Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0009402 (colorectal cancer)
 53,228 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Activation of the receptor tyrosine kinase c-kit by the kit-ligand, also known as stem cell factor (SCF), is essential to melanocyte and germ cell development and during the early stages of hematopoiesis. Deregulated expression of c-kit has been reported in malignancies affecting these lineages, i.e., myeloid leukemias, melanomas, and germ cell tumors. In addition, c-kit and SCF are coexpressed in some breast and colorectal cancer (CRC) cells, raising the question of whether c-kit serves an autocrine role in normal or malignant epithelial tissues. In this study, we demonstrate that human colorectal carcinomas, but not normal colorectal mucosa cells, coexpress SCF and c-kit in situ. Expression of c-kit was also observed in mucosa adjacent to colorectal tumor tissue. Consistent with a growth-regulatory role of SCF in CRC cells, exogenous SCF stimulated anchorage-dependent and anchorage-independent growth in four out of five CRC cell lines. Exogenous transforming growth factor (TGF)-beta 1 added at nanomolar concentrations to HT-29 CRC cells, which express the type I, II, and III TGF-beta receptors, downregulated c-kit expression to background levels and inhibited c-kit-dependent proliferation. Similarly, TGF-beta 1 inhibited SCF-dependent proliferation of three first-passage CRC cell lines. In summary, expression of the potential autocrine SCF/ c-kit axis is a tumor-associated phenomenon in colorectal cancer that can be suppressed by TGF-beta 1 in TGF-beta-responsive CRC cells.
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PMID:Growth stimulation of colorectal carcinoma cells via the c-kit receptor is inhibited by TGF-beta 1. 920 20

The c-met proto-oncogene product is a receptor tyrosine kinase that mediates the effects of the multifunctional cytokine hepatocyte growth factor/scatter factor (HGF/SF). We have studied the expression of both the c-met receptor and HGF/SF at both the protein and message level in colorectal cancer tissues of varying disease stage. All of the tumors displayed an overexpression of the c-met mRNA compared to their normal tissue counterparts while 16 of 21 tissues (75%) displayed up-regulation of c-met protein. No HGF/SF mRNA or protein could be detected in either tissue type. Viable tumor cells extracted from cancer tissue exhibited increased motility in response to HGF/SF stimulation demonstrating that c-met was functionally active. No correlation between expression of c-met and tumor stage or degree of differentiation was observed. HGF/SF is known to be a potent stimulator of tumor cell motility and invasion, two cellular properties essential for the metastatic development of cancers. The overexpression of the HGF/SF receptor in colorectal cancers may result in an increased sensitivity to HGF/SF, which may confer an enhanced metastatic potential to the cancer cells within the tumor body.
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PMID:Expression of the HGF/SF receptor, c-met, and its ligand in human colorectal cancers. 941 56

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

GIPC1/RGS19IP1/GIPC, GIPC2, and GIPC3 are a family of central PDZ-domain proteins with GH1 and GH2 domains. GIPC1 interacts with GTPase-activating protein RGS19/RGS-GAIP, TGFbeta type III receptor, receptor tyrosine kinase TrkA, and integrin alpha6A subunit. Xenopus homologue of human GIPCs interacts with Frizzled-3 class of WNT receptor. We investigated expression of human GIPC1 mRNA in normal tissues, cancer cell lines, and primary tumors. GIP1A probe (nucleotide position 1075-1483 of GIPC1 cDNA) hybridized to GIPC1 mRNA of 1.8 kb in size. GIPC1 mRNA was almost ubiquitously expressed in various normal tissues. Expression level of GIPC1 mRNA was relatively lower in bone marrow and peripheral blood leukocytes. GIPC1 mRNA was relatively highly expressed in gastric cancer cell lines OKAJIMA, TMK1, MKN28, MKN45, MKN74, KATO-III, pancreatic cancer cell line AsPC-1, colorectal cancer cell line SW480, and lung cancer cell line A549. On the other hand, GIPC1 mRNA was almost undetectable in leukemia/lymphoma cell lines HL-60, Raji, and Daudi. Expression of GIPC1 mRNA was down-regulated in 12 out of 14 cases of primary kidney tumors, 10 out of 18 cases of primary colorectal tumors, 3 out of 8 cases of primary gastric cancer, 3 out of 3 cases of primary prostate cancer. Because GIPC1 induces increased expression of TGFbeta type III receptor at the cell surface and enhanced responsiveness to TGFbeta, down-regulation of GIPC1 mRNA in tumors might promote cellular proliferation through interference of TGFbeta signaling.
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PMID:Expression of human GIPC1 in normal tissues, cancer cell lines, and primary tumors. 1195 58

