Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0677930 (primary tumor)
 20,210 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have shown previously that hepatocyte growth factor (HGF), which is produced by lung fibroblasts, is a potent mitogen and motogen for both normal and neoplastic bronchial epithelium, and that expression of the HGF receptor, the c-met proto-oncogene protein, is uniformly found in the human bronchial epithelium and in non-small cell lung carcinomas (NSCLCs; P. Singh-Kaw et al., Am. J. Physiol., 268: L1012-L1020, 1995). Yamashita et al. have reported an association of HGF with poor survival in invasive ductal carcinoma of the breast (Cancer Res., 54: 1630-1633, 1994). There are few prognostic markers for lung cancer, and the high recurrence rate for stage I lung cancer suggests the frequent presence of undetectable tumor burden in such patients. Criteria are needed to evaluate these patients for risk of recurrence. We have now evaluated whether HGF present in resectable lung tumors has prognostic significance. In this study, 56 primary NSCLCs, mainly adenocarcinomas, were examined for presence of HGF by quantitative Western blot. These tumors consisted of tissue from 34 stage I patients, 9 stage II patients, and 13 stage IIIa patients who underwent curative resection for primary NSCLC. Extracts of whole tumor tissue were analyzed after separation of proteins by electrophoresis and transfer of proteins to nitrocellulose membranes. Immunoreactive (ir)-HGF was visualized by reaction with a polyclonal anti-HGF antiserum and quantitated by densitometry. Lung tumor content of ir-HGF varied widely among individuals. Median ir-HGF content in tumor extracts was 15.3 ng/40 microg of tumor protein; mean ir-HGF was 27.2 ng/40 microg of tumor protein. The median and mean ir-HGF were both significantly higher in tumor tissue from patients who suffered a recurrence during the follow-up period compared with those with no evidence or residual disease; this was true of all patients (P = 0.0001) and stage I patients analyzed separately (P = 0.002). Analysis of survival curves indicated that ir-HGF levels higher than the median were associated with poor overall survival (P < 0.03). Univariate analysis showed three factors related to poor overall survival in this set of patients: ir-HGF, tumor (T) status (a measure of primary tumor size and extent), and age. Nodal (N) status and stage were only marginally related to overall survival, most likely because the majority of the patients in the study were stage I. N status, stage, and T status were related to disease-free survival, however. Multivariate Cox analysis showed that ir-HGF, T status, and age independently had a negative impact on overall survival. ir-HGF was a strong independent negative prognostic indicator (P = 0.0001) with a relative risk of 1.022 per unit of ir-HGF (ng/40 microg of protein). This demonstrates that, in this group of patients, the relative risk of ir-HGF content increased continuously as ir-HGF increased, and exceeded 10 at units of ir-HGF of 100 or more. In comparison, in this group of patients, the relative risk of a T status greater than 1 was 4.75 and that of age greater than 65 was 3.95. The combined negative effect of a T status greater than 1 and elevated ir-HGF on survival was also highly pronounced (P < 0.005). In addition, elevated ir-HGF had a negative impact on survival when patients were stratified by stage or N status. Stage I patients with high ir-HGF values had a worse outcome than stage II or stage IIIa patients with low ir-HGF values. Elevated ir-HGF was strongly associated with poor outcome for resectable NSCLC patients as a group, and also identified stage I patients with poor outcome, indicating that it could be a useful indicator of risk of relapse and death in patients who have early lung cancer. The impact of elevated ir-HGF was especially prominent in patients whose T status was greater than 1, suggesting that patients with both risk factors who are stag
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PMID:Association of immunoreactive hepatocyte growth factor with poor survival in resectable non-small cell lung cancer. 901 70

