UMLS:C0178874 - FACTA Search

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

The HER2/neu (c-erbB2) protooncogene, which encodes a transmembrane receptor (p185neu), contributes to tumor cell invasion/metastasis through mechanism(s) which are, at present, poorly defined. Since basement membrane degradation is a prerequisite for tumor progression, we undertook a study to determine if the expression of urokinase, a key protease implicated in extracellular matrix proteolysis, was regulated by this oncogene. Stable overexpression of a cDNA encoding HER2/neu in H460 lung cancer cells led to elevated secretion of urokinase which was a consequence of a higher level of protease mRNA. Transfection of the HER2/neu-overexpressing B 104-1 cells with a CAT reporter construct driven by the urokinase promoter, gave rise to increased CAT activity when compared with parental NIH3T3 cells, which have low levels of HER2/neu, suggesting that the protooncogene can enhance urokinase promoter activity. Since the enhanced expression of HER2/neu results in increased tumor invasion/metastasis (1), these data suggest that, at least in vitro, HER2/neu-induced expression of urokinase may contribute to tumor progression in p185neu-positive cancers.
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PMID:Up-regulation of urokinase-type plasminogen activator expression by the HER2/neu proto-oncogene. 765 95

Scatter factor (SF), a cell motility factor with a multimodular structure, is identical to hepatocyte growth factor (HGF), a potent mitogen of various cell types. The receptor for SF/HGF has recently been identified as the c-Met proto-oncogene product, a transmembrane receptor tyrosine kinase. Depending on the target cells and culture conditions, SF/HGF has several distinct activities in vitro, i.e., it induces cell motility, proliferation, invasiveness, tubular morphogenesis, angiogenesis, or cytotoxicity. In vivo, SF/HGF might be involved in tissue regeneration, tumor progression, and embryological processes.
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PMID:Properties and functions of scatter factor/hepatocyte growth factor and its receptor c-Met. 838 6

We have shown that basic fibroblast growth factor (FGF) is heterogeneously expressed by human pituitary adenomas and may be implicated as a growth stimulus for these tumors. There are four mammalian FGF receptor (FGFR) genes encoding a complex family of transmembrane tyrosine kinases. The prototypic receptor is composed of three Ig-like extracellular ligand-binding domains, a transmembrane domain, and a cytoplasmic split tyrosine kinase. Multiple forms of cell-bound or secretable isoforms of FGFR-1, -2, and -3 can be generated by cell- and tissue-specific alternative splicing, resulting in tissue-specific FGF function. Shifts in isoform expression accompany tumor progression in some systems. We examined the normal human adenohypophysis and 40 pituitary adenomas to determine the pattern of FGFR expression by reverse transcription-PCR; all tumors were characterized clinically and morphologically. Ribonucleic acid (RNA) was extracted from frozen tumor tissue and primers were used to distinguish messenger RNA of the secretable first Ig-like domain (I) and those of the transmembrane and kinase domains (K) of each FGFR subtype. The normal pituitary-expressed mRNAs for FGFR-1 I and K, FGFR-2 I and K, FGFR-3 I and K, and FGFR-4 I but not FGFR-4 K; this represents the first report of a truncated isoform of FGFR-4, indicating possible alternative polyadenylation sites in this receptor. Only 3 tumors had the same pattern of expression of the 4 FGFRs as the normal gland. Although all tumors expressed FGFR-1 I, 1 tumor did not express FGFR-1 K, suggesting the production of only a secretable form of FGFR-1 by this tumor. Four tumors were negative for FGFR-2 I and K; 6 expressed the secretable form only, and 17 expressed FGFR-2 K but not I. All tumors expressed FGFR-3 I; 14 had secretable forms only, and no tumors expressed FGFR-3 K alone. As in the normal gland, 13 tumors expressed only the secretable I form of FGFR-4. Unlike the normal pituitary, however, 22 expressed FGFR-4 I and K, indicating a possible tumor-specific transmembrane receptor. Five tumors were negative for FGFR-4 I and K. Expression of FGFR proteins was confirmed by immunohistochemical localization of the C-terminal portion of FGFR-1, -2, -3, and -4; the results correlated with the RNA data in each case. There was no correlation between tumor type, size, or aggressiveness and the expression pattern of FGFRs. Our study suggests that pituitary adenomas have altered FGFR subtype and isoform expression, which may determine their hormonal and proliferative responses to FGFs.
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PMID:Altered expression of fibroblast growth factor receptors in human pituitary adenomas. 910 May 89

