Home About us Contact
|
Home About us Contact | ||
|
|
||
Metastatic Potential (metastatic + potential)
Kinds of Metastatic Potential Selected AbstractsIsolation of Differentiated Squamous and Undifferentiated Spindle Carcinoma Cell Lines with Differing Metastatic Potential from a 4-Nitroquinoline N-Oxide-induced Tongue Carcinoma in a F344 RatCANCER SCIENCE, Issue 12 2000Shinichi Takeuchi One differentiated squamous cell carcinoma (SCC) cell line (RSC3-E2) and two undifferentiated tumor cell lines (RSC3-LM and RSC3-E2R) with different metastatic potential were established from a 4-nitroquinoline N-oxide (4NQO)-induced differentiated SCC in F344 rat tongue. The RSC3-E2 subline was isolated from a parental cell line (RSC3-P) by single cell cloning in vitro, whereas the RSC3-LM subline was isolated from a lung metastatic focus after subcutaneous (s.c.) injection of RSC3-P cells. The RSC3-E2R cell line was isolated from a lung metastatic focus following s.c. injection of RSC3-E2 cells after X-irradiation in vitro. The RSC3-E2 cell line is keratinpositive and grows as a keratinizing tumor in nude mice, whereas RSC3-LM and RSC3-E2R cells are keratin-negative, vimentin-positive and form undifferentiated tumors. When s.c. injected into nude mice, the RSC3-E2 cell line proved to be non-metastatic, while the RSC3-LM cell line was metastatic by both hematogenous and lymphogenous routes, and the RSC3-E2R cell line was metastatic only hematogenously. In vitro relative growth rates and in vitro invasion activity of these cell lines were in the order RSC3-LM>RSC3-E2R>RSC3-E2. Chromosome analysis revealed two peaks with modal chromosome numbers of 83 and 78 for RSC3-P cells and single peaks at 83, 78 and 56 for RSC3-LM, RSC3-E2 and RSC3-E2R cell lines, respectively. Common structural abnormalities on chromosome 11 were shared by all cell lines. Mutation analysis of the p53 gene using a yeast functional assay demonstrated RSC3-LM cell line to have a point mutation at codon 269, whereas RSC3-E2 and RSC3-E2R had double mutations at codons 106 and 170 on each allele. These results suggest that the two undifferentiated RSC3-LM and RSC3-E2R tumor cell lines with different metastatic potential were generated from differentiated SCC cells via different genetic pathways as a consequence of tumor progression in vivo and in vitro, respectively. These cell lines should provide a useful model for understanding mechanisms of hematogenous and lymphogenous metastasis, as well as tumor progression of oral SCCs. [source] Overexpression of profilin reduces the migration of invasive breast cancer cellsCYTOSKELETON, Issue 2 2004Partha Roy Abstract The exact role profilin plays in cell migration is not clear. In this study, we have evaluated the effect of overexpression of profilin on the migration of breast cancer cells. Overexpression was carried out by stably expressing GFP-profilin in BT474 cells. It was observed that even a moderate level of overexpression of profilin significantly impaired the ability of BT474 cells to spread on fibronectin-coated substrate and migrate in response to EGF. GFP-profilin expressing cells also showed increased resistance to detachment in response to trypsin and increased tyrosine phosphorylation of focal adhesion kinase (FAK) and paxillin compared to the parental and GFP-expressing (control) cell lines. These results suggest that perturbation of profilin levels may offer a good strategy for controlling the metastatic potential of breast cancer cells. Cell Motil. Cytoskeleton 57:84,95, 2004. © 2004 Wiley-Liss, Inc. [source] Decreased expression of thymidine phosphorylase/platelet-derived endothelial cell growth factor in basal cell carcinomasEXPERIMENTAL DERMATOLOGY, Issue 11 2008Pierre E. Stoebner Abstract:, Thymidine phosphorylase (TP)/platelet-derived endothelial cell growth factor is associated with tumor angiogenesis. We evaluated the TP mRNA and protein expression in basal cell carcinomas (BCC) and in various skin tumors including numerous BCC histological simulants. Immunohistochemistry was performed on 99 paraffin sections of formalin-fixed skin tumors using monoclonal antibodies (mAb) against TP. TP mRNA levels were measured by real time RT-PCR in whole BCCs (wBCC) and laser capture microdissected (LCM) BCC tumor cells. TP immunostaining was negative in all BCC variants and in most of the benign trichogeneic tumors studied. By contrast, TP was constantly immunodetected in actinic keratosis (AK), squamous cell carcinomas (SCC), syringomatous carcinomas (SC), basosquamous carcinomas (BSC) and melanomas. TP mRNA levels were low and statistically not different in wBCC and normal skin but were strongly downregulated in LCM-BCC as compared with LCM-normal epidermis. We concluded that (i) anti-TP mAb is an useful marker to differentiate BCC from AK, SCC, BSC and SC but not from trichoblastic tumors, (ii) the lack of TP protein expression in BCC tumoral cells is linked to transcriptional regulatory mechanisms, (iii) the low TP mRNA levels in whole BCC may be related to the low intra-tumoral microvessel density, the slow growth and the very low metastatic potential of these tumors. [source] Insulin/protein kinase B signalling pathway upregulates metastasis-related phenotypes and molecules in H7721 human hepatocarcinoma cell lineFEBS JOURNAL, Issue 18 2003Hui-Ling Qi The effect of insulin on cancer metastatic potential was studied in a human hepatocarcinoma cell line, H7721. Cell adhesion to human umbilical vein endothelial cells (HUVECs) and laminin as well as chemotactic cell migration and invasion were selected as the indices of metastasis-related phenotypes for assessment of metastatic potential ex vivo. The results indicated that insulin enhanced all of these metastasis-related phenotypes. After the cells were treated with specific inhibitor of PI3K (LY294002) or transfected with antisense cDNA of PKB (AS-PKB), all of the above phenotypes were attenuated, and they could not be significantly stimulated by insulin, indicating that the insulin effect on metastatic potential was mediated by PI3K and PKB. Only the monoclonal antibody to the sialyl Lewis X (SLex), but not antibodies to other Lewis antigens, significantly blocked the cell adhesion to HUVECs, cell migration and invasion, suggesting that SLex played a crucial role in the metastatic potential of H7721 cells. The upregulation of cell surface SLex and ,-1,3-fucosyltransferase-VII (,-1,3 Fuc T-VII, enzyme for SLex synthesis) was also mediated by PI3K and PKB, since LY294002 and