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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Various mechanisms of epithelial cell plasticity in morphogenesis have been studied at the genetic and molecular levels. Several control genes have been identified including genes encoding transcription factors and growth factor receptors. These mechanisms may be reactivated during the progression of carcinomas. One of the mechanisms underlying epithelial plasticity is the epithelial-mesenchymal transition. This process has been extensively studied using the NBT-II bladder carcinoma cell line. Cells of this line undergo a reversible transition following exposure to several growth factors including FGF-1, EGF, TGFalpha and SF/HGF, which activate tyrosine kinase surface receptors. Two separate transduction pathways have been identified. The transient activation of c-Src is involved in cytoskeleton remodeling whereas the Ras pathway controls the transcription of genes such as the transcription factor Slug which is involved in the internalization of desmosomes. These two pathways cooperate to induce the morphological transition, scattering and locomotion of fibroblast-like cells. Growth/scatter factor-producing NBT-II cells are more invasive than cells that do not contain this factor, in orthotopic confrontation assay. In vivo, these cells are very tumorigenic and may confer a more malignant phenotype on parental cells via a community effect. The role of several growth factors and their receptors has been investigated in human bladder carcinomas. A subset of these tumors with poor outcomes produce low levels of FGFR2-IIIb. The synthesis of this receptor de novo in bladder cell lines reduces proliferation in vitro and tumor growth in nude mice. FGFR2-IIIb functions as a tumor suppressor, consistent with the differentiation-inducing capacities of FGF receptors in the suprabasal cells of the skin. FGFR2-IIIb signaling may be involved in the maintenance of E-cadherin, the prototype epithelial adhesion molecule, which is only downregulated in a fraction of tumors with low FGFR2-IIIb synthesis. Human bladder tumors may also activate autocrine loops such as that for EGFR and their ligands, as already demonstrated for murine bladder tumors. Therefore, our results suggest that multifunctional growth factors and their receptors are involved in cell proliferation and epithelial cell plasticity, acting either as positive or negative regulators of tumor progression. The effect on the morphological transition is also clearly relevant to the mechanism governing dissemination and the formation of micrometastatic tumor cells. The extrapolation of these discoveries to human carcinomas should provide markers facilitating the more accurate prediction of the biological behavior of a given tumor and identify clinically and pathologically significant parameters. The identification of critical changes in the growth factor pathways involved in tumor progression will not only provide insight into the genetic and molecular basis of this process, but should also identify targets for new therapies.
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PMID:Epithelial cell plasticity in development and tumor progression. 1050 44

There is strong evidence that tyrosine kinases are involved in the regulation of cellular growth and tumor progression. Over-expressions of tyrosine kinases have been documented in a number of neoplasms. To study the roles of tyrosine kinases in colon cancer, we developed a tyrosine-kinase-expression profile for each of the four different stages of colon carcinogenesis, using normal colon mucosa, adenomatous polyps, primary carcinoma and hepatic metastases collected from the same patient. We identified 30 tyrosine kinases expressed in these tissues: they include 10 non-receptor tyrosine kinases (yes, fyn, lyn, brk, abl, arg, jak1, jak3, tyk2 and itk), 17 receptor tyrosine kinases (erbB2, PDGF-Ralpha, PDGF-Rbeta, kit, c-fms, met, ron, FGF-R1, FGF-R2, FGF-R3, FGF-R4, cek5, tie-1, tkt, axl, sky and Ins-R), 2 dual kinases (mek and sek) and one possible novel kinase. Among these kinases, arg kinase appears to be expressed at a higher level in primary carcinoma and metastatic tumor than in adjacent normal mucosa or adenomatous polyp. This result was confirmed by extensive analysis of 50 additional matched sets of normal colon and colon-tumor specimens, using arg-specific primers and RT-PCR reactions. This study identifies a possible role for arg tyrosine kinase in colon carcinogenesis, especially in the transition from adenoma to carcinoma.
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PMID:Comparative tyrosine-kinase profiles in colorectal cancers: enhanced arg expression in carcinoma as compared with adenoma and normal mucosa. 1052 89