In colorectal cancer patients, prognosis is not determined by the primary tumor but by the formation of distant metastases. Molecules that have been implicated in the metastatic process are the proto-oncogene product c-Met and CD44 glycoproteins. Recently, we obtained evidence for functional collaboration between these two molecules: CD44 isoforms decorated with heparan sulfate chains (CD44-HS) can bind the c-Met ligand, the growth and motility factor hepatocyte growth factor/scatter factor (HGF/SF). This interaction strongly promotes signaling through the receptor tyrosine kinase c-Met. In the present study, we explored the expression of CD44-HS, c-Met, and HGF/SF in the normal human colon mucosa, and in colorectal adenomas and carcinomas, as well as their interaction in colorectal cancer cell lines. Compared to the normal colon, CD44v3 isoforms, which contain a site for HS attachment, and c-Met, were both overexpressed on the neoplastic epithelium of colorectal adenomas and on most carcinomas. Likewise, HGF/SF was expressed at increased levels in tumor tissue. On all tested colorectal cancer cell lines CD44v3 and c-Met were co-expressed. As was shown by immunoprecipitation and Western blotting, CD44 on these cells lines was decorated with HS. Interaction with HS moieties on colorectal carcinoma (HT29) cells promoted HGF/SF-induced activation of c-Met and of the Ras-MAP kinase pathway. Interestingly, survival analysis showed that CD44-HS expression predicts unfavorable prognosis in patients with invasive colorectal carcinomas. Taken together, our findings indicate that CD44-HS, c-Met, and HGF/SF are simultaneously overexpressed in colorectal cancer and that HS moieties promote c-Met signaling in colon carcinoma cells. These observations suggest that collaboration between CD44-HS and the c-Met signaling pathway may play an important role in colorectal tumorigenesis.
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PMID:Expression of c-Met and heparan-sulfate proteoglycan forms of CD44 in colorectal cancer. 1107 15

We reported that NK4, composed of the N-terminal hairpin and subsequent four kringle domains of hepatocyte growth factor (HGF), acts as the competitive antagonist for HGF. We now provide the first evidence that NK4 inhibits tumor growth and metastasis as an angiogenesis inhibitor as well as an HGF antagonist. Administration of NK4 suppressed primary tumor growth and lung metastasis of Lewis lung carcinoma and Jyg-MC(A) mammary carcinoma s.c. implanted into mice, although neither HGF nor NK4 affected proliferation and survival of these tumor cells in vitro. NK4 treatment resulted in a remarkable decrease in microvessel density and an increase of apoptotic tumor cells in primary tumors, which suggests that the inhibition of primary tumor growth by NK4 may be achieved by suppression of tumor angiogenesis. In vivo, NK4 inhibited angiogenesis in chick chorioallantoic membranes and in rabbit corneal neovascularization induced by basic fibroblast growth factor (bFGF). In vitro, NK4 inhibited growth and migration of human microvascular endothelial cells induced by bFGF and vascular endothelial growth factor (VEGF) as well as by HGF. HGF and VEGF activated the Met/HGF receptor and the KDR/VEGF receptor, respectively, whereas NK4 inhibited HGF-induced Met tyrosine phosphorylation but not VEGF-induced KDR phosphorylation. NK4 inhibited HGF-induced ERK1/2 (p44/42 mitogen-activated protein kinase) activation, but allowed for bFGF- and VEGF-induced ERK1/2 activation. These results indicate that NK4 is an angiogenesis inhibitor as well as an HGF antagonist, and that the antiangiogenic action of NK4 is independent of its activity as HGF antagonist. The bifunctional properties of NK4 to act as an angiogenesis inhibitor and as an HGF antagonist raises the possibility that NK4 may prove therapeutic for cancer patients.
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PMID:HGF/NK4, a four-kringle antagonist of hepatocyte growth factor, is an angiogenesis inhibitor that suppresses tumor growth and metastasis in mice. 1111 60

The process of metastasis is a highly selective, nonrandom process resulting in the clonal selection of a population of cells that is able to detach from the primary tumor, invade and survive in the circulation, arrest, extravasate, and ultimately survive and proliferate in the secondary organ-specific site. Tumor cell interactions with the microenvironment can profoundly influence the survival and proliferation of the cell at a secondary site. The epidermal growth factor receptor (EGFR) and the hepatocyte growth factor receptor (c-Met) are two such receptor tyrosine kinases (RTKs) that have been causally implicated in colorectal carcinoma (CRC) progression and metastasis. Activation of these RTKs can stimulate a number of specific pathways directly effecting tumor cell migration, survival and proliferation. The aberrant regulation of the RTKs is often noted in advanced CRC and its' liver metastases and can significantly effect the metastatic phenotype of tumor cells.
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PMID:The coordinated functional expression of epidermal growth factor receptor and c-Met in colorectal carcinoma metastasis. 1112 42