AS-PKB also reduced the expressions of SLex and ,-1,3 FucT-VII, and attenuated the response to insulin. Furthermore, the alterations in the expressions of PKB protein and activity were correlated to the changes of metastatic phenotypes and SLex expression. Taken together, the insulin/PKB signalling pathway participated in the enhancement of metastatic potential of H7721 cells, which was mediated by the upregulation of the expression of SLex and ,-1,3 FucT-VII. [source] Transfection of the c- erbB2/neu gene upregulates the expression of sialyl Lewis X, ,1,3-fucosyltransferase VII, and metastatic potential in a human hepatocarcinoma cell lineFEBS JOURNAL, Issue 12 2001Fei Liu The pCMV4 plasmid containing the cancer-promoting gene, c- erbB2/neu, was cotransfected into the human hepatocarcinoma cell line 7721 with the pcDNA3 vector, which contains the ,neo' selectable marker. Several clones showing stable expression of c- erbB2/neu were established and characterized by determination of c- erbB2/neu mRNA and its encoded protein p185. Expression of Lewis antigens and ,1,3-fucosyltransferases and the biological behavior of 7721 cells after c- erbB2/neu transfection were studied using mock cells transfected with the vectors pCMV4 and pcDNA3 as controls. SLex expression on the surface of mock cells was high, whereas expression of SDLex, Lex and SLea was absent or negligible. This is compatible with the abundant expression of ,1,3-fucosyltransferase VII, very low expression of ,fucosyltransferase III/VI, and almost absent expression of ,1,3-fucosyltransferase IV in the mock cells. After transfection of c- erbB2/neu, expression of SLex and ,1,3-fucosyltransferase VII were simultaneously elevated, but that of ,fucosyltransferase III/VI was not altered. The expression of both SLex and ,1,3-fucosyltransferase VII correlated positively with the expression of c- erbB2/neu in different clones, being highest in clone 13, medium in clone 6, and lowest in clone 7. In addition, the adhesion of 7721 cells to human umbilical vein endothelial cells (HUVECs) or P-selectin, as well as cell migration and invasion, were increased in c- erbB2/neu -transfected cells. These increases also correlated positively with the expression intensities of c- erbB2/neu, SLex and ,1,3-fucosyltransferase VII in the different clones, whereas cell adhesion to fibronectin correlated negatively with these variables. mAbs to SLex (KM93) and SDLex (FH6) significantly and slightly, respectively, abolished cell adhesion to HUVECs or P-selectin and cell migration and invasion. mAbs to SDLex and SLea did not suppress cell adhesion to HUVECs nor inhibit cell migration and invasion. Transfection of ,1,3-fucosyltransferase VII cDNA into 7721 cells showed similar results to transfection of c- erbB2/neu, and the increased adhesion to HUVECs, cell migration, and invasion were also inhibited significantly by KM93 and slightly by FH6. These results indicate that expression of ,1,3-fucosyltransferase VII and its specific product, SLex, and their capacity for cell adhesion, migration and invasion are closely related. Therefore, the c- erbB2/neu gene is proposed to be a metastasis-promoting gene, and its effects are at least partially mediated by the increased expression of ,1,3-fucosyltransferase VII and SLex. [source] Upregulation of discoidin domain receptor 2 in nasopharyngeal carcinoma,HEAD & NECK: JOURNAL FOR THE SCIENCES & SPECIALTIES OF THE HEAD AND NECK, Issue 4 2008Huey-Huey Chua PhD Abstract Background. Nasopharyngeal carcinoma (NPC) is associated with Epstein-Barr virus (EBV) and has high metastatic potential. Discoidin domain receptors (DDR1, DDR2) are receptor-type tyrosine kinases activated by collagen. Their ability to induce expression of matrix metalloproteinase is related with tumor invasion. Therefore, we aim to investigate DDRs gene expression and its regulation in NPC. Methods and Results. By use of real-time quantitative polymerase chain reaction (Q-PCR), DDR2 gene expression but not DDR1 was significantly higher in primary and metastatic NPC. DDR2 was predominantly distributed in NPC tumor cells rather than in infiltrating lymphocytes. EBV Z-transactivator (Zta) transfection may distinctly elevate DDR2 level. Furthermore, data from reporter assay indicate that Zta could transactivate DDR2 promoter activity, suggesting the possible upregulation mechanism. Conclusion. DDR2 was differentially upregulated in NPC and modulated by EBV Zta protein. DDR2 may play a role in NPC invasion and serve as a diagnostic and therapeutic target. © 2007 Wiley Periodicals, Inc. Head Neck, 2008 [source] E-cadherin abnormalities resulting from CPG methylation promoter in metastatic and nonmetastatic oral cancerHEAD & NECK: JOURNAL FOR THE SCIENCES & SPECIALTIES OF THE HEAD AND NECK, Issue 1 2008Renato Vieira de Moraes MSc Abstract Background. This study aims to compare the alterations in the methylation profiles of E-cadherin in oral cancer, especially in tumors with lowest metatastic potential. Methods. Nine oral verrucous carcinomas (VCs), 20 oral well-differentiated squamous cell carcinomas without lymph node involvement (SCC-pN0), and 17 with lymph node involvement (SCC-pN+) were analyzed using methylation-specific polymerase chain reaction and immunohistochemical expression of E-cadherin gene. Results. The immunohistochemical expression of E-cadherin in VC was significantly higher (p = .016) when compared with SCC-pN0 and SCC-pN+ groups. The E-cadherin gene methylation was not correlated with its abnormal immunohistochemical expression in VC and SCC-pN0. All tumors of the SCC-pN+ group with unmethylated E-cadherin gene showed significant loss of E-cadherin immunoexpression (p = .044). Conclusions. The E-cadherin gene methylation presence in tumors with lowest invasive and metastatic potential, such as VC, suggests the early involvement of this epigenetic event in the multistep progression of the oral carcinogenesis. © 2007 Wiley Periodicals, Inc. Head Neck, 2008 [source] Hyaluronan and its receptors in mucoepidermoid carcinomaHEAD & NECK: JOURNAL FOR THE SCIENCES & SPECIALTIES OF THE HEAD AND NECK, Issue 2 2006Richard O. Wein MD Abstract Background. Hyaluronan (HA) is a prominent extracellular matrix component undergoing continuous production and degradation. Increased HA levels have been described in a variety of tumors. The objective of this study was to examine the staining patterns of HA and two of its associated receptors (CD44 and HARE) in relation to the metastatic potential of