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Cancer Metastasis (cancer + metastasis)
Kinds of Cancer Metastasis Selected AbstractsRas Farnesylation Inhibitor FTI-277 Restores the E-Cadherin/Catenin Cell Adhesion System in Human Cancer Cells and Reduces Cancer MetastasisCANCER SCIENCE, Issue 9 2002Jeong-Seok Nam The E-cadherin/catenin cell adhesion system is often down-regulated in epithelial tumors. This is thought to play an important role in cancer invasion and metastasis, and restoration of this system may suppress metastatic spread of cancer. In this study, the effects of a Ras farnesylation inhibitor (FTI-277) on E-cadherin-mediated cell-cell adhesion and metastatic potential were examined. In cell aggregation assays, FTI-277 stimulated aggregation of colon, liver and breast cancer cells. In vitro cultures of cancer cells showed that FIT-277 induced strong cell-cell contact. Immunoblotting analysis showed that FTI-277 increased E-cadherin/catenin (,, , and ,) expression and strongly stabilized E-cadherin/catenin with the actin cytoskeleton. Northern blotting studies indicated that the observed increase in the E-cadherin/catenin protein content was due to increased expression of their genes. After inoculation of the spleens of mice with severe combined immunodeficiency (SCID) with cancer cells, FTI-277 treatment for 3 weeks markedly reduced splenic primary tumor growth and the rate of liver metastasis compared with control counterparts. Our data demonstrate that FTI-277 can activate functioning of the E-cadherin-mediated cell adhesion system, which is associated with suppression of cancer cell metastasis. Therefore, selective inhibition of Ras activation may be useful for preventing cancer metastasis. [source] Silibinin inhibits the invasion of human lung cancer cells via decreased productions of urokinase-plasminogen activator and matrix metalloproteinase-2,MOLECULAR CARCINOGENESIS, Issue 3 2004Shu-Chen Chu Abstract Cancer metastasis, involving multiple processes and various cytophysiological changes, is a primary cause of cancer death and may complicate the clinical management, even lead to death. Silibinin is a flavonoid antioxidant and wildly used for its antihepatotoxic properties and recent studies have revealed pleiotropic anticancer and antiproliferative capabilities of silibinin. In this study, we first observed that silibinin exerted a dose- and time-dependent inhibitory effect on the invasion and motility, but hardly on the adhesion, of highly metastatic A549 cells in the absence of cytotoxicity. To look at the precise involvement of silibinin in cancer metastasis, A549 cells were treated with silibinin at various concentrations, up to 100 ,M, for a defined period and then subjected to gelatin zymography, casein zymography and Western blot to investigate the impacts of silibinin on metalloproteinase-2 (MMP-2), urokinase plasminogen activator (u-PA), and tissue inhibitor of metalloproteinase-2 (TIMP-2), respectively. The results showed that a silibinin treatment may decrease the expressions of MMP-2 and u-PA in a concentration- and time-dependent manner and enhance the expression of TIMP-2. Further analysis with semi-quantitative RT-PCR showed that silibinin may regulate the expressions of MMP-2 and u-PA on the transcriptional level while on the translational or post-translational level for TIMP-2. © 2004 Wiley-Liss, Inc. [source] Inhibition of urokinase receptor gene expression and cell invasion by anti-uPAR DNAzymes in osteosarcoma cellsFEBS JOURNAL, Issue 14 2005Charles E. De Bock The urokinase-type plasminogen activator (uPA) receptor (uPAR) has been implicated in signal transduction and biological processes including cancer metastasis, angiogenesis, cell migration, and wound healing. It is a specific cell surface receptor for its ligand uPA, which catalyzes the formation of plasmin from plasminogen, thereby activating the proteolytic cascade that contributes to the breakdown of extracellular matrix, a key step in cancer metastasis. We have synthesized three different DNA enzymes (Dz372, Dz483 and Dz720) targeting uPAR mRNA at three separate purine (A or G),pyrimidine (U or C) junctions. Two of these DNAzymes, Dz483 and Dz720, cleaved uPAR transcript in vitro with high efficacy and specificity at a molar ratio (uPAR to Dz) as low as 1 : 0.2. When analyzed over 2 h with a 200-fold molar excess of DNAzymes to uPAR transcript, Dz720 and Dz483 were able to decrease uPAR transcript in vitro by ,,93% and ,,84%, respectively. They also showed an ability to cleave uPAR mRNA in the human osteosarcoma cell line Saos-2 after transfection. The DNAzyme Dz720 decreased uPAR mRNA within 4 h of transfection, and inhibited uPAR protein concentrations by 55% in Saos-2 cells. The decrease in uPAR mRNA and protein concentrations caused by Dz720 significantly suppressed Saos-2 cell invasion as assessed by an in vitro Matrigel assay. The use of DNAzyme methodology adds a new potential clinical agent for decreasing uPAR mRNA expression and inhibiting cancer invasion and metastasis. [source] Identification of prospective factors promoting osteotropism in breast cancer: a potential role for CITED2INTERNATIONAL JOURNAL OF CANCER, Issue 4 2010Wen Min Lau Abstract Breast cancer metastases develop in the bone more frequently than any other site and are a common cause of morbidity in the form of bone pain, pathological fractures, nerve compression and life-threatening hypercalcemia. Despite ongoing research efforts, the molecular and cellular mechanisms that regulate breast cancer cell homing to and colonization of the bone as well as resultant pathological bone alteration remain poorly understood. To identify key mediators promoting breast cancer metastasis to bone, we utilized an immunocompetent, syngeneic murine model of breast cancer metastasis employing the mammary