated in the sh-IFIT2-meta cells. Blocking TNF-α abolished the angiogenic activity induced by the sh-IFIT2-meta cells. Furthermore, the human-specific TNF-α antibody golimumab significantly inhibited in vivo angiogenesis, tumor growth and metastasis of sh-IFIT2-meta cells. These results demonstrate that IFIT2 depletion results in TNF-α upregulation, leading to angiogenesis and metastasis of OSCC cells.

  14. Genetic landscape of metastatic and recurrent head and neck squamous cell carcinoma

    PubMed Central

    Hedberg, Matthew L.; Goh, Gerald; Chiosea, Simion I.; Bauman, Julie E.; Freilino, Maria L.; Zeng, Yan; Wang, Lin; Diergaarde, Brenda B.; Gooding, William E.; Lui, Vivian W.Y.; Herbst, Roy S.; Lifton, Richard P.; Grandis, Jennifer R.

    2015-01-01

    BACKGROUND. Recurrence and/or metastasis occurs in more than half of patients with head and neck squamous cell carcinoma (HNSCC), and these events pose the greatest threats to long-term survival. We set out to identify genetic alterations that underlie recurrent/metastatic HNSCC. METHODS. Whole-exome sequencing (WES) was performed on genomic DNA extracted from fresh-frozen whole blood and patient-matched tumor pairs from 13 HNSCC patients with synchronous lymph node metastases and 10 patients with metachronous recurrent tumors. Mutational concordance within and between tumor pairs was used to analyze the spatiotemporal evolution of HNSCC in individual patients and to identify potential therapeutic targets for functional evaluation. RESULTS. Approximately 86% and 60% of single somatic nucleotide variants (SSNVs) identified in synchronous nodal metastases and metachronous recurrent tumors, respectively, were transmitted from the primary index tumor. Genes that were mutated in more than one metastatic or recurrent tumor, but not in the respective primary tumors, include C17orf104, inositol 1,4,5-trisphosphate receptor, type 3 (ITPR3), and discoidin domain receptor tyrosine kinase 2 (DDR2). Select DDR2 mutations have been shown to confer enhanced sensitivity to SRC-family kinase (SFK) inhibitors in other malignancies. Similarly, HNSCC cell lines harboring endogenous and engineered DDR2 mutations were more sensitive to the SFK inhibitor dasatinib than those with WT DDR2. CONCLUSION. In this WES study of patient-matched tumor pairs in HNSCC, we found synchronous lymph node metastases to be genetically more similar to their paired index primary tumors than metachronous recurrent tumors. This study outlines a compendium of somatic mutations in primary, metastatic, and/or recurrent HNSCC cancers, with potential implications for precision medicine approaches. FUNDING. National Cancer Institute, American Cancer Society, Agency for Science, Technology and Research of Singapore

  15. Kinase Gene Expression Profiling of Metastatic Clear Cell Renal Cell Carcinoma Tissue Identifies Potential New Therapeutic Targets

    PubMed Central

    Ramaker, Ryne C.; Cooper, Sara J.; Chen, Dongquan; Sudarshan, Sunil; Wei, Shi; Guru, Arjun S.; Zhao, Amy; Cooper, Tiffiny; Della Manna, Deborah L.; Naik, Gurudatta; Myers, Richard M.; Sonpavde, Guru

    2016-01-01

    Kinases are therapeutically actionable targets. Kinase inhibitors targeting vascular endothelial growth factor receptors (VEGFR) and mammalian target of rapamycin (mTOR) improve outcomes in metastatic clear cell renal cell carcinoma (ccRCC), but are not curative. Metastatic tumor tissue has not been comprehensively studied for kinase gene expression. Paired intra-patient kinase gene expression analysis in primary tumor (T), matched normal kidney (N) and metastatic tumor tissue (M) may assist in identifying drivers of metastasis and prioritizing therapeutic targets. We compared the expression of 519 kinase genes using NanoString in T, N and M in 35 patients to discover genes over-expressed in M compared to T and N tissue. RNA-seq data derived from ccRCC tumors in The Cancer Genome Atlas (TCGA) were used to demonstrate differential expression of genes in primary tumor tissue from patients that had metastasis at baseline (n = 79) compared to those that did not develop metastasis for at least 2 years (n = 187). Functional analysis was conducted to identify key signaling pathways by using Ingenuity Pathway Analysis. Of 10 kinase genes overexpressed in metastases compared to primary tumor in the discovery cohort, 9 genes were also differentially expressed in TCGA primary tumors with metastasis at baseline compared to primary tumors without metastasis for at least 2 years: EPHB2, AURKA, GSG2, IKBKE, MELK, CSK, CHEK2, CDC7 and MAP3K8; p<0.001). The top pathways overexpressed in M tissue were pyridoxal 5'-phosphate salvage, salvage pathways of pyrimidine ribonucleotides, NF-kB signaling, NGF signaling and cell cycle control of chromosomal replication. The 9 kinase genes validated to be over-expressed in metastatic ccRCC may represent currently unrecognized but potentially actionable therapeutic targets that warrant functional validation. PMID:27574806

  16. Kinase Gene Expression Profiling of Metastatic Clear Cell Renal Cell Carcinoma Tissue Identifies Potential New Therapeutic Targets.

    PubMed

    Ghatalia, Pooja; Yang, Eddy S; Lasseigne, Brittany N; Ramaker, Ryne C; Cooper, Sara J; Chen, Dongquan; Sudarshan, Sunil; Wei, Shi; Guru, Arjun S; Zhao, Amy; Cooper, Tiffiny; Della Manna, Deborah L; Naik, Gurudatta; Myers, Richard M; Sonpavde, Guru

    2016-01-01

    Kinases are therapeutically actionable targets. Kinase inhibitors targeting vascular endothelial growth factor receptors (VEGFR) and mammalian target of rapamycin (mTOR) improve outcomes in metastatic clear cell renal cell carcinoma (ccRCC), but are not curative. Metastatic tumor tissue has not been comprehensively studied for kinase gene expression. Paired intra-patient kinase gene expression analysis in primary tumor (T), matched normal kidney (N) and metastatic tumor tissue (M) may assist in identifying drivers of metastasis and prioritizing therapeutic targets. We compared the expression of 519 kinase genes using NanoString in T, N and M in 35 patients to discover genes over-expressed in M compared to T and N tissue. RNA-seq data derived from ccRCC tumors in The Cancer Genome Atlas (TCGA) were used to demonstrate differential expression of genes in primary tumor tissue from patients that had metastasis at baseline (n = 79) compared to those that did not develop metastasis for at least 2 years (n = 187). Functional analysis was conducted to identify key signaling pathways by using Ingenuity Pathway Analysis. Of 10 kinase genes overexpressed in metastases compared to primary tumor in the discovery cohort, 9 genes were also differentially expressed in TCGA primary tumors with metastasis at baseline compared to primary tumors without metastasis for at least 2 years: EPHB2, AURKA, GSG2, IKBKE, MELK, CSK, CHEK2, CDC7 and MAP3K8; p<0.001). The top pathways overexpressed in M tissue were pyridoxal 5'-phosphate salvage, salvage pathways of pyrimidine ribonucleotides, NF-kB signaling, NGF signaling and cell cycle control of chromosomal replication. The 9 kinase genes validated to be over-expressed in metastatic ccRCC may represent currently unrecognized but potentially actionable therapeutic targets that warrant functional validation.

  17. Nano-characterization of two closely related melanoma cell lines with different metastatic potential.

    PubMed

    Gostek, Justyna; Prauzner-Bechcicki, Szymon; Nimmervoll, Benedikt; Mayr, Katrin; Pabijan, Joanna; Hinterdorfer, Peter; Chtcheglova, Lilia A; Lekka, Małgorzata

    2015-02-01

    Cutaneous malignant melanoma is one of the most lethal types of skin cancer. Its progression passes through several steps, leading to the appearance of a new population of cells with aggressive biological potential. Here, we focused on the nano-characterization of two different melanoma cell lines with similar morphological appearance but different metastatic potential, namely, WM115 from vertical growth phase (VGP) and WM266-4 derived from metastasis to skin. The first cell line represents cells that progressed to the VGP, while the WM266-4 cell line denotes cells from the metastasis to skin. Exploring with a combination of atomic force and fluorescence microscopes, our goal was to identify cell surface characteristics in both cell lines that may determine differences in the cellular nano-mechanical properties. Cell elasticity was found to be affected by the presence of F-actin-based flexible ridges, rich in F-actin co-localized with β1 integrins in the studied cell lines. These results point out how progressive changes in the surface structure of melanoma cells can affect their bionanomechanical properties.

  18. Histopathological mapping of metastatic tumor cells in sentinel lymph nodes of oral and oropharyngeal squamous cell carcinomas.

    PubMed

    Denoth, Seraina; Broglie, Martina A; Haerle, Stephan K; Huber, Gerhard F; Haile, Sarah R; Soltermann, Alex; Jochum, Wolfram; Stoeckli, Sandro J

    2015-10-01

    Sentinel lymph node biopsy is a reliable technique for accurate determination of the cervical lymph node status in patients with early oral and oropharyngeal cancer but analyses on the distribution pattern of metastatic spread within sentinel lymph nodes are lacking. The localizations of carcinoma deposits were analyzed with a virtual microscope by creating digital images from the microscopic glass slides. Metastatic deposits were not randomly distributed within sentinel lymph nodes but were predominant in the central planes closer to the lymphatic inlet. Initial evaluation of the 4 most central slices achieved a high rate of 90% for the detection of micrometastases and of 80% for the detection of isolated tumor cells (ITCs). Based on the distribution we recommend an initial cut through the hilus and to proceed with the 4 most central 150-µm slices. Complete step sectioning is only required in case of a so far negative result. © 2014 Wiley Periodicals, Inc.

  19. A Novel Nanoprobe for Multimodal Imaging Is Effectively Incorporated into Human Melanoma Metastatic Cell Lines.

    PubMed

    Aasen, Synnøve Nymark; Pospisilova, Aneta; Eichler, Tilo Wolf; Panek, Jiri; Hruby, Martin; Stepanek, Petr; Spriet, Endy; Jirak, Daniel; Skaftnesmo, Kai Ove; Thorsen, Frits

    2015-09-08

    To facilitate efficient drug delivery to tumor tissue, several nanomaterials have been designed, with combined diagnostic and therapeutic properties. In this work, we carried out fundamental in vitro and in vivo experiments to assess the labeling efficacy of our novel theranostic nanoprobe, consisting of glycogen conjugated with a red fluorescent probe and gadolinium. Microscopy and resazurin viability assays were used to study cell labeling and cell viability in human metastatic melanoma cell lines. Fluorescence lifetime correlation spectroscopy (FLCS) was done to investigate nanoprobe stability. Magnetic resonance imaging (MRI) was performed to study T₁ relaxivity in vitro, and contrast enhancement in a subcutaneous in vivo tumor model. Efficient cell labeling was demonstrated, while cell viability, cell migration, and cell growth was not affected. FLCS showed that the nanoprobe did not degrade in blood plasma. MRI demonstrated that down to 750 cells/μL of labeled cells in agar phantoms could be detected. In vivo MRI showed that contrast enhancement in tumors was comparable between Omniscan contrast agent and the nanoprobe. In conclusion, we demonstrate for the first time that a non-toxic glycogen-based nanoprobe may effectively visualize tumor cells and tissue, and, in future experiments, we will investigate its therapeutic potential by conjugating therapeutic compounds to the nanoprobe.

  20. A Novel Nanoprobe for Multimodal Imaging Is Effectively Incorporated into Human Melanoma Metastatic Cell Lines

    PubMed Central

    Aasen, Synnøve Nymark; Pospisilova, Aneta; Eichler, Tilo Wolf; Panek, Jiri; Hruby, Martin; Stepanek, Petr; Spriet, Endy; Jirak, Daniel; Skaftnesmo, Kai Ove; Thorsen, Frits

    2015-01-01

    To facilitate efficient drug delivery to tumor tissue, several nanomaterials have been designed, with combined diagnostic and therapeutic properties. In this work, we carried out fundamental in vitro and in vivo experiments to assess the labeling efficacy of our novel theranostic nanoprobe, consisting of glycogen conjugated with a red fluorescent probe and gadolinium. Microscopy and resazurin viability assays were used to study cell labeling and cell viability in human metastatic melanoma cell lines. Fluorescence lifetime correlation spectroscopy (FLCS) was done to investigate nanoprobe stability. Magnetic resonance imaging (MRI) was performed to study T1 relaxivity in vitro, and contrast enhancement in a subcutaneous in vivo tumor model. Efficient cell labeling was demonstrated, while cell viability, cell migration, and cell growth was not affected. FLCS showed that the nanoprobe did not degrade in blood plasma. MRI demonstrated that down to 750 cells/μL of labeled cells in agar phantoms could be detected. In vivo MRI showed that contrast enhancement in tumors was comparable between Omniscan contrast agent and the nanoprobe. In conclusion, we demonstrate for the first time that a non-toxic glycogen-based nanoprobe may effectively visualize tumor cells and tissue, and, in future experiments, we will investigate its therapeutic potential by conjugating therapeutic compounds to the nanoprobe. PMID:26370983

  1. Mesenchymal stem cells promote tumor engraftment and metastatic colonization in rat osteosarcoma model.

    PubMed

    Tsukamoto, Shinji; Honoki, Kanya; Fujii, Hiromasa; Tohma, Yasuaki; Kido, Akira; Mori, Toshio; Tsujiuchi, Toshifumi; Tanaka, Yasuhito

    2012-01-01

    Although mesenchymal stem cells (MSCs) are considered to be the cells of origin for most sarcomas, the role of MSCs as a source of tumor stroma is not fully understood in this tumor type. The current study investigated whether MSCs affect the tumor growth and metastatic ability in rat osteosarcoma model. Results from subcutaneous co-implantation of rat osteosarcoma COS1NR cells, established in our laboratory, with rat MSCs isolated from femur bone marrow showed that the incidence of tumor formation and tumor growth rate was higher until 5 weeks compared to COS1NR cell inoculation alone. However, no difference was observed in tumor growth afterwards and in the number of metastatic nodules at 9 weeks (0.75 vs. 1.2). Intravenous MSC injection at weeks 3 and 5 after subcutaneous inoculation of COS1NR cells significantly increased the number of lung nodules in the group with MSC injection compared to the group without MSC injection (17.33 vs. 2.0), while no difference was observed in subcutaneous tumor growth between those groups. Pathway analysis from gene expression profile identified that genes involved in focal adhesion, cytokine-cytokine receptor and extracellular matrix-receptor pathways such as CAMs (ICAM and VCAM)-integrins were highly expressed in MSCs, possibly participating in the tumor progression of osteosarcoma. These results suggest that MSCs could provide a source of microenvironments for osteosarcoma cells, and might enhance the ability of settlement and colonization which lead to early onset of growth and metastasis, possibly through their activated pathways interaction.

  2. The Vitamin D Analog, MART-10, Attenuates Triple Negative Breast Cancer Cells Metastatic Potential.

    PubMed

    Chiang, Kun-Chun; Yeh, Ta-Sen; Chen, Shin-Cheh; Pang, Jong-Hwei S; Yeh, Chun-Nan; Hsu, Jun-Te; Chen, Li-Wei; Kuo, Sheng-Fong; Takano, Masashi; Kittaka, Atsushi; Chen, Tai C; Sun, Chi-Chin; Juang, Horng-Heng

    2016-04-21

    Regarding breast cancer treatment, triple negative breast cancer (TNBC) is a difficult issue. Most TNBC patients die of cancer metastasis. Thus, to develop a new regimen to attenuate TNBC metastatic potential is urgently needed. MART-10 (19-nor-2α-(3-hydroxypropyl)-1α,25(OH)₂D₃), the newly-synthesized 1α,25(OH)₂D₃ analog, has been shown to be much more potent in cancer growth inhibition than 1α,25(OH)₂D₃ and be active in vivo without inducing obvious side effect. In this study, we demonstrated that both 1α,25(OH)₂D₃ and MART-10 could effectively repress TNBC cells migration and invasion with MART-10 more effective. MART-10 and 1α,25(OH)₂D₃ induced cadherin switching (upregulation of E-cadherin and downregulation of N-cadherin) and downregulated P-cadherin expression in MDA-MB-231 cells. The EMT(epithelial mesenchymal transition) process in MDA-MB-231 cells was repressed by MART-10 through inhibiting Zeb1, Zeb2, Slug, and Twist expression. LCN2, one kind of breast cancer metastasis stimulator, was also found for the first time to be repressed by 1α,25(OH)₂D₃ and MART-10 in breast cancer cells. Matrix metalloproteinase-9 (MMP-9) activity was also downregulated by MART-10. Furthermore, F-actin synthesis in MDA-MB-231 cells was attenuated as exposure to 1α,25(OH)₂D₃ and MART-10. Based on our result, we conclude that MART-10 could effectively inhibit TNBC cells metastatic potential and deserves further investigation as a new regimen to treat TNBC.

  3. The Vitamin D Analog, MART-10, Attenuates Triple Negative Breast Cancer Cells Metastatic Potential

    PubMed Central

    Chiang, Kun-Chun; Yeh, Ta-Sen; Chen, Shin-Cheh; Pang, Jong-Hwei S.; Yeh, Chun-Nan; Hsu, Jun-Te; Chen, Li-Wei; Kuo, Sheng-Fong; Takano, Masashi; Kittaka, Atsushi; Chen, Tai C.; Sun, Chi-Chin; Juang, Horng-Heng

    2016-01-01

    Regarding breast cancer treatment, triple negative breast cancer (TNBC) is a difficult issue. Most TNBC patients die of cancer metastasis. Thus, to develop a new regimen to attenuate TNBC metastatic potential is urgently needed. MART-10 (19-nor-2α-(3-hydroxypropyl)-1α,25(OH)2D3), the newly-synthesized 1α,25(OH)2D3 analog, has been shown to be much more potent in cancer growth inhibition than 1α,25(OH)2D3 and be active in vivo without inducing obvious side effect. In this study, we demonstrated that both 1α,25(OH)2D3 and MART-10 could effectively repress TNBC cells migration and invasion with MART-10 more effective. MART-10 and 1α,25(OH)2D3 induced cadherin switching (upregulation of E-cadherin and downregulation of N-cadherin) and downregulated P-cadherin expression in MDA-MB-231 cells. The EMT(epithelial mesenchymal transition) process in MDA-MB-231 cells was repressed by MART-10 through inhibiting Zeb1, Zeb2, Slug, and Twist expression. LCN2, one kind of breast cancer metastasis stimulator, was also found for the first time to be repressed by 1α,25(OH)2D3 and MART-10 in breast cancer cells. Matrix metalloproteinase-9 (MMP-9) activity was also downregulated by MART-10. Furthermore, F-actin synthesis in MDA-MB-231 cells was attenuated as exposure to 1α,25(OH)2D3 and MART-10. Based on our result, we conclude that MART-10 could effectively inhibit TNBC cells metastatic potential and deserves further investigation as a new regimen to treat TNBC. PMID:27110769

  4. Does hormonal therapy have a therapeutic role in metastatic primary small cell neuroendocrine breast carcinoma? Case report and literature review.

    PubMed

    Alkaied, Homam; Harris, Kassem; Brenner, Arnold; Awasum, Michael; Varma, Seema

    2012-06-01

    Primary neuroendocrine carcinoma of breast (NECB) is a very rare tumor; the World Health Organization(WHO) subcategorized these tumors into 3 major histologic subtypes: solid, small cell carcinoma (SMCC), and large cell NE carcinoma. The SMCC subtype is the least common and most aggressive and has been reported to be as aggressive as its pulmonary counterpart. SMCC is usually confirmed based on clinical, pathologic,and imaging studies. Local disease is usually managed in a fashion similar to that of the usual ductal breast cancer; in the metastatic SMCC setting, regimens that are implemented in small cell lung cancer are usually attempted, according to case reports and published small case series. Hormone receptors can be expressed in more than 90% of the solid tumor subtype; however its expression is manifested in about 50% of cases of SMCC. Although hormonal therapy can be used successfully to treat the usual metastatic ductal breast cancer,its utility in metastatic SMCC has not been reported. We report an impressive response to hormonal therapy in a patient with late relapse of breast carcinoma with a metastatic SMCC subtype that expressed hormone receptors. The response to hormonal therapy was sustained for about 12 months. The response to hormonal therapy is definitely an interesting finding that, to our knowledge, has not been described before in the setting of metastatic SMCC. We suggest considering adding hormonal therapy to the treatment pipeline for primary SMCC of the breast that express hormone receptors.