Integrin alpha2beta1 is a heterodimeric transmembrane receptor for collagens. In osteogenic cells the expression of alpha2beta1 integrin is induced by both Kirsten sarcoma virus and chemical transformation. The association of alpha2 integrin with transformed cell phenotype was studied further by testing the effects of two tumor promoters, 12-O-tetradecanoylphorbol 13-acetate (TPA) and okadaic acid (OA), on human MG-63 osteosarcoma cells. TPA, an activator of protein kinase C, increased the cell surface expression of alpha2 integrin and the corresponding mRNA levels. Nuclear run-on assays indicated that TPA activated the transcription of alpha2 integrin gene. TPA also slightly increased the expression of alpha3 integrin but had no effect on the transcription of alpha5, alphav, or beta1 integrin subunits. OA, an inhibitor of serine/threonine phosphatases, increased alpha2 integrin gene transcription and mRNA levels, but in contrast to TPA, OA decreased alpha3 integrin expression. The increased expression of alpha2 integrin on TPA-treated MG-63 cells led to faster cell spreading on type I collagen. Our results link the enhanced transcription of alpha2 integrin gene to tumor progression and show the independent regulation of alpha2 integrin compared to other integrin genes.
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PMID:Transcription of alpha2 integrin gene in osteosarcoma cells is enhanced by tumor promoters. 971 43

This short review presents the current stage of knowledge of our laboratory on the mechanism of action of cathepsin D and estrogens on tumor progression, mostly based on studies of human breast and ovarian cancer cell lines. Cathepsin D (cath-D) overexpression in breast cancer cells is associated with increased risk of metastasis in patients as confirmed by a recent meta-analysis of clinical studies on node negative breast cancer patients. Transfection of a human cDNA cath-D expression vector increases the metastatic potential of a rat tumor cells line when intravenously injected into nude mice. The mechanism of cath-D induced metastasis seems to require maturation of the pro-enzyme, mostly in large acidic compartments identified as phagosomes. Cath-D is mitogenic in different cell types, and different substrates (growth inhibitors, precursors of growth factor etc.) are proposed to mediate this activity. A mitogenic effect of the pro-enzyme on transmembrane receptor is not totally excluded. The mitogenic activity of estrogens in several estrogen receptor positive breast and ovarian cancer cell lines is well established in our and other laboratories. By contrast the role of estrogens during early steps of metastasis, involving cell invasion through the basement membrane and cell motility is more controversial. The motility of several estrogen receptor (ER) positive breast (MCF7, T47D) and ovarian (BG-1, SKOV3, PEO4) cancer cell lines were studied in our laboratory using a modified Boyden chamber assay. We observed, in all cases, estradiol-induced inhibition of cancer cell invasion and motility. A similar inhibitory effect of estradiol was found when the wild-type ER was stably transfected in the ER-negative MDA-MB231 cells and 3Y1-Ad12 cancer cells. The mechanism of this inhibitory effect is unknown. In ovarian cancer, however it may involve intermediary proteins such as fibulin-1, an extracellular matrix protein that strongly interacts with fibronectin and which is induced by estrogen and secreted by ovarian cancer cells. In breast cancer cells other estrogen regulated proteins may be involved. We conclude that estrogens in ER-positive breast and ovarian cancers have a dual effect, since they stimulate tumor growth but inhibit invasion and motility. This may be consistent with the good initial prognostic value of ER-positive breast cancers compared to ER negative breast cancers noted in several clinical studies, and with the better prognosis of breast cancer occurring after a prolonged treatment of menopause by estrogen as described by the collaborative group on hormonal factors in breast cancer.
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PMID:[Estrogens, cathepsin D and metastasis in cancers of the breast and ovary: invasion or proliferation?]. 984 Oct 98