Overexpression of the receptor tyrosine kinase Met is an early event in the colorectal adenoma-carcinoma sequence. This suggests a link with disruption of adenomatous polyposis coli-controlled regulation of beta-catenin/T-cell factor (TCF)-mediated transcriptional activation, which is crucial in initiating tumorigenesis. Indeed, in intestinal biopsies from patients with familial adenomatous polyposis, we find Met already overexpressed in dysplastic aberrant crypt foci, the earliest neoplastic lesions of colorectal cancer (CRC). Moreover, in CRC cells, induction of dominant-negative TCF proteins and the consequent abrogation of beta-catenin/TCF-mediated transcriptional activation lead to a strong down-regulation of Met expression. Our results indicate that Met expression is part of a genetic program controlled by the Wnt pathway and suggest a role for Met in controlling the turnover and differentiation of intestinal epithelium.
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PMID:Wnt signaling regulates expression of the receptor tyrosine kinase met in colorectal cancer. 1223 72

Although relatively little is known about the molecular mechanisms underlying tumor progression, recently CD44 glycoproteins and the c-Met receptor tyrosine kinase have been identified as potentially important components of the metastatic cascade. CD44 is a family of transmembrane receptors generated from a single gene by alternative splicing and differential glycosylation. Important biological processes involving CD44 glycoproteins include cell adhesion, lymphocyte homing, hematopoiesis, tumor progression and metastasis. The precise mechanism via which CD44 promotes tumorigenesis have not yet been elucidated. We evaluated the expression of adhesion molecule CD44 variant 6 in pulmonary metastases from colorectal carcinomas and its correlation with clinicopathological parameters. Twenty patients were randomly selected from the patients who had undergone a resection of pulmonary metastasis from colorectal cancer. Formalin-fixed, paraffin-embedded archival specimens of tumor tissues and adjacent normal mucosa from these patients were the subjects of the present study. Immunoreactivity for CD44 was quantified. Specimens were considered positive if almost 25% of the neoplastic cells were stained. CD44 v6 expression was related to the interval between colon resection and metastases diagnosis, the number of pulmonary metastases, and the survival after lung resection. No statistical correlation was found between CD44 v6 positivity and disease-free interval after colon resection, number of metastases or 2-year survival after lung resection. Probably CD44 v6 is necessary and sufficient to confer metastatic potential to carcinoma cells increasing the migration capacity and participating in invasion via changes in adhesion to the extracellular ligands, but is not necessary to modify the clinical history of the metastases. Therefore the evaluation of CD44 v6 expression in lung metastases does not influence the therapeutic scheme.
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PMID:Evaluation of CD44 variant 6 expression and clinicopathological factors in pulmonary metastases from colon carcinoma. 1453 11

Analysis of human colorectal cancer specimens revealed overexpression of the EphB2 receptor tyrosine kinase. Monoclonal antibodies (MAbs) to extracellular sequence of EphB2 were raised and tested for activity against colorectal cancer cells. One of the MAbs, 2H9, effectively blocked the interaction of ephB2 with ephrin ligands and inhibited the resulting autophosphorylation of the receptor. However, this antibody did not affect the proliferation of cancer cells expressing ephB2. Immunocytochemical analysis revealed rapid internalization of the MAb 2H9 on binding ephB2, suggesting that target-dependent cell killing could be achieved with an antibody-drug conjugate. When MAb 2H9 was conjugated to monomethylauristatin E through a cathepsin B-cleavable linker, it specifically killed ephB2-expressing cancer cells in vitro and in vivo. Our results suggest that ephB2 is an attractive target for immunoconjugate cancer therapy.
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PMID:EphB2 as a therapeutic antibody drug target for the treatment of colorectal cancer. 1487 99