Hepatocyte growth factor (HGF) is a multifunctional cytokine which acts as a mitogen, motogen, morphogen and angiogenic factor of epithelial cells. HGF receptor is encoded by a proto-oncogene, c-met, which is overexpressed in various cancers. The role of HGF and c-Met in prostate carcinogenesis, especially in the early stages, is undefined. In this study, prostatic dysplasia and carcinomas were induced by testosterone propionate and 17 beta-estradiol in Noble rats. The expression of HGF and c-Met was assessed at a protein level by immunohistochemistry and western blot analysis. Intense immunostaining for HGF alpha and c-Met beta-chain was co-localized in dysplastic lesions and in primary and metastatic cancer cells. The levels of HGF alpha expression were similar among normal control, dysplastic and cancerous prostate tissues, as determined by western blot analysis. Immunoblot study for c-Met under reducing conditions identified two bands at 145 kDa (beta-subunit of c-Met) and 170 kDa (precursor form of c-Met) in rat liver extracts. However, two bands at approximately 220 and 245 kDa were detected in hormone-treated dysplastic prostate tissues and primary tumors. Overexpression of the 220 kDa band was observed in long-term (10-12 months) hormone-treated prostate and primary tumor extracts. Metastatic tumors consistently exhibited up-regulation of a single 245 kDa band. Under non-reducing conditions, however, protein bands of 220, 280 or 300 kDa were seen in the blots. The hormone-treated prostate tissues and metastatic tumors expressed the 220 and 300 kDa proteins, respectively. The majority of primary tumors expressed the 280 kDa protein. In summary, HGF and its receptor, c-Met, were co-expressed in dysplastic and tumor cells, suggesting that an autocrine mode of action may be involved in prostate carcinogenesis. The close correlation of expression of the high-molecular-weight isoforms of c-Met with different stages of carcinogenesis implicates that they might play differential roles in the onset, progression, growth and metastasis in prostate cancer.
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PMID:Aberrant expression of hepatocyte growth factor and its receptor, c-Met, during sex hormone-induced prostatic carcinogenesis in the Noble rat. 1113 7

Many human breast cancer cell lines have been in culture for several years, serving as model systems for studying aspects of breast cancer biology. Molecular alterations might occur in these cells during cultivation, and it remains unknown to which extent findings in these cell lines can be related to human disease. Hereby, we describe the establishment of a breast cancer cell line, MW1, from malignant pleural effusion. We compare expression patterns of several molecular markers in breast biopsy tissue, in cultivated tumor cells derived from pleural effusion reflecting the metastatic state, and in late passages of a lineage derived from the pleural culture. Our data show that expression of estrogen and progesterone receptors was lost in the cultivated tumor cells derived from pleural effusion as shown by immunohistochemical staining. Cytokeratin expression patterns remained luminal. During cultivation, the growth rate of MW1 cells increased dramatically and the morphology underwent alterations. As shown by Western blotting, E-cadherin expression remained unchanged whereas P-cadherin expression had increased after 4 years of cultivation of the cell line. Integrin beta4 expression was low in early passages of the pleural effusion whereas the cell line exhibited high expression levels of beta4. HGF receptor (c-Met), EGF receptor, VEGF and VEGF receptor-2 (KDR) expression was detectable by semiquantitative RT-PCR and remained unchanged during cultivation. In contrast, VEGF receptor-1 (flt-1) expression showed lower expression after 4 years of cultivation. The cell line migrated towards HGF, but not towards VEGF. This study provides exemplary insight into the molecular metamorphosis tumor cells undergo in vivo or in vitro on their way from the primary tumor via an equivalent of the metastatic state and during the development of a clonal cell line.
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PMID:A novel breast cancer cell line initially established from pleural effusion: evolution towards a more aggressive phenotype. 1727 57

The hepatocyte growth factor/scatter factor (HGF/SF) tyrosine kinase (TK) receptor c-Met plays a crucial role in the development of the invasive phenotype of tumors and thus represents an attractive candidate for targeted therapies in a variety of malignancies, including human malignant melanoma (MM). In contrast to what has been shown previously, we were not able to detect any genetic alterations, either in the juxtamembrane- or in the TK-domain of c-Met, in the studied MM cell lines. Nevertheless, c-Met was constitutively active in these cell lines without exogenous HGF/SF stimulation. The active receptor was localized to the adhesion sites of the cells. Addition of the c-Met TK inhibitor SU11274 specifically decreased the phosphotyrosine signal at the focal adhesions sites, which was accompanied by a decrease in cell proliferation as well as an increase in apoptotic cells. In addition, non-apoptotic concentrations of SU11274 significantly reduced the in vitro migratory capacity of MM cells in the modified Boyden-chamber assay. Administration of SU11274 significantly decreased primary tumor growth as well as the capacity for liver colony formation of MM cells in SCID mice. Our study provides the first evidence for an in vivo antitumor activity of SU11274 in a human melanoma xenograft model, and suggests c-Met as a valid target for the therapy of MM. Consequently, SU11274 treatment might represent a useful strategy for controlling melanoma progression and metastasis in patients with MM.
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PMID:Inhibition of c-Met with the specific small molecule tyrosine kinase inhibitor SU11274 decreases growth and metastasis formation of experimental human melanoma. 2037 Jun 83