mucoepidermoid carcinoma (MC). Immunohistochemical staining of preserved surgical specimens was used. Methods. Tissues from 12 patients with a histologic diagnosis of salivary MC (10 parotid, one submandibular gland, one minor salivary gland) were studied. Half (six of 12) of the patients had regional metastases. Tumor, normal salivary tissue, and regional lymph nodes were stained for HA, CD44, and HARE expression. Specimens were graded for staining intensity and a percent of the specimen stained. Results. Normal salivary tissue did not demonstrate epithelial cell surface HA expression, whereas HA was expressed on tumor cells and in regional lymph nodes containing metastases. These differences were both significant using Student's t test (p < .00002, and p < .0022, respectively). Tumors with positive nodes tended to have greater cell surface HA. Decreased expression or downregulation of HARE was also noted in involved lymph nodes. No differences in CD44 expression were seen between primary specimens and lymph nodes. The observed staining patterns for CD44 and HARE were not reflective of the metastatic potential of the primary MC. Conclusions. Increased HA expression was seen on mucoepidermoid carcinoma cells compared with adjacent normal salivary gland epithelium. This observation may assist in explaining the development of regional metastasis in these tumors. We did not identify specific HA, CD44, or HARE staining patterns in primary lesions that were predictive of regional metastases. © 2005 Wiley Periodicals, Inc. Head Neck27: XXX,XXX, 2005 [source] Melittin prevents liver cancer cell metastasis through inhibition of the Rac1-dependent pathway,HEPATOLOGY, Issue 6 2008Shujing Liu Melittin, a water-soluble toxic peptide derived from bee venom of Apis mellifera was reported to have inhibitory effects on hepatocellular carcinoma (HCC). However, its role in antimetastasis and the underlying mechanism remains elusive. By utilizing both HCC cell lines and an animal model based assay system, we found that Rac1, which has been shown to be involved in cancer cell metastasis, is highly expressed in aggressive HCC cell lines and its activity correlated with cell motility and cytoskeleton polymerization. In addition, Rac1-dependent activity and metastatic potential of aggressive HCC cells are remarkably high in both cellular and nude mouse models. We provide evidence here that melittin inhibits the viability and motility of HCC cells in vitro, which correlates with its suppression of Rac1-dependent activity, cell motility, and microfilament depolymerization. Furthermore, melittin suppresses both HCC metastasis and Rac1-dependent activity in nude mouse models. The specificity of the effect of melittin on Rac1 was confirmed in HCC cells both in vitro and in vivo. Conclusion: Melittin inhibits tumor cell metastasis by reducing cell motility and migration via the suppression of Rac1-dependent pathway, suggesting that melittin is a potential therapeutic agent for HCC. (HEPATOLOGY 2008;47:1964,1973.) [source] Tumor metastasis and the lymphatic vasculatureINTERNATIONAL JOURNAL OF CANCER, Issue 12 2009Jonathan P. Sleeman Abstract Tumor-associated lymphatic vessels act as a conduit by which disseminating tumor cells access regional lymph nodes and form metastases there. Lymph node metastasis is of major prognostic significance for many types of cancer, although lymph node metastases are themselves rarely life-threatening. These observations focus our attention on understanding how tumor cells interact with the lymphatic vasculature, and why this interaction is so significant for prognosis. Tumors interact with the lymphatic vasculature in a number of ways, including vessel co-option, chemotactic migration and invasion into lymphatic vessels and induction of lymphangiogenesis. Tumor-induced lymphangiogenesis both locally and in regional lymph nodes has been correlatively and functionally associated with metastasis formation and poor prognosis. The investigation of the molecular regulation of lymphangiogenesis has identified ways of interfering with prolymphangiogenic signaling. Blockade of tumor-induced lymphangiogenesis in preclinical models inhibits metastasis formation in lymph nodes and often also in other organs, suggesting that blocking the lymphatic route of dissemination might suppress metastasis formation not only in lymph nodes but also in other organs. However, randomized clinical trials that have investigated the efficacy of therapeutic removal of lymph nodes have concluded that lymph node metastases act only as indicators that primary tumors have developed metastatic potential, and do not govern the further spread of metastatic cells. To reconcile these apparently paradoxical observations we suggest a model in which tumor-induced lymphangiogenesis and lymph node metastasis formation act as indicators that tumors are producing factors that can act systemically to promote metastasis formation in distant organs. © 2009 UICC [source] TIP30 is associated with progression and metastasis of prostate cancerINTERNATIONAL JOURNAL OF CANCER, Issue 4 2008Hui Zhang Abstract Tat-interacting protein 30 (TIP30), a transcriptional repressor for ER,-mediated transcription, possesses several characteristics of a tumor suppressor in certain human and mouse cells. It is reported that deletion of TIP30 gene preferentially increases tumorigenesis in the female knockout mice. Here, we analyzed TIP30 gene expression in the databases of several DNA microarray studies of human prostate cancer and show that TIP30 is specifically overexpressed in metastatic prostate cancers. We demonstrate that TIP30 nuclear expression is associated with prostate cancer progression and metastasis by immunohistochemical analysis in primary and metastatic prostate cancers. Consistent with these data, we also show that knockdown of TIP30 expression, through use of a short hairpin RNA-expressing plasmid, suppresses the cellular growth of PC3 and LNCaP prostate cancer cells. Ectopic overexpression of TIP30 stimulates metastatic potential of prostate cancer cells in an in vitro invasion assay, whereas knockdown of TIP30 inhibits the prostate cancer cells invasion. Finally, we demonstrate that ectopic overexpression of TIP30 enhances androgen receptor mediated transcription, whereas knockdown of TIP30 results in a decreased transcription activity. These data provide evidence that TIP30 plays a role in prostate cancer progression and that TIP30 overexpression may promote prostate cancer cell