UMLS:C0699790 - FACTA Search

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Query: UMLS:C0699790 (colon cancer)
28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We report the immunological characterization of three colon carcinoma cell lines, COLO 205, SW620 and SW403, which we selected to combine with cytokine-secreting fibroblasts for the development of an allogeneic tumour cell vaccine. The cell lines expressed HLA-A2 as well as shared tumour-associated antigens (TAAs) representative of colon carcinomas: CEA, Ep-CAM, MUC1, HER2/neu and MAGE antigens. They did not secrete high levels of the immunosuppressive factors TGF-beta, IL-10 or prostaglandins. The lines presented TAAs in a manner recognized by immune effector cells, which was demonstrated by the lysis of SW620 by HLA-A2-restricted anti-p53 cytotoxic T lymphocytes (CTL). COLO 205 and SW620 were genetically modified to express the co-stimulatory molecule CD80 (B7.1), which increased the ability of the cells to stimulate CTL in vitro. CTL clones derived from HLA-A2+ peripheral blood mononuclear cells stimulated with the CD80-expressing lines lysed the stimulator cell and an HLA-A2+ colon cancer cell line, but did not lyse an isogeneic fibroblast line or an HLA-A2- colon cancer cell line. CTL clones derived from colon carcinoma patients immunized with an allogeneic vaccine containing these lines demonstrated killing of autologous tumour cells, the vaccine cell lines and other HLA-A2+ colon cancer cell lines, but not fibroblasts isogeneic to certain of the target cell lines. Our studies demonstrate that these colon carcinoma cell lines express shared TAAs that can induce CTLs which recognize and lyse other colon carcinoma cells, and support the continued clinical evaluation of the CD80 gene modified allogeneic colon cell/cytokine-secreting fibroblast carcinoma vaccine.
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PMID:Antigenic and immunologic characterization of an allogeneic colon carcinoma vaccine. 1210 28

The HER-2/neu oncogene encodes a 185 kD protein that is phosphorylated upon ligand binding to other HER/erbB members and regulates cell growth and differentiation. Given that HER-2 receptor blockade can inhibit the growth of colon cancer cell lines and tumor xenografts, we investigated the frequency, localization and phosphorylation status of HER-2 in colon cancer cell lines and in human tumors. Protein expression was analyzed in relation to mRNA levels, HER-2 amplification, and clinicopathological variables. Colon cancer cell lines constitutively expressed HER-2 proteins and none showed HER-2 amplification by fluorescence in situ hybridization. Cell fractionation and immunoblotting showed HER-2 in both the membrane and cytosolic compartments. Primary colorectal carcinomas (n = 96) and their metastases (n = 25) were examined by immunohistochemistry. Strong membrane HER-2 staining was detected in 5 (5%) of primaries and in 3 (12%) metastases (p = 0.36). Membrane but not cytoplasmic localization was strongly associated with HER-2 gene amplification (p = 0.007). Cytoplasmic HER-2 staining was found in 61 (63.5%) of primary tumors and localization was confirmed by immunoelectron microscopy that also showed plasma membrane HER-2. Using real-time quantitative RT-PCR, HER-2 mRNA was increased in tumors with membrane compared to cytoplasmic staining (r = 0.66, p = 0.001). Cytoplasmic HER-2 was associated with tumor differentiation (p = 0.018), but not other clinicopathological variables. By immunoblotting, heterogeneity was seen in HER-2 levels with downregulation in 4 of 7 tumors relative to normal epithelia that uniformly expressed HER-2. Phosphorylated HER-2 was detected in approximately 50% of tumors and in normal mucosa. In conclusion, HER-2 is expressed constitutively in colon cancer cell lines and demonstrates relatively distinct localization patterns in human tumors. Strong membrane immunoreactivity is associated with high levels of HER-2 mRNA and gene amplification whereas cytoplasmic HER-2 is detected frequently and seems to be a marker of tumor differentiation.
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PMID:HER-2 receptor expression, localization, and activation in colorectal cancer cell lines and human tumors. 1469 18

