Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chronic inflammation has been reported to accelerate neoplasmas in gastrointestinal tract. Certain bacteria including Helicobacter pylori directly interact with host cells, induce proinflammatory cytokines and stimulate production of free radicals. Free radicals cause mutations in target cells so that neoplastic clones are established. Accumulation of such genetic alterations may cause malignant transformation of some established clones. In addition, inflammatory alterations may promote growth, expansion and invasion of gastrointestinal epithelial cells. The latter changes caused by inflammation may occur even without further genetic mutations or epigenetic alterations, and therefore may be categorized as 'perigenetic alterations' of neoplastic cells. For an example, tumour necrosis factor alpha (TNF-alpha) plays pivotal roles not only in the reduction but also in the growth, invasion and metastases of certain neoplasmas. Our studies show that TNF-alpha increases intracellular radical production, degradates E-cadherin / beta-catenin complex and promotes dispersion and migration in epithelial cells transformed with an activated src oncogene (v-src). These data indicate that an inflammatory cytokine induces the malignant potential of src-activated neoplastic cells. Interestingly, TNF-alpha also induced these phenotypic changes in nonmutated cells whose c-Src was activated by TGF-alpha, suggesting that the invasive properties of the cell were not necessarily related to gene mutation. Furthermore, certain radical scavengers suppressed the invasive phenotype of the cells. These results indicate that perigenetic alterations are an important target of pharmacological intervention of carcinogenesis.
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PMID:Review article: inflammation-related promotion of gastrointestinal carcinogenesis--a perigenetic pathway. 1292 44

Oncogenes, growth factors, cell surface receptors, and cell-cycle and apoptotic regulatory proteins have been implicated in the growth regulation and progression of Barrett's-associated neoplasia. Among these, insulin-like growth factor 1 receptor (IGF1-R) and c-Src are reported to be key regulators of mitogenesis and tumorigenesis. In addition, c-Src may exert its transforming capability by inducing increased expression of IGF1-R on the neoplastic cells. Bcl-X(L), a member of the Bcl-2 family, blocks apoptosis and has been reported to increase in Barrett's-associated neoplasia. To study the modifications in IGF1-R, c-Src, and Bcl-X(L) protein expression during the progression of Barrett's-associated neoplasia, we analyzed 34 resected gastroesophagectomy specimens by immunohistochemistry using antibodies to human IGF1-R, c-Src, and Bcl-X(L). In these cases, we found 22 intestinal (Barrett's) metaplasias (IMs), 25 low-grade dysplasias (LGDs), 28 high-grade dysplasias (HGDs), 34 invasive adenocarcinomas (CAs), and 19 lymph node metastases. High IGF1-R cytoplasmic staining was present in 14 of 19 (74%) node metastases, in 28 of 34 (82%) CAs, in 18 of 28 (64%) HGDs, in 13 of 25 (52%) LGDs, and in 5 of 22 (23%) IMs. Strong and diffuse c-Src expression was identified in 17 of 19 (89%) node metastases, in 29 of 34 (85%) Cas, in 26 of 28 (93%) HGDs, in 18 of 25 (72%) LGDs, and in 9 of 22 (41%) IMs. Bcl-X(L) cytoplasmic staining was evident in 12 of 19 (63%) node metastases, in 20 of 34 (59%) Cas, in 20 of 28 (71%) HGDs, in 15 of 25 (60%) LGDs, and in 6 of 22 (27%) IMs. In 11 cases, c-Src activity was measured by kinase assay and reflected the immunohistochemical results. Our data indicate that expression levels of IGF1-R, c-Src, and Bcl-X(L) proteins are coordinately elevated in Barrett's-associated neoplasia. These findings indicate important roles of these growth regulatory proteins in the malignant progression of Barrett's-associated neoplasia.
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PMID:Modification of insulin-like growth factor 1 receptor, c-Src, and Bcl-XL protein expression during the progression of Barrett's neoplasia. 1460 30

The pathogenesis of metastasis depends on multiple favorable interactions of tumor cells with host homeostatic mechanisms. Interruption of one or more of these interactions can lead to the inhibition or eradication of cancer metastases. For many years, all efforts to treat cancer concentrated on the inhibition of growth or the destruction of tumor cells. A strategy of both eradication of tumor cells (e.g. by chemotherapy and immunotherapy) and modulation of the host microenvironment (e.g. tumor vasculature and hypoxia) is an additional, relatively novel approach to cancer treatment. Recent advances in our understanding of the biological basis of cancer metastasis open up unprecedented opportunities for translating basic research to clinical treatment of cancer. This research includes the unraveling of the genetic make-up of tumors and genome-wide expression analyses, thereby identifying many potential targets for therapy. Drugs acting on tumor cells which have a metastasis-prone mutational or expression status (by classical or targeted chemotherapy) as well as drugs affecting host-mediated survival pathways must be combined in order to create therapeutic synergy. Therapeutic maneuvers may target receptor tyrosine kinases (EGFR, VEGFR, FGFR), chemokines or G-protein-coupled receptors (CXCR4, CXCR2, EphB2), hypoxia-inducible factor (HIF), and signaling pathways (c-Src, PI3K, Akt, chaperon complexes) in tumor cells. Moreover, stromal and immunological cells and their cytokines coordinate critical pathways that exert important roles in the ability of tumors to invade and metastasize, thus suppressive cytokines (IL-6 and IL-10) and neutralizing specific antibodies might subvert conditions for metastasis.
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PMID:Metastases and their microenvironments: linking pathogenesis and therapy. 1609 51