Altered expression of receptor tyrosine kinases contributes to tumorigenic behaviors of epithelial cancers. In this study, the pathogenic roles of receptor tyrosine kinase RON (recepteur d'origine nantais) in regulating oncogenic phenotypes in colorectal epithelial cells were studied. Increased expression of RON and its variants resulted in colony formation and motile activities of colonic epithelial AA/C1 cells as evident in soft-agar and migration assays, respectively. These results suggest that overexpression of wild-type RON mediates the transformed phenotypes in immortalized colon epithelial cells. In colorectal cancer cells (HT-29, HCT116, and SW620) that naturally express RON, the RON gene expression was silenced by RNA interference. The introduction of RON-specific small interfering (si) RNA significantly affected cancer cell proliferation, motility, and led to increased apoptotic cell death. Focus-forming activities and anchorage-independent growth of colon cancer cells were also dramatically reduced. Moreover, it was demonstrated in tumor growth assays that silencing RON gene expression significantly reduces tumorigenic activities of SW620 cells in vivo. By analysing signaling proteins involved in colon carcinogenesis, we found that the effect of RON-specific siRNA is associated with diminished expression of beta-catenin, a critical component in the Wnt signaling pathway. Taken together, our results demonstrate that altered expression of RON in colon cancer cells is required to maintain tumorigenic phenotypes. Thus, silencing RON gene expression could have potential to reverse malignant activities of colon tumors in vivo.
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PMID:RNA-mediated gene silencing of the RON receptor tyrosine kinase alters oncogenic phenotypes of human colorectal carcinoma cells. 1537 25

A receptor tyrosine kinase for ephrin ligands, EphB2 is expressed in colorectal cancer and has been proposed as a target for immunoconjugate therapy. The aim of this study was to perform a detailed histologic analysis of EphB2 expression in normal and neoplastic colorectal tissues. In addition, we sought to evaluate EphB2 expression as a prognostic factor in colorectal cancer. Expression of EphB2 was examined in normal colon (n = 28), colorectal cell lines (n = 20), colorectal adenomas (n = 148), primary cancers (n = 28), and metastases (n = 39) using immunohistochemistry. In addition, a series of primary cancers and matched normal (n = 342) with outcome data were profiled in tissue microarrays. The intensity of EphB2 expression was assessed in the entire series by immunohistochemistry, and in a subset by in situ hybridization. Overall survival and recurrence-free survival were correlated with EphB2 protein expression in retrospective subset analyses. Epithelial EphB2 expression was shown at all stages of colorectal tumorigenesis, including the base of all normal crypts, 77% of adenomas, 82% of primary cancers, and 64% of metastases. Although homogeneous expression was observed in adenomas, the pattern of staining was focal (mean 25%) in most malignant lesions. Patients whose tumor stained 2+ for EphB2 expression (versus 0/1+) exhibited significantly prolonged overall survival: mean duration of survival, 2,514 versus 1,044 days; hazard ratio, 0.45; 95% confidence interval, 0.18 to 0.95 (P = 0.035). In summary, EphB2 is expressed in normal crypts, colorectal adenomas, primary cancers, and metastases. High levels of EphB2 expression are associated with a longer mean duration of survival in colorectal cancer.
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PMID:EphB2 is a prognostic factor in colorectal cancer. 1603 34

Inhibition of the epidermal growth factor receptor (EGFR) represents one of the most important avenues for research and development in the field of cancer therapy. The EGFR is a member of the ErbB receptor tyrosine kinase (TK) family, which also includes ErbB-2 (HER2/neu), ErbB-3 (HER3), and ErbB-4 (HER4). Current EGFR therapies available for use include monoclonal antibodies, such as cetuximab, and small-molecule EGFR TK inhibition by agents such as erlotinib. Side effects of these agents include dermatologic manifestations without the bone marrow suppressive properties of chemotherapy. Understanding of rash and how it relates to EGFR inhibitor toxicity and, perhaps more importantly, EGFR inhibitor response must be more clearly defined with clinical trials. The optimum management of rash in patients receiving anti-EGFR therapy remains somewhat controversial; this is secondary to imprecise classification of rash as well as the lack of clinical trials to determine the most appropriate treatment algorithm for these patients. We propose a treatment strategy to help aggressively treat dermatologic side effects allowing patients to continue receiving therapy without dose interruption or drug discontinuation.
Clin Colorectal Cancer 2005 Nov
PMID:Management of rash and other toxicities in patients treated with epidermal growth factor receptor-targeted agents. 1633 49


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