  5. The pro-metastatic role of bone marrow-derived cells: a focus on MSCs and regulatory T cells

    PubMed Central

    Koh, Bong Ihn; Kang, Yibin

    2012-01-01

    Several bone marrow-derived cells have been shown to promote tumour growth and progression. These cells can home to the primary tumour and become active components of the tumour microenvironment. Recent studies have also identified bone marrow-derived cells—such as mesenchymal stem cells and regulatory T cells—as contributors to cancer metastasis. The innate versatility of these cells provides diverse functional aid to promote malignancy, ranging from structural support to signal-mediated suppression of the host immune response. Here, we review the role of mesenchymal stem cells and regulatory T cells in cancer metastasis. A better understanding of the bipolar nature of these bone marrow-derived cells in physiological and malignant contexts could pave the way for new therapeutics against metastatic disease. PMID:22473297

  6. Identification and validation of dysregulated metabolic pathways in metastatic renal cell carcinoma.

    PubMed

    White, Nicole M A; Newsted, Daniel W; Masui, Olena; Romaschin, Alexander D; Siu, K W Michael; Yousef, George M

    2014-03-01

    Metastatic renal cell carcinoma (mRCC) is a devastating disease with a 5-year survival rate of approximately 9 % and low response to chemotherapy and radiotherapy. Targeted therapies have slightly improved patient survival, but are only effective in a small subset of patients, who eventually develop resistance. A better understanding of pathways contributing to tumor progression and metastasis will allow for the development of novel targeted therapies and accurate prognostic markers. We performed extensive bioinformatics coupled with experimental validation on proteins dysregulated in mRCC. Gene ontology analysis showed that many proteins are involved in oxidation reduction, metabolic processes, and signal transduction. Pathway analysis showed metabolic pathways are altered in mRCC including glycolysis and pyruvate metabolism, the citric acid cycle, and the pentose phosphate pathway. RT-qPCR analysis showed that genes involved in the citric acid cycle were downregulated in metastatic RCC while genes of the pentose phosphate pathway were overexpressed. Protein-protein interaction analysis showed that most of the 198 proteins altered in mRCC clustered together and many were involved in glycolysis and pyruvate metabolism. We identified 29 reported regions of chromosomal aberrations in metastatic disease that correlate with the direction of protein dysregulation in mRCC. Furthermore, 36 proteins dysregulated in mRCC are predicted to be targets of metastasis-related miRNAs. A more comprehensive understanding of the pathways dysregulated in metastasis can be useful for the development of new therapies and novel prognostic markers. Also, multileveled analyses provide a unique "snapshot" of the molecular "environment" in RCC with prognostic and therapeutic implications.

  7. Relationship between primary and metastatic testicular germ cell tumors: a clinicopathologic analysis of 100 cases.

    PubMed

    Tarrant, William P; Czerniak, Bogdan A; Guo, Charles C

    2013-10-01

    Testicular germ cell tumors (GCTs) commonly metastasize to the retroperitoneal lymph nodes (RPLNs). We evaluated 100 cases of RPLN dissection specimens with viable GCTs after chemotherapy and compared them with their corresponding orchiectomy specimens. The mean age of patients was 28 years (range, 15-58 years). The testicular tumors consisted of mixed GCT (n = 72), teratoma (n = 18), seminoma (n = 4), embryonal carcinoma (n = 3), yolk sac tumor (n = 1), and no viable tumor (n = 2). Somatic malignant components were found in 5 cases. The metastatic tumors in the RPLNs consisted of only teratoma (n = 77) and non-teratomatous GCT (n = 23). Twenty-one patients had only teratoma in the RPLNs but not in the testis, and 10 patients had metastatic non-teratomatous GCT components that were not observed in the testis. Six patients had somatic malignant components in the RPLNs, but only one of them had such a component in the testis. Overall, 13 patients died of disease in a mean of 42 months, and the patients with only teratoma in the RPLNs had a lower mortality rate (9%) than those with non-teratomatous components (26%) (P = .044). One patient with somatic components in the primary GCT and 3 patients with somatic components in the metastases died of disease. Our study demonstrates that there is frequent discordance of histologic composition between primary and metastatic testicular GCTs. Teratoma is the most common component in treated GCTs and is usually associated with a more favorable clinical outcome than non-teratomatous GCTs. The presence of somatic components in the RPLNs metastasis indicates a poor prognosis.

  8. Dynamic epigenetic changes to VHL occur with sunitinib in metastatic clear cell renal cancer

    PubMed Central

    Stewart, Grant D.; Powles, Thomas; Van Neste, Christophe; Meynert, Alison; O'Mahony, Fiach; Laird, Alexander; Deforce, Dieter; Van Nieuwerburgh, Filip; Trooskens, Geert; Van Criekinge, Wim; De Meyer, Tim; Harrison, David J.

    2016-01-01

    Background Genetic intratumoral heterogeneity (ITH) hinders biomarker development in metastatic clear cell renal cancer (mccRCC). Epigenetic relative to genetic ITH or the presence of consistent epigenetic changes following targeted therapy in mccRCC have not been evaluated. The aim of this study was to determine methylome/genetic ITH and to evaluate specific epigenetic and genetic changes associated with sunitinib therapy. Patients and methods Multi-region DNA sampling performed on sequential frozen pairs of primary tumor tissue from 14 metastatic ccRCC patients, in the Upfront Sunitinib (SU011248) Therapy Followed by Surgery in Patients with Metastatic Renal Cancer: a Pilot Phase II Study (SuMR; ClinicalTrials.gov identifier: NCT01024205), at presentation (biopsy) and after 3-cycles of 50mg sunitinib (nephrectomy). Untreated biopsy and nephrectomy samples before and after renal artery ligation were controls. Ion Proton sequencing of 48 key ccRCC genes, and MethylCap-seq DNA methylation analysis was performed, data was analysed using the statistical computing environment R. Results Unsupervised hierarchical clustering revealed complete methylome clustering of biopsy and three nephrectomy samples for each patient (14/14 patients). For mutational status, untreated biopsy and all treated nephrectomy samples clustered together in 8/13 (61.5%) patients. The only methylation target significantly altered following sunitinib therapy was VHL promoter region 7896829 which was hypermethylated with treatment (FDR=0.077, P<0.001) and consistent for all patients (pre-treatment 50% patients had VHL mutations, 14% patients VHL hypermethylation). Renal artery ligation did not affect this result. No significant differences in driver or private mutation count was found with sunitinib treatment. Conclusions Demonstration of relative methylome homogeneity and consistent VHL hypermethylation, after sunitinib, may overcome the hurdle of ITH present at other molecular levels for

  9. Carboplatin, Paclitaxel, Cetuximab, and Erlotinib Hydrochloride in Treating Patients With Metastatic or Recurrent Head and Neck Squamous Cell Cancer

    ClinicalTrials.gov

    2017-04-11

    Metastatic Squamous Neck Cancer With Occult Primary Squamous Cell Carcinoma; Recurrent Metastatic Squamous Neck Cancer With Occult Primary; Recurrent Salivary Gland Cancer; Recurrent Squamous Cell Carcinoma of the Hypopharynx; Recurrent Squamous Cell Carcinoma of the Larynx; Recurrent Squamous Cell Carcinoma of the Lip and Oral Cavity; Recurrent Squamous Cell Carcinoma of the Nasopharynx; Recurrent Squamous Cell Carcinoma of the Oropharynx; Recurrent Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Recurrent Verrucous Carcinoma of the Larynx; Recurrent Verrucous Carcinoma of the Oral Cavity; Salivary Gland Squamous Cell Carcinoma; Stage IV Salivary Gland Cancer; Stage IV Squamous Cell Carcinoma of the Hypopharynx; Stage IV Squamous Cell Carcinoma of the Larynx; Stage IV Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IV Squamous Cell Carcinoma of the Nasopharynx; Stage IV Squamous Cell Carcinoma of the Oropharynx; Stage IV Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Stage IV Verrucous Carcinoma of the Larynx; Stage IV Verrucous Carcinoma of the Oral Cavity; Tongue Cancer; Untreated Metastatic Squamous Neck Cancer With Occult Primary

  10. Prevalence and heterogeneity of circulating tumour cells in metastatic cutaneous melanoma.

    PubMed

    Khoja, Leila; Shenjere, Patrick; Hodgson, Clare; Hodgetts, Jackie; Clack, Glen; Hughes, Andrew; Lorigan, Paul; Dive, Caroline

    2014-02-01

    We previously demonstrated that circulating tumour cells (CTCs) are detectable by the MelCAM and high molecular weight melanoma-associated antigen (HMW-MAA)-dependent CellSearch platform. However, CTCs which do not express these capture and detection markers are not detectable by CellSearch. Consequently, we explored the use of isolation by size of epithelial tumour cells (ISET), a marker independent, filtration-based device to determine the prevalence and heterogeneity of CTCs in metastatic cutaneous melanoma patients. Ninety patients were prospectively recruited and blood samples taken before treatment. Patients' blood was filtered using the ISET platform. CTCs were enumerated using dual immunohistochemistry with positive selection by S100 expression and exclusion of leucocytes and endothelial cells expressing CD45 or CD144, respectively. A panel of markers (Melan-A, MITF, MelCAM, high molecular melanoma-associated antigen, CD271 and MAGEC) was also examined. Fifty-one patients (57%) had CTCs (range 1-44 CTCs/4 ml blood) and 12 patients also had circulating tumour microemboli. Seven patients had S100- CTCs, 11 patients' CTCs were S100+ and 33 patients had S100+ and S100- CTCs. Substantial intrapatient and interpatient heterogeneity was observed for all other melanoma-associated markers. CTCs in metastatic cutaneous melanoma are detectable using the flexible marker-independent ISET platform. CTCs display significant marker expression heterogeneity implying that marker-dependent platforms would not detect all CTCs and multimarker assays are now required to reveal the biological significance of this CTC heterogeneity.

  11. Circulating dendritic cells in early and advanced cancer patients: diminished percent in the metastatic disease.

    PubMed

    Lissoni, P; Vigore, L; Ferranti, R; Bukovec, R; Meregalli, S; Mandala, M; Barni, S; Tancini, G; Fumagalli, L; Giani, L

    1999-01-01

    Despite the well demonstrated fundamental role of dendritic cells (DC) in generating antitumor immunity in experimental conditions, to date there are only few preliminary studies which investigate the percent of DC in the peripheral blood of cancer patients. Several cell surface markers have now been described which are specific to cultured DC, however their expression in vivo is still controversial. Recently, however, two DC subsets, consisting of immature and mature DC, have been shown to be present in peripheral blood, which can be recognized as CD123+ and CD11c+ cells, respectively. On this basis, we decided to investigate the presence of both mature and immature DC in the peripheral blood of early or advanced cancer patients. The study included 40 solid tumor patients, 18 of whom had a locally limited disease, while the other 22 showed distant organ metastases. CD123+ and CD11c+ cells were detected by FACS using monoclonal antibodies, and expressed as the percent of total leukocytes. The control group consisted of 50 healthy subjects. The mean percent of both CD123+ and CD11c+ cells was significantly lower in cancer patients than in controls. Moreover, the mean percent of both DC subsets was significantly lower in metastatic patients than in the non-metastatic ones. This study, demonstrating significantly lower percents of both immature and mature DC in the peripheral blood of cancer patients, particularly in those with distant organ metastases, suggests that DC deficiency may play a role in inducing cancer-related immunosuppression. Therefore, the demonstration of a diminished percent of DC in peripheral blood may represent a new interesting biological marker predicting a poor prognosis in human neoplasms, as with lymphocytopenia, the unfavourable prognostic significance of which has been well demonstrated.

  12. Metastatic renal cell carcinoma from a native kidney of a renal transplant patient diagnosed by endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) biopsy

    PubMed Central

    Alastal, Yaseen; Hammad, Tariq A; Rafiq, Ehsan; Nawras, Mohamad; Alaradi, Osama

    2015-01-01

    Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) biopsy sampling of enlarged lymph nodes is increasingly used to diagnose metastatic tumors, especially of the gastrointestinal tract and the lungs. Herein, we describe the diagnosis of metastatic renal cell carcinoma from a native kidney of a 54 year-old male patient, who had a 5-years history of renal transplant, by EUS-FNA of mediastinal and celiac lymph nodes. Histological and immunohistochemical findings confirmed the origin of metastatic tumor. EUS-FNA with proper cytological evaluation can be useful in the diagnosis of metastatic renal cell carcinoma in renal transplant patients. PMID:28326261

  13. Programmed death-1 ligand 1 and 2 are highly expressed in pleomorphic carcinomas of the lung: Comparison of sarcomatous and carcinomatous areas.

    PubMed

    Kim, Sehui; Kim, Moon-Young; Koh, Jaemoon; Go, Heounjeong; Lee, Dong Soo; Jeon, Yoon Kyung; Chung, Doo Hyun

    2015-11-01

    Pleomorphic carcinoma (PC) of the lung is a rare type of poorly differentiated non-small cell lung carcinoma (NSCLC) that belongs to sarcomatoid carcinoma (SC). It exhibits aggressive behaviour and resistance to chemotherapy and radiotherapy. Recently, immunotherapy targeting the programmed death-1 (PD-1)/PD ligand 1 (PD-L1) pathway has demonstrated favourable clinical outcomes in NSCLC. However, the expression patterns of PD-1-related molecules in pulmonary PC remain elusive. PD-L1 and PD-L2 expression was estimated in 41 cases of PC using immunohistochemistry. CD8(+) and PD-1(+) tumour-infiltrating lymphocytes (TILs) were also evaluated. PD-L1 and PD-L2 were highly expressed in pulmonary PCs (90.2% [37/41)]; 87.8% [36/41]). The amount of CD8(+) or PD-1(+) TILs and the ratio of PD-1(+)/CD8(+) TILs in PC were higher in males, smokers and older patients. PD-L1-positive PCs were infiltrated by higher numbers of CD8(+) TILs compared to PD-L1-negative cases (P=0.006). Of note, PD-L1 expression in pulmonary PCs was significantly higher in sarcomatous areas than in the carcinomatous portion (P=0.006). PC patients with a high ratio of PD-1(+)/CD8(+) TILs showed a shorter progression-free survival (P=0.036), whereas PD-L1 and PD-L2 expression had no prognostic implications. Our study demonstrates that pulmonary PCs very frequently express PD-L1 and PD-L2. Moreover, their expression is higher in sarcomatous cells than in carcinomatous areas. Thus, targeting the PD-1/PD-L1 pathway may represent a potential therapeutic candidate for this aggressive tumour.

  14. [A case of metastatic pulmonary cancer from renal cell carcinoma masquerading as pulmonary vein varix].

    PubMed

    Mizuno, Kotaro; Endo, Katsuhiko; Fukai, Ichiro

    2010-07-01

    A 66-year-old woman underwent nephrectomy to treat renal cell carcinoma 5 years previously. Enhanced CT to locate the tumor revealed a lesion very close to the right upper pulmonary vein. Six months later, the nodule grew to 14mm in maximum dimension and it seemed to be a varix of the right upper pulmonary vein on 3D-CT. However, pulmonary artery angiography (PAG) denied this possibility. PET-CT revealed the nodule to be positive for FDG uptake (maxSUV 2.7 in the early phase and 2.2 in the late phase), suggesting that it contained solid tissue with malignant characteristics. Eventually, right upper lobectomy was performed. The nodule was a metastatic renal cell carcinoma with extremely abundant vascular components. This conspicuous feature of the tumor appeared to mimic a pulmonary vein varix on enhanced CT scan and 3D angiogram.

  15. Metastatic clear cell carcinoma of the kidney: therapeutic role of bevacizumab.

    PubMed

    Bukowski, Ronald M

    2010-03-26

    The biology and pathogenesis of clear cell carcinoma of the kidney has been extensively investgated, and the role of von Hipple-Landau gene inactivation and tumor associated angiogenesis is now recognized. Development of vascular endothelial growth factor inhibitors and phase 3 clinical trials utilizing this class of agents has produced a new treatment paradigm for patients with metastatic renal cell carcinoma (RCC). One of the active regimens identified is the combination of bevacizumab and interferon-α. Recently published reports provided evidence of the clinical and biologic activity of this therapy. The current manuscript reviews the background and rationale for the activity of bevacizumab in RCC, and results from recent clinical trials with this agent alone or in combination with targeted agents or cytokines. The role of this therapy in contrast to other targeted agents is reviewed, and the potential utility as well as questions raised by recent studies are discussed.

  16. Metastatic clear cell carcinoma of the kidney: therapeutic role of bevacizumab

    PubMed Central

    Bukowski, Ronald M

    2010-01-01

    The biology and pathogenesis of clear cell carcinoma of the kidney has been extensively investgated, and the role of von Hipple-Landau gene inactivation and tumor associated angiogenesis is now recognized. Development of vascular endothelial growth factor inhibitors and phase 3 clinical trials utilizing this class of agents has produced a new treatment paradigm for patients with metastatic renal cell carcinoma (RCC). One of the active regimens identified is the combination of bevacizumab and interferon-α. Recently published reports provided evidence of the clinical and biologic activity of this therapy. The current manuscript reviews the background and rationale for the activity of bevacizumab in RCC, and results from recent clinical trials with this agent alone or in combination with targeted agents or cytokines. The role of this therapy in contrast to other targeted agents is reviewed, and the potential utility as well as questions raised by recent studies are discussed. PMID:21188099

  17. Locally advanced and metastatic basal cell carcinoma: molecular pathways, treatment options and new targeted therapies.

    PubMed

    Ruiz Salas, Veronica; Alegre, Marta; Garcés, Joan Ramón; Puig, Lluis

    2014-06-01

    The hedgehog (Hh) signaling pathway has been identified as important to normal embryonic development in living organisms and it is implicated in processes including cell proliferation, differentiation and tissue patterning. Aberrant Hh pathway has been involved in the pathogenesis and chemotherapy resistance of different solid and hematologic malignancies. Basal cell carcinoma (BCC) and medulloblastoma are two well-recognized cancers with mutations in components of the Hh pathway. Vismodegib has recently approved as the first inhibitor of one of the components of the Hh pathway (smoothened). This review attempts to provide current data on the molecular pathways involved in the development of BCC and the therapeutic options available for the treatment of locally advanced and metastatic BCC, and the new targeted therapies in development.

  18. Characterization of a Novel Metastatic Prostate Cancer Cell Line of LNCaP Origin

    PubMed Central

    Castanares, Mark A.; Copeland, Ben T.; Chowdhury, Wasim H.; Liu, Minzhi M.; Rodriguez, Ronald; Pomper, Martin G.; Lupold, Shawn E.; Foss, Catherine A.

    2016-01-01

    Background The LNCaP cell line was originally isolated from the lymph node of a patient with metastatic prostate cancer. Many cell lines have been derived from LNCaP by selective pressures to study different aspects of prostate cancer progression. When injected subcutaneously into male athymic nude mice, LNCaP and its derivatives rarely metastasize. Methods Here, we describe the characteristics of a new LNCaP derivative, JHU-LNCaPSM, which was generated by long term passage in normal cell culture conditions. Results Short tandem repeat (STR) analysis and genomic sequencing verified JHU-LNCaP-SM derivation from parental LNCaP cells. JHU-LNCaP-SM cells express the same mutated androgen receptor (AR) but unlike LNCaP, are no longer androgen dependent for growth. The cells demonstrate an attenuated androgen responsiveness in transcriptional assays and retain androgen sensitive expression of PSA, AR, and PSMA. Unlike parental LNCaP, JHU-LNCaP-SM cells quickly form subcutaneous tumors in male athymic nude mice, reliably metastasize to the lymph nodes and display a striking intra-tumoral and spreading hemorrhagic phenotype as tumor xenografts. Conclusions The JHU-LNCaP-SM cell line is a new isolate of LNCaP, which facilitates practical, preclinical studies of spontaneous metastasis of prostate cancer through lymphatic tissues. PMID:26499105

  19. Neural stem cell-based dual suicide gene delivery for metastatic brain tumors.

    PubMed

    Wang, C; Natsume, A; Lee, H J; Motomura, K; Nishimira, Y; Ohno, M; Ito, M; Kinjo, S; Momota, H; Iwami, K; Ohka, F; Wakabayashi, T; Kim, S U

    2012-11-01

    In our previous works, we demonstrated that human neural stem cells (NSCs) transduced with the cytosine deaminase (CD) gene showed remarkable 'bystander killer effect' on glioma and medulloblastoma cells after administration of the prodrug 5-fluorocytosine (5-FC). In addition, herpes simplex virus thymidine kinase (TK) is a widely studied enzyme used for suicide gene strategies, for which the prodrug is ganciclovir (GCV). To apply this strategy to brain metastasis treatment, we established here a human NSC line (F3.CD-TK) expressing the dual suicide genes CD and TK. We examined whether F3.CD-TK cells intensified the antitumor effect on lung cancer brain metastases. In vitro studies showed that F3.CD-TK cells exerted a marked bystander effect on human lung cancer cells after treatment with 5-FC and GCV. In a novel experimental brain metastases model, intravenously administered F3 cells migrated near lung cancer metastatic lesions, which were induced by the injection of lung cancer cells via the intracarotid artery. More importantly, F3.CD-TK cells in the presence of prodrugs 5-FC and GCV decreased tumor size and considerably prolonged animal survival. The results of the present study indicate that the dual suicide gene-engineered, NSC-based treatment strategy might offer a new promising therapeutic modality for brain metastases.