Focal adhesion kinase (FAK) is one of the central signaling molecules found at focal adhesion sites, which are specific areas on the cell membrane where cells attach to extracellular matrix proteins. Focal adhesion kinase interacts with multiple signaling and adaptor molecules and effects several signaling pathways. Overexpression of FAK and its substrate c-Src has been implicated in malignant transformation and acquisition of an invasive tumor phenotype of different tissues. Overexpression of the multidomain protein paxillin, which is also a FAK ligand and a c-Src substrate, has been associated with less malignant tumor behavior. The purpose of this study was to analyze the involvement of integrin signaling molecules FAK, c-Src, and paxillin in malignant transformation of the breast epithelium. Using phosphospecific antibodies FAK-pY(397) and Src-pY(416), we demonstrated that neither activation of FAK nor activation of c-Src correlates with development of invasive tumor properties. However, activation of both FAK and c-Src correlates with malignant transformation. We further demonstrated that overexpression of paxillin also correlates with malignant transformation and is a marker of a less invasive tumor phenotype. Using tissue microarray, we demonstrated that expression and activation of paxillin inversely correlated with lymph node metastases and lymphovascular invasion, respectively. No correlation between paxillin expression and activation and tumor grade, estrogen, progesterone, and Her2/Neu receptor expression was found. In summary, focal adhesion proteins FAK and c-Src can be used as markers of malignant transformation in epithelial cells but not invasive phenotype, whereas expression and activation of paxillin may represent a good prognosticator in breast carcinoma.
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PMID:Focal adhesion proteins as markers of malignant transformation and prognostic indicators in breast carcinoma. 1693 35

The non-receptor tyrosine kinases c-Src and focal adhesion kinase (Fak) mediate signal transduction pathways that regulate cell proliferation, survival, invasion, and metastasis. Here, we investigated whether c-Src and Fak are activated during progression of hormone-dependent breast cancer. Maximally active c-Src was overexpressed in a subset of tamoxifen-resistant variants and in metastases of recurrent hormone-treated breast cancer. Active Fak was also frequently observed in these tumors. We also show that estrogen receptor (ER) can bind to Fak and that estrogen can modulate Fak autophosphorylation supporting a cross-talk between these two pathways. Inhibition of c-Src activity blocked proliferation of all tamoxifen-resistant variants, suggesting that inhibitors of c-Src-Fak activity may delay or prevent progression and metastasis of ER-positive tumors. These studies also raise the possibility that fully active forms of c-Src and Fak in breast tumors may be biomarkers to predict tamoxifen resistance and/or risk of recurrence in ER-positive breast cancer.
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PMID:Role of c-Src and focal adhesion kinase in progression and metastasis of estrogen receptor-positive breast cancer. 1641 80

The nonreceptor protein tyrosine kinase Src is overexpressed in 70% of pancreatic adenocarcinomas. Here, we describe the effect of molecular and pharmacological down-regulation of Src on incidence, growth, and metastasis of pancreatic tumor cells in an orthotopic model. Src expression in L3.6pl human pancreatic tumor cells was reduced by stable expression of a plasmid encoding small interfering RNA (siRNA) to c-src. In stable siRNA clones, Src expression was reduced >80%, with no change in expression of the related kinases c-Yes and c-Lyn, and proliferation rates were similar in all clones. Phosphorylation of Akt and p44/42 Erk mitogen-activated protein kinase and production of VEGF and IL-8 in culture supernatants were also reduced (P < 0.005). On orthotopic implantation of varying cell numbers into nude mice, tumor incidence was unchanged; however, in the siRNA clones, large tumors failed to develop, and incidence of metastasis was significantly reduced, suggesting that c-Src activity is critical to tumor progression. To examine this possibility further, animals bearing established wild-type tumors were treated with the Src/Abl-selective inhibitor BMS-354825 (dasatinib). Tumor size was decreased, and incidence of metastases was significantly reduced in treated mice compared with controls. These results demonstrate that Src activation contributes to pancreatic tumor progression in this model, offering Src as a candidate for targeted therapy.
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PMID:Inhibition of SRC expression and activity inhibits tumor progression and metastasis of human pancreatic adenocarcinoma cells in an orthotopic nude mouse model. 1650 11