The growth of supportive tissue during the progression of solid tumors is an absolute requirement for the nourishment of the tumor. The blockade of this proliferative response of normal tissues to the growing tumor should hence inhibit tumor progression. We have shown earlier, that the heparinoid pentosan polysulfate (PPS) can block tumor growth and neoangiogenesis induced by Kaposi's FGF as well as by other heparin-binding growth factors (HBGFs). We now report on the effects of a bacterial polysaccharide, tecogalan, on tumor xenografts of human breast cancer cells. Tecogalan inhibited FGF-dependent SW-13 cells in vitro very similarly to PPS. Growth factor-independent MDA-MB 231 cells were used in animal studies to assess the in vivo potential of tecogalan. Subcutaneous growth of tumors was inhibited by once weekly i.v. administration of tecogalan. PPS single weekly administration showed a similar effect. No gross side effects were observed. Based on our previous studies with these models, we conclude, that tecogalan acts by blocking HBGFs released from tumor cells. Interestingly, single weekly dosing of either PPS or tecogalan appears to be strikingly more efficacious than spreading the dose over several administrations. These findings with a novel compound, tecogalan, and a novel treatment regimen, PPS, suggests a different approach to planning of therapies with these types of drugs.
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PMID:The bacterial polysaccharide tecogalan blocks growth of breast cancer cells in vivo. 1111 90

Basic fibroblast growth factor (FGF-2) is an important stimulator of angiogenesis that has been implicated in neoplastic progression. Attempts to neutralize or modulate FGF-2 have met with some success in controlling neovascularity and tumor growth. In the present study, two peptides: one corresponding to the heparin binding domain and the other to the receptor binding domain of FGF-2, exerted dose-dependent inhibition of FGF-2-stimulated human umbilical vein endothelial cell proliferation (IC(50)=70 and 20 microg/ml, respectively). The identification of these functional regions suggested that targeting these domains might be an approach for the modulation of FGF-2 function. To investigate this possibility, we vaccinated mice with either the heparin binding domain peptide or the receptor binding domain peptide of FGF-2 in a liposome/adjuvant format, and analyzed the effect of vaccination on FGF-2-driven angiogenesis, tumor development and immune status. Mice vaccinated with the heparin binding domain peptide generated a specific antibody response to FGF-2, blocked neovascularization in a gelfoam sponge model of angiogenesis, and inhibited experimental metastasis by >90% in two tumor models: the B16BL6 melanoma and the Lewis lung carcinoma. These effects were not observed in mice treated with the receptor binding domain peptide conjugated to liposomes or liposomes lacking conjugated peptide. These data suggest that a heparin binding domain peptide of FGF-2, when presented to a host in a liposomal adjuvant formulation, can ultimately lead to inhibition of angiogenesis and tumor growth.
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PMID:Administration of a liposomal FGF-2 peptide vaccine leads to abrogation of FGF-2-mediated angiogenesis and tumor development. 1113 69

The t(4;14) translocation occurs frequently in multiple myeloma (MM) and results in the simultaneous dysregulated expression of 2 potential oncogenes, FGFR3 (fibroblast growth factor receptor 3) from der(14) and multiple myeloma SET domain protein/Wolf-Hirschhorn syndrome candidate gene 1 from der(4). It is now shown that myeloma cells carrying a t(4;14) translocation express a functional FGFR3 that in some cases is constitutively activated by the same mutations that cause thanatophoric dysplasia. As with activating mutations of K-ras and N-ras, which are reported in approximately 40% of patients with MM, activating mutations of FGFR3 occur during tumor progression. However, the constitutive activation of ras and FGFR3 does not occur in the same myeloma cells. Thus the activated forms of these proteins appear to share an overlapping role in tumor progression, suggesting that they also share the signaling cascade. Consistent with this prediction, it is shown that activated FGFR3-when expressed at levels similar to those seen in t(4;14) myeloma-is an oncogene that acts through the MAP kinase pathway to transform NIH 3T3 cells, which can then generate tumors in nude mice. Thus, FGFR3, when overexpressed in MM, may be not only oncogenic when stimulated by FGF ligands in the bone marrow microenvironment, but is also a target for activating mutations that enable FGFR3 to play a ras-like role in tumor progression.
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PMID:Activated fibroblast growth factor receptor 3 is an oncogene that contributes to tumor progression in multiple myeloma. 1151 Apr 69

