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Tumor Cell Invasion (tumor + cell_invasion)
Selected AbstractsThe hepatitis B virus X protein promotes hepatocellular carcinoma metastasis by upregulation of matrix metalloproteinasesINTERNATIONAL JOURNAL OF CANCER, Issue 6 2007Di-Peng Ou Abstract The hepatitis B virus (HBV) is a major cause of human hepatocellular carcinoma (HCC) which has a very high mortality rate due to high incidence of metastasis. It is unknown whether HBV contributes to HCC metastasis. In this report, we present clinical data obtained from HCC patients indicating that the expression of hepatitis B virus X protein (HBx) in HCC is associated with an increased expression of membrane-type 1 matrix metalloproteinase (MT1-MMP), and matrix metalloproteinase-2(MMP-2), which correlates with a poor prognosis. We further demonstrate experimentally that HBx upregulates MT1-MMP, which in turn induces MMP-2. Significantly, HBx-mediated MMP activation is associated with a marked increase of cell migration, as revealed by both wound-healing and transwell migration assays, suggesting that HBx may facilitate tumor cell invasion by upregulation of MMPs and subsequent destruction of the extracellular matrix. Together, our results support a model in which HBx contributes to HCC metastasis by upregulation of MMPs. © 2006 Wiley-Liss, Inc. [source] Escape from microenvironmental control and progression of intraepithelial neoplasiaINTERNATIONAL JOURNAL OF CANCER, Issue 6 2005Weitian Zhang Abstract We previously reported that normal human keratinocytes controlled neoplastic progression of tumor cells at an early stage of transformation in stratified squamous epithelium. We now studied if cells at a more advanced stage of transformation were also subject to such microenvironmental control. To accomplish this, 3D human tissues that mimic intraepithelial neoplasia were fabricated by mixing genetically marked (,-gal), early-stage (II-4 cells) or advanced-stage (SCC13) transformed keratinocytes with normal keratinocytes, and tumor cell fate and phenotype were monitored in organotypic culture and after surface transplantation to nude mice. In vivo, SCC13 cells evaded local growth suppression to undergo connective tissue invasion at significantly lower tumor cell volumes (12:1, 50:1 normal:tumor cells) than II-4 cells. This behavior was explained by the growth suppression of II-4 cells, while advanced-stage tumor cells escaped this control and continued to undergo clonal expansion in mixed cultures to form large, intraepithelial tumor clusters. These communities of tumor cells underwent autonomous growth that was associated with altered expression of markers of differentiation (keratin 1) and cell,cell communication (connexin-43). Furthermore, significantly greater numbers of SCC13 cells expanded into a basal position after low-calcium stripping of suprabasal cells of mixed cultures compared to II-4 cells, suggesting that expansion of these cells enabled tumor cell invasion after transplantation. These findings demonstrated that early tumor development in human stratified squamous epithelium required escape from microenvironmental growth control that was dependent on the transformation stage of intraepithelial tumor cells during the premalignant stage of cancer progression. © 2005 Wiley-Liss, Inc. [source] The cofilin activity cycle in lamellipodia and invadopodiaJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 6 2009Matthew Oser Abstract The actin severing protein cofilin is essential for directed cell migration and chemotaxis, in many cell types and is also important for tumor cell invasion during metastasis. Through its severing activity, cofilin increases the number of free barbed ends to initiate actin polymerization for actin-based protrusion in two distinct subcellular compartments in invasive tumor cells: lamellipodia and invadopodia. Cofilin severing activity is tightly regulated and multiple mechanisms are utilized to regulate cofilin activity. In this prospect, we have grouped the primary on/off regulation into two broad categories, both of which are important for inhibiting cofilin from binding to F-actin or G-actin: (1) Blocking cofilin activity by the binding of cofilin to either PI(4,5)P2 at lamellipodia, or cortactin at invadopodia. (2) Blocking cofilin's ability to bind to actin via serine phosphorylation. Although the literature suggests that these cofilin regulatory mechanisms may be cell-type dependent, we propose the existence of a common cofilin activity cycle in which both operate. In this common cycle, the mechanism used to initiate cofilin activity is determined by the starting point in the cycle in a given subcellular compartment. J. Cell. Biochem. 