tumor cell line NT2.5. Following intracardiac injection of NT2.5 cells in neu-N mice, metastases developed in the bone, liver and lung, closely mimicking the anatomical distribution of metastases in patients with breast cancer. Using an in vivo selection process, we established NT2.5 sublines demonstrating an enhanced ability to colonize the bone and liver. Genome-wide cDNA microarray analysis comparing gene expression between parental NT2.5 cells and established sublines revealed both known and novel mediators of bone metastasis and osteolysis, including the transcriptional co-activator CITED2. In further studies, we found that expression of CITED2 was elevated in human primary breast tumors and bone metastasis compared to normal mammary epithelium and was highest in breast cancer cell lines that cause osteolytic bone metastasis in animal models. In addition, reducing CITED2 expression in NT2.5 cells inhibited the establishment of bone metastasis and osteolysis in vivo, suggesting a potential role for CITED2 in promoting breast cancer bone metastasis. [source] Upregulation of myosin Va by Snail is involved in cancer cell migration and metastasisINTERNATIONAL JOURNAL OF CANCER, Issue 1 2010Linxiang Lan Abstract Cell migration, which involves acto-myosin dynamics, cell adhesion, membrane trafficking and signal transduction, is a prerequisite for cancer cell metastasis. Here, we report that an actin-dependent molecular motor, unconventional myosin Va, is involved in this process and implicated in cancer metastasis. The mRNA expression of myosin Va is increased in a number of highly metastatic cancer cell lines and metastatic colorectal cancer tissues. Suppressing the expression of myosin Va by lentivirus-based RNA interference in highly metastatic cancer cells impeded their migration and metastasis capabilities both in vitro and in vivo. In addition, the levels of myosin Va in cancer cell lines are positively correlated with the expression of Snail, a transcriptional repressor that triggers epithelial,mesenchymal transition. Repression or overexpression of Snail in cancer cells caused reduced or elevated levels of myosin Va, respectively. Furthermore, Snail can bind to an E-box of the myosin Va promoter and induce its activity, which indicates that Snail might act as a transcriptional activator. These data demonstrate an essential role of myosin Va in cancer cell migration and metastasis, and suggest a novel target for Snail in its regulation of cancer progression. [source] CNTO 859, a humanized anti-tissue factor monoclonal antibody, is a potent inhibitor of breast cancer metastasis and tumor growth in xenograft modelsINTERNATIONAL JOURNAL OF CANCER, Issue 6 2007Cam V. Ngo Abstract Thromboembolic complications are frequently associated with advanced cancer. Interestingly, one of the major initiators of blood coagulation, tissue factor (TF), is reported to be overexpressed in several tumor types and can be found on both tumor cells and tumor vasculature. Although the exact mechanisms have yet to be elucidated, TF expressed on tumor cells can trigger intracellular signaling events through various pathways that can lead to tumor angiogenesis, proliferation, and metastasis. There exists preclinical evidence that disruption of TF dependent signaling can effectively inhibit tumor cell migration, metastasis, and angiogenesis. Here, we report for the first time that an antibody to tissue factor can also prevent tumor growth in vivo. Prophylactic administration of CNTO 859, a humanized anti-human TF antibody, was shown to inhibit experimental lung metastasis of MDA-MB-231 human breast carcinoma cells by over 99% compared to a control antibody. Furthermore, therapeutic doses of CNTO 859 were shown to reduce tumor incidence and growth of orthotopically implanted MDA-MB-231 cells. © 2006 Wiley-Liss, Inc. [source] Quantitative analysis of lymphangiogenic markers for predicting metastasis of human gastric carcinoma to lymph nodesINTERNATIONAL JOURNAL OF CANCER, Issue 3 2005Yasuhiko Kitadai Abstract The spread of tumor cells to regional lymph nodes is an early event of gastric cancer metastasis. In our study, we assessed the expression of lymphangiogenic factors and lymphatic endothelial markers in gastric carcinoma tissues and compared expression levels with the status of lymph node metastasis. We also examined the correlation between lymphatic vessel density (LVD) in primary tumors and lymph node metastasis. Paired biopsy samples (tumor and corresponding normal mucosa) of gastric tissue were obtained from 39 patients with gastric carcinoma. The expression of VEGF-C, VEGF-D, VEGFR-3 and podoplanin mRNAs was assessed by real-time quantitative PCR. The expression of VEGF-C (but not of VEGF-D) was significantly greater in patients with lymph node metastasis than in those without metastasis. The expression of lymphatic endothelial markers VEGFR-3 and podoplanin was also significantly greater in the node-positive group. LVD, as assessed by immunohistochemistry for podoplanin, was correlated with lymph node metastasis. These results indicate that quantitative analysis of lymphangiogenic markers in gastric biopsy specimens may be useful in predicting metastasis of gastric cancer to regional lymph nodes. © 2005 Wiley-Liss, Inc. [source] Lymphatics at the crossroads of angiogenesis and lymphangiogenesisJOURNAL OF ANATOMY, Issue 6 2004Claudio Scavelli Abstract The lymphatic system is implicated in interstitial fluid balance regulation, immune cell trafficking, oedema and cancer metastasis. However, the sequence of events that initiate and coordinate lymphatic vessel development (lymphangiogenesis) remains obscure. In effect, the understanding of physiological regulation of lymphatic vasculature has been overshadowed by the greater emphasis focused on angiogenesis, and delayed by a lack of specific