  20. Polyethylenimine-coated SPION exhibits potential intrinsic anti-metastatic properties inhibiting migration and invasion of pancreatic tumor cells.

    PubMed

    Mulens-Arias, Vladimir; Rojas, José Manuel; Pérez-Yagüe, Sonia; Morales, María del Puerto; Barber, Domingo F

    2015-10-28

    Due to its aggressive behavior, pancreatic cancer is one of the principal causes of cancer-related deaths. The highly metastatic potential of pancreatic tumor cells demands the development of more effective anti-metastatic approaches for this disease. Although polyethylenimine-coated superparamagnetic iron oxide nanoparticles (PEI-coated SPIONs) have been studied for their utility as transfection agents, little is known of their effect on tumor cell biology. Here we demonstrated that PEI-coated SPIONs have potent inhibitory effects on pancreatic tumor cell migration/invasion, through inhibition of Src kinase and decreased expression of MT1-MMP and MMP2 metalloproteinases. When treated with PEI-coated SPIONs, the pancreatic tumor cell line Pan02 showed reduced invadosome density and thus, a decrease in their ability to invade through basement membrane. These nanoparticles temporarily downmodulated microRNA-21, thereby upregulating the cell migration inhibitors PTEN, PDCD4 and Sprouty-1. PEI-coated SPIONs thus show intrinsic, possibly anti-metastatic properties for modulating pancreatic tumor cell migration machinery, which indicates their potential as anti-metastatic agents for treatment of pancreatic cancer.

  1. Highly metastatic 13762NF rat mammary adenocarcinoma cell clones stimulate bone marrow by secretion of granulocyte-macrophage colony-stimulating factor/interleukin-3 activity.

    PubMed

    McGary, C T; Miele, M E; Welch, D R

    1995-12-01

    Circulating neutrophil (polymorphonuclear leukocyte levels rise 50-fold in 13762NF tumor-bearing rats in proportion to the tumor's metastatic potential. Purified tumor-elicited neutrophils enhance metastasis of syngeneic tumor cells when co-injected intravenously; however, circulating and phorbol ester-activated polymorphonuclear neutrophils do not. The purpose of this study was to elucidate the source of tumor-elicited neutrophils in metastatic tumor-bearing rats. We examined the bone marrow in rats bearing tumors of poorly, moderately, and highly metastatic cell clones. Marrow from rats with highly metastatic tumors had increased cellularity (100%), myeloid to erythroid ratio (10:1), and megakaryocytes compared with control rats (cellularity, approximately 80%; myeloid to erythroid ratio, 5:1), with marrows from rats with moderately metastatic tumors having intermediate values. This suggested production of a colony-stimulating factor by the metastatic cells. To confirm this, bone marrow colony formation from control and tumor-bearing rats was compared. Colony number increased in proportion to the metastatic potential of the tumor. Conditioned medium from metastatic cells supported growth of the granulocyte-macrophage colony-stimulating factor/interleukin-3-dependent 32Dcl3 cell line, but media from nonmetastatic or moderately metastatic cells did not. Antibodies to murine granulocyte-macrophage colony-stimulating factor neutralized 32Dcl3 growth in tumor cell conditioned medium. These results suggest production of a granulocyte-macrophage colony-stimulating factor or interleukin-3-like activity by highly metastatic 13762NF clones and implicate a possible role for colony-stimulating factors in regulating the metastatic potential of mammary adenocarcinoma cell clones.

  2. Life quality of patients with metastatic renal cell carcinoma and chemo-immunotherapy--a pilot study.

    PubMed

    Kröger, M J; Menzel, T; Gschwend, J E; Bergmann, L

    1999-01-01

    Renal cell cancer (RCC) accounts for 2-3% of all malignant tumors in adults. Due to the indolent course of disease and the few signs and symptoms in early stages the majority of patients presents with metastatic disease when diagnosed. The aims of systemic therapy of RCC are therefore palliative. Recent research shows the key role of immune mechanisms in the course of RCC. The therapeutic use of cytokines, mainly interleukin-2 (IL-2) and interferon-alpha (IFN) results in improvement of remission rates. To date it is unknown to what extent multiple cycles of chemo-immunotherapy alter the life quality (LQ) of patients with metastatic RCC. We monitored life quality during therapy in a three-armed protocol with interferon-alpha 2a, interleukin-2, 5-fluorouracil (5-FU), isotretinoin (ISO) and vinblastin (VBL). Life quality was impaired by two factors: response to chemo-immunotherapy and therapy side effects. A steep decrease of LQ-scores was seen in week 1 of therapy, LQ improved then for patients with stable disease (SD) and partial remission (PR) but not for those with progressive disease (PD).

  3. Non-metastatic upper tract transitional cell carcinoma: single center experience.

    PubMed

    Demirci, Umut; Canda, Abdullah Erdem; Dede, Didem Sener; Cakici, Ozer Ural; Akinci, Muhammed Bulent; Yalcin, Bulent

    2013-01-01

    Upper tract transitional cell carcinomas (UTCC) are relatively uncommon but prognosis is generally worse than TCC of bladder. Between March 2004 and June 2012, patients with initial non- metastatic UTCC were assessed in the Medical Oncology and Urology Departments of Ataturk Training and Research Hospital. A total of 11 patients with initially non-metastatic UTCC were detected in the 8 year period, all males. Median age of was 62 (range, 38-74). Six lesions were located in the renal pelvis and 5 in the ureter. Nephroureterectomy was performed in 9 patients, and distal ureterectomy and cuff excision of the bladder in the remaining 2. The majority (n= 9) had high grade tumors. Median primary tumor diameter was 3.5 cm (range, 0.7-10). Five patients (45.5%) were stage I, 2 (18.2%) were stage II, and 4 (36.4%) were stage III. While adjuvant chemotherapy was not applied for stage I and II disease (n= 7), 4 to 6 courses were applied for 3 of the stage III patients. Also one stage III case received adjuvant radiotherapy. Up to 100 months follow-up, median overall survival was 13 months (range, 5-100 months). While stage I and II patients are following-up without muscle-invasive progression, 2 of stage III patients demonstrated progression. We need more collaborative studies to determine management of especially pT3-pT4 patients with UTCC.

  4. Can Biomarker Assessment on Circulating Tumor Cells Help Direct Therapy in Metastatic Breast Cancer?

    PubMed Central

    Turner, Natalie; Pestrin, Marta; Galardi, Francesca; De Luca, Francesca; Malorni, Luca; Di Leo, Angelo

    2014-01-01

    Circulating tumor cell (CTC) count has prognostic significance in metastatic breast cancer, but the predictive utility of CTCs is uncertain. Molecular studies on CTCs have often been limited by a low number of CTCs isolated from a high background of leukocytes. Improved enrichment techniques are now allowing molecular characterisation of single CTCs, whereby molecular markers on single CTCs may provide a real-time assessment of tumor biomarker status from a blood test or “liquid biopsy”, potentially negating the need for a more invasive tissue biopsy. The predictive ability of CTC biomarker analysis has predominantly been assessed in relation to HER2, with variable and inconclusive results. Limited data exist for other biomarkers, such as the estrogen receptor. In addition to the need to define and validate the most accurate and reproducible method for CTC molecular analysis, the clinical relevance of biomarkers, including gain of HER2 on CTC after HER2 negative primary breast cancer, remains uncertain. This review summarises the currently available data relating to biomarker evaluation on CTCs and its role in directing management in metastatic breast cancer, discusses limitations, and outlines measures that may enable future development of this approach. PMID:24670368

  5. Precision Oncology: Identifying Predictive Biomarkers for the Treatment of Metastatic Renal Cell Carcinoma

    PubMed Central

    Modi, Parth K.; Farber, Nicholas J.; Singer, Eric A.

    2016-01-01

    The recent FDA approval of multiple new pharmaceutical agents for metastatic renal cell carcinoma (RCC) has left physicians with several options for first- and second- line therapy. With limited head-to-head comparisons, however, there is a paucity of evidence to recommend the use of one agent over another. To address this knowledge gap, Voss et al. identified serum biomarkers from specimens collected during the RECORD-3 trial, a comparative study of first-line sunitinib versus first-line everolimus. Of the biomarkers identified, the 5 most strongly associated with first-line everolimus progression-free survival (PFS1L) were combined to form a composite biomarker score (CBS). The CBS was significantly associated with everolimus PFS1L in multivariate regression analysis. This study is an example of the additional value offered by a randomized trial with prospective biospecimen collection and a significant step towards identifying predictive biomarkers for the treatment of metastatic RCC. As further comparative trials are performed, it will be essential that biomarkers are appropriately identified and validated in order to further the goal of precision oncology. PMID:27540511

  6. Sialoglycoproteins of murine RAW117 large cell lymphoma/lymphosarcoma sublines of various metastatic colonization properties

    SciTech Connect

    Irimura, T.; Tressler, R.J.; Nicolson, G. L.

    1986-01-01

    A metastatic model for large-cell lymphoma/lymphosarcoma has been developed by sequential selection in vivo of the murine RAW117 cell line for enhanced liver metastasis or in vitro for loss of lectin-binding properties. The metastatic variants obtained from such selections show alterations in cell surface lectin-binding components, such as the wheat germ agglutinin (WGA)-reactive sialoglycoproteins. Detergent lysates from RAW117 cells were analyzed by polyacrylamide gel electrophoresis (PAGE) followed by reaction with /sup 125/I-labeled WGA. The (/sup 125/I)WGA became bound to a diffuse band of M/sub r/ 120,000-200,000 in the gels that overlapped with the major sialoglycoprotein band revealed by the periodate-sodium borotritide labeling. However, the (/sup 125/I)WGA reactivity diminished when gels were pretreated with mild acid to remove sialic acid in situ. The binding of (/sup 125/I)WGA to the glycoprotein(s) was greater in the high liver-colonizing RAW117--H10 subline than in the parental RAW117-P line. Another lectin with different saccharide specificity, Ricinus communis agglutinin I (RCA/sub I/), became bound to a similar class of sialoglycoproteins, as well as to glycoproteins of lower M/sub r/, but only when the gels were pretreated with mild acid to remove sialic acid. /sup 125/)WGA reactivity to the sialoglycoprotein components, before and after Smith degradation in situ, strongly suggests that the oligosaccharide back-bones are highly branched and asparagine-linked.

  7. Active angiogenesis in metastatic renal cell carcinoma predicts clinical benefit to sunitinib-based therapy

    PubMed Central

    del Puerto-Nevado, L; Rojo, F; Zazo, S; Caramés, C; Rubio, G; Vega, R; Chamizo, C; Casado, V; Martínez-Useros, J; Rincón, R; Rodríguez-Remírez, M; Borrero-Palacios, A; Cristóbal, I; Madoz-Gúrpide, J; Aguilera, O; García-Foncillas, J

    2014-01-01

    Background: Sunitinib represents a widely used therapy for metastatic renal cell carcinoma patients. Even so, there is a group of patients who show toxicity without clinical benefit. In this work, we have analysed pivotal molecular targets involved in angiogenesis (vascular endothelial growth factor (VEGF)-A, VEGF receptor 2 (KDR), phosphorylated (p)KDR and microvascular density (MVD)) to test their potential value as predictive biomarkers of clinical benefit in sunitinib-treated renal cell carcinoma patients. Methods: Vascular endothelial growth factor-A, KDR and pKDR-Y1775 expression as well as CD31, for MVD visualisation, were determined by immunohistochemistry in 48 renal cell carcinoma patients, including 23 metastatic cases treated with sunitinib. Threshold was defined for each biomarker, and univariate and multivariate analyses for progression-free survival (PFS) and overall survival (OS) were carried out. Results: The HistoScore mean value obtained for VEGF-A was 121.6 (range, 10–300); for KDR 258.5 (range, 150–300); for pKDR-Y1775 10.8 (range, 0–65) and the mean value of CD31-positive structures for MVD visualisation was 49 (range, 10–126). Statistical differences for PFS (P=0.01) and OS (P=0.007) were observed for pKDR-Y1775 in sunitinib-treated patients. Importantly, pKDR-Y1775 expression remained significant after multivariate Cox analysis for PFS (P=0.01; HR: 5.35, 95% CI, 1.49–19.13) and for OS (P=0.02; HR: 5.13, 95% CI, 1.25–21.05). Conclusions: Our results suggest that the expression of phosphorylated (i.e., activated) KDR in tumour stroma might be used as predictive biomarker for the clinical outcome in renal cell carcinoma first-line sunitinib-treated patients. PMID:24786599

  8. Modulating the vascular behavior of metastatic breast cancer cells by curcumin treatment

    PubMed Central

    Palange, Anna L.; Mascolo, Daniele Di; Singh, Jaykrishna; Franceschi, Maria S. De; Carallo, Claudio; Gnasso, Agostino; Decuzzi, Paolo

    2012-01-01

    The spreading of tumor cells to secondary sites (tumor metastasis) is a complex process that involves multiple, sequential steps. Vascular adhesion and extravasation of circulating tumor cells (CTCs) is one, critical step. Curcumin, a natural compound extracted from Curcuma longa, is known to have anti-tumoral, anti-proliferative, anti-inflammatory properties and affect the expression of cell adhesion molecules, mostly by targeting the NF-κB transcription factor. Here, upon treatment with curcumin, the vascular behavior of three different estrogen receptor negative (ER–) breast adenocarcinoma cell lines (SK-BR-3, MDA-MB-231, MDA-MB-468) is analyzed using a microfluidic system. First, the dose response to curcumin is characterized at 24, 48, and 72 h using a XTT assay. For all three cell lines, an IC50 larger than 20 µM is observed at 72 h; whereas no significant reduction in cell viability is detected for curcumin concentrations up to 10 µM. Upon 24 h treatment at 10 µM of curcumin, SK-BR3 and MDA-MB-231 cells show a decrease in adhesion propensity of 40% (p = 0.02) and 47% (p = 0.001), respectively. No significant change is documented for the less metastatic MDA-MB-468 cells. All three treated cell lines show a 20% increase in rolling velocity from 48.3 to 58.7 µm/s in SK-BR-3, from 64.1 to 73.77 µm/s in MDA-MB-231, and from 57.5 to 74.4 µm/s in MDA-MB-468. Collectively, these results suggest that mild curcumin treatments could limit the metastatic potential of these adenocarcinoma cell lines, possibly by altering the expression of adhesion molecules, and the organization and stiffness of the cell cytoskeleton. Future studies will elucidate the biophysical mechanisms regulating this curcumin-induced behavior and further explore the clinical relevance of these findings. PMID:23162792

  9. Adoptive transfer of MART-1 T cell receptor transgenic lymphocytes and dendritic cell vaccination in patients with metastatic melanoma

    PubMed Central

    Chodon, Thinle; Comin-Anduix, Begonya; Chmielowski, Bartosz; Koya, Richard C; Wu, Zhongqi; Auerbach, Martin; Ng, Charles; Avramis, Earl; Seja, Elizabeth; Villanueva, Arturo; McCannel, Tara A.; Ishiyama, Akira; Czernin, Johannes; Radu, Caius G.; Wang, Xiaoyan; Gjertson, David W.; Cochran, Alistair J.; Cornetta, Kenneth; Wong, Deborah J.L.; Kaplan-lefko, Paula; Hamid, Omid; Samlowski, Wolfram; Cohen, Peter A.; Daniels, Gregory A.; Mukherji, Bijay; Yang, Lili; Zack, Jerome A.; Kohn, Donald B.; Heath, James R.; Glaspy, John A.; Witte, Owen N.; Baltimore, David; Economou, James S.; Ribas, Antoni

    2014-01-01

    Purpose It has been demonstrated that large numbers of tumor-specific T cells for adoptive cell transfer (ACT) can be manufactured by retroviral genetic engineering of autologous peripheral blood lymphocytes and expanding them over several weeks. In mouse models, this therapy is optimized when administered with dendritic cell (DC) vaccination. We developed a short one-week manufacture protocol to determine the feasibility, safety and antitumor efficacy of this double cell therapy. Experimnetal Design A clinical trial (NCT00910650) adoptively transferring MART-1 T cell receptor (TCR) transgenic lymphocytes together with MART-1 peptide pulsed DC vaccination in HLA-A2.1 patients with metastatic melanoma. Autologous TCR transgenic cells were manufactured in 6 to 7 days using retroviral vector gene transfer, and re-infused with (n = 10) or without (n = 3) prior cryopreservation. Results 14 patients with metastatic melanoma were enrolled and nine out of 13 treated patients (69%) showed evidence of tumor regression. Peripheral blood reconstitution with MART-1-specific T cells peaked within two weeks of ACT indicating rapid in vivo expansion. Administration of freshly manufactured TCR transgenic T cells resulted in a higher persistence of MART-1-specific T cells in the blood as compared to cryopreserved. Evidence that DC vaccination could cause further in vivo expansion was only observed with ACT using non-cryopreserved T cells. Conclusion Double cell therapy with ACT of TCR engineered T cells with a very short ex vivo manipulation and DC vaccines is feasible and results in antitumor activity, but improvements are needed to maintain tumor responses. PMID:24634374

  10. Limitations of preoperative biopsy in patients with metastatic renal cell carcinoma: comparison to surgical pathology in 405 cases.