108: 1252,1262, 2009. © 2009 Wiley-Liss, Inc. [source] Down-regulation of uPA and uPAR by 3,3,-diindolylmethane contributes to the inhibition of cell growth and migration of breast cancer cellsJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 4 2009Aamir Ahmad Abstract 3,3,-Diindolylmethane (DIM) is a known anti-tumor agent against breast and other cancers; however, its exact mechanism of action remains unclear. The urokinase plasminogen activator (uPA) and its receptor (uPAR) system are involved in the degradation of basement membrane and extracellular matrix, leading to tumor cell invasion and metastasis. Since uPA-uPAR system is highly activated in aggressive breast cancer, we hypothesized that the biological activity of B-DIM could be mediated via inactivation of uPA-uPAR system. We found that B-DIM treatment as well as silencing of uPA-uPAR led to the inhibition of cell growth and motility of MDA-MB-231 cells, which was in part due to inhibition of VEGF and MMP-9. Moreover, silencing of uPA-uPAR led to decreased sensitivity of these cells to B-DIM indicating an important role of uPA-uPAR in B-DIM-mediated inhibition of cell growth and migration. We also found similar effects of B-DIM on MCF-7, cells expressing low levels of uPA-uPAR, which was due to direct down-regulation of MMP-9 and VEGF, independent of uPA-uPAR system. Interestingly, over-expression of uPA-uPAR in MCF-7 cells attenuated the inhibitory effects of B-DIM. Our results, therefore, suggest that B-DIM down-regulates uPA-uPAR in aggressive breast cancers but in the absence of uPA-uPAR, B-DIM can directly inhibit VEGF and MMP-9 leading to the inhibition of cell growth and migration of breast cancer cells. J. Cell. Biochem. 108: 916,925, 2009. © 2009 Wiley-Liss, Inc. [source] Heparanase mechanisms of melanoma metastasis to the brain: Development and use of a brain slice modelJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 2 2006Brian P. Murry Abstract Heparanase (HPSE-1) is an endo-,- D -glucuronidase that cleaves heparan sulfate (HS) chains of proteoglycans (HSPG), and its expression has been associated with increased cell growth, invasion, and angiogenesis of tumors as well as with embryogenesis and tissue development. Since metastatic cancer cells express HPSE-1, we have developed an orthotopic brain slice model to study HPSE-1 involvement in brain-metastatic melanoma. This model allows for the characterization of tumor cell invasion at both quantitative and qualitative levels. Brain-metastatic melanoma cells (B16B15b) showed augmenting levels of HPSE-1 protein expression in a time-dependent manner. Secondly, B16B15b cells pre-treated with HPSE-1 showed a significant increase in the number of cells that invaded into the brain tissue. Finally, HPSE-1 exposure-augmented invasion depth in brain sections by brain-metastatic melanoma cells. We concluded that applying this brain slice model can be beneficial to investigate HPSE-1- related in vivo modalities in brain-metastatic melanoma and brain invasion in general. These results also further emphasize the potential relevance of using this model to design therapies for controlling this type of cancer by blocking HPSE-1 functionality. © 2005 Wiley-Liss, Inc. [source] Transforming growth factor-,1-dependent activation of Smad2/3 and up-regulation of PAI-1 expression is negatively regulated by Src in SKOV-3 human ovarian cancer cellsJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 3 2004Kiyoshi Wakahara Abstract The net balance between urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor type-1 (PAI-1) has been implicated in tumor cell invasion and metastasis. To elucidate the mechanism of the transforming growth factor-,1 (TGF-,1)-dependent up-regulation of PAI-1 expression, we investigated which signaling pathway transduced by TGF-,1 is responsible for this effect. Here, we show (1) nontoxic concentrations of TGF-,1 