markers, thereby limiting this field to no more than a descriptive characterization. Recently, new insights into lymphangiogenesis research have been due to the discovery of lymphatic-specific markers and growth factors of vascular endothelial growth factor (VEGF) family, such as VEGF-C and VEGF-D. Studies using transgenic mice overexpressing VEGF-C and VEGF-D have demonstrated a crucial role for these factors in tumour lymphangiogenesis. Knowledge of lymphatic development has now been redefined at the molecular level, providing an interesting target for innovative therapies. This review highlights the recent insights and advances into the field of lymphatic vascular research, outlining the most important aspects of the embryo development, structure, specific markers and methods applied for studying lymphangiogenesis. Finally, molecular mechanisms involved in the regulation of lymphangiogenesis are described. [source] Cover Picture: J. Biophoton.JOURNAL OF BIOPHOTONICS, Issue 1-2 20091-2/200 Left panel: Photomicrograph, at 40× magnification, of a 1 × 1 mm stained section of axillary lymph node from a sentinel lymph node recession. The pink areas are due to the capsule, and the dark purple areas to lymphocytes. Right panel: Overlay of areas identified to contain abnormal tissue from a breast cancer metastasis via spectral imaging. (© 2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim) [source] Osteopontin promotes gastric cancer metastasis by augmenting cell survival and invasion through Akt-mediated HIF-1, up-regulation and MMP9 activationJOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 8b 2009Gang Song Abstract Osteopontin (OPN) is a secreted, integrin-binding matrix phosphorylated glycoprotein. OPN has been shown to facilitate the progression and metastasis of malignancies and has prognostic value in several types of cancer, including gastric cancer. However, the functional mechanism of OPN mediated metastatic growth in gastric cancer remains unclear. Here, using multiple in vitro and in vivo models, we report that OPN strongly promoted the progression and metastasis of gastric cancer. Immunohistochemical staining revealed that OPN, matrix metalloproteinase (MMP)9 and hypoxia-inducible factor (HIF)-1, have statistically significant different expression patterns between well- and poorly differentiated tissue samples (P < 0.05). Correlations existed between OPN and MMP9, and between OPN and HIF-1, (r1= 0.872, p1 < 0.01 and r2= 0.878, p2 < 0.01). Furthermore, OPN dramatically increased colony formation and invasion of gastric cancer cells in vitro and promoted tumour growth and metastasis in vivo. In addition, OPN potently protected gastric cancer cells from serum depletion-induced apoptosis. Further study shows that OPN activated phosphoinositide 3-kinase/Akt survival pathway and up-regulated HIF-1,via binding to ,v,3 integrins in gastric cancer cells. Moreover, we found that OPN could activate MMP9 and up-regulate MMP2. Taken together, our results suggest that the survival-promoting function is crucial for OPN to promote the development of gastric cancer, and HIF-1, and MMP9 may play key roles during this process. Thus, targeting OPN and its related signalling network may develop an effective therapeutic approach for the management of gastric cancer. [source] High aldehyde dehydrogenase and expression of cancer stem cell markers selects for breast cancer cells with enhanced malignant and metastatic abilityJOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 8b 2009Alysha K. Croker Abstract Cancer stem cells (CSCs) have recently been identified in leukaemia and solid tumours; however, the role of CSCs in metastasis remains poorly understood. This dearth of knowledge about CSCs and metastasis is due largely to technical challenges associated with the use of primary human cancer cells in pre-clinical models of metastasis. Therefore, the objective of this study was to develop suitable pre-clinical model systems for studying stem-like cells in breast cancer metastasis, and to test the hypothesis that stem-like cells play a key role in metastatic behaviour. We assessed four different human breast cancer cell lines (MDA-MB-435, MDA-MB-231, MDA-MB-468, MCF-7) for expression of prospective CSC markers CD44/CD24 and CD133, and for functional activity of aldehyde dehydrogenase (ALDH), an enzyme involved in stem cell self-protection. We then used fluorescence-activated cell sorting and functional assays to characterize differences in malignant/metastatic behaviour in vitro (proliferation, colony-forming ability, adhesion, migration, invasion) and in vivo (tumorigenicity and metastasis). Sub-populations of cells demonstrating stem-cell-like characteristics (high expression of CSC markers and/or high ALDH) were identified in all cell lines except MCF-7. When isolated and compared to ALDHlowCD44low/, cells, ALDHhiCD44+CD24, (MDA-MB-231) and ALDHhiCD44+CD133+ (MDA-MB-468) cells demonstrated increased growth (P < 0.05), colony formation (P < 0.05), adhesion (P < 0.001), migration (P < 0.001) and invasion (P < 0.001). Furthermore, following tail vein or mammary fat pad injection of NOD/SCID/IL2, receptor null mice, ALDHhiCD44+CD24, and ALDHhiCD44+CD133+ cells showed enhanced tumorigenicity and metastasis relative to ALDHlowCD44low/, cells (P < 0.05). These novel results suggest that stem-like ALDHhiCD44+CD24, and ALDHhiCD44+CD133+ cells may be important mediators of breast cancer metastasis. [source] Pro-metastasis function of TGF, mediated by the smad pathwayJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 6 2006Yibin Kang Abstract The transforming growth factor beta (TGF,) signaling pathway plays a vital role in the development and homeostasis of normal tissues. Abnormal function of this pathway contributes to the initiation and progression of cancer. Smad