Endometrial cancer is the most commonly diagnosed gynecologic malignancy in the United States. In 2008, approximately 40,000 cases were newly diagnosed. Although the majority of these cancers are curable by means of hysterectomy and radiotherapy, a subset of endometrial tumors exhibits an aggressive phenotype characterized by lymphovascular invasion, high histological grade, and myometrial invasion, leading to poor prognosis. The mechanisms involved in this aggressive transformation are largely unknown, however, interactions between the primary tumor mass and the surrounding stroma likely play a role in this transformation. Despite the fact that research in other common malignancies has elucidated important associations between stromal protein expression and invasion, these mechanisms have been poorly explored in the area of endometrial cancer. In fact, few investigations have been conducted in the area of tumor microenvironment for endometrial tumors. Invasion and metastasis are two primary reasons for treatment failure related to endometrial cancer. Expression of stromal-derived proteins can potentially serve as biomarkers of aggressive disease as well as biomarkers for remission monitoring. In order to study how expression of these proteins relates to the prognosis of endometrial cancer, these proteins need to be explored in large sets of existing data and/or tissue banks. In this paper, we briefly review the role of three stromal related pathways, SDF-1alpha/CXCR4, HGF/c-Met, and VEGF-A in endometrial cancer prognosis as an overview of the literature. We report that the role of SDF-1alpha/CXCR4 and HGF/c-Met in endometrial cancer prognosis remains unclear, whereas the evidence pertaining to VEGF indicates that overexpression is involved in tumor growth and metastasis. Finally, we would like to highlight the need to explore stromal proteins as a potential tool for the detection of aggressive endometrial tumors and explore some of the molecular approaches that can be utilized in the exploration of the tumor environment.
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PMID:Future directions in the field of endometrial cancer research: the need to investigate the tumor microenvironment. 2052 27

c-Met is a receptor tyrosine kinase that has been implicated in the pathogenesis and growth of a wide variety of human malignancies, including CRC, but its role in metastasis is largely unknown. We compared c-Met expression in primary human colorectal carcinomas and distant metastases from the same patients. Formalin-fixed paraffin-embedded tissue samples from 69 colorectal cancer patients were obtained. The protein expression of c-Met was evaluated immunohistochemically using a commercial antibody. The difference in expression between primary tumors and their corresponding distant metastases was analyzed using the Wilcoxon signed-rank test. c-Met expression was statistically significantly lower in the distant metastases compared to their corresponding primary tumors (p<0.001), whereas no difference was found between lymph node metastases and their corresponding primary tumors (p=0.957). The degree of c-Met expression was not related to clinicopathological characteristics such as tumor grade and Dukes' stage at the time of primary tumor diagnosis, or to the location of the distant metastases. We demonstrated that c-Met expression is often reduced in distant metastases compared to their corresponding primary colorectal tumors. Additional studies of c-Met activation and signal transduction will increase our knowledge about the role of c-Met in colorectal cancer metastasis.
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PMID:c-Met expression in primary tumors and their corresponding distant metastases. 2147 86

The components of the extracellular matrix (ECM) are more than just adhesion sites for migrating tumor cells: following enzymatic degradation of the ECM, the release of sequestrated growth factors increases, thus they become available for tumor cells. In a number of cancers dysfunction of epidermal growth factor receptor (EGFR) or hepatocyte growth factor receptor (c-Met) contribute to the malignant transformation that directly regulates cell proliferation, survival and motility. Furthermore, intracellular calcium level plays an important role in the regulation of the tyrosine kinase pathway. In our preclinical experiments, by administering heparin-derived oligosaccharides we influenced the interaction between human melanoma cells and ECM. In vitro cell migration was inhibited by heparin fragments. Moreover, two of the effective oligosaccharides reduced the number of lung colonies formed in SCID mice. In human melanoma cells an important element of Ca2+ homeostasis, the purinergic Ca2+ channel P2X7 proved to be an anti-apoptotic protein. EGFR and c-Met showed constitutive activity in human melanoma cells, and their inhibition in vitro caused decreased proliferation, migration and elevated apoptosis. Administration of a selective c-Met-TKI significantly decreased primary tumor growth in vivo as well as the capacity for liver colony formation in SCID mice. Selective EGFR-TKI had less inhibitory effect on metastasis formation, and had no effect on the primary tumor. Our results suggest the necessity of a rational dual-specific drug design for the purpose in the therapy of malignant melanoma.
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PMID:[Study of motogenic signal in human melanoma cells]. 2161 91


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