up-regulates uPA expression in HRA and SKOV-3 human ovarian cancer cells, (2) TGF-,1 activates Smads (phosphorylation of Smad2 and nuclear translocation of Smad3) and subsequently up-regulates PAI-1 expression in HRA cells, whereas TGF-,1 neither activates Smads nor up-regulates PAI-1 in SKOV-3 cells, (3) pharmacological Src inhibitor PP2 or antisense (AS) c-Src oligodeoxynucleotide (ODN) treatment significantly induces TGF-,1-dependent activation of Smads, leading to PAI-1 synthesis, compared with controls, in SKOV-3 cells, (4) combination of TGF-,1 and PP2, which activates PAI-1 expression and reduces uPA expression in SKOV-3, results in decreased invasiveness, (5) pharmacological inhibitors for mitogen-activated protein kinase (MAPK) (PD98059) and phosphoinositide-3-kinase (PI3K) (LY294002 and wortmannin) or AS-PI3K ODN transfection do not affect TGF-,1-induced Smad signaling and up-regulation of PAI-1 expression in SKOV-3 cells pr treated with PP2, and (6) the induction of PAI-1 protein was partially inhibited by an inhibitor of Sp1-DNA binding, mithramycin, implicating, at least in part, Sp1 in the regulation of this gene by TGF-,1. In conclusion, TGF-,1-dependent activation of Smad2/3, leading to PAI-1 synthesis, may be negatively regulated by Src, but not its downstream targets MAPK and PI3K in SKOV-3 cells. These data also reflect the complex biological effect of uPA-PAI-1 system. © 2004 Wiley-Liss, Inc. [source] siRNA mediated inhibition of MMP-1 reduces invasive potential of a human chondrosarcoma cell lineJOURNAL OF CELLULAR PHYSIOLOGY, Issue 3 2005Xiaoling Jiang Matrix metalloproteinases (MMPs) play a crucial role in tumor cell invasion and metastasis. Expression of MMP-1 has been reported as a prognostic predictor of recurrence in human chondrosarcoma, and studies using human chondrosarcoma cell lines indicate that MMP-1 expression levels correlate with in vitro invasiveness. These observations suggest that MMP-1 activity has a central role in cell egress from the primary tumor at an early step in the metastatic cascade. In this study, siRNA was used to investigate whether knock down of the MMP-1 gene could be used to inhibit invasiveness in a human chondrosarcoma cell line. The inhibitory effect of siRNA on endogenous MMP-1 gene expression and protein synthesis was demonstrated via RT-PCR, Northern blotting, Western blotting, collagenase activity assay, and an in vitro cell migration assay. The siRNA inhibited MMP-1 expression specifically, since it did not affect the expression of endogenous glyceraldehyde phosphate dehydrogenase (GAPDH) nor other collagenases. Most importantly, the siRNA mediated reduction in MMP-1 expression correlated with a decreased ability of chondrosarcoma cells to invade a Type I collagen matrix. The reduction of invasive behavior demonstrated by human chondrosarcoma cells transfected with MMP-1 siRNA and the specificity of this inhibition supports the hypothesis that this metalloproteinase molecule is involved in initiation of chondrosarcoma metastasis. © 2004 Wiley-Liss, Inc. [source] Serum autoantibody to sideroflexin 3 as a novel tumor marker for oral squamous cell carcinomaPROTEOMICS - CLINICAL APPLICATIONS, Issue 4 2008Ryuichi Murase Abstract The purpose of this study is to establish a tumor marker that can be applied for the early detection and follow-up of oral cancer patients. Employing the proteomic approach using MALDI TOF-MS, 2-DE, patient's sera and culturing cell lines, the serum autoantibodies (autoAbs) were screened and the serum levels were estimated by ELISA. Targeting the tumor cell invasion into the surrounding stromal tissues, MRC-5 human fibroblasts were employed as the target cells and a mitochondrial membrane protein, sideroflexin 3 (SFXN3), was identified. The serum anti-SFXN3-autoAb levels elevated in patients with the oral squamous cell carcinoma significantly: with 77% sensitivity and 89% specificity against control samples. The serum anti-SFXN3-autoAb levels were mildly correlated with the primary tumor sizes, however, the levels were slightly highly elevated in T1 early cancer. An immunohistochemical analysis revealed that the SFXN3 protein is expressed in the stromal fibroblasts between the caner nests and also in the basal layer of the squamous epithelium. Changes in the serum anti-SFXN3-autoAb levels