proteins are key signal transducers of the TGF, pathway and are essential for the growth suppression function of TGF,. Smads are bona fide tumor suppressors whose mutation, deletion, and silencing are associated with many types of human cancer. However, the involvement and functional mechanism of Smad proteins in cancer metastasis are poorly defined. Recent studies using genetically modified cancer cells and mouse tumor models have provided concrete evidence for a Smad-dependent mechanism for metastasis promotion by TGF,. Understanding the dual roles of Smad proteins in tumor initiation and progression has important implications for cancer therapeutics. J. Cell. Biochem. © 2006 Wiley-Liss, Inc. [source] Molecular markers and determinants of prostate cancer metastasisJOURNAL OF CELLULAR PHYSIOLOGY, Issue 3 2001Rahul V. Gopalkrishnan Although intensely studied, the molecular and biochemical determinants of prostate cancer development and progression remain ill-defined. Moreover, current markers and methodologies cannot distinguish between a tumor that will remain indolent and not impinge on patient survival, versus a tumor with aggressive traits culminating in metastatic spread and death. Once prostate cancer is confirmed the most significant threat to a patient's survival and quality of life involves tumor metastasis. Radical surgery notwithstanding, prostate cancer accounts for 10% of all cancer-related deaths primarily arising through development of metastasis. Metastasis markers demonstrating an acceptable level of reliability are an obvious necessity if disproportionate and costly treatment is to be avoided and a reasonably accurate determination of clinical prognosis and measure of successful response to treatment is to be made. Therapeutic strategies that specifically inhibit metastatic spread are not presently possible and may not become available in the immediate future. This is because, while localized tumorigenesis has been relatively amenable to detection, analysis and treatment, metastasis remains a relatively undefined, complex and underexplored area of prostate cancer research. New findings in the field such subclasses of genes called metastasis suppressors and cancer progression suppressors, have opened up exciting avenues of investigation. We review current methodological approaches, model experimental systems and genes presently known or having potential involvement in human prostate cancer metastasis. © 2001 Wiley-Liss, Inc. [source] Decreased expression of Ep-CAM protein is significantly associated with the progression and prognosis of oral squamous cell carcinomas in TaiwanJOURNAL OF ORAL PATHOLOGY & MEDICINE, Issue 1 2009Emily Ya-Chi Hwang Background:, The epithelial cell adhesion molecule (Ep-CAM) is involved in cell signaling, migration, proliferation, cell-cycle regulation, and cancer metastasis. Methods:, This study used an immunohistochemical technique to examine the expression of Ep-CAM protein in 84 specimens of oral squamous cell carcinoma (OSCC), 98 specimens of oral epithelial dysplasia (OED, 31 mild, 41 moderate, and 26 severe OED cases), and 15 specimens of normal oral mucosa (NOM). Results:, We found that the mean Ep-CAM labeling indices (LIs) decreased significantly from NOM (80 ± 18%) and mild OED (76 ± 14%) through moderate OED (66 ± 22%) and severe OED (55 ± 20%) to OSCC samples (46 ± 16%, P < 0.001). A significant correlation was found between the lower mean Ep-CAM LI and OSCCs with larger tumor size (P = 0.003), positive lymph node metastasis (P = 0.022), more advanced clinical stages (P < 0.001), cancer recurrence (P = 0.021), or extracapsular spread of lymph node (P = 0.015). However, only Ep-CAM LI < 50% (P < 0.0001) was identified as an independent unfavorable prognosis factor by multivariate analyses with Cox proportional hazard regression model. Kaplan,Meier curve showed that OSCC patients with an Ep-CAM LI < 50% had a significantly poorer cumulative survival than those with an Ep-CAM LI , 50% (P < 0.00001, log-rank test). Conclusions:, We conclude that the decreased expression of Ep-CAM protein is an early event in oral carcinogenesis. The Ep-CAM LI in OSCC samples can predict the progression of OSCCs and the survival of OSCC patients. [source] The correlation between alteration of p16 gene and clinical status in oral squamous cell carcinomaJOURNAL OF ORAL PATHOLOGY & MEDICINE, Issue 9 2001Chung-Hung Tsai Abstract: The purpose of the study was to evaluate the presence of alteration of the tumor suppressor gene p16 and to correlate these changes with the clinical status of the patients in oral squamous cell carcinoma. Forty-eight oral squamous cell carcinomas were included in the analyses. Deletion analysis was performed by the polymerase chain reaction (PCR). Mutation analysis was restricted to exon 1 and exon 2 of the p16 gene, previously shown to have a high incidence of mutations. The sequences containing exon 1 and exon 2 were amplified by PCR and screened with a single-strand conformation polymorphism (SSCP) technique. Samples showing band shifts in SSCP were sequenced by PCR direct sequencing. Western blots were used to detect the protein expression of the p16 gene, and the results were evaluated with regard to their biological relevance in correlation with clinicopathological factors. Seven (14.6%) deletions were found; 5 (10.4%) mutations were discovered and located in different codons; 26 (54%) specimens had no p16 protein expression; in 11 specimens with p16 deletion or mutation, p16 protein could not be detected. One mutation was non-sense. The p16 gene alterations showed no relationship with location and clinical stage of cancer; however, a close relationship between p16 alterations and cancer metastasis to neck lymph node was found. The alteration rate gradually elevated from well to poorly differentiated