    PubMed

    Abel, E Jason; Carrasco, Alonso; Culp, Stephen H; Matin, Surena F; Tamboli, Pheroze; Tannir, Nizar M; Wood, Christopher G

    2012-12-01

    Study Type--Diagnostic (cohort) Level of Evidence: 2b. What's known on the subject? and What does the study add? Although there have been many investigations of biopsy for small renal masses, there are scant data on the accuracy of biopsy in the setting of metastatic renal cell carcinoma (mRCC). We report a large series of biopsies and compare with nephrectomy pathology in patients with mRCC. The present study highlights the inaccuracy of biopsy in the setting of metastatic disease, which is related to sampling error because of heterogeneity within the tumour and among metastases. These limitations are important to realize when designing trials that depend on pathological findings from biopsy and not nephrectomy. In addition, we found that biopsy of primary tumours were more likely than biopsy of metastatic sites to be diagnostic of RCC. Future studies with multiquadrant biopsies of primary tumours could yield the most accurate pathological results for future studies. • To evaluate the ability of preoperative biopsy to identify high-risk pathological features by comparing pathology from preoperative metastatic site and primary tumour biopsies with nephrectomy pathology in patients with metastatic renal cell carcinoma (mRCC). •  We reviewed clinical and pathological data from patients who underwent biopsy before cytoreductive nephrectomy for mRCC at MD Anderson Cancer Center (MDACC) from 1991 to 2007. • Percutaneous biopsy techniques included fine-needle aspiration, core needle biopsy or a combination of both techniques. • The pathology of 405 preoperative biopsies (239 metastatic site, 166 primary tumour) from 378 patients was reviewed at MDACC before cytoreductive nephrectomy. • The biopsy and nephrectomy specimens had the same histological subtype in 96.0% of clear-cell renal cell carcinomas (RCCs) and 72.7% of non-clear-cell RCCs. • Of 76 nephrectomy specimens where sarcomatoid de-differentiation was identified, only seven (9.2%) were able to be

  11. Modelling Circulating Tumour Cells for Personalised Survival Prediction in Metastatic Breast Cancer

    PubMed Central

    2015-01-01

    Ductal carcinoma is one of the most common cancers among women, and the main cause of death is the formation of metastases. The development of metastases is caused by cancer cells that migrate from the primary tumour site (the mammary duct) through the blood vessels and extravasating they initiate metastasis. Here, we propose a multi-compartment model which mimics the dynamics of tumoural cells in the mammary duct, in the circulatory system and in the bone. Through a branching process model, we describe the relation between the survival times and the four markers mainly involved in metastatic breast cancer (EPCAM, CD47, CD44 and MET). In particular, the model takes into account the gene expression profile of circulating tumour cells to predict personalised survival probability. We also include the administration of drugs as bisphosphonates, which reduce the formation of circulating tumour cells and their survival in the blood vessels, in order to analyse the dynamic changes induced by the therapy. We analyse the effects of circulating tumour cells on the progression of the disease providing a quantitative measure of the cell driver mutations needed for invading the bone tissue. Our model allows to design intervention scenarios that alter the patient-specific survival probability by modifying the populations of circulating tumour cells and it could be extended to other cancer metastasis dynamics. PMID:25978366

  12. Highly effective NK cells are associated with good prognosis in patients with metastatic prostate cancer

    PubMed Central

    Pasero, Christine; Gravis, Gwenaëlle; Granjeaud, Samuel; Guerin, Mathilde; Thomassin-Piana, Jeanne; Rocchi, Palma; Salem, Naji; Walz, Jochen; Moretta, Alessandro; Olive, Daniel

    2015-01-01

    Clinical outcome of patients with metastatic prostate cancer (mPC) at diagnosis is heterogeneous and unpredictable; thus alternative treatments such as immunotherapy are investigated. We retrospectively analyzed natural killer (NK) cells by flow cytometry in peripheral blood from 39 mPC patients, with 5 year-follow-up, and their correlation with time to castration resistance (TCR) and overall survival (OS). In parallel, NK functionality was carried out against prostate tumor cell lines, analyzed for the expression of NK cell ligands, to identify the receptors involved in PC recognition. NK cells from patients with longer TCR and OS displayed high expression of activating receptors and high cytotoxicity. The activating receptors NKp30 and NKp46 were the most obvious predictive markers of OS and TCR in a larger cohort of mPC patients (OS: p= 0.0018 and 0.0009; TCR: p= 0.007 and < 0.0001 respectively, log-rank test). Importantly, blocking experiments revealed that NKp46, along with NKG2D and DNAM-1 and, to a lesser extent NKp30, were involved in prostate tumor recognition by NK cells. These results identify NK cells as potential predictive biomarkers to stratify patients who are likely to have longer castration response, and pave the way to explore therapies aimed at enhancing NK cells in mPC patients. PMID:25961317

  13. Clinical significance of occult metastatic cells in bone marrow of breast cancer patients.

    PubMed

    Braun, S; Pantel, K

    2001-01-01

    The early and clinically occult spread of viable tumor cells to the organism is increasingly considered a hallmark in cancer progression, as emerging data suggest that these cells are precursors of subsequent distant relapse. Using monoclonal antibodies to epithelial cytokeratins or tumor-associated cell membrane glycoproteins, individual carcinoma cells can be detected on cytologic bone marrow preparations at frequencies of 10(-5) to 10(-6). Prospective clinical studies have shown that the presence of these immunostained cells in bone marrow, as a frequent site of overt metastases, is prognostically relevant with regard to relapse-free and overall survival. This screening approach may be, therefore, used to improve tumor staging and guide the stratification of patients for adjuvant therapy in clinical trials. Another promising application is monitoring the response of micrometastatic cells to adjuvant therapies, which, at present, can only be assessed retrospectively after an extended period of clinical follow-up. The present review summarizes the current data on the clinical significance of occult metastatic breast cancer cells in bone marrow.

  14. Treatment of pulmonary metastatic tumors in mice using lentiviral vector-engineered stem cells

    PubMed Central

    Zhang, X; Zhao, P; Kennedy, C; Chen, K; Wiegand, J; Washington, G; Marrero, L; Cui, Y

    2008-01-01

    Active cancer immunotherapy relies on functional tumor-specific effector T lymphocytes for tumor elimination. Dendritic cells (DCs), as most potent antigen-presenting cells, have been popularly employed in clinical and experimental tumor treatments. We have previously demonstrated that lentiviral vector-mediated transgene delivery to DC progenitors, including bone marrow cells and hematopoietic stem cells, followed by transplantation supports systemic generation of great numbers of tumor antigen-presenting DCs. These DCs subsequently stimulate marked and systemic immune activation. Here, we examined whether this level of immune activation is sufficient to overcome tumor-induced tolerogenic environment for treating an established aggressive epithelial tumor. We showed that a combination treatment of granulocyte macrophage-colony stimulating factor and cytosine-phosphate-guanine-containing oligonucleotide stimulated large numbers of tumor antigen-presenting DCs in situ from transgene-modified stem cells. Moreover, these in situ generated and activated DCs markedly stimulated activation of antigen-specific CD4 and CD8 T cells by augmenting their numbers, as well as function, even in a tumor-bearing tolerogenic environment. This leads to significant improvement in the therapeutic efficacy of established pulmonary metastases. This study suggests that lentiviral vector-modified stem cells as DC progenitors may be used as an effective therapeutic regimen for treating metastatic epithelial tumors. PMID:18084244

  15. Metastatic pancreatic polypeptide-secreting islet cell tumor in a dog.

    PubMed

    Cruz Cardona, Janice A; Wamsley, Heather L; Farina, Lisa L; Kiupel, Matti

    2010-09-01

    A 14-year-old female spayed Golden Retriever was presented to the University of Florida's Veterinary Medical Center with history of lymphoplasmacytic gastroenteritis, intermittent vomiting, watery diarrhea, and weight loss for over a year. CBC, biochemical profile, and urinalysis were within reference intervals. Abdominal ultrasonographic examination revealed mesenteric and jejunal lymphadenopathy and hyperechoic hepatic nodules. Cytologic examination of the enlarged lymph nodes revealed loosely cohesive cells with moderate nuclear pleomorphism and rare punctate eosinophilic cytoplasmic granules. The cytologic interpretation was metastatic neuroendocrine neoplasia. On surgical exploration, a mass was detected in the right lobe of the pancreas. Histologic evaluation determined the mass to be an islet cell tumor. Approximately 98% of cells were positive by immunolabeling for pancreatic polypeptide (PP), and only rare cells were positive for insulin or somatostatin. All cells were negative for glucagon, gastrin, vasoactive intestinal polypeptide, protein gene product 9.5, synaptophysin, and chromogranins A and B. Pancreatic tumors that primarily produce PP are rare in dogs, and this is the first report of both the cytologic and histologic features of an islet cell tumor predominantly secreting PP. Clinical signs for these tumors are typically absent or nonspecific; signs may include watery diarrhea, as noted in this dog, although the diarrhea may have resulted from lymphoplasmacytic gastroenteritis. Additional case studies are needed to further characterize the cytomorphologic features and clinical presentation of PP-secreting islet cell tumor, or polypeptidoma, in dogs.

  16. Intracellular calcium oscillations in strongly metastatic human breast and prostate cancer cells: control by voltage-gated sodium channel activity.

    PubMed

    Rizaner, Nahit; Onkal, Rustem; Fraser, Scott P; Pristerá, Alessandro; Okuse, Kenji; Djamgoz, Mustafa B A

    2016-10-01

    The possible association of intracellular Ca(2+) with metastasis in human cancer cells is poorly understood. We have studied Ca(2+) signaling in human prostate and breast cancer cell lines of strongly versus weakly metastatic potential in a comparative approach. Intracellular free Ca(2+) was measured using a membrane-permeant fluorescent Ca(2+)-indicator dye (Fluo-4 AM) and confocal microscopy. Spontaneous Ca(2+) oscillations were observed in a proportion of strongly metastatic human prostate and breast cancer cells (PC-3M and MDA-MB-231, respectively). In contrast, no such oscillations were observed in weakly/non metastatic LNCaP and MCF-7 cells, although a rise in the resting Ca(2+) level could be induced by applying a high-K(+) solution. Various parameters of the oscillations depended on extracellular Ca(2+) and voltage-gated Na(+) channel activity. Treatment with either tetrodotoxin (a general blocker of voltage-gated Na(+) channels) or ranolazine (a blocker of the persistent component of the channel current) suppressed the Ca(2+) oscillations. It is concluded that the functional voltage-gated Na(+) channel expression in strongly metastatic cancer cells makes a significant contribution to generation of oscillatory intracellular Ca(2+) activity. Possible mechanisms and consequences of the Ca(2+) oscillations are discussed.

  17. Inoculated Cell Density as a Determinant Factor of the Growth Dynamics and Metastatic Efficiency of a Breast Cancer Murine Model

    PubMed Central

    Gregório, Ana C.; Fonseca, Nuno A.; Moura, Vera; Lacerda, Manuela; Figueiredo, Paulo; Simões, Sérgio; Dias, Sérgio; Moreira, João Nuno

    2016-01-01

    4T1 metastatic breast cancer model have been widely used to study stage IV human breast cancer. However, the frequent inoculation of a large number of cells, gives rise to fast growing tumors, as well as to a surprisingly low metastatic take rate. The present work aimed at establishing the conditions enabling high metastatic take rate of the triple-negative murine 4T1 syngeneic breast cancer model. An 87% 4T1 tumor incidence was observed when as few as 500 cancer cells were implanted. 4T1 cancer cells colonized primarily the lungs with 100% efficiency, and distant lesions were also commonly identified in the mesentery and pancreas. The drastic reduction of the number of inoculated cells resulted in increased tumor doubling times and decreased specific growth rates, following a Gompertzian tumor expansion. The established conditions for the 4T1 mouse model were further validated in a therapeutic study with peguilated liposomal doxorubicin, in clinical used in the setting of metastatic breast cancer. Inoculated cell density was proven to be a key methodological aspect towards the reproducible development of macrometastases in the 4T1 mouse model and a more reliable pre-clinical assessment of antimetastatic therapies. PMID:27820870

  18. Non-small cell lung cancer: Spectral computed tomography quantitative parameters for preoperative diagnosis of metastatic lymph nodes.

    PubMed

    Yang, Fengfeng; Dong, Jie; Wang, Xiuting; Fu, Xiaojiao; Zhang, Tong

    2017-04-01

    To investigate the application value of spectral computed tomography (CT)quantitative parameters for preoperative diagnosis of metastatic lymph nodes in patients with non-small cell lung cancer (NSLC). 84 patients with suspected lung cancer who underwent chest dual-phase enhanced scan with gemstone spectral CT imaging (GSI) mode were selected. GSI quantitative parameters including normalized iodine concentrations (NIC), water concentration, slope of the spectral Hounsfield unit curve (λHU) were measured. The two-sample t test was used to statistically compare these quantitative parameters. Receiver operating characteristic (ROC) curves were drawn to establish the optimal threshold values. A total of 144 lymph nodes were included, with 48 metastatic lymph nodes and 96 non-metastatic lymph nodes. The slope of the spectral Hounsfeld unit curve (λHU) measured during both arterial and venous phases were signifcantly higher in metastatic than in benign lymph nodes (P<0.05). The area under the ROC curve (AUC=0.951) of λHU of the arterial phase (AP) was the largest. When the optimal threshold values of λHU was 2.75, the sensitivity, specificity, and overall accuracy in the diagnosis of metastatic lymph nodes were 88.2%, 88.4%, 87.0%, respectively. Conventional CT diagnostic criteria established in accordance with size (lymph node maximal short axis diameter ≥10mm) as the basis for judging metastatic lymph node. In quantitative assessment using spectral CT imaging, quantitative parameters showed higher accuracy than qualitative assessment of conventional CT based on the size for preoperative diagnosis of metastatic lymph nodes. Copyright © 2017 Elsevier B.V. All rights reserved.

  19. Elevated cyclin A associated kinase activity promotes sensitivity of metastatic human cancer cells to DNA antimetabolite drug.

    PubMed

    Wang, Jin; Yin, Hailin; Panandikar, Ashwini; Gandhi, Varsha; Sen, Subrata

    2015-08-01

    Drug resistance is a major obstacle in successful systemic therapy of metastatic cancer. We analyzed the involvement of cell cycle regulatory proteins in eliciting response to N (phosphonoacetyl)-L-aspartate (PALA), an inhibitor of de novo pyrimidine synthesis, in two metastatic variants of human cancer cell line MDA-MB-435 isolated from lung (L-2) and brain (Br-1) in nude mouse, respectively. L-2 and Br-l cells markedly differed in their sensitivity to PALA. While both cell types displayed an initial S phase delay/arrest, Br-l cells proliferated but most L-2 cells underwent apoptosis. There was distinct elevation in cyclin A, and phosphorylated Rb proteins concomitant with decreased expression of bcl-2 protein in the PALA treated L-2 cells undergoing apoptosis. Markedly elevated cyclin A associated and cdk2 kinase activities together with increased E2F1-DNA binding were detected in these L-2 cells. Induced ectopic cyclin A expression sensitized Br-l cells to PALA by activating an apoptotic pathway. Our findings demonstrate that elevated expression of cyclin A and associated kinase can activate an apoptotic pathway in cells exposed to DNA antimetabolites. Abrogation of this pathway can lead to resistance against these drugs in metastatic variants of human carcinoma cells.

  20. Endoscopy-guided orthotopic implantation of colorectal cancer cells results in metastatic colorectal cancer in mice.

    PubMed

    Bettenworth, Dominik; Mücke, Marcus M; Schwegmann, Katrin; Faust, Andreas; Poremba, Christopher; Schäfers, Michael; Domagk, Dirk; Lenz, Philipp

    2016-08-01

    Advanced stage colorectal cancer (CRC) is still associated with limited prognosis. For preclinical evaluation of novel therapeutic approaches, murine models with orthotopic tumor growth and distant metastases are required. However, these models usually require surgical procedures possibly influencing tumor immunogenicity and development. The aim of this study was to establish a minimal-invasive endoscopy-based murine orthotopic model of metastatic CRC. During colonoscopy of CD-1 nude and non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mice, implantation of Caco-2 and HT-29 CRC cells was performed subcutaneously (s.c.) or orthotopic into the colonic submucosa. White light endoscopy (WLE) and fluorescence endoscopy (FE) were applied for tumor detection in vivo. Ex vivo, resected tumors were examined by fluorescence reflectance imaging (FRI), histology, gelatin zymography and immunohistochemistry. In CD-1 nude mice, marked tumor growth was observed within 14 days after subcutaneous implantation while submucosal implantation failed to induce CRC after 17 weeks. In contrast, in NOD/SCID mice submucosal injection of HT-29 cells resulted in pronounced tumor growth 12 days post injectionem. Subsequently, rapid tumor expansion occurred, occupying the entire colonic circumference. Importantly, post mortem histological analyses confirmed liver metastases in 28.6 % and peritoneal metastases in 14.3 % of all mice. FRI and gelatin zymography did not detect a significantly increased matrix metalloproteinases (MMPs) expression in s.c. implanted tumors while MMP-tracer uptake was significantly enhanced in orthotopic implanted tumors. Neither s.c. nor orthotopic Caco-2 cell implantation resulted in tumor development. We successfully established an endoscopy-based model of metastatic CRC in immunodeficient mice.

  1. Final results from the large sunitinib global expanded-access trial in metastatic renal cell carcinoma

    PubMed Central

    Gore, M E; Szczylik, C; Porta, C; Bracarda, S; Bjarnason, G A; Oudard, S; Lee, S-H; Haanen, J; Castellano, D; Vrdoljak, E; Schöffski, P; Mainwaring, P; Hawkins, R E; Crinò, L; Kim, T M; Carteni, G; Eberhardt, W E E; Zhang, K; Fly, K; Matczak, E; Lechuga, M J; Hariharan, S; Bukowski, R

    2015-01-01

    Background: We report final results with extended follow-up from a global, expanded-access trial that pre-regulatory approval provided sunitinib to metastatic renal cell carcinoma (mRCC) patients, ineligible for registration-directed trials. Methods: Patients ⩾18 years received oral sunitinib 50 mg per day on a 4-weeks-on–2-weeks-off schedule. Safety was assessed regularly. Tumour measurements were scheduled per local practice. Results: A total of 4543 patients received sunitinib. Median treatment duration and follow-up were 7.5 and 13.6 months. Objective response rate was 16% (95% confidence interval (CI): 15–17). Median progression-free survival (PFS) and overall survival (OS) were 9.4 months (95% CI: 8.8–10.0) and 18.7 months (95% CI: 17.5–19.5). Median PFS in subgroups of interest: aged ⩾65 years (33%), 10.1 months; Eastern Cooperative Oncology Group performance status ⩾2 (14%), 3.5 months; non-clear cell histology (12%), 6.0 months; and brain metastases (7%), 5.3 months. OS was strongly associated with the International Metastatic Renal-Cell Carcinoma Database Consortium prognostic model (n=4065). The most common grade 3/4 treatment-related adverse events were thrombocytopenia (10%), fatigue (9%), and asthenia, neutropenia, and hand–foot syndrome (each 7%). Conclusion: Final analysis of the sunitinib expanded-access trial provided a good opportunity to evaluate the long-term side effects of a tyrosine kinase inhibitor used worldwide in mRCC. Efficacy and safety findings were consistent with previous results. PMID:26086878

  2. Twist1 in tumor cells and α-smooth muscle actin in stromal cells are possible biomarkers for metastatic giant basal cell carcinoma.

    PubMed

    Motegi, Sei-ichiro; Yamada, Kazuya; Ishikawa, Osamu

    2013-08-01

    We previously reported a case of giant basal cell carcinoma (BCC) in a 75-year-old Japanese man, who subsequently developed a pulmonary metastasis. With regard to the pathogenesis of metastasis of BCC, recently, it has been reported that high levels of expression of Twist1 and N-cadherin in primary and metastatic tumor cells, suggesting that Twist1 expression and an epithelial-mesenchymal transition (EMT) of tumor cells are important for the promotion of tumor invasion and subsequent metastasis. In this report, we identified the expressions of Twist1 in tumor cells and α-smooth muscle actin (α-SMA) in stromal cells in the primary and metastatic sites of giant BCC. These results suggest that Twist1-induced EMT of tumor cells might have been associated with distant organ metastasis in our case, and the presence of α-SMA-positive myofibroblasts surrounding a BCC nest can be one of hallmarks of the aggressiveness of BCC.

  3. Metastatic renal cell carcinoma of spleen diagnosed by fine-needle aspiration.

    PubMed

    McGregor, Douglas H; Wu, Yaping; Weston, Allan P; McAnaw, Mary P; Bromfield, Cecil; Bhattatiry, Manu M

    2003-07-01

    Splenic metastases are infrequent, and determination of the primary site by fine-needle aspiration (FNA) can be complex. We report the case of a 65-year-old man who was found to have a large heterogeneously enhancing 8 x 7-inch splenic mass by abdominal computed tomography (CT). FNA by transesophageal endoscopic ultrasonography demonstrated atypical cells conclusive for malignancy and consistent with metastatic renal cell carcinoma based on cytomorphology, histochemical lipid positivity, and immunohistochemical positivity for cytokeratin, vimentin, and renal cell carcinoma marker. Repeat CT with and without arteriovenous contrast demonstrated bilateral renal cysts, including a 0.9 x 0.8-cm lesion on the left with significant enhancement. Splenectomy confirmed the radiological and cytological findings, and left kidney exploration and nephrectomy demonstrated a small (1.5 cm) lower pole renal cell carcinoma of chromophil (papillary) type, histologically similar to the splenic metastasis. This case demonstrates the diagnostic importance of interdisciplinary involvement (oncology, radiology, gastroenterology, pathology, and general and urologic surgery); cytomorphology; histochemistry, including fat stain on frozen cell block; and immunohistochemistry, including the recently developed renal cell carcinoma marker.