after therapy correlated with the clinical tumor burden. These findings demonstrated that the serum anti-SFXN3-autoAb is worthy of clinical evaluation as a potentially of the novel tumor maker for the early detection of oral squamous cell carcinoma. [source] Molecular cloning, chromosomal localization and expression pattern of porcine ADP-ribosylation factor(Arf) gene familyANIMAL SCIENCE JOURNAL, Issue 4 2010Rongrong ZHANG ABSTRACT Adenosine diphosphate-ribosylation factors (Arfs) are a family of guanosine triphosphate-binding proteins involved in fundamental biological processes including secretion, endocytosis, phagocytosis, cytokinesis, cell adhesion and tumor cell invasion. We report here the molecular cloning, chromosome localization and expression analysis of porcine Arf1,6, of which Arf1,3 (Class I) have >93% similarity to each other and encode nearly similar proteins with 181 amino acids in length. Arf4 and Arf5 (Class II) are 78,81% homologous to Class I Arfs and both encode a protein of 180 amino acids, Arf6 (Class III) shows 64,68% homology to the other Arfs and encodes 175 amino acids. With radiation hybrid mapping, porcine Arf1,6 are assigned to chromosomes 14q21-q22, 12p14, 5p12-q11, 13q21.1, 18q24, 1q21-q27, respectively. Moreover, real-time quantitative RT-PCR assays show that porcine Arf1-6 are ubiquitous in all tissues examined, with the highest levels in the kidney and stomach and the lowest in muscle and the heart. This is the first report of molecular characterization of the Arf gene family in pigs. [source] Immunohistochemical expression of SPARC is correlated with recurrence, survival and malignant potential in meningiomasAPMIS, Issue 9 2009SUHEYLA UYAR BOZKURT Meningioma is a common neoplasm that constitutes almost 30% of all primary central nervous system tumors and is associated with inconsistent clinical outcomes. The extracellular matrix proteins play a crucial role in meningioma cell biology and are important in tumor cell invasion and in progression to malignancy. SPARC (secreted protein, acidic and rich in cysteine) (osteonectin) is a matricellular glycoprotein that regulates cell function by interacting with different extracellular matrix proteins. The aim of this study was to evaluate the expression of SPARC with proliferation index, p53 reactivity in WHO grade 1 (benign), grade 2 (atypical) and grade 3 (anaplastic) meningiomas and correlate with clinical features of the patients, including location of the tumor, recurrence of the tumor and survival of patients. We studied 111 meningiomas, 69 being benign, 34 being atypical and eight being anaplastic meningiomas of various histological types. Using immunohistochemical analysis, we evaluated the expression of SPARC, Ki-67 (MIB-1) and p53 in meningiomas. Immunohistochemical scores of SPARC were determined as the sum of frequency (0,3) and intensity (0,3) of immunolabeling of the tumor cells. A high immunohistochemical score (4,6) for SPARC was more frequent in atypical and in anaplastic meningiomas than in benign meningiomas (p < 0.01). MIB-1 proliferation index showed significant association between tumor grades in meningiomas (p < 0.01). At the end of a follow-up period of 47.53 ± 25.04 months, 30 tumors recurred. A high SPARC expression was significantly associated with tumor recurrence (p = 0.02). The immunoreactivity of p53 protein and MIB-1 score were significantly higher in recurrent meningiomas than in non-recurrent meningiomas. The cumulative survival of patients with high SPARC expression was significantly lower than patients with low SPARC expression. The high SPARC expression scores were predominantly identified in meningothelial, fibrous and chordoid meningiomas; low SPARC expression scores were mostly spotted in secretory and psammomatous meningiomas. Evaluating SPARC expression might help assessing recurrence risk and survival estimation in meningiomas. [source] Increased lymphatic vascular density is seen before colorectal cancers reach stage II and growth factor FGF-2 is downregulated in tumor tissue compared with normal mucosaAPMIS, Issue 3 2009EIRIK SUNDLISÆTER Lymphangiogenesis is an important event in progression of colorectal cancer (CRC), and the estimated lymphatic vascular density (LVD) probably indicates facilitated lymphatic tumor cell invasion and