growth and metastasis. © 2008 Wiley-Liss, Inc. [source] IFN-, withdrawal after immunotherapy potentiates B16 melanoma invasion and metastasis by intensifying tumor integrin ,v,3 signalingINTERNATIONAL JOURNAL OF CANCER, Issue 3 2008Wei Gong Abstract Immunotherapy can effectively suppress tumor, yet complete tumor eradication occurs infrequently. The metastatic potential of remnant tumor cells after immunotherapy and the underlying mechanisms have not been fully elucidated. Here, we report that the termination of immunotherapy strikingly increases the metastatic potential of remnant melanoma. This is mainly due to the withdrawal of IFN-, after immunotherapy. The relief of IFN-, stress led to the increase of ,v,3 integrin expression in B16 cells, which increased the adhesion of B16 cells to fibrinogen, fibronectin and laminin. Through ,v,3 signaling, the activation of FAK, upregulation of cdc2, production of active MMP-2 and MMP-9 and actin polymerization were intensified in B16 cells stimulated with ECM molecules 24 h after the withdrawal of IFN-,. The i.v. injection of such tumor cells into mice resulted in more metastatic tumor nodes in lung and shortened the survival of mice. The pitfall of immunotherapy termination can be remedied by the administration of recombinant CBD-HepII polypeptide of fibronectin, which effectively inhibits ,v,3 signaling. These findings suggest that the risk of tumor metastasis can be increased after the termination of immunotherapy, due to the withdrawal of IFN-, and that targeting ,v,3 signaling pathway can improve the therapeutic effect of immunotherapeutic approaches by reducing such metastatic risk. © 2008 Wiley-Liss, Inc. [source] Comparison of two in vivo models for prostate cancer: Orthotopic and intratesticular inoculation of LNCaP or PC-3 cellsINTERNATIONAL JOURNAL OF UROLOGY, Issue 12 2004KIYOSHI KOSHIDA Abstract, Background:, The critical events in the clinical course of prostate cancer are the occurrence of metastasis and the induction of the hormone-refractory status of the disease. In order to investigate the factors responsible for these events, we need appropriate in vivo models. Materials and methods:, Orthotopic and intratesticular models were created by the injection of LNCaP cells or PC-3 cells into the prostate or testis of severe combined immunodeficient mice. Results:, LNCaP cells in the intratesticular model showed a higher incidence of tumor formation and lymph node metastasis when compared with those in the orthotopic model, while PC-3 cells were highly tumorigenic and metastastic in both models. A high concentration of androgens might play a role in tumor aggressiveness of LNCaP cells, given that enhanced mRNA expressions of integrin ,V and vascular endothelial growth factor was induced by dehydrotestosterone administration in vitro. The high expression of metastasis-related genes, including the urokinase plasminogen activator system, metalloproteinases and vascular endothelial growth factor-C, might be attributed to the high metastatic potential in both models. Interestingly, testicular xenografts of LNCaP cells were able to survive on the subcutis back of castrated male mice as well female mice. Conclusions:, Intratesticular models of prostate cancer appear to be suitable for studying the mechanisms of metastasis and for evaluating various treatment strategies. [source] siRNA-targeted COL8A1 inhibits proliferation, reduces invasion and enhances sensitivity to D -limonence treatment in hepatocarcinoma cellsIUBMB LIFE, Issue 1 2009Yongfu Zhao Abstract The COL8A1 (collagen type VIII, alpha-1) gene, which encodes the alpha 1 chain of collagen, type VIII, may modulate migration, proliferation and adherence of various cells. Only very sparse information exists on COL8A1 expression in hepatocarcinoma. To investigate the possible role of COL8A1 in the mouse hepatocarcinoma cell line Hca-F with highly metastatic potential in the lymph nodes, we used an RNA interference (RNAi) approach to silence COL8A1 expression. The results showed that a small interfering RNA (siRNA) targeted against COL8A1 significantly impeded Hca-F cells proliferation and colony formation in soft agar. This reduction of COL8A1 expression also led to the decreased invasion of Hca-F cells dramatically in vitro. Furthermore, the downregulation of COL8A1 expression also sensitized cells to the action of D -limonene. These data together provide insights into the function of COL8A1 and suggest that COL8A1 might represent a new potential target for gene therapy in hepatocarcinoma. © 2008 IUBMB IUBMB Life, 61(1): 74,79, 2009 [source] Sorafenib and rapamycin induce growth suppression in mouse models of hepatocellular carcinomaJOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 8b 2009Hung Huynh Abstract Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide. Vascular endothelial growth factor, platelet derived growth factor and the Raf/mitogen-activated protein kinase/extracellular signal regulated kinase (Raf/MEK/ERK) signalling pathway regulates the growth, neovascularization, invasiveness and metastatic potential of HCC. In this study, we investigated the in vivo antitumour activity and mechanisms of action of sorafenib tosylate on four patient-derived HCC xenografts. Sorafenib dosed at 50 mg/kg and 100 mg/kg inhibited tumour growth by 85% and 96%, respectively. Sorafenib-induced growth suppression and apoptosis were associated with inhibition of angiogenesis, down-regulation of phospho-platelet-derived growth factor receptor , Tyr1021, phospho-eIF4E Ser209, phospho-c-Raf Ser259, c-Raf, Mcl-1, Bcl-2, Bcl-x and positive cell cycle regulators, up-regulation of apoptosis signalling kinase-1, p27 and p21. Expression of IGF-1R, and phosphorylation of c-Raf Ser338, MEK1/2 Ser217/221 and ERK1/2 Thr202/Tyr204 were increased by sorafenib treatment. Phosphorylation of mammalian target-of-rapamycin (mTOR) targets (p70S6K, S6R and 4EBP1) was reduced by sorafenib in sorafenib-sensitive lines but activated in sorafenib-less-sensitive 10,0505 xenograft. Sorafenib-induced phosphorylation of c-met, p70S6K and 4EBP1 was significantly reduced when 10,0505 cells were co-treated with anti-human anti-HGF antibody, suggesting that treatment with sorafenib leads to increased HGF secretion and activation of c-met and mTOR targets. Treatment of 10,0505 tumours with sorafenib plus rapamycin resulted in growth inhibition, inhibition of vascular endothelial growth factor receptor-2 phosphorylation, increased apoptosis and completely blocked