grades. We perceive two results. First, the alterations of the p16 gene are common in oral squamous cell carcinoma. Second, the alterations of the p16 gene may attribute to the metastatic behavior or histological grade of cancer cells. [source] The effects of RANK blockade and osteoclast depletion in a model of pure osteoblastic prostate cancer metastasis in boneJOURNAL OF ORTHOPAEDIC RESEARCH, Issue 6 2005Peter G. Whang Abstract Adenocarcinoma of the prostate exhibits a clear propensity for bone and is associated with the formation of osteoblastic metastases. It has previously been suggested that osteoclast activity may be necessary for the development of these osteoblastic metastases based on data from lytic and mixed lytic-blastic tumors. Here we investigate the effects of complete in vivo osteoclast depletion via the blockade of receptor activator of NF:,B (RANK) on the establishment and progression of purely osteoblastic (LAPC-9 cells) bone lesions induced by human prostate cancer cells using a SCID mouse intratibial injection model. The subcutaneous administration of the RANK antagonist (15 mg/kg) RANK:Fc did not prevent the formation of purely osteoblastic lesions, indicating that osteoclasts may not be essential to the initial development of osteoblastic metastases. However, RANK:Fc protein appeared to inhibit the progression of established osteoblastic lesions, suggesting that osteoclasts may be involved in the subsequent growth of these tumors once they are already present. In contrast, RANK:Fc treatment effectively blocked the establishment and progression of purely osteolytic lesions formed by PC-3 cells, which served as a positive control. These results indicate that in vivo RANK blockade may not be effective for the prevention of osteoblastic metastasis but may potentially represent a novel therapy that limits the growth of established metastatic CaP lesions in bone. © 2005 Published by Elsevier Ltd. on behalf of Orthopaedic Research Society. [source] Intratumoural chemotherapy of lung cancer for diagnosis and treatment of draining lymph node metastasisJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 3 2010Firuz Celikoglu Abstract Objectives Reviewed here is the potential effectiveness of cytotoxic drugs delivered by intratumoural injection into endobronchial tumours through a bronchoscope for the treatment of non-small cell lung cancer and the diagnosis of occult or obvious cancer cell metastasis to mediastinal lymph nodes. Key findings Intratumoural lymphatic treatment may be achieved by injection of cisplatin or other cytotoxic drugs into the malignant tissue located in the lumen of the airways or in the peribronchial structures using a needle catheter through a flexible bronchoscope. This procedure is termed endobronchial intratumoural chemotherapy and its use before systemic chemotherapy and/or radiotherapy or surgery may provide a prophylactic or therapeutic treatment for eradication of micrometastases or occult metastases that migrate to the regional lymph nodes draining the tumour area. Conclusions To better elucidate the mode of action of direct injection of cytotoxic drugs into tumours, we review the physiology of lymphatic drainage and sentinel lymph node function. In this light, the potential efficacy of intratumoural chemotherapy for prophylaxis and locoregional therapy of cancer metastasis via the sentinel and regional lymph nodes is indicated. Randomized multicenter clinical studies are needed to evaluate this new and safe procedure designed to improve the condition of non-small cell lung cancer patients and prolong their survival. [source] Antivascular therapy of cancer metastasisJOURNAL OF SURGICAL ONCOLOGY, Issue 3 2006Isaiah J. Fidler DVM No abstract is available for this article. [source] Tetraspanins and Intercellular InteractionsMICROCIRCULATION, Issue 3 2001MARÍA YÁÑEZ-MÓ ABSTRACT The superfamily of tetraspanins comprises a group of polypeptides with four transmembrane domains that form large supramolecular structures in the plasma membrane through their associations to multiple integral membrane proteins. They are involved in homo- and heterotypic intercellular interactions in different processes such as hematopoiesis, lymphocyte activation, cancer metastasis, and fertilization. Intercellularly located tetraspanins regulate the juxtacrine activity of growth factors, cell fusion, and myelin formation. On the other hand, in motile cells they relocalize from cell-cell junctions to actin-based structures such as filopodia or growth cones and regulate cell motility in wound healing and angiogenesis processes. [source] Silibinin inhibits the invasion of human lung cancer cells via decreased productions of urokinase-plasminogen activator and matrix metalloproteinase-2,MOLECULAR CARCINOGENESIS, Issue 3 2004Shu-Chen Chu Abstract Cancer metastasis, involving multiple processes and various cytophysiological changes, is a primary cause of cancer death and may complicate the clinical management, even lead to death. Silibinin is a flavonoid antioxidant and wildly used for its antihepatotoxic properties and recent studies have revealed pleiotropic anticancer and antiproliferative capabilities of silibinin. In this study, we first observed that silibinin exerted a dose- and time-dependent inhibitory effect on the invasion and motility, but hardly on the adhesion, of highly metastatic A549 cells in the absence of cytotoxicity. To look at the precise involvement of silibinin in cancer metastasis, A549 cells were treated with silibinin at various concentrations, up to 100 ,M, for a defined period and then subjected to gelatin zymography, casein zymography and Western blot to investigate the impacts of silibinin on metalloproteinase-2 (MMP-2), urokinase plasminogen activator (u-PA), and tissue inhibitor of metalloproteinase-2 (TIMP-2), respectively. The