c-Src is a proto-oncogene, belonging to the nonreceptor protein kinases family, which plays a prominent role in carcinogenesis. In this study, we tested the hypothesis that c-Src could promote breast cancer metastasis acting on several cell types and that pharmacological disruption of its kinase activity could be beneficial for the treatment of metastases. Female BALB/c-nu/nu mice were subjected to intracardiac injection of the human breast cancer cells MDA-MB-231 (MDA-231), which induced prominent bone and visceral metastases. These were pharmacologically reduced by treatment with the c-Src inhibitor [7-{4-[2-(2-methoxy-ethylamino-ethoxy]-phenyl}-5-(3-methoxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine] CGP76030 (100 mg/kg/day p.o.), resulting in decreased morbidity and lethality. Metastases were more severe in mice injected with MDA-231 cells stably transfected with wild-type c-Src (MDA-231-SrcWT), whereas transfection in injected cells of a c-Src kinase-dead dominant-negative construct (MDA-231-SrcDN) resulted in reduced morbidity, lethality, and incidence of metastases similar to the mice treated with the inhibitor. An analogous beneficial effect of c-Src inhibition was observed in subcutaneous and intratibial implanted tumors. In vitro, c-Src suppression reduced MDA-231 cell aggressiveness. It also impaired osteoclast bone resorption both directly and by reducing expression by osteoblasts of the osteoclastogenic cytokines interleukin-1beta and interleukin-6, whereas parathyroid hormone-related peptide was not implicated. c-Src was also modestly but consistently involved in the enhancement of endothelial cell proliferation in vitro and angiogenesis in vivo. In conclusion, we propose that c-Src disruption affects the metastatic process and thus is a therapeutic target for the treatment of breast cancer.
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PMID:Inhibition of protein kinase c-Src reduces the incidence of breast cancer metastases and increases survival in mice: implications for therapy. 1662 50

The levels and activity of c-Src in colorectal cancer cells increase steadily during the course of colorectal carcinogenesis and are most highly elevated in advanced metastatic disease. However, the effects of increases in c-Src activity on the proliferation of colorectal cancer cells during early and late stages of tumorigenesis remain elusive. To study the consequences of increases in c-Src levels and activity on the growth of colorectal cancer cells in later stages of colorectal carcinogenesis, we developed human colorectal cancer cell lines in which c-Src levels and activity could be inducibly increased by a tightly controlled expression of wild-type c-Src or of the constitutively active mutant of c-Src, c-SrcY527F. Src induction activated multiple signaling pathways (often associated with a proliferative response) but promoted neither cell proliferation in vitro nor tumor growth in a xenograft model in vivo. These results indicate that, in more advanced stages of colorectal carcinogenesis, increases in c-Src levels and activity are likely to have functions other than the direct promotion of tumor growth.
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PMID:Increases in c-Src expression level and activity do not promote the growth of human colorectal carcinoma cells in vitro and in vivo. 1713 22

Anoikis, a Bax-dependent apoptosis triggered by detachment from the extracellular matrix, is often dysfunctional in metastatic cancer cells. Using wild-type and c-Src-transformed NIH3T3 cells as a model, we identified Mcl-1 degradation and Bim up-regulation as a critical determinant of anoikis initiation. Detachment rapidly degraded Mcl-1 via a GSK-3beta-dependent proteasomal pathway and transcriptionally up-regulated Bim expression. Mcl-1 degradation in the presence of Bim was sufficient to induce anoikis. By analyzing nonmetastatic Saos-2 and metastatic derivative LM7 cells, we confirmed that dysregulation of Mcl-1 degradation and Bim induction during detachment contributes to decreased anoikis sensitivity of metastatic cells. Furthermore, knockdown of Mcl-1 or pharmacologic inhibition of the phosphoinositide-3-kinase/Akt and mitogen-activated protein kinase pathways that suppress Mcl-1 degradation and Bim expression could markedly sensitize metastatic breast cancer cells to anoikis and prevent metastases in vivo. Therefore, Mcl-1 degradation primes the cell for Bax activation and anoikis, which can be blocked by oncogenic signaling in metastatic cells.
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PMID:Anoikis, initiated by Mcl-1 degradation and Bim induction, is deregulated during oncogenesis. 1800 17

The c-Src non-receptor tyrosine kinase is overexpressed in a large number of human malignancies. It is linked to tumour development and progression to distant metastases by promoting cell proliferation, invasion, and motility. Recently, promising anticancer therapeutics targeting c-Src have been developed that are under clinical investigation.
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PMID:Src kinase and pancreatic cancer. 1808 59


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