sorafenib-induced phosphorylation of mTOR targets and cyclin B1 expression. These data also provide a strong rationale for clinical investigation of sorafenib in combination with mTOR inhibitors in patients with HCC. [source] Regulation of gene expression in melanoma: New approaches for treatmentJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 1 2005Michael C. Leslie Abstract The molecular changes associated with the transition of melanoma cells from radial growth phase (RGP) to vertical growth phase (VGP, metastatic phenotype) are not yet well defined. We have demonstrated that the progression of human melanoma is associated with loss of expression of the transcription factor AP-2. In metastatic melanoma cells, this loss resulted in overexpression of MCAM/MUC18, MMP-2, the thrombin receptor (PAR-1), and lack of c-KIT expression. The transition from RGP to VGP is also associated with overexpression of the angiogenic factor IL-8. Additionally, the transition of melanoma cells from RGP to VGP is associated with overexpression of the transcription factors CREB and ATF-1, both of which may act as survival factors for human melanoma cells. Inactivation of CREB/ATF-1 activities in metastatic melanoma cells by dominant-negative CREB or by anti-ATF-1 single chain antibody fragment (ScFv), resulted in deregulation of MMP-2 and MCAM/MUC18, increased the sensitivity of melanoma cells to apoptosis, and inhibition of their tumorigenicity and metastatic potential in vivo. In this prospect article, we summarize our data on the role of AP-2 and CREB/ATF-1 in the progression of human melanoma and report on the development of new fully human antibodies anti-MCAM/MUC18 and anti-IL-8 which could serve as new modalities for the treatment of melanoma. © 2004 Wiley-Liss, Inc. [source] Symplastic glomus tumor , a rare but distinct benign histological variant with analogy to other ,ancient' benign skin neoplasmsJOURNAL OF CUTANEOUS PATHOLOGY, Issue 10 2009Jivko Kamarashev A 78-year-old woman presented with a nail deformity of the index finger of the left hand associated with paroxysmal pain upon cold exposure. Histologically, a well-circumscribed tumor of 3 mm diameter was found in the dermis. The neoplastic cells in some areas were of pronouncedly variable size and cytomorphology, mostly epithelioid in shape, with eosinophilic cytoplasm and indistinctly defined cell borders. Pronounced nuclear pleomorphism and atypia were striking features, but no mitotic figures were noted. Multinuclear cells were present as were numerous small-to-medium vessels throughout the tumor. The tumor stroma showed myxoid areas. Immunohistochemistry showed cytoplasmic and membranous expression of smooth muscle actin and vimentin. The histological features and immunoprofile were consistent with the diagnosis of symplastic glomus tumor, a rare histological variant, which has been defined as a glomus tumor exhibiting marked nuclear atypia, in the absence of any other criteria for malignancy. The biological behavior of the tumor is benign. It is essential to differentiate this entity from malignant glomus tumor, which has metastatic potential. Even prominent cellular atypia and nuclear pleomorphism in a glomus tumor as in our case is not a marker of malignancy in the absence of additional criteria. [source] Chemokine receptor expression in non-melanoma skin cancerJOURNAL OF CUTANEOUS PATHOLOGY, Issue 7 2008Jeff Basile Background:, Previous studies suggest that chemokines and chemokine receptors have a role in the metastatic process. A correlation exists between the specific expression of these chemoattractive, pro-inflammatory cytokines and the ability of cancer to disseminate. Prior studies have shown that in metastatic melanoma and squamous cell carcinoma of the head and neck upregulation of CXC (,) chemokine receptor (CXCR)4 and CC (,) chemokine receptor (CCR)7 expression is accompanied by downregulation of the chemokine receptor CCR6. However, the expression patterns of CCR6, CCR7 and CXCR4 in non-melanoma skin cancer have yet to be elucidated. Methods:, The expression patterns of CCR6, CCR7 and CXCR4 were determined using an immunohistochemical approach on formalin-fixed, paraffin-embedded normal, pre-cancerous actinic (solar) keratosis, squamous cell carcinoma and basal cell carcinoma tissues. Results:, Analysis of chemokine receptor expression showed downregulation of CCR6 and upregulation of CCR7 and CXCR4 in potentially metastatic non-melanoma skin cancer, invasive squamous cell carcinoma, but this pattern did not exist in non-melanoma skin cancer with no metastatic potential, basal cell carcinoma; or actinic keratosis, when compared with normal skin. Conclusions:, Chemokine receptor expression may influence the biological behavior of non-melanoma skin cancer. The exact mechanism by which this occurs requires further study. [source] Cutaneous squamous cell carcinoma: a comprehensive clinicopathologic classificationJOURNAL OF CUTANEOUS PATHOLOGY, Issue 4 2006Part Two Cutaneous squamous cell carcinoma (SCC) includes many subtypes with widely varying clinical behaviors, ranging from indolent to aggressive tumors with significant metastatic potential. However, the tendency for pathologists and clinicians alike is to refer to all squamoid neoplasms as generic SCC. No definitive, comprehensive clinicopathological system dividing cutaneous SCCs into categories based upon their aggressiveness has yet been promulgated. Therefore, we have proposed the following based upon the malignant potential of SCC variants, separating them into categories of low (,2% metastatic rate), intermediate (3,10%), high (greater than 10%), and indeterminate behavior. Low-risk SCCs include SCC arising in actinic keratosis, HPV-associated SCC, tricholemmal carcinoma, and spindle cell SCC (unassociated with radiation). Intermediate-risk SCCs include adenoid (acantholytic) SCC, intraepidermal epithelioma with invasion, and lymphoepithelioma-like carcinoma of the skin. High-risk subtypes include de novo SCC, SCC arising in association with predisposing factors (radiation, burn scars, and immunosuppression), invasive Bowen's disease, adenosquamous carcinoma, and malignant proliferating pilar tumors. The indeterminate category includes signet ring cell SCC, follicular SCC, papillary SCC, SCC arising in adnexal cysts, squamoid eccrine ductal carcinoma, and clear-cell SCC. Subclassification of SCC into these risk-based categories, along with enumeration of other factors including tumor size, differentiation, depth