results showed that a silibinin treatment may decrease the expressions of MMP-2 and u-PA in a concentration- and time-dependent manner and enhance the expression of TIMP-2. Further analysis with semi-quantitative RT-PCR showed that silibinin may regulate the expressions of MMP-2 and u-PA on the transcriptional level while on the translational or post-translational level for TIMP-2. © 2004 Wiley-Liss, Inc. [source] ,-Catenin dysregulation in cancer: interactions with E-cadherin and beyond,THE JOURNAL OF PATHOLOGY, Issue 2 2010Qun Lu Abstract Stable E-cadherin-based adherens junctions are pivotal in maintaining epithelial tissue integrity and are the major barrier for epithelial cancer metastasis. Proteins of the p120ctn subfamily have emerged recently as critical players for supporting this stability. The identification of the unique juxtamembrane domain (JMD) in E-cadherin that binds directly to ,-catenin/NPRAP/neurojungin (CTNND2) and p120ctn (CTNND1) provides a common motif for their interactions. Recently, crystallographic resolution of the JMD of p120ctn further highlighted possibilities of intervening between interactions of p120ctn subfamily proteins and E-cadherin for designing anti-cancer therapeutics. For most epithelial cancers, studies have demonstrated a reduction of p120ctn expression or alteration of its subcellular distribution. On the other hand, ,-catenin, a primarily neural-enriched protein in the brain of healthy individuals, is up-regulated in all cancer types that have been studied to date. Two research articles in the September 2010 issue of The Journal of Pathology increase our understanding of the involvement of these proteins in lung cancer. One reports the identification of rare p120ctn (CTNND1) gene amplification in lung cancer. One mechanism by which ,-catenin and p120ctn may play a role in carcinogenesis is their competitive binding to E-cadherin through the JMD. The other presents the first vigorous characterization of ,-catenin overexpression in lung cancer. Unexpectedly, the authors observed that ,-catenin promotes malignant phenotypes of non-small cell lung cancer by non-competitive binding to E-cadherin with p120ctn in the cytoplasm. Looking towards the future, the understanding of ,-catenin and p120ctn with and beyond their localization at the cell,cell junction should provide further insight into their roles in cancer pathogenesis. Copyright © 2010 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Invited Commentary for Castillo et al. Gene amplification of the transcription factor DP1 and CTNND1 in human lung cancer, Journal of Pathology, 2010; 222: 89,98. And for Zhang et al. ,-Catenin promotes malignant phenotype of non-small cell lung cancer by non-competative binding to E-cadherin with p120ctn in cytoplasm. Journal of Pathology, 2010; 222: 76,88. [source] Androgen receptor as a potential sign of prostate cancer metastasisTHE PROSTATE, Issue 15 2009Marie-Hélène Lévesque Abstract BACKGROUND Androgen receptor (AR) expression and its modulation through the carcinogenesis process have been investigated in several studies with conflicting results. MATERIALS AND METHODS In situ hybridization and immunocytochemistry were used to examine AR expression in prostatic needle core biopsies of benign, high grade prostatic intraepithelial neoplasia (HGPIN) and prostatic adenocarcinoma. RESULTS A significant increase in AR mRNA levels was found in the cancerous prostatic cells when compared with the benign tissue biopsies. AR abundance in HGPIN was found to be almost half-way between that observed in benign and in cancerous tissue. In the benign prostatic epithelium, the immunocytochemistry data show that AR is exclusively expressed in the nuclei of epithelial cells. However, in 72% of examined cancer biopsies, AR was expressed in both the cytoplasm and nuclei. After examination of medical records of 100 patients diagnosed with prostate cancer, it was found that the AR was expressed in both cellular compartments of cancer cells in 81% of cases when cancer was found to have metastasized outside the prostate. In contrast, when the cancer was organ-confined, AR was localized in both the nuclei and cytoplasm in only 66% of cases. Moreover, when the AR was expressed in the cytoplasm of cancerous cells, consecutive serial sections immunostained with the mitochondrial marker suggest that AR is localized in the mitochondria. CONCLUSIONS AR mRNA expression is significantly higher in prostate cancer when compared to benign prostatic tissue. Prostate 69: 1704,1711, 2009. © 2009 Wiley-Liss, Inc. [source] Presence of prostate cancer metastasis correlates with lower lymph node reactivity,THE PROSTATE, Issue 16 2006Gannon Philippe Olivier Abstract BACKGROUND Several reports suggest that the dissemination of neoplastic cells and cancer progression are associated with the generation of an immunosuppressive environment. METHODS In this report, we investigated immunological effects of prostate cancer by comparing metastastic and non-metastatic pelvic lymph nodes (LNs) from 25 patients with carcinomatous involvement of LNs to the non-metastatic LNs from 26 control patients with no metastatic involvement by immunohistochemistry and histological analyses. RESULTS Our results showed a decreased abundance of CD20+ B lymphocytes (P,=,0.031), CD38+ activated lymphocytes (P,=,0.038), and CD68+ macrophages (P,<,0.001), and less evidence of follicular hyperplasia (P,=,0.014), sinus hyperplasia (P,<,0.001), and fibrosis (P=0.028) in metastatic LNs comparatively to control LNs. Finally, we observed that metastatic LNs were significantly smaller than control LNs (P,=,0.005). CONCLUSIONS Our results suggest that the development of prostate cancer LN metastasis is accompanied with smaller LN size and decreased LN reactivity suggesting the development of an immununosuppressive