metastasis. However, at what time point during tumor progression this process is triggered, is unclear. The aim of this study was twofold. Firstly, to examine LVD in paired samples of CRC tissue and normal mucosa with specific emphasis on possible difference in LVD between tumors stages II and III, and secondly, the expression of the lymphangiogenic growth factor fibroblast growth factor-2 (FGF-2). Eighteen patients were studied. Immunostaining for podoplanin was performed to highlight lymphatic vessels. FGF-2 mRNA expression was determined by quantitative real-time RT-PCR, whereas protein expression was quantitatively assessed by densitometric analysis of Western blot signal intensity. The immunoblots were further validated by FGF-2 immunostaining of histological sections. LVD was significantly increased in tumor tissue compared with the normal mucosa but no changes in LVD between stages II and III CRC was observed. FGF-2 was found to be downregulated both at the mRNA and protein level in tumor tissues compared with normal mucosa. Lymphangiogenesis was triggered early in tumor development. An increased LVD was established before the tumor reached stage II. FGF-2 was downregulated in tumor tissue. The importance of this finding remains unclear. [source] Study of tumor cell invasion by Fourier transform infrared microspectroscopyBIOPOLYMERS, Issue 6 2005Ying Yang Abstract Lung cancer is usually fatal once it becomes metastatic. However, in order to develop metastases, a tumor usually invades the basal membrane and enters the vascular or lymphatic system. In this study, a three-dimensional artificial membrane using collagen type I, one of the main components of basal membranes, was established in order to investigate tumor cell invasion. Lung cancer cell line CALU-1 was seeded on this artificial membrane and cell invasion was studied using the Fourier transform infrared (FTIR) imaging technique. This approach allowed identification of tumor cells invading the collagen type I membrane by means of their infrared spectra and images. The mapping images obtained with FTIR microspectroscopy were validated with standard histological section analysis. The FTIR image produced using a single wavenumber at 1080 cm,1, corresponding to PO groups in DNA from cells, correlated well with the histological section, which clearly revealed a cell layer and invading cells within the membrane. Furthermore, the peaks corresponding to amide A, I, and II in the spectra of the invading cells shifted compared to the noninvading cells, which may relate to the changes in conformation and/or heterogeneity in the phenotype of the cells. The data presented in this study demonstrate that FTIR microspectroscopy can be a fast and reliable technique to assess tumor invasion in vitro. © 2005 Wiley Periodicals, Inc. Biopolymers 78: 311,317, 2005 This article was originally published online as an accepted preprint. The "Published Online" date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com [source] Immunohistochemical expression of vascular endothelial growth factor, matrix metalloproteinase 2, and matrix metalloproteinase 9 in cutaneous melanocytic lesionsCANCER, Issue 9 2002M.D., Oriana Simonetti Ph.D. Abstract BACKGROUND Vascular endothelial growth factor (VEGF), an endothelial cell mitogen, plays a hierarchical role in regulating physiologic and pathologic angiogenesis. Moreover, the transformation from noninvasive to invasive carcinomas is accompanied by focal disruption and discontinuity of the basement membrane. Several groups of proteases have been implicated in tumor cell invasion, including the 72-kDa gelatinase A/Type IV collagenase (matrix metalloproteinase 2 [MMP-2]) and the 92-kDa gelatinase B/Type IV collagenase (MMP-9). METHODS The authors assessed the immunohistochemical expression of VEGF and metalloproteinases MMP-2 and MMP-9 in paraffin embedded biopsy specimens of malignant melanomas (18 invasive melanomas and 10 in situ melanomas); dysplastic nevi with architectural disorder and cytologic atypia of melanocytes; Spitz nevi; and compound or predominantly intradermal, ordinary, benign melanocytic nevi. RESULTS Strong cytoplasmic staining for VEGF was observed in melanoma cells in as many as 77% of primary invasive melanomas, whereas only 25% of the in situ melanomas exhibited a detectable