Tumor cells are characterized by uncontrolled growth, invasion to surrounding tissues, and metastatic spread to distant sites. Mortality from cancer is often due to metastasis since surgical removal of tumors can enhance and prolong survival. The integrins constitute a family of transmembrane receptor proteins composed of heterodimeric complexes of noncovalently linked alpha and beta chains. Integrins function in cell-to-cell and cell-to-extracellular matrix (ECM) adhesive interactions and transduce signals from the ECM to the cell interior and vice versa. Hence, the integrins mediate the ECM influence on cell growth and differentiation. Since these properties implicate integrin involvement in cell migration, invasion, intra- and extra-vasation, and platelet interaction, a role for integrins in tumor growth and metastasis is obvious. These findings are underpinned by observations that the integrins are linked to the actin cytoskeleton involving talin, vinculin, and alpha-actinin as intermediaries. Such cytoskeletal changes can be manifested by rounded cell morphology, which is often coincident with tumor transformation via decreased or increased integrin expression patterns. For the various types of cancers, different changes in integrin expression are further associated with tumor growth and metastasis. Tumor progression leading to metastasis appears to involve equipping cancer cells with the appropriate adhesive (integrin) phenotype for interaction with the ECM. Therapies directed at influencing integrin cell expression and function are presently being explored for inhibition of tumor growth, metastasis, and angiogenesis. Such therapeutic strategies include anti-integrin monoclonal antibodies, peptidic inhibitors (cyclic and linear), calcium-binding protein antagonists, proline analogs, apoptosis promotors, and antisense oligonucleotides. Moreover, platelet aggregation induced by tumor cells, which facilitates metastatic spread, can be inhibited by the disintegrins, a family of viper venom-like peptides. Therefore, adhesion molecules from the integrin family and components of angiogenesis might be useful as tumor progression markers for prognostic and for diagnostic purposes. Development of integrin cell expression profiles for individual tumors may have further potential in identifying a cell surface signature for a specific tumor type and/or stage. Thus, recent advances in elucidating the structure, function, ECM binding, and signaling pathways of the integrins have led to new and exciting modalities for cancer therapeutics and diagnoses.
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PMID:Role of integrins in cancer: survey of expression patterns. 1056 36

Activated Ras but not Raf can transform RIE-1 and other epithelial cells, indicating the critical importance of Raf-independent effector function in Ras transformation of epithelial cells. To elucidate the nature of these Raf-independent activities, we utilized representational difference analysis to identify genes aberrantly expressed by Ras through Raf-independent mechanisms in RIE-1 cells. We identified a total of 22 genes, both known and novel, whose expression was either activated or abolished by Ras but not Raf. The genes up-regulated encode proteins involved in protein or DNA synthesis, regulation of protease activity, or ligand binding, whereas those genes down-regulated encode actin cytoskeletal-, extracellular matrix-, and gap junction-associated proteins, and transmembrane receptor- or cytokine-like proteins. These results suggest that a key function of Raf-independent signaling involves deregulation of gene expression. We further characterized transgelin as a gene whose expression was abolished by Ras. Transgelin was identified previously as a protein whose expression was lost in virally transformed cell lines. We show that this loss is regulated at the level of gene expression and that both Raf-dependent and Raf-independent pathways are required to cause Ras down-regulation of transgelin in RIE-1 cells, whereas Raf alone is sufficient to cause its loss in NIH 3T3 fibroblasts. We also found that Ras-dependent and Ras-independent mechanisms can cause the down-regulation of transgelin in human breast and colon carcinoma cells lines and patient-derived tumor samples. We conclude that loss of transgelin gene expression may be an important early event in tumor progression and a diagnostic marker for breast and colon cancer development.
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PMID:Loss of transgelin in breast and colon tumors and in RIE-1 cells by Ras deregulation of gene expression through Raf-independent pathways. 1177 51