microenvironment. © 2006 Wiley-Liss, Inc. [source] Laparoscopic sentinel node navigation surgery for early gastric cancerASIAN JOURNAL OF ENDOSCOPIC SURGERY, Issue 1 2009H Takeuchi Abstract The sentinel node (SN) concept has revolutionized how the surgical staging of both melanoma and breast cancer are approached. Applying this concept can yield benefits for the patient by avoiding various complications relating to unnecessary prophylactic regional lymph node dissection in cases with negative SN for cancer metastasis. Clinical application of SN mapping for early gastric cancer had been controversial for years. However, single institutional results of laparoscopic SN mapping for early gastric cancer are considered acceptable in terms of detection rate and accuracy in determining lymph node status. For early stage gastric cancer such as cT1N0M0 , in which a better prognosis was generally achieved through conventional surgical approaches , an individualized, minimally invasive surgery that might retain the patient's quality of life should be established as the next surgical challenge. Although there are many issues still to resolve, laparoscopic minimized gastrectomy with SN navigation surgery or combined endoscopic mucosal resection and endoscopic submucosal dissection has the potential to achieve this goal. [source] SUMOylation and cell signallingBIOTECHNOLOGY JOURNAL, Issue 12 2009Artemisia M. Andreou Abstract SUMOylation is a highly transient post-translational protein modification. Attachment of SUMO to target proteins occurs via a number of specific activating and ligating enzymes that form the SUMO-substrate complex, and other SUMO-specific proteases that cleave the covalent bond, thus leaving both SUMO and target protein free for the next round of modification. SUMO modification has major effects on numerous aspects of substrate function, including subcellular localisation, regulation of their target genes, and interactions with other molecules. The modified SUMO-protein complex is a very transient state, and it thus facilitates rapid response and actions by the cell, when needed. Like phosphorylation, acetylation and ubiquitination, SUMOylation has been associated with a number of cellular processes. In addition to its nuclear role, important sides of mitochondrial activity, stress response signalling and the decision of cells to undergo senescence or apoptosis, have now been shown to involve the SUMO pathway. With ever increasing numbers of reports linking SUMO to human disease, like neurodegeneration and cancer metastasis, it is highly likely that novel and equally important functions of components of the SUMOylation process in cell signalling pathways will be elucidated in the near future. [source] Involvement of E-cadherin, ,-catenin, Cdc42 and CXCR4 in the progression and prognosis of cutaneous melanomaBRITISH JOURNAL OF DERMATOLOGY, Issue 6 2007M.G. Tucci Summary Background, A key event in cancer metastasis is the migration of tumour cells from their original location to a secondary site. The development of melanoma may be viewed as a consequence of the disruption of homeostatic mechanisms in the skin of the original site. Objectives, To investigate whether dysregulation of cell motility (Cdc42 expression), escaping the control of cell,cell and cell,matrix interactions (E-cadherin, ,-catenin expression), enhances melanoma progression, and whether chemokine receptors (CXCR4) mediate cell migration and activation during invasion and metastasis development. Methods, The immunohistochemical expression of Cdc42, E-cadherin, ,-catenin and CXCR4 was investigated in 30 patients with surgically treated nodular melanoma, 18 alive and disease free and 12 with a fatal outcome due to metastatic disease. Results, E-cadherin expression was significantly reduced (P < 0·05) and cytoplasmic ,-catenin was increased in the patients who had died compared with disease-free individuals, while membrane expression of ,-catenin was similar in the two groups. Patients with fatal outcome had increased Cdc42 (P < 0·01) and CXCR4 (P < 0·05). In this group a positive correlation was found between melanocytic Cdc42 expression and Breslow thickness (r = 0·598, P < 0·05) and between CXCR4 expression and Breslow thickness (r = 0·583, P < 0·05). Conclusions, Findings suggest that primary cutaneous melanoma with a high Breslow thickness is characterized by tumour cells with high motility and invasion ability, in line with the hypothesis that low E-cadherin levels and overexpression of Cdc42 and CXCR4 could be prognostic markers of poor outcome. [source] Vascular and Biology 05BRITISH JOURNAL OF SURGERY (NOW INCLUDES EUROPEAN JOURNAL OF SURGERY), Issue S1 2002L. Yea Background: Tight junctions govern the permeability of endothelial and epithelial cells. Changes in tight junction function are thus an early and key event in cancer metastasis and tissue permeability. This study sought to determine the role of oestrogen in the regulation of tight junctions and expression of occludin in endothelial cells. Methods: Human vascular endothelial cell line was incubated with 17-,-oestradiol at different concentrations (from 10,11m to 10,7m) over 1,24 h. Expression of occludin mRNA was determined using RT-PCR, and change of occludin protein using Western blotting. Transendothelial resistance (TER) was measured with an EVOM, and transendothelial cell permeability was determined using fluorescence labelled dextran (FITC-dextran 10) with a multichannel fluorescence reader. Results: 17-,-oestradiol reduced the expression of occludin mRNA in a time and concentration dependent manner with an obvious effect starting from 4 h. Reduced level of occludin protein was similarly seen after treatment with 17-,-oestradiol. Incubation of HECV with 17-,-oestradiol resulted in an increase in paracellular permeability