immunoreactivity for VEGF. It is interesting to note that no immunoreactivity was shown by any nevi; Spitz nevi, in particular, showed negative immunoreactivity to VEGF. Invasive melanomas and in situ melanomas displayed coexpression of MMP-2 and MMP-9, although to a variable extent. In particular, high MMP-2 staining was observed in 14 of 18 invasive melanomas; moreover, strong MMP-2 expression also was observed in 60% of in situ melanomas, whereas the residual 40% of those melanomas showed a moderate level of positivity. CONCLUSIONS On the basis of the current data showing that malignant melanocytic tumors displayed strong VEGF expression, whereas benign melanocytic proliferations showed no immunoreactivity for VEGF, VEGF also may be used as a discriminating factor to distinguish malignant melanoma from lesions of uncertain histology. Cancer 2002;95:1963,70. © 2002 American Cancer Society. DOI 10.1002/cncr.10888 [source] Matrix metalloproteinase-7 expression and biologic aggressiveness of cholangiocellular carcinomaCANCER, Issue 2 2002Shiro Miwa M.D. Abstract BACKGROUND Matrix metalloproteinase-7 (MMP-7) recently has been reported to play a role in tumor cell invasion. The objective of the current study was to examine the expression of MMP-7 in patients with cholangiocellular carcinoma. METHODS Twenty-six patients underwent resection of cholangiocellular carcinoma, leaving no macroscopic evidence of residual tumor. Immunostaining was performed to evaluate the relation between MMP-7 expression and clinicopathologic features and patient prognosis. The immunostaining pattern of the tumor cells for MMP-7 was classified as negative (,) (n = 9), positive (+) (n = 11), or strongly positive (++) (n = 6). Western blot analysis was performed to investigate the expression of active or latent forms in cancerous and noncancerous lesions in four patients. RESULTS The survival rates in patients with MMP-7 expression judged to be (,), (+), and (++) were 75%, 80%, and 0%, respectively, at 1 year, and 47%, 24%, and 0%, respectively, at 3 years. The survival rate of MMP-7 (++) patients was significantly lower than that of MMP-7 (+) patients (P = 0.003) and MMP (,) patients (P = 0.008). At last follow-up, 3 patients in the MMP-7 (,) group had survived for > 5 years. Western blot analysis demonstrated that there were two types of cholangiocellular carcinoma: those producing both latent and active MMP-7 and those producing only the latent form. CONCLUSIONS Although the results of the current study are based on a small number of patients, they suggest that MMP-7 expression is a significant prognostic factor in patients with cholangiocellular carcinoma and that cholangiocellular carcinoma demonstrating strongly positive expression of MMP-7 on immunostaining may have a higher malignant potential compared with that showing negative or positive expression of MMP-7. Cancer 2002;94:428,34. © 2002 American Cancer Society. [source] Sole Expression of Laminin ,hain in Invading Tumor Cells and Its Association with Stromal Fibrosis in Lung AdenocarcinomasCANCER SCIENCE, Issue 2 2001Yuumi Kagesato Laminin-5 (LN-5), an important basement membrane (BM) protein consisting of laminin ,3, ,3 and ,2 chains, has been suggested to be involved in tumor cell invasion and tissue repair. In this study, the distribution of the LN-5 subunits in atypical adenomatous hyperplasia (AAH)and different types of adenocarcinomas of the lung was examined by immunohistochemical analysis. In AAH and non-sclerosing, well-differentiated adenocarcinomas, the LN ,2 chain was frequently detected along with the continuous BMs. These BMs were also positive for both LN,3 and ,3 chains, suggesting that LN-5 had been deposited. In contrast, the cytoplasmic staining for the LN,2 chain was frequently observed in tumor cells of sclerosing, well-differentiated adenocarcinomas, as well as of moderately and poorly differentiated adenocarcinomas, without any evidence of co-expression of the LN,3 and ,3 chains. This staining pattern of the LN,2 chain was prominent in carcinoma cells invading into interstitial stroma and was associated with the formation of a central scar in the tumor tissues. These results suggest that the LN,2 chain monomer could be an important indicator of progression of lung adenocarcinoma. [source] | |||||||||||||