of invasion, and perineural invasion will provide prognostically relevant information and facilitate the most optimal treatment for patients. [source] Pleiotrophin expression correlates with melanocytic tumor progression and metastatic potentialJOURNAL OF CUTANEOUS PATHOLOGY, Issue 2 2005H. Wu Background:, Gene expression profiling of melanoma and nevic tissue has demonstrated that pleiotrophin (PTN) is significantly overexpressed in human melanomas. Methods:, To further evaluate PTN expression in melanocytic lesions, protein immunohistochemistry was performed on the spectrum of melanocytic lesions. Results:, Melanocytic nevi were consistently negative (n = 58). In contrast, the great majority of metastatic melanomas were positive (33/34, 97%). The analysis of 34 primary melanomas demonstrated PTN positivity in 20 lesions while 14 lesions were negative. Within the primary melanomas, PTN immunoreactivity was associated with metastasis (p = 0.0004) and decreased melanoma-related survival (p = 0.0444). Univariate analysis of PTN immunoreactivity predicted an increased risk for metastasis (relative risk 9.1, p = 0.003). Conclusions:, The results of this study confirm previous gene profiling data showing differential PTN expression between melanocytic nevi and melanomas. In addition, lesional PTN expression is associated with metastatic potential and may be a prognostic factor for melanomas. [source] Screening of gastric cancer cell sublines using the adhesion methodJOURNAL OF DIGESTIVE DISEASES, Issue 3 2001Xiangrong Chen OBJECTIVE: To screen subpopulations of gastric cancer cell lines with different malignant phenotypes. METHODS: Two subpopulations from the human gastric cancer cell line MKN-45 were separated by using the laminin adhesion method. One subpopulation was less invasive and non-metastatic, whereas the other was more invasive and metastatic. The relative invasiveness and migratory capacities of the two subgroups were observed by using the Boyden chamber and by inoculating the cells into nude mice. RESULTS: The two subgroups, the laminin-adherent cells (Lm+) and the laminin non-adherent cells (Lm,), were separated. During in vitro experiments, the Lm+ cells were more invasive and their migratory ability was greater relative to the Lm, cells. The rates of tumor formation after subcutaneous inoculation in nude mice and of lung tumor foci formation after tail vein inoculation were higher in Lm+ cells than those in Lm, cells. In vivo, Lm+ cells were found to have higher metastatic potential and to be more invasive. CONCLUSIONS: In vitro, the adhesion method is a simple and time-saving way to screen a particular phenotypic cell subpopulation with a high success rate. There are discrepancies in invasiveness and migratory ability between in vitro Lm+ and Lm, cells, which suggests that these properties of gastric cancer cells are closely related to their adhesiveness to the basement membrane and extracellular matrix. [source] Mortality association of enhanced CD44v6 expression is not mediated through occult lymphatic spread in stage II colorectal cancerJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 9 2000Gerard Clarke Abstract Background and Aims: In the absence of other metastatic disease, the presence of lymph node metastasis remains the most important determinant of survival in colorectal cancer (CRC). Cluster designation 44 variant 6 (CD44v6) over-expression is associated with worse outcome in all stages of CRC. The CD44v6 is believed to confer metastatic potential through its facilitation of migration, extravasation and proliferation, although the specific means by which it conveys an adverse prognosis in CRC is unknown. The aim of the present study was to determine if CD44v6 over-expression in Stage II CRC subjects was associated with the presence of lymph node micrometastases. Methods: We assessed tumour CD44v6 expression in 43 randomly sampled subjects who had resections for Stage II CRC between 1984 and 1991 by using immunohistochemistry. Micrometastases were sought in corresponding lymph node (LN) sections using keratin immunohistochemistry. Results: There was a statistical trend between tumour CD44v6 over-expression and mortality (P = 0.09) and a significant relationship between LN cytokeratins and mortality (P = 0.01). There was no association between the detection of LN cytokeratins and tumour CD44v6 over-expression. Conclusion: We conclude that the adverse survival effect of CD44v6 over-expression is not mediated though lymphatic spread and postulate that it may therefore facilitate haematogenous metastasis. [source] RECK expression in osteosarcoma: correlation with matrix metalloproteinases activation and tumor invasivenessJOURNAL OF ORTHOPAEDIC RESEARCH, Issue 5 2007Hyun-Guy Kang Abstract Osteosarcoma is a malignant tumor of bone characterized by its high metastatic potential. For the development of metastasis, activation of matrix metalloproteinases (MMPs) is required. A novel MMPs inhibitor, reversion inducing cysteine rich protein with Kazal motifs (RECK), is known to down-regulate MMPs and suppress the invasive and metastatic potential in many tumor-derived cell lines and some types of tumors. The expression of RECK and its role in tumor invasiveness have never been studied in osteosarcoma. We examined RECK mRNA expression and MMPs activation in osteosarcoma using quantitative real time PCR, gelatin zymography, invasion assay, and transfection experiments. RECK was expressed but down-regulated in osteosarcoma cells. Activation of pro-MMP-2 was observed in all samples, whereas activation of MMP-2 and pro-MMP-9 was detected in only 11% and 7% of the samples, respectively. MMP-9 was not activated in any of the samples. The level of RECK expression was inversely correlated with pro-MMP-2 activation, and overexpression of RECK by transfection resulted in decreased pro-MMP-2 activation and reduced tumor invasiveness. These findings suggest that RECK plays an important role in the invasiveness of osteosarcoma. © 2007 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 25:696,702, 2007 [source] Elevated activities of MMP-2 in the non-tumorous lung tissues of curatively resected stage I NSCLC patients are associated with tumor recurrence and a poor survival,JOURNAL OF SURGICAL ONCOLOGY, Issue 4 2007Sang-Hui Kim Abstract Background and Objectives We wanted to assess whether the level of enzyme activity for a particular matrix metalloproteinase (MMP), and not the amount of expressed protein, in lung tissue could