by 9.9 ± 8.9 per cent at 10,10m (P > 0.05 versus control), 42.1 ± 15.2 per cent at 10,9m (P < 0.05 versus control), and 40.1 ± 22.4 per cent at 10,8m (P < 0.05, versus control). A decrease in the transendothelial cell resistance (TER) was seen with oestradiol (a reduction by 18.6 ± 16.6 per cent (P > 0.05 versus control), 31.5 ± 10.6 per cent (P < 0.01), or 44.4 ± 18.4 per cent (P < 0.01), at concentration 10,10, 10,9, 10,8m, respectively. Conclusions: This study shows a perturbation of tight junction functions in endothelial cells by oestrogen, which may have implications in the aetiology of mastalgia and vascular spread of breast cancer. [source] Wilms tumor gene protein 1 is associated with ovarian cancer metastasis and modulates cell invasionCANCER, Issue 7 2008Maria V. Barbolina PhD Abstract BACKGROUND Although metastatic disease is the primary cause of death from epithelial ovarian carcinoma, to the authors' knowledge the cellular mechanisms that regulate intraperitoneal metastasis are largely unknown. Metastasizing ovarian carcinoma cells encounter a collagen-rich microenvironment because the submesothelial matrix is comprised mainly of interstitial collagens Types I and III. METHODS Immunohistochemistry using primary and metastatic ovarian carcinoma samples was employed to detect expression of Wilms tumor gene protein 1 (WT1). Three-dimensional (3D) collagen culture, real-time reverse transcriptase-polymerase chain reaction, and immunofluorescent staining were used to evaluate changes in WT1 RNA and protein expression in response to 3D collagen culture. Boyden chamber invasion assay, scratch-wound motility assay, and Western blot analysis were used to establish the function of WT1 in ovarian carcinoma cells. RESULTS To model intraperitoneal invasion in vitro, ovarian cancer cells were cultured in a 3D collagen microenvironment. 3D collagen culture resulted in robust induction of WT1 at the mRNA and protein levels. WT1 expression was prevalent in primary ovarian tumors and was retained in paired peritoneal metastases. Functional studies supported a role for WT1 in intraperitoneal invasion, because siRNA knockdown of WT1 expression reduced the ability of ovarian cancer cells to invade 3D collagen gels. CONCLUSIONS The data from the current study identify a novel regulatory mechanism for the control of WT1 expression and provide evidence for a functional role of WT1 protein in the control of cellular invasive activity. Cancer 2008. ©2008 American Cancer Society. [source] Chemokine receptors in cancer metastasis and cancer cell-derived chemokines in host immune responseCANCER SCIENCE, Issue 11 2007Keiichi Koizumi The chemotactic cytokines called chemokines are a superfamily of small secreted cytokines that were initially characterized through their ability to prompt the migration of leukocytes. Attention has been focused on the chemokine receptors expressed on cancer cells because cancer cell migration and metastasis show similarities to leukocyte trafficking. CXC chemokine receptor 4 (CXCR4) was first investigated as a chemokine receptor that is associated with lung metastasis of breast cancers. Recently, CXCR4 was reported to be a key molecule in the formation of peritoneal carcinomatosis in gastric cancer. In the present review, we highlight current knowledge about the role of CXCR4 in cancer metastases. In contrast to chemokine receptors expressed on cancer cells, little is known about the roles of cancer cell-derived chemokines. Cancer tissue consists of both cancer cells and various stromal cells, and leukocytes that infiltrate into cancer are of particular importance in cancer progression. Although colorectal cancer invasion is regulated by the chemokine CCL9-induced infiltration of immature myeloid cells into cancer, high-level expression of cancer cell-derived chemokine CXCL16 increases infiltrating CD8+ and CD4+ T cells into cancer tissues, and correlates with a good prognosis. We discuss the conflicting biological effects of cancer cell-derived chemokines on cancer progression, using CCL9 and CXCL16 as examples. (Cancer Sci 2007; 98: 1652,1658) [source] Carbohydrate-mediated cell adhesion in cancer metastasis and angiogenesisCANCER SCIENCE, Issue 5 2004Reiji Kannagi Malignant transformation is associated with abnormal glycosylation, resulting in the synthesis and expression of altered carbohydrate determinants including sialyl Lewisa and sialyl Lewisx. The sialyl Lewisa and sialyl Lewisx determinants appear in the sera of patients with cancer, and are extensively utilized for serum diagnosis of cancers in Japan. Sialyl Lewisa and sialyl Lewisx are involved in selectin-mediated adhesion of cancer cells to vascular endothelium, and these determinants are thought to be closely associated with hematogenous metastasis of cancers. Recent progress in this area includes the following: 1. Substantial increases in solid clinical statistics that further confirm the contribution of these determinants in the progression of a wide variety of cancers; 2. Elucidation of the ligand specificity of the three family members of selectins and evaluation of the roles of these molecules in cancer cell adhesion; and 3. Advances in the study of the mechanism that leads to the enhanced expression of the sialyl Lewisa/x determinants in malignant cells. These recent results have confirmed that these determinants are not merely markers for cancers, but are functionally implicated in the malignant behavior of cancer cells. The results also suggested that the increase of these determinants in malignant cells is an inevitable consequence of the malignant transformation of cells. Considerable new knowledge has also been accumulated regarding the therapeutic implications for suppression of hematogenous metastasis targeting this cell adhesion system. [source] | ||||||||||||||||||||||||||||