  4. Favorable prognostic influence of T-box transcription factor Eomesodermin in metastatic renal cell cancer patients.

    PubMed

    Dielmann, Anastasia; Letsch, Anne; Nonnenmacher, Anika; Miller, Kurt; Keilholz, Ulrich; Busse, Antonia

    2016-02-01

    T-box transcription factors, T-box expressed in T cells (T-bet) encoded by Tbx21 and Eomesodermin (Eomes), drive the differentiation of effector/memory T cell lineages and NK cells. The aim of the study was to determine the prognostic influence of the expression of these transcription factors in peripheral blood (pB) in a cohort of 41 metastatic (m) RCC patients before receiving sorafenib treatment and to analyze their association with the immunophenotype in pB. In contrast to Tbx21, in the multivariate analysis including clinical features, Eomes mRNA expression was identified as an independent good prognostic factor for progression-free survival (PFS, p = 0.042) and overall survival (OS, p = 0.001) in addition to a favorable ECOG performance status (p = 0.01 and p = 0.008, respectively). Eomes expression correlated positively not only with expression of Tbx21 and TGFβ1 mRNA, but also with mRNA expression of the activation marker ICOS, and with in vivo activated HLA-DR(+) T cells. Eomes expression was negatively associated with TNFα-producing T cells. On protein level, Eomes was mainly expressed by CD56(+)CD3(-) NK cells in pB. In conclusion, we identified a higher Eomes mRNA expression as an independent good prognostic factor for OS and PFS in mRCC patients treated with sorafenib.

  5. Enrichment of circulating melanoma cells (CMCs) using negative selection from patients with metastatic melanoma

    PubMed Central

    Joshi, Powrnima; Jacobs, Barbara; Derakhshan, Adeeb; Moore, Lee R.; Elson, Paul; Triozzi, Pierre L.; Borden, Ernest; Zborowski, Maciej

    2014-01-01

    Circulating tumor cells have emerged as prognostic biomarkers in the treatment of metastatic cancers of epithelial origins viz., breast, colorectal and prostate. These tumors express Epithelial Cell Adhesion Molecule (EpCAM) on their cell surface which is used as an antigen for immunoaffinity capture. However, EpCAM capture technologies are of limited utility for non-epithelial cancers such as melanoma. We report a method to enrich Circulating Melanoma Cells (CMCs) that does not presuppose malignant cell characteristics. CMCs were enriched by centrifugation of blood samples from healthy (N = 10) and patient (N = 11) donors, followed by RBC lysis and immunomagnetic depletion of CD45-positive leukocytes in a specialized magnetic separator. CMCs were identified by immunocytochemistry using Melan-A or S100B as melanoma markers and enumerated using automated microscopy image analyses. Separation was optimized for maximum sensitivity and recovery of CMCs. Our results indicate large number of CMCs in Stage IV melanoma patients. Analysis of survival suggested a trend toward decreased survival with increased number of CMCs. Moreover, melanoma-associated miRs were found to be higher in CMC-enriched fractions in two patients when compared with the unseparated samples, validating this method as applicable for molecular analyses. Negative selection is a promising approach for isolation of CMCs and other EpCAM -negative CTCs, and is amenable to molecular analysis of CMCs. Further studies are required to validate its efficacy at capturing specific circulating cells for genomic analysis, and xenograft studies. PMID:24811334

  6. Enrichment of circulating melanoma cells (CMCs) using negative selection from patients with metastatic melanoma.

    PubMed

    Joshi, Powrnima; Jacobs, Barbara; Derakhshan, Adeeb; Moore, Lee R; Elson, Paul; Triozzi, Pierre L; Borden, Ernest; Zborowski, Maciej

    2014-05-15

    Circulating tumor cells have emerged as prognostic biomarkers in the treatment of metastatic cancers of epithelial origins viz., breast, colorectal and prostate. These tumors express Epithelial Cell Adhesion Molecule (EpCAM) on their cell surface which is used as an antigen for immunoaffinity capture. However, EpCAM capture technologies are of limited utility for non-epithelial cancers such as melanoma. We report a method to enrich Circulating Melanoma Cells (CMCs) that does not presuppose malignant cell characteristics. CMCs were enriched by centrifugation of blood samples from healthy (N = 10) and patient (N = 11) donors, followed by RBC lysis and immunomagnetic depletion of CD45-positive leukocytes in a specialized magnetic separator. CMCs were identified by immunocytochemistry using Melan-A or S100B as melanoma markers and enumerated using automated microscopy image analyses. Separation was optimized for maximum sensitivity and recovery of CMCs. Our results indicate large number of CMCs in Stage IV melanoma patients. Analysis of survival suggested a trend toward decreased survival with increased number of CMCs. Moreover, melanoma-associated miRs were found to be higher in CMC-enriched fractions in two patients when compared with the unseparated samples, validating this method as applicable for molecular analyses. Negative selection is a promising approach for isolation of CMCs and other EpCAM -negative CTCs, and is amenable to molecular analysis of CMCs. Further studies are required to validate its efficacy at capturing specific circulating cells for genomic analysis, and xenograft studies.

  7. Cancer stemness and metastatic potential of the novel tumor cell line K3: an inner mutated cell of bone marrow-derived mesenchymal stem cells.

    PubMed

    Qian, Hui; Ding, Xiaoqing; Zhang, Jiao; Mao, Fei; Sun, Zixuan; Jia, Haoyuan; Yin, Lei; Wang, Mei; Zhang, Xu; Zhang, Bin; Yan, Yongmin; Zhu, Wei; Xu, Wenrong

    2017-06-13

    Mesenchymal stem cells (MSCs) transplantation has been used for therapeutic applications in various diseases. Here we report MSCs can malignantly transform in vivo. The novel neoplasm was found on the tail of female rat after injection with male rat bone marrow-derived MSCs (rBM-MSCs) and the new tumor cell line, K3, was isolated from the neoplasm. The K3 cells expressed surface antigens and pluripotent genes similar to those of rBM-MSCs and presented tumor cell features. Moreover, the K3 cells contained side population cells (SP) like cancer stem cells (CSCs), which might contribute to K3 heterogeneity and tumorigenic capacity. To investigate the metastatic potential of K3 cells, we established the nude mouse models of liver and lung metastases and isolated the corresponding metastatic cell lines K3-F4 and K3-B6. Both K3-F4 and K3-B6 cell lines with higher metastatic potential acquired more mesenchymal and stemness-related features. Epithelial-mesenchymal transition is a potential mechanism of K3-F4 and K3-B6 formation.

  8. Chemotherapy With or Without Bevacizumab in Treating Patients With Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma

    ClinicalTrials.gov

    2017-04-14

    Recurrent Hypopharyngeal Squamous Cell Carcinoma; Recurrent Laryngeal Squamous Cell Carcinoma; Recurrent Laryngeal Verrucous Carcinoma; Recurrent Lip and Oral Cavity Squamous Cell Carcinoma; Recurrent Metastatic Squamous Cell Carcinoma in the Neck With Occult Primary; Recurrent Nasal Cavity and Paranasal Sinus Squamous Cell Carcinoma; Recurrent Oral Cavity Verrucous Carcinoma; Recurrent Oropharyngeal Squamous Cell Carcinoma; Recurrent Salivary Gland Carcinoma; Salivary Gland Squamous Cell Carcinoma; Squamous Cell Carcinoma Metastatic in the Neck With Occult Primary; Stage IV Hypopharyngeal Squamous Cell Carcinoma AJCC v7; Stage IV Major Salivary Gland Cancer AJCC v7; Stage IVA Laryngeal Squamous Cell Carcinoma; Stage IVA Laryngeal Verrucous Carcinoma; Stage IVA Lip and Oral Cavity Squamous Cell Carcinoma AJCC v6 and v7; Stage IVA Major Salivary Gland Cancer AJCC v7; Stage IVA Nasal Cavity and Paranasal Sinus Squamous Cell Carcinoma; Stage IVA Oral Cavity Verrucous Carcinoma; Stage IVA Oropharyngeal Squamous Cell Carcinoma AJCC v7; Stage IVB Laryngeal Squamous Cell Carcinoma; Stage IVB Laryngeal Verrucous Carcinoma; Stage IVB Lip and Oral Cavity Squamous Cell Carcinoma AJCC v6 and v7; Stage IVB Major Salivary Gland Cancer AJCC v7; Stage IVB Nasal Cavity and Paranasal Sinus Squamous Cell Carcinoma; Stage IVB Oral Cavity Verrucous Carcinoma; Stage IVB Oropharyngeal Squamous Cell Carcinoma AJCC v7; Stage IVC Laryngeal Squamous Cell Carcinoma; Stage IVC Laryngeal Verrucous Carcinoma; Stage IVC Lip and Oral Cavity Squamous Cell Carcinoma AJCC v6 and v7; Stage IVC Major Salivary Gland Cancer AJCC v7; Stage IVC Nasal Cavity and Paranasal Sinus Squamous Cell Carcinoma; Stage IVC Oral Cavity Verrucous Carcinoma; Stage IVC Oropharyngeal Squamous Cell Carcinoma AJCC v7; Tongue Carcinoma; Untreated Metastatic Squamous Cell Carcinoma to Neck With Occult Primary

  9. Sorafenib Tosylate, Cisplatin, and Docetaxel in Treating Patients With Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck

    ClinicalTrials.gov

    2017-03-01

    Metastatic Squamous Neck Cancer With Occult Primary Squamous Cell Carcinoma; Recurrent Metastatic Squamous Neck Cancer With Occult Primary; Recurrent Salivary Gland Cancer; Recurrent Squamous Cell Carcinoma of the Hypopharynx; Recurrent Squamous Cell Carcinoma of the Larynx; Recurrent Squamous Cell Carcinoma of the Lip and Oral Cavity; Recurrent Squamous Cell Carcinoma of the Nasopharynx; Recurrent Squamous Cell Carcinoma of the Oropharynx; Recurrent Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Recurrent Verrucous Carcinoma of the Larynx; Recurrent Verrucous Carcinoma of the Oral Cavity; Salivary Gland Squamous Cell Carcinoma; Stage IV Squamous Cell Carcinoma of the Hypopharynx; Stage IV Squamous Cell Carcinoma of the Nasopharynx; Stage IVA Salivary Gland Cancer; Stage IVA Squamous Cell Carcinoma of the Larynx; Stage IVA Oral Cavity Squamous Cell Carcinoma; Stage IVA Squamous Cell Carcinoma of the Oropharynx; Stage IVA Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Stage IVA Verrucous Carcinoma of the Larynx; Stage IVA Verrucous Carcinoma of the Oral Cavity; Stage IVB Salivary Gland Cancer; Stage IVB Squamous Cell Carcinoma of the Larynx; Stage IVB Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IVB Squamous Cell Carcinoma of the Oropharynx; Stage IVB Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Stage IVB Verrucous Carcinoma of the Larynx; Stage IVB Verrucous Carcinoma of the Oral Cavity; Stage IVC Salivary Gland Cancer; Stage IVC Squamous Cell Carcinoma of the Larynx; Stage IVC Squamous Cell Carcinoma of the Lip and Oral Cavity; Stage IVC Squamous Cell Carcinoma of the Oropharynx; Stage IVC Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Stage IVC Verrucous Carcinoma of the Larynx; Stage IVC Verrucous Carcinoma of the Oral Cavity; Tongue Cancer; Untreated Metastatic Squamous Neck Cancer With Occult Primary

  10. Sequential pathogenesis of metastatic VHL mutant clear cell renal cell carcinoma: putting it together with a translational perspective.

    PubMed

    Shenoy, N; Pagliaro, L

    2016-09-01

    Clear cell renal cell carcinoma (ccRCC) accounts for ∼80% of all RCC, and biallelic Von Hippel-Lindau (VHL) gene defects occur in ∼75% of sporadic ccRCC. The etiopathogenesis of VHL mutant metastatic RCC, based on our understanding to date of molecular mechanisms involved, is a sequence of events which can be grouped under the following: (i) loss of VHL activity (germline/somatic mutation + inactivation of the wild-type copy); (ii) constitutive activation of the hypoxia-inducible factor (HIF) pathway due to loss of VHL activity and transcription of genes involved in angiogenesis, epithelial-mesenchymal transition, invasion, metastasis, survival, anaerobic glycolysis and pentose phosphate pathway; (iii) interactions of the HIF pathway with other oncogenic pathways; (iv) genome-wide epigenetic changes (potentially driven by an overactive HIF pathway) and the influence of epigenetics on various oncogenic, apoptotic, cell cycle regulatory and mismatch repair pathways (inhibition of multiple tumor suppressor genes); (v) immune evasion, at least partially caused by changes in the epigenome. These mechanisms interact throughout the pathogenesis and progression of disease, and also confer chemoresistance and radioresistance, making it one of the most difficult metastatic cancers to treat. This article puts together the sequential pathogenesis of VHL mutant ccRCC by elaborating these mechanisms and the interplay of oncogenic pathways, epigenetics, metabolism and immune evasion, with a perspective on potential therapeutic strategies. We reflect on the huge gap between our understanding of the molecular biology and currently accepted standard of care in metastatic ccRCC, and present ideas for better translational research involving therapeutic strategies with combinatorial drug approach, targeting different aspects of the pathogenesis.

  11. Combination of miR-21 with Circulating Tumor Cells Markers Improve Diagnostic Specificity of Metastatic Breast Cancer.

    PubMed

    Yang, Xingwang; Wang, Xiaoming; Shen, Hongyan; Deng, Rong; Xue, Kecheng

    2015-09-01

    Circulating miR-21 is upregulated in breast cancer. However, correlation of miR-21 expression with clinic pathologic characteristics remains questionable. In this study, we investigate whether combination of circulation miR-21 with circulating tumor cells (CTCs) marker (EpCAM, MUS1, HER2) could improve diagnostic specificity of metastatic breast cancer. Total 223 breast cancer patients were included. 89 % patients were associated with upregulation of miR-21 compared with health control. 20 % patients were detected for CTCs marker positive. For higher specificity purpose, triple marker positive samples were selected as true CTCs positive, which only occupied 59.5 % of total metastatic breast cancer patients. Specificity of detection of CTCs was 96.7 %. Furthermore, 59.5 % metastatic breast cancer patients were shown both abnormal miR-21 and true CTCs positive according to distribution of true CTCs positive and abnormal miR-21; Combination of miR-21 and CTCs was increased specificity of metastatic detection to 100 %. Our findings suggested that combination of miR-21 with CTCs marker could be used for better diagnosis of metastatic breast cancer in the future.

  12. Immunophenotypic features of metastatic lymph node tumors to predict recurrence in N2 lung squamous cell carcinoma

    PubMed Central

    Matsuwaki, Rie; Ishii, Genichiro; Zenke, Yoshitaka; Neri, Shinya; Aokage, Keiju; Hishida, Tomoyuki; Yoshida, Junji; Fujii, Satoshi; Kondo, Haruhiko; Goya, Tomoyuki; Nagai, Kanji; Ochiai, Atsushi

    2014-01-01

    Patients with mediastinal lymph node metastasis (N2) in squamous cell carcinoma (SqCC) of the lung have poor prognosis after surgical resection of the primary tumor. The aim of this study was to clarify predictive factors of the recurrence of pathological lung SqCC with N2 focusing on the biological characteristics of both cancer cells and cancer-associated fibroblasts (CAFs) in primary and metastatic lymph node tumors. We selected 64 patients with pathological primary lung N2 SqCC who underwent surgical complete resection and investigated the expressions of four epithelial–mesenchymal transition-related markers (caveolin, clusterin, E-cadherin, ZEB2), three cancer stem cell-related markers (ALDH-1, CD44 variant6, podoplanin) of cancer cells, and four markers of CAFs (caveolin, CD90, clusterin, podoplanin) in both primary and matched metastatic lymph node tumors in the N2 area. In the primary tumors, the expressions of all the examined molecules were not related to recurrence. However, in the metastatic lymph node tumors, high clusterin and ZEB2 expressions in the cancer cells and high podoplanin expression in the CAFs were significantly correlated with recurrence (P = 0.03, 0.04, and 0.007, respectively). In a multivariate analysis, only podoplanin expression in the CAFs in metastatic lymph node tumors was identified as a significantly independent predictive factor of recurrence (P = 0.03). Our study indicated that the immunophenotypes of both cancer cells and CAFs in metastatic lymph node tumors, but not primary tumors, provide useful information for predicting the recurrence of pathological N2 lung SqCC. PMID:24814677

  13. Do Mesenchymal Stromal Cells Influence Microscopic Residual or Metastatic Osteosarcoma in a Murine Model?

    PubMed

    Aanstoos, Megan E; Regan, Daniel P; Rose, Ruth J; Chubb, Laura S; Ehrhart, Nicole P

    2016-03-01

    Mesenchymal stromal cells (MSCs) have been shown in rodent models to promote primary and pulmonary metastatic sarcoma growth when injected in the presence of gross tumor. In theory, this would limit their use in a clinical setting after limb salvage treatment for osteosarcoma. Although concerning, these models do not translate to the clinical setting wherein MSCs could be used after primary tumor resection to aid in bone healing and incorporation of tumor endoprostheses. If we can determine whether the use of MSCs in this setting is safe, it might improve our ability to augment bone healing in patients undergoing limb salvage. The purpose of this study was to determine (1) whether MSCs promote pulmonary metastatic disease progression in a murine osteosarcoma model; and/or (2) whether they affect local disease recurrence in the presence of microscopic residual osteosarcoma. An orthotopic model of luciferase-expressing osteosarcoma was developed. At 10 days, resection of the primary tumor was performed. One hundred fourteen female C3H mice were inoculated with DLM8-luc osteosarcoma in the proximal tibia. Ninety-four mice developed orthotopic osteosarcoma with luciferase expression. Mice with bioluminescent evidence of a primary tumor received either a microscopically "clean" amputation at a time when residual microscopic metastatic disease was present in the lungs (pulmonary metastasis group; n = 65) or a "dirty" amputation (local recurrence group; n = 29). Mice were randomized to receive intravenous MSCs, MSCs at the surgical site, or no MSCs. Mice were monitored for development and progression of pulmonary metastasis and local recurrence by bioluminescence imaging and daily measurements at the surgical site. The number of pulmonary nodules, time to first evidence of metastasis, and size of recurrent tumor were compared using Kruskal-Wallis, analysis of variance, Welch's, t-tests, or Mann-Whitney tests as appropriate for the specific data sets with p < 0

  14. Jejunal perforation: an unusual presentation of metastatic cutaneous squamous cell carcinoma (SCC) in an immunosuppressed patient.

    PubMed

    Hitchen, N; Warnapala, D; Fisher, R M; Dua, J; Pratsou, P; Freebairn, A

    2017-01-06

    We report the rare occurrence of a small bowel perforation secondary to a metastatic cutaneous squamous cell carcinoma (cSCC). A 70-year-old woman, who had previously undergone renal transplantation, presented with severe, sudden-onset abdominal pain. She was peritonitic on initial examination, with evidence of free intra-abdominal air on radiographic imaging. During an exploratory laparotomy, she was found to have a perforated jejunum secondary to disseminated metastases seen throughout her peritoneum. Following histopathological analysis, as well as further imaging studies, the primary malignancy was eventually identified as a cSCC on her upper back. Palliative care was started and the patient died 8 weeks following her initial presentation. 2017 BMJ Publishing Group Ltd.

  15. Hypertension and Angiotensin System Inhibitors in Patients with Metastatic Renal Cell Carcinoma

    PubMed Central

    Derosa, Lisa; Izzedine, Hassane; Albiges, Laurence; Escudier, Bernard

    2016-01-01

    Arterial hypertension (HTN) is a class effect of anti-vascular endothelial growth factor (VEGF) therapies, including the monoclonal antibody bevacizumab. Data are conflicting regarding the role of the renin-angiotensin system on angiogenesis and recent data suggest that the use of angiotensin system inhibitors (ASIs; angiotensin receptor blockers or angiotensin-converting enzyme inhibitors) is associated with improved survival in metastatic renal cell carcinoma (mRCC), particularly when used with VEGF targeted therapies. The aim of this review is to discuss the available treatment options for mRCC and associated incidence of hypertension as well as summarize the known data about ASIs use and mRCC. Additionally, given that the optimal management of HTN remains unclear, we will focus on prevention strategies and propose potential therapeutic approaches. PMID:27994768

  16. Vismodegib: the first drug approved for advanced and metastatic basal cell carcinoma.

    PubMed

    Dubey, A K; Dubey, S; Handu, S S; Qazi, M A

    2013-01-01

    Treatment of basal cell carcinoma (BCC) usually involves surgical interventions and laser ablation, but in locally advanced BCC, which arise either from earlier untreated lesions or from recurrence of aggressive BCC, surgery and radiotherapy are not helpful. Vismodegib, the first oral-targeted therapy for locally advanced and metastatic BCC, unsuitable for surgery or radiotherapy, was recently approved by US Food and Drug Administration (FDA). The drug was under the priority review program of FDA and was approved on the basis of promising results of phase II trial. Vismodegib acts by targeting the hedgehog pathway, which is activated abnormally in most BCCs. Approval of vismodegib is a big step ahead in the treatment of advanced BCC, where there was no other effective drug therapy till now.