be used as a reliable prognostic biomarker for tumor recurrence leading to poorer survival in a certain subgroup of patients who have undergone curative resection for stage I human NSCLC. Methods We determined what type of MMP was significant for tumor recurrence by using a mouse model of pulmonary metastasis with inoculating the footpad with H460 human cancer cells. We then looked for any association between tumor recurrence and the level of enzyme activities for the selected MMP in the tumor and also in the pathologically non-tumorous tissues from 34 stage I lung cancer patients. Results We obtained H460/PM6 cells having a highly metastatic potential after six repeated cycles of pulmonary metastasis by using the mouse footpad inoculated with the metastasized cancer cells in the previous cycle. We started with human lung cancer cells, H460, and we found that among the tested MMPs we tested for, the level of MMP-2 mRNA was elevated. No significant difference was seen in the level of enzyme activity of the MMP-2 cells from the curatively resected tumor tissues of the stage I NSCLC patients who were later found with or without recurrence. However, the level of MMP-2 enzyme activity was found to be significantly different between the non-tumorous lung tissues from patients later found with and without recurrence, and it was associated with the 5-year survival rate. Conclusions This observation suggests that the higher level of MMP-2 enzyme activity in the non-tumorous tissues from the patients could be used as a prognostic biomarker to predict post-operative tumor recurrence and survival for patients with stage I NSCLC. The elevated enzyme activity of MMP-2 in the non-tumorous tissue resected from stage I NSCLC could be used as a prognostic indicator for post-operative tumor recurrence and the patients' poor survival. Further, this could be an important aid for physicians' making decision on whether to subject particular patients to post-operative adjunct chemotherapy. J. Surg. Oncol. 2007;95:337,346. © 2007 Wiley-Liss, Inc. [source] Phase I study on sentinel lymph node mapping in colon cancer: A preliminary report,JOURNAL OF SURGICAL ONCOLOGY, Issue 2 2002Yves Bendavid Abstract Background and Objectives Lymph node (LN) metastasis is one of the most significant prognostic factor in colorectal cancer. In fact, therapeutic decisions are based on LN status. However, multiple studies have reported on the limitations of the conventional pathological LN examination techniques, and therefore, the actual number of patients with LN positive colorectal cancer is probably underestimated. We assume that lymphatic tumor dissemination follows an orderly sequential route. We report here a simple and harmless coloration technique that was recently elaborated, and that allows us to identify the sentinel LN(s) (SLN) or first relay LNs in colorectal cancer patients. The main endpoint of this clinical trial is the feasibility of the technique. Methods Twenty patients treated by surgery for a colic cancer were admitted in this protocol. A subserosal peritumoral injection of lymphazurin 1% was performed 10 min before completing the colic resection. A pathologist immediately examined the specimens, harvested the colored SLN, and examined them by serial cuts (200 ,m) with H&E staining, followed by immunohistochemical staining (AE1-AE3 cytokeratin markers), when serial sections were classified as cancer free. Results The preoperative identification of the SLN was impossible in at least 50 of the cases, however, SLNs were identified by the pathologist in 90% of cases. In two patients (10%) SLN was never identified. The average number of SLN was 3.9. Immunohistochemical analysis of the SLN has potentially changed the initial staging (from Dukes B to Dukes C) for 5 of the 20 patients (25%). On the other hand, there was one patient (5%) with hepatic metastasis from adenocarcinoma for whom SLN pathology was negative for metastasis (skip metastasis). Conclusions SLN biopsy is readily feasible with identification of SLN in at least 90% of patients with colorectal cancers. Our results indicate that 45% of patients initially staged as Dukes B had tumor cells identified in their SLN when these were subjected to our protocol. This represented a 25% upgrading rate when our complete study population is considered. However, controversy persist about the clinical significance and metastatic potential of these often very small clusters of tumor cells. J. Surg. Oncol. 2002;79:81,84. © 2002 Wiley-Liss, Inc. [source] Increased metastatic potential of tumor cells in von Willebrand factor-deficient miceJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 3 2006V. TERRAUBE Summary.,Background:,The key role played by von Willebrand factor (VWF) in platelet adhesion suggests a potential implication in various pathologies, where this process is involved. In cancer metastasis development, tumor cells interact with platelets and the vessel wall to extravasate from the circulation. As a potential mediator of platelet,tumor cell interactions, VWF could influence this early step of tumor spread and therefore play a role in cancer metastasis.Objectives:,To investigate whether VWF is involved in metastasis development.Methods:,In a first step, we characterized the interaction between murine melanoma cells B16-BL6 and VWF in vitro. In a second step, an experimental metastasis model was used to compare the formation of pulmonary metastatic foci in C57BL/6 wild-type and VWF-null mice following the injection of B16-BL6 cells or Lewis lung carcinoma cells.Results:,In vitro adhesion assays revealed that VWF is able to promote a dose-dependent adhesion of B16-BL6 cells via its Arg-Gly-Asp (RGD) sequence. In the experimental metastasis model, we found a significant increase in the number of pulmonary metastatic foci in VWF-null mice compared with the wild-type mice, a phenotype that could be corrected by restoring VWF plasma levels. We also showed that increased survival of the tumor cells in the lungs during the first 24 h in the absence of VWF was the cause of this increased metastasis.Conclusion:,These findings suggest that VWF plays a protective role against tumor cell dissemination in vivo. Underlying mechanisms remain to be investigated. [source] Liver grafts from donors with central nervous system tumors: A single-center perspectiveLIVER TRANSPLANTATION, Issue 10 2009Randeep Kashyap Traditionally, patients who die with a malignancy have been excluded from donation. However, it has become