Most cellular proto-oncogenes encode proteins that participate in signaling pathways by which cells receive and execute instructions that lead to mitogenesis, differentiation, lineage determination, cell migration, extracellular matrix production, and apoptosis, among others. These proto-oncogene protein products include transmembrane receptor tyrosine kinases and receptor substrates, serine/threonine kinases, receptor adaptor molecules, low-molecular-weight GTPases, and transcription factors that, when overexpressed or mutationally activated, can lead to cell transformation and tumor progression. The large number of oncogenic protein tyrosine kinases plus the rare presence of phosphotyrosine in nontransformed cells argue persuasively that tyrosine phosphorylation and activation of signaling molecules downstream from receptor tyrosine kinases are critical events in growth control and transformation and are, therefore, rational targets for anticancer molecular therapies. We will review some of the more recent treatment strategies in non-small cell and small cell lung cancer targeted to dysregulated signaling pathways that are causally associated with tumor maintenance and progression.
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PMID:Overview of rationale and clinical trials with signal transduction inhibitors in lung cancer. 1189 10

The hallmark of tumor metastasis is the dissemination of cells from the primary growth site to distant organs. Autocrine motility factor (AMF), a tumor-associated C-X-X-C cytokine, the ligand for a unique 78 kDa seven transmembrane receptor, is a potent simulator of cell motility, a process that is a prerequisite for tumor progression and metastasis. Because little is known about AMF-dependent signaling, we sought to study whether AMF signaling involves family members of the Rho-like GTPases. AMF stimulation of human melanoma cells resulted in stress-fiber formation, concomitant with up-regulation and activation of both RhoA and Rac1 expression with no apparent changes in the expression level or activation state of Cdc42. Treatment of the cells with C3 exoenzyme before AMF stimulation inhibited both the formation of stress-fiber-like structures and the activation of RhoA. In addition, both c-Jun NH(2)-terminal kinase 1 and c-Jun NH(2)-terminal kinase 2 were simultaneously activated by AMF, supporting the notion that they are involved in the signaling pathway of RhoA. We thus conclude that AMF signaling shares a similar pathway to previously established paracrine factors signaling involving cytoskeletal rearrangement and morphological alterations mediated by the small RhoA-like GTPases.
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PMID:Activation of small GTPase Rho is required for autocrine motility factor signaling. 1215 59

Tie-1 is a transmembrane receptor expressed in vascular endothelium during angiogenic events and during embryonal growth in most mammalian species. The monoclonal antibodies (mAbs) used here are generated against the extracellular part of the Tie-1 receptor protein. We analyzed the specific binding of (125)I-labeled Tie-1 mAbs in the metastatic tumor model in mouse and in human serum samples to determine the possible use of the Tie-1 mAbs in detecting malignant growth. The in vivo biodistribution of (125)I-Tie-1 mAbs (IgG1) was evaluated in the mouse model. The same Tie-1 mAbs were used to analyze Tie-1 in patient serum samples. A high accumulation of two (125)I-Tie-1 mAbs, clones 10f11g6 and 3c4c7, was detected in the lung metastases of mouse tumor model. The uptake in the metastases is 12% injected dose/gram (ID/g; 10f11g6) and 7.8% ID/g (3c4c7) at 96 h after the injections of (125)I-Tie-1 mAbs, and the accumulation to the blood is 7% and 5% ID/g with the two mAbs, respectively. The finding directed us to analyze serum samples from lung, ovarian, and breast cancer patients. High levels of Tie-1 were detected in samples related to new pelvic or thoracic metastases in patients. Here we connect the Tie-1 levels in serum to tumor progression. The results suggest that Tie-1 mAbs can be used as a surrogate marker of progressive disease.
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PMID:The new Tie-1 monoclonal antibodies detect angiogenesis in metastatic malignancies. 1450 79

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