  17. Metastatic Calcinosis Cutis: A Case in a Child with Acute Pre-B Cell Lymphoblastic Leukemia

    PubMed Central

    Castanedo-Cázares, Juan Pablo; Reyes-Herrera, Amalia; Hernández-Blanco, Diana; Oros-Ovalle, Cuauhtémoc; Torres-Álvarez, Bertha

    2015-01-01

    Hypercalcemia in children with malignancy is an uncommon condition. It has been described in leukemia patients with impaired renal excretion of calcium or osteolytic lesions. Metastatic calcinosis cutis (MCC) may develop if hypercalcemia persists. We report the case of a 5-year-old girl with an atypical dermatosis and unspecific gastrointestinal symptoms. Considered clinical diagnoses were xanthomas, histiocytosis, molluscum contagiosum, and nongenital warts. Cutaneous histological analysis showed amorphous basophilic deposits in the dermis suggestive of calcium deposits. Laboratory tests confirmed serum hypercalcemia. Extensive investigations such as bone marrow biopsy established the diagnosis of an acute pre-B cell lymphoblastic leukemia. Hypercalcemia in hematopoietic malignancies is unusual, especially as initial manifestation of the disease. Careful review of the literature fails to reveal previous reports of these peculiar cutaneous lesions of MCC in children with leukemia. PMID:26346120

  18. Metastatic transitional cell carcinoma of the urinary bladder presenting as a mandibular gingival swelling.

    PubMed

    de Courten, A; Irle, C; Samson, J; Lombardi, T

    2001-05-01

    Oral cavity metastases mostly originate from the breasts, lungs, or kidneys. Transitional cell carcinoma (TCC), the most frequent malignant tumor of the urinary bladder, rarely metastasizes to the jaws. To the best of our knowledge, only 8 cases of bladder carcinoma have been reported in the English literature to metastasize to the jawbones. A new case of mandibular metastasis of urinary bladder TCC with extension to the gingiva is presented in a 64-year-old white man. The patient was referred for a periodontal infection of the upper right first molar. The clinical examination also showed a gingival swelling located in the lower left premolar region with a hypoasthesia of the left side of the lower lip. The gingival mass was biopsied, and the microscopy showed a mandibular metastatic TCC of the urinary bladder extending to the gingiva. Periodontists should be aware that, although gingival metastases are rare, when they occur they may mimic other local benign pathological conditions.

  19. Alternative therapies for metastatic breast cancer: multimodal approach targeting tumor cell heterogeneity

    PubMed Central

    Sambi, Manpreet; Haq, Sabah; Samuel, Vanessa; Qorri, Bessi; Haxho, Fiona; Hill, Kelli; Harless, William; Szewczuk, Myron R

    2017-01-01

    One of the primary challenges in developing effective therapies for malignant tumors is the specific targeting of a heterogeneous cancer cell population within the tumor. The cancerous tumor is made up of a variety of distinct cells with specialized receptors and proteins that could potentially be viable targets for drugs. In addition, the diverse signals from the local microenvironment may also contribute to the induction of tumor growth and metastasis. Collectively, these factors must be strategically studied and targeted in order to develop an effective treatment protocol. Targeted multimodal approaches need to be strategically studied in order to develop a treatment protocol that is successful in controlling tumor growth and preventing metastatic burden. Breast cancer, in particular, presents a unique problem because of the variety of subtypes of cancer that can arise and the multiple drug targets that could be exploited. For example, the tumor stage and subtypes often dictate the appropriate treatment regimen. Alternate multimodal therapies should consider the importance of time-dependent drug administration, as well as targeting the local and systemic tumor environment. Many reviews and papers have briefly touched on the clinical implications of this cellular heterogeneity; however, there has been very little discussion on the development of study models that reflect this diversity and on multimodal therapies that could target these subpopulations. Here, we summarize the current understanding of the origins of intratumoral heterogeneity in breast cancer subtypes, and its implications for tumor progression, metastatic potential, and treatment regimens. We also discuss the advantages and disadvantages of utilizing specific breast cancer models for research, including in vitro monolayer systems and three-dimensional mammospheres, as well as in vivo murine models that may have the capacity to encompass this heterogeneity. Lastly, we summarize some of the current

  20. Alternative therapies for metastatic breast cancer: multimodal approach targeting tumor cell heterogeneity.

    PubMed

    Sambi, Manpreet; Haq, Sabah; Samuel, Vanessa; Qorri, Bessi; Haxho, Fiona; Hill, Kelli; Harless, William; Szewczuk, Myron R

    2017-01-01

    One of the primary challenges in developing effective therapies for malignant tumors is the specific targeting of a heterogeneous cancer cell population within the tumor. The cancerous tumor is made up of a variety of distinct cells with specialized receptors and proteins that could potentially be viable targets for drugs. In addition, the diverse signals from the local microenvironment may also contribute to the induction of tumor growth and metastasis. Collectively, these factors must be strategically studied and targeted in order to develop an effective treatment protocol. Targeted multimodal approaches need to be strategically studied in order to develop a treatment protocol that is successful in controlling tumor growth and preventing metastatic burden. Breast cancer, in particular, presents a unique problem because of the variety of subtypes of cancer that can arise and the multiple drug targets that could be exploited. For example, the tumor stage and subtypes often dictate the appropriate treatment regimen. Alternate multimodal therapies should consider the importance of time-dependent drug administration, as well as targeting the local and systemic tumor environment. Many reviews and papers have briefly touched on the clinical implications of this cellular heterogeneity; however, there has been very little discussion on the development of study models that reflect this diversity and on multimodal therapies that could target these subpopulations. Here, we summarize the current understanding of the origins of intratumoral heterogeneity in breast cancer subtypes, and its implications for tumor progression, metastatic potential, and treatment regimens. We also discuss the advantages and disadvantages of utilizing specific breast cancer models for research, including in vitro monolayer systems and three-dimensional mammospheres, as well as in vivo murine models that may have the capacity to encompass this heterogeneity. Lastly, we summarize some of the current

  1. Patterns of interstitial lung disease during everolimus treatment in patients with metastatic renal cell carcinoma.

    PubMed

    Mizuno, Ryuichi; Asano, Koichiro; Mikami, Shuji; Nagata, Hirohiko; Kaneko, Gou; Oya, Mototsugu

    2012-05-01

    To elucidate the patterns of interstitial lung disease during everolimus treatment in patients with metastatic renal cell carcinoma, we reviewed seven cases of everolimus-induced interstitial lung disease. Seven patients with metastatic renal cell carcinoma, which continued to progress despite treatment with sunitinib or sorafenib, developed interstitial lung disease after treatment with everolimus. Chest X-ray demonstrated diffuse infiltrates in lung fields, and chest computed tomography showed bilateral reticular and ground-glass opacities. Serum levels of lactate dehydrogenase (7/7), C-reactive protein (6/7), pulmonary surfactant associated protein D (1/7) and Krebs von den Lungen 6 (5/7) were elevated. The bronchoalveolar lavage fluid obtained from four patients with Grade 3 interstitial lung disease showed lymphocytosis. The transbronchial lung biopsy specimens showed interstitial lymphocytic infiltration and septal thickening of alveolar walls. In two cases with mild interstitial lung disease, the everolimus therapy was successfully continued. In four cases with Grade 3 interstitial lung disease, the drug was discontinued and steroid therapy was initiated. Pulmonary symptoms and radiological abnormalities resolved within 2 months. Serum Krebs von den Lungen 6 was elevated compared with baseline in all cases with interstitial lung disease. Some patients who developed mild interstitial lung disease during everolimus treatment could continue to receive the treatment. Even when severe interstitial lung disease developed, withdrawal of the drug and short-term use of high-dose steroids resulted in rapid recovery. Prompt recognition of interstitial lung disease exacerbation as well as exclusion of progressive disease or infection is of primary importance.

  2. Pemetrexed disodium in recurrent locally advanced or metastatic squamous cell carcinoma of the head and neck

    PubMed Central

    Pivot, X; Raymond, E; Laguerre, B; Degardin, M; Cals, L; Armand, J P; Lefebvre, J L; Gedouin, D; Ripoche, V; Kayitalire, L; Niyikiza, C; Johnson, R; Latz, J; Schneider, M

    2001-01-01

    This phase II study determined response rate of patients with locally advanced or metastatic head and neck cancer treated with pemetrexed disodium, a new multitargeted antifolate that inhibits thymidylate synthase, dihydrofolate reductase and glycinamide ribonucleotide formyl transferase. 35 patients with local or metastatic relapse of squamous cell carcinoma of the head and neck (31 male, 4 female; median age 53 years) were treated with pemetrexed 500 mg m2 administered as a 10-minute infusion on day 1 of a 21-day cycle. Patients received 1 to 8 cycles of therapy. 9 patients (26.5%) had an objective response, with a median response duration of 5.6 months (range 2.9–20 months). 15 (44.1%) had stable disease, and 8 (23.5%) had progressive disease. 2 patients were not assessable for response. Median overall survival was 6.4 months (range 0.7–28.1 months; 95% CI: 3.9–7.7 months). 24 patients (68.6%) experienced grade 3/4 neutropenia, with febrile neutropenia in 4 (11.4%). Grade 3/4 anaemia and thrombocytopenia occurred in 11 (34.3%) and 6 (17.1%) patients, respectively. The most frequent non-haematological toxicity was grade 3/4 mucositis (17.1%; 6 patients). In conclusion, pemetrexed is active in squamous cell carcinoma of the head and neck. Although substantial haematological toxicities were experienced by patients, subsequent studies have shown that these toxicities can be proactively managed by folic acid and vitamin B12 supplementation. © 2001 Cancer Research Campaign http://www.bjcancer.com PMID:11531245

  3. Bone metastases in patients with metastatic renal cell carcinoma: are they always associated with poor prognosis?

    PubMed

    Santoni, Matteo; Conti, Alessandro; Procopio, Giuseppe; Porta, Camillo; Ibrahim, Toni; Barni, Sandro; Guida, Francesco Maria; Fontana, Andrea; Berruti, Alfredo; Berardi, Rossana; Massari, Francesco; Vincenzi, Bruno; Ortega, Cinzia; Ottaviani, Davide; Carteni, Giacomo; Lanzetta, Gaetano; De Lisi, Delia; Silvestris, Nicola; Satolli, Maria Antonietta; Collovà, Elena; Russo, Antonio; Badalamenti, Giuseppe; Luzi Fedeli, Stefano; Tanca, Francesca Maria; Adamo, Vincenzo; Maiello, Evaristo; Sabbatini, Roberto; Felici, Alessandra; Cinieri, Saverio; Montironi, Rodolfo; Bracarda, Sergio; Tonini, Giuseppe; Cascinu, Stefano; Santini, Daniele

    2015-02-05

    Aim of this study was to investigate for the presence of existing prognostic factors in patients with bone metastases (BMs) from RCC since bone represents an unfavorable site of metastasis for renal cell carcinoma (mRCC). Data of patients with BMs from RCC were retrospectively collected. Age, sex, ECOG-Performance Status (PS), MSKCC group, tumor histology, presence of concomitant metastases to other sites, time from nephrectomy to bone metastases (TTBM, classified into three groups: <1 year, between 1 and 5 years and >5 years) and time from BMs to skeletal-related event (SRE) were included in the Cox analysis to investigate their prognostic relevance. 470 patients were enrolled in this analysis. In 19 patients (4%),bone was the only metastatic site; 277 patients had concomitant metastases in other sites. Median time to BMs was 16 months (range 0 - 44y) with Median OS of 17 months. Number of metastatic sites (including bone, p = 0.01), concomitant metastases, high Fuhrman grade (p < 0.001) and non-clear cell histology (p = 0.013) were significantly associated with poor prognosis. Patients with TTBM >5 years had longer OS (22 months) compared to patients with TTBM <1 year (13 months) or between 1 and 5 years (19 months) from nephrectomy (p < 0.001), no difference was found between these two last groups (p = 0.18). At multivariate analysis, ECOG-PS, MSKCC group and concomitant lung or lymph node metastases were independent predictors of OS in patients with BMs. Our study suggest that age, ECOG-PS, histology, MSKCC score, TTBM and the presence of concomitant metastases should be considered in order to optimize the management of RCC patients with BMs.

  4. Human fibronectin contains distinct adhesion- and motility-promoting domains for metastatic melanoma cells

    PubMed Central

    1986-01-01

    The active migration of tumor cells through extracellular matrices has been proposed to play a role in certain aspects of metastasis. Metastatic tumor cells migrate in vitro in response to substratum-bound adhesive glycoproteins such as fibronectin. The present studies use affinity-purified proteolytic fragments of fibronectin to determine the nature of adhesion- and/or motility-promoting domains within the protein. Two distinct fragments were identified with cell adhesion- promoting activities. By a number of criteria, the adhesive activity promoted by these two fragments was distinct. One fragment, a 75-kD tryptic fragment purified by monoclonal antibody chromatography, promoted the adhesion, spreading, and haptotactic motility of melanoma cells. Experiments using a synthetic cell attachment peptide in solution indicated that at least part of the attachment activity exhibited by the 75-kD fragment is mediated by the sequence arg-gly-asp- ser. It was not possible to demonstrate migration-stimulating activity using a small (11.5 kD) peptic fragment containing this sequence (Pierschbacher, M.D., E. G. Hayman, and E. Ruoslahti, 1981, Cell, 26:259-267) suggesting that another cell-binding activity within the 75 kD fragment distinct from arg-gly-asp-ser might be required for motility. The second fragment that stimulated melanoma adhesion was a 33-kD tryptic/catheptic carboxyl-terminal heparin-binding fragment, which is localized to the A chain of fibronectin. This fragment promotes adhesion and spreading but not the motility of these cells. Melanoma adhesion to this heparin-binding fragment was sensitive to the effects of cycloheximide, which contrasted adhesion to the haptotaxis- promoting fragment. Importantly, these studies illustrate that haptotaxis in response to fibronectin is not due to simple adhesion gradients of this protein. The results are discussed in light of a model for multiple distinct cell surface constituents mediating cell adhesion and motility on

  5. Heterogeneous proliferative potential of occult metastatic cells in bone marrow of patients with solid epithelial tumors

    PubMed Central

    Solakoglu, Oender; Maierhofer, Christine; Lahr, Georgia; Breit, Elisabeth; Scheunemann, Peter; Heumos, Isabella; Pichlmeier, Uwe; Schlimok, Günter; Oberneder, Ralph; Köllermann, Manfred W.; Köllermann, Jens; Speicher, Michael R.; Pantel, Klaus

    2002-01-01

    Bone marrow is a major homing site for circulating epithelial tumor cells. The present study was aimed to assess the proliferative capacity of occult metastatic cells in bone marrow of patients with operable solid tumors especially with regard to their clinical outcome. We obtained bone marrow aspirates from 153 patients with carcinomas of the prostate (n = 46), breast (n = 45), colon (n = 33), and kidney (n = 29). Most of the patients (87%) had primary disease with no clinical signs of overt metastases [tumor-node-metastasis (TNM)-stage UICC (Union Internationale Contre le Cancer) I-III]. After bone marrow was cultured for 21–102 days under special cell culture conditions, viable epithelial cells were detected by cytokeratin staining in 124 patients (81%). The cultured epithelial cells harbored Ki-ras2 mutations and numerical chromosomal aberrations. The highest median number of expanded tumor cells was observed in prostate cancer (2,619 per flask). There was a significant positive correlation between the number of expanded tumor cells and the UICC-stage of the patients (P = 0.03) or the presence of overt metastases (P = 0.04). Moreover, a strong expansion of tumor cells was correlated to an increased rate of cancer-related deaths (P = 0.007) and a reduced survival of the patients (P = 0.006). In conclusion, the majority of cancer patients have viable tumor cells in their bone marrow at primary tumor diagnosis, and the proliferative potential of these cells determines the clinical outcome. PMID:11854519

  6. CRISPR-Mediated VHL Knockout Generates an Improved Model for Metastatic Renal Cell Carcinoma.

    PubMed

    Schokrpur, Shiruyeh; Hu, Junhui; Moughon, Diana L; Liu, Peijun; Lin, Lucia C; Hermann, Kip; Mangul, Serghei; Guan, Wei; Pellegrini, Matteo; Xu, Hua; Wu, Lily

    2016-06-30

    Metastatic renal cell carcinoma (mRCC) is nearly incurable and accounts for most of the mortality associated with RCC. Von Hippel Lindau (VHL) is a tumour suppressor that is lost in the majority of clear cell RCC (ccRCC) cases. Its role in regulating hypoxia-inducible factors-1α (HIF-1α) and -2α (HIF-2α) is well-studied. Recent work has demonstrated that VHL knock down induces an epithelial-mesenchymal transition (EMT) phenotype. In this study we showed that a CRISPR/Cas9-mediated knock out of VHL in the RENCA model leads to morphologic and molecular changes indicative of EMT, which in turn drives increased metastasis to the lungs. RENCA cells deficient in HIF-1α failed to undergo EMT changes upon VHL knockout. RNA-seq revealed several HIF-1α-regulated genes that are upregulated in our VHL knockout cells and whose overexpression signifies an aggressive form of ccRCC in the cancer genome atlas (TCGA) database. Independent validation in a new clinical dataset confirms the upregulation of these genes in ccRCC samples compared to adjacent normal tissue. Our findings indicate that loss of VHL could be driving tumour cell dissemination through stabilization of HIF-1α in RCC. A better understanding of the mechanisms involved in this phenomenon can guide the search for more effective treatments to combat mRCC.

  7. CRISPR-Mediated VHL Knockout Generates an Improved Model for Metastatic Renal Cell Carcinoma

    PubMed Central

    Schokrpur, Shiruyeh; Hu, Junhui; Moughon, Diana L.; Liu, Peijun; Lin, Lucia C.; Hermann, Kip; Mangul, Serghei; Guan, Wei; Pellegrini, Matteo; Xu, Hua; Wu, Lily

    2016-01-01

    Metastatic renal cell carcinoma (mRCC) is nearly incurable and accounts for most of the mortality associated with RCC. Von Hippel Lindau (VHL) is a tumour suppressor that is lost in the majority of clear cell RCC (ccRCC) cases. Its role in regulating hypoxia-inducible factors-1α (HIF-1α) and -2α (HIF-2α) is well-studied. Recent work has demonstrated that VHL knock down induces an epithelial-mesenchymal transition (EMT) phenotype. In this study we showed that a CRISPR/Cas9-mediated knock out of VHL in the RENCA model leads to morphologic and molecular changes indicative of EMT, which in turn drives increased metastasis to the lungs. RENCA cells deficient in HIF-1α failed to undergo EMT changes upon VHL knockout. RNA-seq revealed several HIF-1α-regulated genes that are upregulated in our VHL knockout cells and whose overexpression signifies an aggressive form of ccRCC in the cancer genome atlas (TCGA) database. Independent validation in a new clinical dataset confirms the upregulation of these genes in ccRCC samples compared to adjacent normal tissue. Our findings indicate that loss of VHL could be driving tumour cell dissemination through stabilization of HIF-1α in RCC. A better understanding of the mechanisms involved in this phenomenon can guide the search for more effective treatments to combat mRCC. PMID:27358011

  8. Effect of Citrus bergamia juice on human neuroblastoma cells in vitro and in metastatic xenograft models.

    PubMed

    Navarra, M; Ursino, M R; Ferlazzo, N; Russo, M; Schumacher, U; Valentiner, U

    2014-06-01

    Neuroblastoma is the most common extracranial pediatric solid tumor with poor prognosis in children with disseminated stage of disease. A number of studies show that molecules largely distributed in commonly consumed fruits and vegetables may have anti-tumor activity. In this study we evaluate the effect of Citrus bergamia (bergamot) juice (BJ) in vitro and in a spontaneous metastatic neuroblastoma SCID mouse model. Qualitative and quantitative characterizations of BJ flavonoid fractions were performed by RP-HPLC/PDA/MS. We show that BJ significantly affects SK-N-SH and LAN-1 cell proliferation in vitro, but fails to reduce primary tumor weight in vivo. Moreover, BJ reduced cell adhesiveness and invasion of LAN-1 and SK-N-SH cells in vitro and the number of pulmonary metastases under consideration of the number of tumor cells in the blood in mice inoculated with LAN-1 cells in vivo. These effects without any apparent sign of systemic toxicity confirm the potential clinical interest of BJ and lay the basis for further investigation in cancer. Copyright © 2014. Published by Elsevier B.V.