The work described in this review addresses the multifunctional roles of growth factors and their cognate receptors in normal development and in tumorigenesis. The concept of epithelial cell plasticity is described in the context of embryonic development during which frequent remodeling occurs in epithelial tissues. The critical role of one member of the FGF family of growth factors is demonstrated in lung branching morphogenesis. Several members of this family have been shown to induce an epithelial-mesenchymal transition in a bladder carcinoma line. In vivo the same factors act in an autocrine or paracrine mode to favor tumor progression. It is suggested that an EGFR-ligand autocrine loop exerts a positive role in tumor progression of human bladder carcinoma whereas FGFR2 acts as a phenotypic tumor suppressor gene. Unexpectedly, constitutive activating mutations in FGFR3 have been uncovered in the majority of the Ta superficial tumors which progress only very rarely to the invasive stages. In contrast, in situ carcinoma, which are considered to be associated with a strong malignant potential, do not carry the FGFR3 mutations. The presence or absence of the mutations defines two distinct oncogenic pathways in bladder carcinogenesis. The studies reveal the complexities in defining the putative functions of growth factors at different times and differentiation stages during development and in tumor progression. These results emphasize the need for caution in the interpretation of studies evaluating the potential of novel anti-cancer agents and for better designs of in vitro and in vivo biological assays.
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PMID:[Role of growth factor signaling in epithelial cell plasticity during development and in carcinogenesis]. 1197 24

Tumor progression is often regulated through interactions between carcinoma cells and host stromal cells. In this study of endometrial cancer, we investigated one mechanism potentially involved in hepatocyte growth factor (HGF)-mediated cancer-stromal interactions. Endometrial cancer cells (HEC-1 and ISHIKAWA) expressed the c-met receptor, but HGF did not. HGF, however, did stimulate the proliferation and invasion of these cells. The HGF gene was expressed in stromal cells, which had been separated from primary cultures of endometrial cancers, 6.4 times more than in isolated normal endometrial stromal cells. Immunohistochemical staining revealed immunoreactive HGF in cancer stromal cells, the staining intensity being more pronounced in cancer tissue than in normal endometrium. The conditioned medium from normal epithelial cells and cancer cell lines induced HGF production in normal stromal cells. We identified basic fibroblast growth factor as an HGF inducer derived from endometrial cancer cell lines. Basic fibroblast growth factor derived from tumor cells may induce HGF in endometrial stromal cells, whereas stromal cell-derived HGF leads to the invasive growth of carcinoma cells. These interactions, mediated by HGF and HGF inducers, may play a significant role in the progression of endometrial cancer.
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PMID:Induction of hepatocyte growth factor in stromal cells by tumor-derived basic fibroblast growth factor enhances growth and invasion of endometrial cancer. 1199 90

FGF-1 and FGF-2 are pleiotropic growth factors for many cell types, operating through the activation of specific transmembrane FGF receptors (FGFRs). The role of these factors in tumor progression was investigated, with specific discrimination between their autocrine and non autocrine cellular activity. The rat bladder carcinoma NBT-II cells were engineered to produce FGF-1 or 18 kDa FGF-2 in the presence or absence of their specific receptor. Non-autocrine cells that produced FGF-1 or FGF-2 but lacked FGFRs were epithelial and reminiscent of the parental NBT-II cells. Whilst autocrine cells, which both constitutively produced and secreted the growth factor and expressed FGFRs, had a highly invasive mesenchymal phenotype. Correspondingly, the autocrine cells were highly tumorigenic in vivo compared to the parental and non-autocrine cells, which correlated with the increased production of uPAR and active uPA and increased in vitro invasive potential. Although all cells produced VEGF, only tumors derived from cells that produced FGF-1 or FGF-2 were highly vascularized, suggesting that these two growth factors could be involved in the angiogenic process by activating host endothelial cells. As a result of activation of the FGFR in autocrine cells, changes in cell morphology and an increase in the invasive and tumorigenic properties were observed, however no in vitro or in vivo differential functions between FGF-1 and FGF-2 could be identified in this system. In conclusion, our data demonstrates that rapid tumor development is not dependent upon increased tumor vascularization, suggesting that 'basal' angiogenesis, probably mediated by VEGF, is sufficient to support tumor growth.
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PMID:Rapid tumor development and potent vascularization are independent events in carcinoma producing FGF-1 or FGF-2. 1244 48