a common practice to accept organs from donors that have low-grade tumors or tumors with low metastatic potential. The aim of this study was to analyze our experience with the use of liver grafts from donors with central nervous system (CNS) tumors. A retrospective review of 1173 liver transplants performed between 1992 and 2006 identified 42 donors diagnosed with a CNS tumor. Thirty-two tumors were malignant, and 10 tumors were benign. Forty-two liver transplant recipients received livers from these donors. All patients were followed until May 2007 with a mean follow-up of 29 ± 17 months. Among 42 donors, there were 28 males and 14 females. The mean donor risk index was 1.78 ± 0.39. Twenty (47.6%) of the CNS tumors were glioblastoma multiforme (astrocytoma grade IV), 11 (26.2%) were other astrocytomas, and 1 (2.4%) was an anaplastic ependymoma. Twenty (62.5%) neoplasms were grade IV tumors, 8 (25%) were grade II tumors, and 4 (12.5%) were grade III tumors. Over 80% of the patients had at least 1 kind of invasive procedure violating the blood-brain barrier. The rate of recurrence for the entire group was 2.4% (all CNS tumors). There were 7 (7.2%) deaths in all. The most common cause of death was sepsis (n = 3, 7.2%). There was no difference in survival between recipients of grafts from donors with CNS tumors and recipients of grafts from donors without CNS tumors (1 year: 82% versus 83.3%, P = not significant; 3 years: 77.4% versus 72%, P = not significant). In conclusion, in our experience, despite violation of the blood-brain barrier and high-grade CNS tumors, recurrence was uncommon. Grafts from these donors are often an overlooked source of high-quality organs from younger donors and can be appropriately used, particularly in patients who, despite low Model for End-Stage Liver Disease scores, carry a high risk of mortality. Liver Transpl 15:1204,1208, 2009. © 2009 AASLD. [source] Nm23-H1 promotes adhesion of CAL 27 cells in vitroMOLECULAR CARCINOGENESIS, Issue 9 2009ica Bago Abstract nm23-H1 was found to diminish metastatic potential of carcinoma cell lines and therefore was placed in the group of metastatic suppressor genes. Its protein product has a function of a nucleoside diphosphate kinase (NDPK) as well as protein kinase and nuclease. Though it was found that Nm23-H1 is involved in many cellular processes, it is still not known how it promotes metastatic suppressor activity. Since the process of metastasis is dependent on adhesion properties of cells, the goal of our work was to describe the adhesion properties of CAL 27 cells (oral squamous cell carcinoma of the tongue) overexpressing FLAG/nm23-H1. In our experiments, cells overexpressing nm23-H1 show reduced migratory and invasive potential. Additionally, cells overexpressing nm23-H1 adhere stronger on substrates (collagen IV and fibronectin) and show more spread morphology than the control cells. Results obtained by EGF induction of migration revealed that the adhesion strength predetermined cell response to chemoattractant and that Nm23-H1, in this cell type, does not interfere with, EGF induced, Ras signaling pathway. These data contribute to the overall knowledge about nm23-H1 and its role in cell adhesion, migration, and invasion, especially in oral squamous cell carcinoma. © 2009 Wiley-Liss, Inc. [source] Photodynamic therapy for the treatment of a giant superficial basal cell carcinomaPHOTODERMATOLOGY, PHOTOIMMUNOLOGY & PHOTOMEDICINE, Issue 1 2009Donato Calista Summary A 74-year-old man was referred to our department for the treatment of a 15 × 15 cm superficial basal cell carcinoma (BCC) on his lumbar region. As surgical excision was considered too destructive, photodynamic therapy (PDT) was proposed. Methyl 5-aminolevulinate (MAL) cream was applied under occlusion for 3 h before illumination with a light-emitting diode lamp with an emission peak of 632 nm, a fluence rate of 83.3 mW/cm, and a light dose of 37 J/cm. A second MAL-PDT session was repeated 1 week later. The neoplastic area healed in 30 days. No recurrence has occurred after a 40-month follow-up period, but clinical observation continues. Although surgery still remains the treatment of choice for giant BCC, for which the local invasiveness and metastatic potential are well known, we offered our patient the option of PDT because we believed that classical surgery could hardly provide the same satisfactory outcome. As far as we know, this is the first case of giant BCC treated with PDT. [source] Differential protein expression on the cell surface of colorectal cancer cells associated to tumor metastasisPROTEINS: STRUCTURE, FUNCTION AND BIOINFORMATICS, Issue 5 2010Jose Luis Luque-García Abstract Progression to metastasis is the critical point in colorectal cancer (CRC) survival. However, the proteome associated to CRC metastasis is very poorly understood at the moment. In this study, we used stable isotope labeling by amino acids in cell culture to compare two CRC cell lines: KM12C and KM12SM, representing poorly versus highly metastatic potential, to find and quantify the differences in protein expression, mostly at the cell surface level. After biotinylation followed by affinity purification, membrane proteins were separated by SDS-PAGE and analyzed using nanoflow LC-ESI-LTQ. A total of 291 membrane and membrane-associated proteins were identified with a p value<0.01, from which 60 proteins were found to be differentially expressed by more than 1.5-fold. We identified a number of cell signaling, CDs, integrins and other cell adhesion molecules (cadherin 17, junction plakoglobin (JUP)) among the most deregulated proteins. They were validated by Western blot, confocal microscopy and flow cytometry analysis. Immunohistochemical analysis of paired tumoral samples confirmed that these differentially expressed proteins were also altered in human tumoral tissues. A good correlation with a major abundance in late tumor stages was observed for JUP and 17-,-hydroxysteroid dehydrogenase type 8 (HSD17B8). Moreover, the combined increase in JUP, occludin and F11 receptor expression together with cadherin 17 expression could suggest a reversion to a more epithelial phenotype in highly metastatic cells. Relevant changes were observed also at the metabolic level in the pentose phosphate pathway and several amino acid transporters. In summary, the identified proteins provide us with a better understanding of the events involved in liver colonization and CRC metastasis. [source] | |||||||||||||||||||||||||||||||||||||