  9. Pro-metastatic NEDD9 regulates individual cell migration via caveolin-1-dependent trafficking of integrins

    PubMed Central

    Kozyulina, Polina Y.; Loskutov, Yuriy V.; Kozyreva, Varvara K.; Rajulapati, Anuradha; Ice, Ryan J.; Jones, Brandon. C.; Pugacheva, Elena N.

    2014-01-01

    The dissemination of tumor cells relies on efficient cell adhesion and migration, which in turn depends upon endocytic trafficking of integrins. In the current work, it was found that depletion of pro-metastatic protein, NEDD9, in breast cancer (BC) cells results in a significant decrease in individual cell migration due to impaired trafficking of ligand-bound integrins. NEDD9 deficiency does not affect the expression or internalization of integrins but heightens caveolae-dependent trafficking of ligand-bound integrins to early endosomes. Increase in mobility of ligand-bound integrins is concomitant with an increase in tyrosine phosphorylation of caveolin-1 (CAV1) and volume of CAV1-vesicles. NEDD9 directly binds to CAV1 and co-localizes within CAV1 vesicles. In the absence of NEDD9, the trafficking of ligand-bound integrins from early to late endosomes is impaired, resulting in a significant decrease in degradation of ligand/integrin complexes and an increase in recycling of ligand-bound integrins from early endosomes back to the plasma membrane without ligand disengagement, thus leading to low adhesion and migration. Re-expression of NEDD9 or decrease in the amount of active, tyrosine 14 phosphorylated (Tyr14) CAV1 in NEDD9 depleted cells rescues the integrin trafficking deficiency and restores cellular adhesion and migration capacity. Collectively, these findings indicate that NEDD9 orchestrates trafficking of ligand-bound integrins through the attenuation of CAV1 activity. PMID:25319010

  10. Combined effects of terazosin and genistein on a metastatic, hormone-independent human prostate cancer cell line.

    PubMed

    Chang, Kee-Lung; Cheng, Hsiao-Ling; Huang, Li-Wen; Hsieh, Bau-Shan; Hu, Yu-Chen; Chih, Tsai-Tung; Shyu, Huey-Wen; Su, Shu-Jem

    2009-04-08

    Metastatic prostate cancer progresses from androgen-dependent to androgen-independent. Terazosin, a long-acting selective alpha1-adrenoreceptor antagonist, induces apoptosis of prostate cancer cells in an alpha1-adrenoreceptor-independent manner, while genistein, a major soy isoflavone, inhibits the growth of several types of cancer cells. The present study was designed to test the therapeutic potential of a combination of terazosin and genistein using a metastatic, hormone-independent prostatic cancer cell line, DU-145. Terazosin or genistein treatment inhibited the growth of DU-145 cells in a dose-dependent manner, whereas had no effect on normal prostate epithelial cells. Addition of 1 microg/ml of terazosin, which was inactive alone, augmented the growth inhibitory effect of 5 microg/ml of genistein. Co-treatment with terazosin resulted in the genistein-induced arrest of DU-145 cells in G2/M phase being overridden and an increase in apoptotic cells, as evidenced by procaspase-3 activation and PARP cleavage. The combination also caused a greater decrease in the levels of the apoptosis-regulating protein, Bcl-XL, and of VEGF165 and VEGF121 than genistein alone. In conclusion, the terazosin/genistein combination was more effective in inhibiting cell growth and VEGF expression as well as inducing apoptosis of the metastatic, androgen-independent prostate cancer cell line, DU-145, than either alone. The doses used in this study are in lower and nontoxic anticancer dosage range, suggesting this combination has potential for therapeutic use.

  11. Biophysical and morphological effects of nanodiamond/nanoplatinum solution (DPV576) on metastatic murine breast cancer cells in vitro

    NASA Astrophysics Data System (ADS)

    Ghoneum, Alia; Zhu, Huanqi; Woo, JungReem; Zabinyakov, Nikita; Sharma, Shivani; Gimzewski, James K.

    2014-11-01

    Nanoparticles have recently gained increased attention as drug delivery systems for the treatment of cancer due to their minute size and unique chemical properties. However, very few studies have tested the biophysical changes associated with nanoparticles on metastatic cancer cells at the cellular and sub-cellular scales. Here, we investigated the mechanical and morphological properties of cancer cells by measuring the changes in cell Young’s Modulus using AFM, filopodial retraction (FR) by time lapse optical light microscopy imaging and filopodial disorganization by high resolution AFM imaging of cells upon treatment with nanoparticles. In the current study, nanomechanical changes in live murine metastatic breast cancer cells (4T1) post exposure to a nanodiamond/nanoplatinum mixture dispersed in aqueous solution (DPV576), were monitored. Results showed a decrease in Young’s modulus at two hours post treatment with DPV576 in a dose dependent manner. Partial FR at 20 min and complete FR at 40 min were observed. Moreover, analysis of the retraction distance (in microns) measured over time (minutes), showed that a DPV576 concentration of 15%v/v yielded the highest FR rate. In addition, DPV576 treated cells showed early signs of filopodial disorganization and disintegration. This study demonstrates the changes in cell stiffness and tracks early structural alterations of metastatic breast cancer cells post treatment with DPV576, which may have important implications in the role of nanodiamond/nanoplatinum based cancer cell therapy and sensitization to chemotherapy drugs.

  12. Concerns of patients undergoing palliative chemotherapy for end-stage carcinomatous peritonitis.

    PubMed

    Kakuta, Mayumi; Kakikawa, Fusako; Chida, Misao

    2015-12-01

    We sought to identify how nurses can help to alleviate the concerns of inpatients undergoing palliative chemotherapy when the treatment effects are weakening. Semistructured interviews were conducted with 8 inpatients receiving palliative chemotherapy for end-stage carcinomatous peritonitis at a university hospital. Qualitative inductive analysis of the interview data revealed 7 categories of patient concerns. Overall, patients faced many dilemmas and expressed concerns about wanting to continue chemotherapy while also thinking about discontinuing it. However, they also expressed hope, the strength of which was influenced and changed in complex ways by each treatment outcome and the severity of their physical symptoms. From these results, we suggest specific aspects of nursing care for patients with end-stage cancer who are receiving palliative chemotherapy that is becoming less effective. © The Author(s) 2014.

  13. Intratumoral stages of metastatic cells: a synthesis of ontogeny, Rho/Rac GTPases, epithelial-mesenchymal transitions, and more.

    PubMed

    Bustelo, Xosé R

    2012-09-01

    Metastasis is one of the clinical parameters that has a strong negative influence on the prognosis of cancer patients. In recent years, significant advances have furthered our understanding of this process at the molecular and biological levels. This paper will discuss recent discoveries relating to the earliest, intra-tumoral stages of metastasis in cancer cells, specifically focusing on: (i) the development of metastatic traits during primary tumorigenesis; (ii) intrinsic and extrinsic cancer cell programs associated with malignant traits; (iii) the intra-tumoral migration patterns of cancer cells and the dynamic roles played by the Rho/Rac GTPases and epithelial-mesenchymal transitions in this process; and (iv) the genetic strategies used by metastatic cancer cells to promote intra-tumoral cell migration and their subsequent escape to peripheral tissues. Finally, the therapeutic and diagnostic relevance of this information will be discussed, as well as potential future developments. Copyright © 2012 WILEY Periodicals, Inc.

  14. Differing Von Hippel Lindau Genotype in Paired Primary and Metastatic Tumors in Patients with Clear Cell Renal Cell Carcinoma

    PubMed Central

    Vaziri, Susan A. J.; Tavares, Emmanuel J.; Golshayan, Ali R.; Rini, Brian I.; Aydin, Hakan; Zhou, Ming; Sercia, Linda; Wood, Laura; Ganapathi, Mahrukh K.; Bukowski, Ronald M.; Ganapathi, Ram

    2012-01-01

    In sporadic clear cell renal cell carcinoma (CCRCC), the von Hippel Lindau (VHL) gene is inactivated by mutation or methylation in the majority of primary (P) tumors. Due to differing effects of wild-type (WT) and mutant (MT) VHL gene on downstream signaling pathways regulating angiogenesis, VHL gene status could impact clinical outcome. In CCRCC, comparative genomic hybridization analysis studies have reported genetic differences between paired P and metastatic (M) tumors. We thus sequenced the VHL gene in paired tumor specimens from 10 patients to determine a possible clonal relationship between the P tumor and M lesion(s) in patients with CCRCC. Using paraffin-embedded specimens, genomic DNA from microdissected samples (>80% tumor) of paired P tumor and M lesions from all 10 patients, as well as in normal tissue from 6 of these cases, was analyzed. The DNA was used for PCR-based amplification of each of the 3 exons of the VHL gene. Sequences derived from amplified samples were compared to the wild-type VHL gene sequence (GenBank Accession No. AF010238). Methylation status of the VHL gene was determined using VHL methylation-specific PCR primers after DNA bisulfite modification. In 4/10 (40%) patients the VHL gene status differed between the P tumor and the M lesion. As expected, when the VHL gene was mutated in both the P tumor and M lesion, the mutation was identical. Further, while the VHL genotype differed between the primary tumor in different kidneys or multiple metastatic lesions in the same patient, the VHL germline genotype in the normal adjacent tissue was always wild-type irrespective of the VHL gene status in the P tumor. These results demonstrate for the first time that the VHL gene status can be different between paired primary and metastatic tissue in patients with CCRCC. PMID:22655276

  15. Successful hepatectomy for metastatic squamous cell carcinoma of the anal canal—a case report

    PubMed Central

    Sousa, Tercia Tarciane; Belotto, Marcos; Peixoto, Renata D’Alpino

    2016-01-01

    Despite rare, metastatic anal carcinoma confers a poor prognosis. Systemic chemotherapy is the mainstay of treatment for advanced disease while the role of biologics and/or surgical resection of metastatic disease are anecdotal. Compared to isolated liver colorectal or neuroendocrine cancer liver metastases, there is far less experience with resection or nonsurgical local ablative procedures for patients with metastatic anal carcinoma to the liver. We report the case of a 67-year-old woman with metastatic anal carcinoma to the liver who was successfully treated with liver resection and remains free of relapse more than one year later. PMID:28078133

  16. Novel inhibitors of urokinase-type plasminogen activator and matrix metalloproteinase expression in metastatic cancer cell lines.

    PubMed

    Cakarovski, Kristina; Leung, Jenny Y; Restall, Christina; Carin-Carlson, Anna; Yang, Eunice; Perlmutter, Patrick; Anderson, Robin; Medcalf, Robert; Dear, Anthony E

    2004-07-01

    The plasminogen-activating (PA) and matrix metalloproteinase (MMP) enzyme systems are implicated in proteolytic turnover of the extracellular matrix (ECM) associated with biologic processes including wound healing, inflammation and angiogenesis. Aberrant expression of components of the PA and MMP enzyme systems occurs in the pathogenesis of metastatic cancer. Oxamflatin (Ox), a novel hydroxamic acid derivative, inhibits u-PA mRNA expression and proteolytic activity while simultaneously upregulating the expression of the natural inhibitor of u-PA, plasminogen activator inhibitor type 2 (PAI-2) in metastatic cancer cells. We have characterized the effects of Ox and a novel derivative, Metacept-1 (MCT-1), on PA and MMP-mediated proteolysis and invasion in several metastatic tumor lines. Both compounds are able to inhibit u-PA-, MMP-2- and MMP-9-mediated gene expression at low micromolar concentrations as well as u-PA- and MMP-mediated proteolysis as assessed by zymography, with MCT-1 being the more effective of the 2 agents in some assays. Cellular invasion assays correlate with gene expression and zymography experiments identifying both Ox and MCT-1 as able to inhibit invasion of metastatic cancer cell lines through matrigel at nanomolar concentrations, with MCT-1 more effective than Ox in 2 of the 3 cancer cell lines assessed.

  17. Proteolysis-a characteristic of tumor-initiating cells in murine metastatic breast cancer.

    PubMed

    Hillebrand, Larissa E; Bengsch, Fee; Hochrein, Jochen; Hülsdünker, Jan; Bender, Julia; Follo, Marie; Busch, Hauke; Boerries, Melanie; Reinheckel, Thomas

    2016-09-06

    Tumor initiating cells (TICs) have been identified and functionally characterized in hematological malignancies as well as in solid tumors such as breast cancer. In addition to their high tumor-initiating potential, TICs are founder cells for metastasis formation and are involved in chemotherapy resistance. In this study we explored molecular pathways which enable this tumor initiating potential for a cancer cell subset of the transgenic MMTV-PyMT mouse model for metastasizing breast cancer. The cell population, characterized by the marker profile CD24+CD90+CD45-, showed a high tumorigenicity compared to non-CD24+CD90+CD45- cancer cells in colony formation assays, as well as upon orthotopic transplantation into the mammary fat pad of mice. In addition, these orthotopically grown CD24+CD90+CD45- TICs metastasized to the lungs. The transcriptome of TICs freshly isolated from primary tumors by cell sorting was compared with that of sorted non-CD24+CD90+CD45- cancer cells by RNA-seq. In addition to more established TIC signatures, such as epithelial-to-mesenchymal transition or mitogen signaling, an upregulated gene set comprising several classes of proteolytic enzymes was uncovered in the TICs. Accordingly, TICs showed high intra- and extracellular proteolytic activity. Application of a broad range of protease inhibitors to TICs in a colony formation assay reduced anchorage independent growth and had an impact on colony morphology in 3D cell culture assays. We conclude that CD24+CD90+CD45- cells of the MMTV- PyMT mouse model possess an upregulated proteolytic signature which could very well represent a functional hallmark of metastatic TICs from mammary carcinomas.

  18. Proteolysis-a characteristic of tumor-initiating cells in murine metastatic breast cancer

    PubMed Central

    Hillebrand, Larissa E.; Bengsch, Fee; Hochrein, Jochen; Hülsdünker, Jan; Bender, Julia; Follo, Marie; Busch, Hauke; Boerries, Melanie; Reinheckel, Thomas

    2016-01-01

    Tumor initiating cells (TICs) have been identified and functionally characterized in hematological malignancies as well as in solid tumors such as breast cancer. In addition to their high tumor-initiating potential, TICs are founder cells for metastasis formation and are involved in chemotherapy resistance. In this study we explored molecular pathways which enable this tumor initiating potential for a cancer cell subset of the transgenic MMTV-PyMT mouse model for metastasizing breast cancer. The cell population, characterized by the marker profile CD24+CD90+CD45−, showed a high tumorigenicity compared to non-CD24+CD90+CD45− cancer cells in colony formation assays, as well as upon orthotopic transplantation into the mammary fat pad of mice. In addition, these orthotopically grown CD24+CD90+CD45− TICs metastasized to the lungs. The transcriptome of TICs freshly isolated from primary tumors by cell sorting was compared with that of sorted non-CD24+CD90+CD45− cancer cells by RNA-seq. In addition to more established TIC signatures, such as epithelial-to-mesenchymal transition or mitogen signaling, an upregulated gene set comprising several classes of proteolytic enzymes was uncovered in the TICs. Accordingly, TICs showed high intra- and extracellular proteolytic activity. Application of a broad range of protease inhibitors to TICs in a colony formation assay reduced anchorage independent growth and had an impact on colony morphology in 3D cell culture assays. We conclude that CD24+CD90+CD45− cells of the MMTV- PyMT mouse model possess an upregulated proteolytic signature which could very well represent a functional hallmark of metastatic TICs from mammary carcinomas. PMID:27542270

  19. Akt1 mediates prostate cancer cell microinvasion and chemotaxis to metastatic stimuli via integrin β3 affinity modulation

    PubMed Central

    Goc, A; Liu, J; Byzova, T V; Somanath, P R

    2012-01-01

    Background: Activation of Akt and increased expression of integrin β3 are the two most important changes that have been linked to the attainment of metastatic potential by prostate cancer cells. However, a direct link between Akt activity and inside-out activation of integrin β3 in mediating prostate cancer cell metastatic properties is not established. Methods: Using functional and biochemical approaches, we examined the role of Akt1 in the affinity modulation of integrin β3 in prostate cancer cells. Results: Although expression of murine TRAMP and human PC3 cells with constitutively active Akt1 (CA-Akt1) enhanced their affinity for integrin αvβ3 specific ligands and motility on various extracellular matrix proteins, the reverse was observed with the expression of dominant-negative Akt1 (DN-Akt1). Although enhanced motility and transendothelial migration of CA-Akt1-expressing cells were blunted by co-expression with DN-integrin β3 or upon pre-treatment with integrin β3-blocking antibodies (LM 609), impaired motility and transendothelial migration of DN-Akt1-expressing cells were rescued by pre-treatment of prostate cancer cells with integrin β3-activating antibodies, AP7.4. Conclusion: Our data is the first to demonstrate a link between Akt1 activity and affinity modulation of integrin β3 in the regulation of prostate cancer cell motility, transendothelial migration and chemotaxis to metastatic stimuli. PMID:22767145

  20. Radiation-induced increase in expression of the alpha IIb beta 3 integrin in melanoma cells: effects on metastatic potential.

    PubMed

    Onoda, J M; Piechocki, M P; Honn, K V

    1992-06-01

    We investigated the effects of nonlethal gamma radiation on the metastatic potential of the murine tumor cell line, B16 melanoma. The ability of B16 cells to adhere to fibronectin, which is in part mediated by the alpha IIb beta 3 integrin receptor, is predictive of metastatic potential. We determined that exposure to 0.25-2.5 Gy gamma radiation significantly enhanced B16 cell adhesion to fibronectin. The radiation-enhanced adhesion was dependent on enhanced expression of the alpha IIb beta 3 integrin. We observed that 15 min after 0.5 Gy radiation, 99% of irradiated B16 tumor cells were positively labeled with monoclonal antibodies directed against alpha IIb beta 3 compared to 22% of sham-irradiated cells. Radiation-enhanced expression of the alpha IIb beta 3 receptor is reversible and down-regulation begins within 2-4 h postirradiation. Finally, we found that irradiation significantly enhanced the ability of B16 cells to form metastases in a lung colony assay. It is concluded that a relationship exists between radiation effects on the B16 tumor cells, alpha IIb beta 3 receptor expression, adhesion in vitro, and metastasis in vivo. We suggest that low-dose radiation, at levels comparable to those used in fractionated or hyperfractionated radiotherapy, may alter the metastatic phenotype and potential of surviving tumor cells via a rapid alteration in their surface expression of alpha IIb beta 3 integrin receptors.

  1. Establishment of an animal model of spontaneous cervical lymph node metastasis of laryngeal squamous cell carcinoma and obtaining laryngocarcinoma cells with high metastatic potential.

    PubMed

    Chen, L W; Wang, J L; Zhang, L Y; Yang, S M; Li, C S; Yu, N; Zhao W, J D; Zhao, L D; Li, K; Liu, M B; Zhai, S Q

    2013-01-01

    To establish an animal model of spontaneous cervical lymph node metastasis of laryngeal squamous cell carcinoma and obtain laryngocarcinoma cells with high metastatic potential, laryngeal squamous cell carcinoma cell line HEP-2 in logarithmic phase were inoculated under the lingual margin mucosa of nude mice. HEP-2 cells metastasized to the cervical lymph nodes were isolated, cultured, and re-inoculated under the lingual margin mucosa of nude mice twice. The tumor formation in the tongue and in the cervical lymph nodes was confirmed by pathological examination. Carcinoma cells' ability of invasion and migration was detected by transwell assay. Human specific Alu sequences were detected by PCR, which indicated that the tumor cells originated from human laryngeal squamous cell carcinoma cell line HEP-2. Finally, an animal model of spontaneous lymph node metastasis of laryngeal squamous cell carcinoma was successfully established. Laryngeal squamous cell carcinoma cells with high metastatic potential to lymph nodes were obtained through repeated inoculations. .