Tenascin-C (TN-C) and matrix metalloproteinases (MMPs) are highly expressed in cancer tissues and probably promote cell migration during cancer progression. TN-C and MMPs are often co-localized in areas of active tissue remodeling in pathologic conditions, suggesting reciprocal regulation. To investigate whether TN-C regulates MMPs expression in cancer cells, we first exposed mammary cancer cells derived from TN-C-deficient mice to TN-C and examined MMPs expression. TN-C was then compared with fibronectin (FN), laminin (LN), basic fibroblast growth factor (b-FGF) and transforming growth factor-beta1 (TGF-beta1). Results of endpoint RT-PCR, quantitative real-time RT-PCR and gelatin zymography demonstrated that TN-C, strongly and dose dependently, upregulates MMP-9 expression in murine mammary cancer cells. TN-C weakly induced MMP-2, MMP-3 and MMP-13. FN and LN induced MMP-9 to lesser extents compared with TN-C. b-FGF had no effect on MMP-9 expression. TGF-beta1 induced MMP-9 expression in a dose-dependent manner, and this induction was significantly enhanced by addition of TN-C. TN-C and TGF-beta1 also upregulated MMP-9 expression in the human breast cancer cell line MDA-MB-231. Neutralization with specific anti-TGF-beta1 antibody showed decreased expression of MMP-9, indicating that TGF-beta controls the baseline MMP-9 expression by a direct autocrine mechanism. Under neutralization of TGF-beta, addition of TN-C still upregulated MMP-9. Conversely, neutralization of endogenous TN-C (in a TN-C-positive mammary cancer cell line) downregulated TGF-beta-induced MMP-9 expression. Thus, TN-C induces MMP-9 expression directly and by collaboration with TGF-beta. These findings reveal a novel role of TN-C in breast cancer progression.
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PMID:Tenascin-C upregulates matrix metalloproteinase-9 in breast cancer cells: direct and synergistic effects with transforming growth factor beta1. 1267 30

Dysregulated signaling contributes to altered cellular growth, motility, and survival during cancer progression. We have evaluated the ability of several factors to stimulate migration in WM1341D, a cell line derived from an invasive human vertical growth phase melanoma. Basic fibroblast growth factor, hepatocyte growth factor, interleukin-8, and CCL27 each slightly increased migration. Insulin-like growth factor I (IGF-I), however, stimulated a 15-fold increase in migration. This response required the IGF-I receptor, which activates phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathways. Both pathways have been implicated in migration in a variety of cell types, but the signaling required for IGF-I-induced melanoma cell migration is not well defined. IGF-I-stimulated activation of MAPK/ERK signaling in WM1341D cells was inhibited by U0126, but a 33-fold higher dose of U0126 was needed to inhibit IGF-I-stimulated cellular migration. In contrast, similar concentrations of either wortmannin or LY294002 were required to inhibit both IGF-I-induced PI3K activation and migration. These results indicate that IGF-I-stimulated migration of WM1341D cells requires PI3K activation but is independent of MAPK/ERK signaling. Determining the contributions of IGF-I signaling pathways to migration will help us to understand melanoma progression and may lead to new therapeutic targets of this highly metastatic cancer.
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PMID:Insulin-like growth factor I-stimulated melanoma cell migration requires phosphoinositide 3-kinase but not extracellular-regulated kinase activation. 1272 1


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