  2. Metastatic Signet-Ring Cell Carcinoma of the Bladder in Cerebrospinal Fluid.

    PubMed

    Lin, Diana Murro; Park, Ji-Weon; Gattuso, Paolo

    2017-01-01

    Primary bladder signet-ring cell carcinoma (SRCC) is extremely rare and associated with an aggressive course. To our knowledge, we describe the first metastatic bladder SRCC identified in cerebrospinal fluid (CSF). A 68-year-old male with 1 year history of primary bladder SRCC with spinal metastasis presented with multiple falls and loss of consciousness. Brain imaging showed high signal in the frontoparietal sulci and superior cerebellum. CSF analysis was significant for increased leukocytes with monocyte predominance while protein and glucose values were within normal range. There was a hypercellular population of pleomorphic tumor cells with signet-ring morphology, similar to those seen in his diagnostic bladder biopsies. The signet-ring cells were positive for cytokeratin 7 and 20 and negative for CDX-2 and prostate-specific antigen. The patient's clinical condition rapidly deteriorated and he died less than a week after presentation. At autopsy, brain sections revealed signet ring cells in the meninges overlying the cerebrum, cerebellum, brainstem, spinal cord, and pituitary with superficial invasion of the brain parenchyma. No brain parenchymal lesions were present. This case illustrates a unique complication of primary bladder SRCC. Diagn. Cytopathol. 2017;45:73-76. © 2016 Wiley Periodicals, Inc.

  3. miR-493 induction during carcinogenesis blocks metastatic settlement of colon cancer cells in liver

    PubMed Central

    Okamoto, Koji; Ishiguro, Tatsuya; Midorikawa, Yutaka; Ohata, Hirokazu; Izumiya, Masashi; Tsuchiya, Naoto; Sato, Ai; Sakai, Hiroaki; Nakagama, Hitoshi

    2012-01-01

    Liver metastasis is a major lethal complication associated with colon cancer, and post-intravasation steps of the metastasis are important for its clinical intervention. In order to identify inhibitory microRNAs (miRNAs) for these steps, we performed ‘dropout' screens of a miRNA library in a mouse model of liver metastasis. Functional analyses showed that miR-493 and to a lesser extent miR-493* were capable of inhibiting liver metastasis. miR-493 inhibited retention of metastasized cells in liver parenchyma and induced their cell death. IGF1R was identified as a direct target of miR-493, and its inhibition partially phenocopied the anti-metastatic effects. High levels of miR-493 and miR-493*, but not pri-miR-493, in primary colon cancer were inversely related to the presence of liver metastasis, and attributed to an increase of miR-493 expression during carcinogenesis. We propose that, in a subset of colon cancer, upregulation of miR-493 during carcinogenesis prevents liver metastasis via the induction of cell death of metastasized cells. PMID:22373578

  4. Genomic profiling of isolated circulating tumor cells from metastatic breast cancer patients

    PubMed Central

    Magbanua, Mark Jesus M.; Sosa, Eduardo V.; Roy, Ritu; Eisenbud, Lauren E.; Scott, Janet H.; Olshen, Adam; Pinkel, Dan; Rugo, Hope; Park, John W.

    2014-01-01

    Molecular characterization of circulating tumor cells (CTCs) from blood is technically challenging because cells are rare and difficult to isolate. We developed a novel approach to isolate CTCs from blood via immunomagnetic enrichment followed by fluorescence activated cell sorting (IE/FACS). Isolated CTCs were subjected to genome-wide copy number analysis via array comparative genomic hybridization (aCGH). In clinical studies, CTCs were isolated from 181 patients with metastatic breast cancer, 102 of which were successfully profiled, including matched archival primary tumor from five patients. CTCs revealed a wide range of copy number alterations including those previously reported in breast cancer. Comparison with two published aCGH datasets of primary breast tumors revealed similar frequencies of recurrent genomic copy number aberrations. In addition, serial testing of CTCs confirmed reproducibility and indicated genomic change over time. Comparison of CTCs with matched archival primary tumors confirmed shared lineage with notable divergence. We demonstrate that it is feasible to isolate CTCs away from hematopoietic cells with high purity via IE/FACS and profile them via aCGH analysis. Our approach may be utilized to explore genomic events involved in cancer progression and to monitor therapeutic efficacy of targeted therapies in clinical trials in a relatively non-invasive manner. PMID:23135909

  5. Tumor cell-driven extracellular matrix remodeling drives haptotaxis during metastatic progression

    PubMed Central

    Oudin, Madeleine J.; Jonas, Oliver; Kosciuk, Tatsiana; Broye, Liliane C.; Guido, Bruna C.; Wyckoff, Jeff; Riquelme, Daisy; Lamar, John M.; Asokan, Sreeja B.; Whittaker, Charlie; Ma, Duanduan; Langer, Robert; Cima, Michael J.; Wisinski, Kari B.; Hynes, Richard O.; Lauffenburger, Douglas A.; Keely, Patricia J.; Bear, James E.; Gertler, Frank B.

    2016-01-01

    Fibronectin (FN) is a major component of the tumor microenvironment, but its role in promoting metastasis is incompletely understood. Here we show that FN gradients elicit directional movement of breast cancer cells, in vitro and in vivo. Haptotaxis on FN gradients requires direct interaction between α5β1 integrin and Mena, an actin regulator, and involves increases in focal complex signaling and tumor-cell-mediated extracellular matrix (ECM) remodeling. Compared to Mena, higher levels of the pro-metastatic MenaINV isoform associate with α5, which enables 3D haptotaxis of tumor cells towards the high FN concentrations typically present in perivascular space and in the periphery of breast tumor tissue. MenaINV and FN levels were correlated in two breast cancer cohorts, and high levels of MenaINV were significantly associated with increased tumor recurrence as well as decreased patient survival. Our results identify a novel tumor-cell-intrinsic mechanism that promotes metastasis through ECM remodeling and ECM guided directional migration. PMID:26811325

  6. Low-temperature plasma needle effects on cultured metastatic breast cancer cells

    NASA Astrophysics Data System (ADS)

    Knecht, Sean; Bilen, Sven; Micci, Michael; Brubaker, Timothy; Wilson, Michael; Cook, Ian; Czesak, Nicholas; Hipkins, Garret

    2015-11-01

    The Penn State Low-Temperature Plasma group is presently investigating the applications of low-temperature plasma for biomedical applications, including the effects on MDA-MB-231 metastatic breast cancer cells. A plasma needle system has been designed and constructed that consists of a 22-gauge stainless steel syringe needle, which acts as the high-voltage electrode, covered with PEEK tubing as the dielectric with a ring ground electrode on the outside. The system is driven by a low-frequency AC voltage amplifier, with typical operating conditions of 2-5 kV peak voltage at 5 kHz. Helium is used as the working fluid and produces a plasma jet with ~ cm's visible extent. Cultured breast cancer cells were provided by our collaborator and exposed to the plasma needle for varying doses and detachment of cells was observed. The effects are attributed to reactive oxygen and nitrogen species generation and transport through the cell culture medium. Plasma needle characterization and the results of the breast cancer experiments will be presented.

  7. Interplay between YB-1 and IL-6 promotes the metastatic phenotype in breast cancer cells

    PubMed Central

    Castellana, Bàrbara; Aasen, Trond; Moreno-Bueno, Gema; Dunn, Sandra E.; Ramón y Cajal, Santiago

    2015-01-01

    Epithelial to mesenchymal transition (EMT) induces cell plasticity and promotes metastasis. The multifunctional oncoprotein Y-box binding protein-1 (YB-1) and the pleiotropic cytokine interleukin 6 (IL-6) have both been implicated in tumor cell metastasis and EMT, but via distinct pathways. Here, we show that direct interplay between YB-1 and IL-6 regulates breast cancer metastasis. Overexpression of YB-1 in breast cancer cell lines induced IL-6 production while stimulation with IL-6 increased YB-1 expression and YB-1 phosphorylation. Either approach was sufficient to induce EMT features, including increased cell migration and invasion. Silencing of YB-1 partially reverted the EMT and blocked the effect of IL-6 while inhibition of IL-6 signaling blocked the phenotype induced by YB-1 overexpression, demonstrating a clear YB-1/IL-6 interdependence. Our findings describe a novel signaling network in which YB-1 regulates IL-6, and vice versa, creating a positive feed-forward loop driving EMT-like metastatic features during breast cancer progression. Identification of signaling partners or pathways underlying this co-dependence may uncover novel therapeutic opportunities. PMID:26512918

  8. Profiling of differential expression of messenger RNA in normal, benign, and metastatic prostate cell lines.

    PubMed

    Chakrabarti, Ratna; Robles, Liza D; Gibson, Jane; Muroski, Megan

    2002-12-01

    To understand the phenotypic changes associated with prostate cancer development and metastasis, we investigated differential gene expression in primary and established prostate cell lines used as models. We have used a differential display of messenger RNA (DDRT-PCR) technique using 168 primer combinations and total RNA from BPH-1, LNCaP, and PC3 cells to identify filter-based cDNA microarrays containing 18,376 nonredundant clones of genes and expressed sequence tags (EST) using mRNA from PrEC and MDAPCa2a cells to identify genes that are differentially expressed in normal, benign, and cancerous prostate cell lines. Twenty-five cDNA with a significant difference in expression of 76 candidate cDNA, as identified by DDRT-PCR and confirmed by slot-blot analysis, were selected for sequence analysis. Of these, 14 cDNA were further confirmed by Northern blot analysis. Analysis of the cDNA microarray data showed that a variety of genes/EST were up- or down-regulated in the metastatic prostate tumor cells and a majority of these genes encode cytoskeletal proteins and proteins with regulatory function. Expression profile of two EST was confirmed by reverse transcription polymerase chain reaction. We also have identified a number of genes exhibiting differential expression in prostate cancer cells, which were not known earlier to be involved in prostate cancer. This report provides a comparative analysis of differential gene expression between normal prostatic epithelial cells and prostate cancer cells, and a foundation to facilitate in-depth studies on the mechanism of prostate cancer development and metastasis.

  9. Assessment of biological effectiveness of boron neutron capture therapy in primary and metastatic melanoma cell lines.

    PubMed

    Rossini, Andrés E; Dagrosa, Maria A; Portu, Agustina; Saint Martin, Giselle; Thorp, Silvia; Casal, Mariana; Navarro, Aimé; Juvenal, Guillermo J; Pisarev, Mario A

    2015-01-01

    In order to optimize the effectiveness of Boron Neutron Capture Therapy (BNCT), Relative Biological Effectiveness (RBE) and Compound Biological Effectiveness (CBE) were determined in two human melanoma cell lines, M8 and Mel-J cells, using the amino acid p-boronophenylalanine (BPA) as boron carrier. The effects of BNCT on the primary amelanotic cell line M8 and on the metastatic pigmented melanoma cell line Mel-J were studied using colony formation assay. The RBE values were determined using both a gamma ray source, and the neutron beam from the Nuclear Reactor of the National Atomic Energy Commission (RA-3). For the determination of the RBE, cells were irradiated with increasing doses of both sources, between 1 and 8 Gy; and for the determination of CBE factors, the cells were pre-incubated with BPA before irradiation. Afterwards, the cell surviving fraction (SF) was determined for each treatment. Marked differences were observed between both cell lines. Mel-J cells were more radioresistant than the M8 cell line. The clonogenic assays showed that for a SF of 1%, the RBE values were 1.3 for M8 cells and 1.5 for Mel-J cells. Similarly, the CBE values for a 1% SF were 2.1 for M8 and 3 for Mel-J cell lines. For the endpoint of 0.1% of SF the RBE values obtained were 1.2 for M8 and 1.4 for Mel-J cells. Finally, CBE values calculated for a 0.1% were 2 and 2.6 for M8 and Mel-J cell lines respectively. In order to estimate the uptake of the non-radioactive isotope Boron 10 ((10)B), a neutron induced autoradiographic technique was performed showing discrepancies in (10)B uptake between both cell lines. These obtained in vitro results are the first effectiveness factors determined for human melanoma at the RA-3 nuclear reactor and show that BNCT dosimetry planning for patients could be successfully performed using these new factors.

  10. Hitting the Bull’s-Eye in Metastatic Cancers—NSAIDs Elevate ROS in Mitochondria, Inducing Malignant Cell Death

    PubMed Central

    Ralph, Stephen John; Pritchard, Rhys; Rodríguez-Enríquez, Sara; Moreno-Sánchez, Rafael; Ralph, Raymond Keith

    2015-01-01

    Tumor metastases that impede the function of vital organs are a major cause of cancer related mortality. Mitochondrial oxidative stress induced by hypoxia, low nutrient levels, or other stresses, such as genotoxic events, act as key drivers of the malignant changes in primary tumors to enhance their progression to metastasis. Emerging evidence now indicates that mitochondrial modifications and mutations resulting from oxidative stress, and leading to OxPhos stimulation and/or enhanced reactive oxygen species (ROS) production, are essential for promoting and sustaining the highly metastatic phenotype. Moreover, the modified mitochondria in emerging or existing metastatic cancer cells, by their irreversible differences, provide opportunities for selectively targeting their mitochondrial functions with a one-two punch. The first blow would block their anti-oxidative defense, followed by the knockout blow—promoting production of excess ROS, capitulating the terminal stage—activation of the mitochondrial permeability transition pore (mPTP), specifically killing metastatic cancer cells or their precursors. This review links a wide area of research relevant to cellular mechanisms that affect mitochondria activity as a major source of ROS production driving the pro-oxidative state in metastatic cancer cells. Each of the important aspects affecting mitochondrial function are discussed including: hypoxia, HIFs and PGC1 induced metabolic changes, increased ROS production to induce a more pro-oxidative state with reduced antioxidant defenses. It then focuses on how the mitochondria, as a major source of ROS in metastatic cancer cells driving the pro-oxidative state of malignancy enables targeting drugs affecting many of these altered processes and why the NSAIDs are an excellent example of mitochondria-targeted agents that provide a one-two knockout activating the mPTP and their efficacy as selective anticancer metastasis drugs. PMID:25688484

  11. EpCAM-Independent Enrichment of Circulating Tumor Cells in Metastatic Breast Cancer

    PubMed Central

    Schneck, Helen; Gierke, Berthold; Uppenkamp, Frauke; Behrens, Bianca; Niederacher, Dieter; Stoecklein, Nikolas H.; Templin, Markus F.; Pawlak, Michael; Fehm, Tanja; Neubauer, Hans

    2015-01-01

    Circulating tumor cells (CTCs) are the potential precursors of metastatic disease. Most assays established for the enumeration of CTCs so far–including the gold standard CellSearch—rely on the expression of the cell surface marker epithelial cell adhesion molecule (EpCAM). But, these approaches may not detect CTCs that express no/low levels of EpCAM, e.g. by undergoing epithelial-to-mesenchymal transition (EMT). Here we present an enrichment strategy combining different antibodies specific for surface proteins and extracellular matrix (ECM) components to capture an EpCAMlow/neg cell line and EpCAMneg CTCs from blood samples of breast cancer patients depleted for EpCAM-positive cells. The expression of respective proteins (Trop2, CD49f, c-Met, CK8, CD44, ADAM8, CD146, TEM8, CD47) was verified by immunofluorescence on EpCAMpos (e.g. MCF7, SKBR3) and EpCAMlow/neg (MDA-MB-231) breast cancer cell lines. To test antibodies and ECM proteins (e.g. hyaluronic acid (HA), collagen I, laminin) for capturing EpCAMneg cells, the capture molecules were first spotted in a single- and multi-array format onto aldehyde-coated glass slides. Tumor cell adhesion of EpCAMpos/neg cell lines was then determined and visualized by Coomassie/MitoTracker staining. In consequence, marginal binding of EpCAMlow/neg MDA-MB-231 cells to EpCAM-antibodies could be observed. However, efficient adhesion/capturing of EpCAMlow/neg cells could be achieved via HA and immobilized antibodies against CD49f and Trop2. Optimal capture conditions were then applied to immunomagnetic beads to detect EpCAMneg CTCs from clinical samples. Captured CTCs were verified/quantified by immunofluorescence staining for anti-pan-Cytokeratin (CK)-FITC/anti-CD45 AF647/DAPI. In total, in 20 out of 29 EpCAM-depleted fractions (69%) from 25 metastatic breast cancer patients additional EpCAMneg CTCs could be identified [range of 1–24 CTCs per sample] applying Trop2, CD49f, c-Met, CK8 and/or HA magnetic enrichment. Ep

  12. Two-dimensional electrophoretic comparison of metastatic and non-metastatic human breast tumors using in vitro cultured epithelial cells derived from the cancer tissues

    PubMed Central

    Vydra, Jan; Selicharová, Irena; Smutná, Kateřina; Šanda, Miloslav; Matoušková, Eva; Buršíková, Eva; Prchalová, Markéta; Velenská, Zuzana; Coufal, David; Jiráček, Jiří

    2008-01-01

    Background Breast carcinomas represent a heterogeneous group of tumors diverse in behavior, outcome, and response to therapy. Identification of proteins resembling the tumor biology can improve the diagnosis, prediction, treatment selection, and targeting of therapy. Since the beginning of the post-genomic era, the focus of molecular biology gradually moved from genomes to proteins and proteomes and to their functionality. Proteomics can potentially capture dynamic changes in protein expression integrating both genetic and epigenetic influences. Methods We prepared primary cultures of epithelial cells from 23 breast cancer tissue samples and performed comparative proteomic analysis. Seven patients developed distant metastases within three-year follow-up. These samples were included into a metastase-positive group, the others formed a metastase-negative group. Two-dimensional electrophoretical (2-DE) gels in pH range 4–7 were prepared. Spot densities in 2-DE protein maps were subjected to statistical analyses (R/maanova package) and data-mining analysis (GUHA). For identification of proteins in selected spots, liquid chromatography-tandem mass spectrometry (LC-MS/MS) was employed. Results Three protein spots were significantly altered between the metastatic and non-metastatic groups. The correlations were proven at the 0.05 significance level. Nucleophosmin was increased in the group with metastases. The levels of 2,3-trans-enoyl-CoA isomerase and glutathione peroxidase 1 were decreased. Conclusion We have performed an extensive proteomic study of mammary epithelial cells from breast cancer patients. We have found differentially expressed proteins between the samples from metastase-positive and metastase-negative patient groups. PMID:18416831

  13. Wide spetcrum mutational analysis of metastatic renal cell cancer: a retrospective next generation sequencing approach.

    PubMed

    Fiorentino, Michelangelo; Gruppioni, Elisa; Massari, Francesco; Giunchi, Francesca; Altimari, Annalisa; Ciccarese, Chiara; Bimbatti, Davide; Scarpa, Aldo; Iacovelli, Roberto; Porta, Camillo; Virinder, Sarhadi; Tortora, Giampaolo; Artibani, Walter; Schiavina, Riccardo; Ardizzoni, Andrea; Brunelli, Matteo; Knuutila, Sakari; Martignoni, Guido

    2017-01-31

    Renal cell cancer (RCC) is characterized by histological and molecular heterogeneity that may account for variable response to targeted therapies. We evaluated retrospectively with a next generation sequencing (NGS) approach using a pre-designed cancer panel the mutation burden of 32 lesions from 22 metastatic RCC patients treated with at least one tyrosine kinase or mTOR inhibitor. We identified mutations in the VHL, PTEN, JAK3, MET, ERBB4, APC, CDKN2A, FGFR3, EGFR, RB1, TP53 genes. Somatic alterations were correlated with response to therapy. Most mutations hit VHL1 (31,8%) followed by PTEN (13,6%), JAK3, FGFR and TP53 (9% each). Eight (36%) patients were wild-type at least for the genes included in the panel.A genotype concordance between primary RCC and its secondary lesion was found in 3/6 cases. Patients were treated with Sorafenib, Sunitinib and Temsirolimus with partial responses in 4 (18,2%) and disease stabilization in 7 (31,8%). Among the 4 partial responders, 1 (25%) was wild-type and 3 (75%) harbored different VHL1 variants. Among the 7 patients with disease stabilization 2 (29%) were wild-type, 2 (29%) PTEN mutated, and single patients (14% each) displayed mutations in VHL1, JAK3 and APC/CDKN2A. Among the 11 non-responders 7 (64%) were wild-type, 2 (18%) were p53 mutated and 2 (18%) VHL1 mutated.No significant associations were found among RCC histotype, mutation variants and response to therapies. In the absence of predictive biomarkers for metastatic RCC treatment, a NGS approach may address single patients to basket clinical trials according to actionable molecular specific alterations.