Little information is available as to the potential role of HER-2 as a therapeutic target in colon cancers, which express much fewer HER-2 receptors than breast cancer cells. Treatment of certain human colon cancer cell lines with the HER-2 inhibitory antibody mAb 4D5 demonstrated a role for HER-2 in mediating proliferation, apoptosis and tumorigenicity. However, only the cell lines that were dependent on autocrine EGFR-mediated cell proliferation were susceptible to the antiproliferative and antitumorigenic effects of HER-2 inhibition. The relative levels of HER-2, EGFR, HER-3 and HER-4 were not predictive of responsiveness to mAb 4D5. Treatment with HER-2 antibodies caused a decrease in HER-2 protein levels in all of the colon cancer cell lines and also significantly decreased EGFR levels but only in the EGFR-dependent cell lines. Treatment with mAb 4D5 caused the rapid ubiquitination and ligand-dependent downregulation of the EGFR in an EGFR-dependent colon cancer cell line. Treatment of athymic mice engrafted with EGFR-dependent colon cancer cells with mAb 4D5 caused tumor regression and a decrease in EGFR tyrosine phosphorylation in the tumor cells. EGFR-independent colon cancer cell xenografts were resistant to mAb 4D5 therapy. Combined inhibition of HER-2 and EGFR caused large areas of necrosis in EGFR-dependent colon cancer xenografts, suggesting a benefit of combined HER-2 and EGFR inhibitor therapy. Predicting clinical responsiveness of human colon cancer cells to anti-HER-2 and anti-EGFR therapy may require demonstration of EGFR tyrosine kinase dependency of the cells.
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PMID:Effects of trastuzumab on epidermal growth factor receptor-dependent and -independent human colon cancer cells. 1475 Jan 83

Within the revolution of molecular biology in cancer, it should be pointed out the role of monoclonal antibodies clinically utilized as if they were "magic bullets". From the works of Kohler and Milstein in 1975 the evolution has been fast and its inclusion in daily clinical practice gradual. Among the more significant there is anti-CD20 that has revolutionized the treatment of lymphomas. Currently, antibodies conjugated with isotopes derived from anti-CD20 have been produced. Trastuzumab antibody against HER2/neu has opened new prospects in the treatment of breast cancer. Cetuximab antibody against EGFR has achieved good results in the treatment of chemotherapy-resistent colon cancer. Bevacizumab is perhaps the most promising antibody against solid tumors, having shown effectiveness as first line therapy in metastatic colon cancer in combination with chemotherapy.
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PMID:[Antibodies against cancer]. 1571 74

HER-2 is constitutively activated and overexpressed in many cancers, and its inhibition in colon cancer cells diminishes tumorigenicity and induces apoptosis. Little is known about the regulation of HER-2 signaling in colon cancer cells. Integrin alpha5/beta1 expression is frequently lost in colorectal cancer cells compared with normal intestinal epithelium, and colon cancer cells lacking integrin alpha5/beta1 expression utilize HER-2 signaling for proliferation and tumorigenicity. Re-expression of integrin alpha5/beta1 in colon cancer cells abrogated their tumorigenicity, but how this occurs is not well known. Stable expression of integrin alpha5/beta1 in colon cancer cells with little or no detectable integrin alpha5/beta1 protein expression resulted in the post-transcriptional down-regulation of HER-2 protein. Integrin alpha5/beta1 was found to interact with HER-2, and the cytoplasmic domain of integrin alpha5/beta1 was sufficient to mediate HER-2 down-regulation. Integrin alpha5/beta1-mediated down-regulation of HER-2 was the result of increased lysosomal targeting. The inhibition of HER-2 signaling represents a potential mechanism by which integrin alpha5/beta1 exerts its tumor suppressor-like activity in colon cancer cells. These results also suggest that a novel function for integrin alpha5/beta1 is the control of HER-2 expression.
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PMID:Integrin alpha5/beta1 expression mediates HER-2 down-regulation in colon cancer cells. 1575 8

The IGF/IGF-1R system, which includes the IGF, IGF-1R, and IGFBPs proteins, plays an important role in the development and growth of colorectal cancer. We previously reported that in the HT29 human colon cancer cell line EGCG, the major biologically active component of green tea, inhibits activation of the RTKs EGFR, HER2, and HER3, and that this is associated with inhibition of multiple downstream signaling pathways. Since IGF-1R is also a RTK, in this study we examined the effects of EGCG on the activity of IGF/IGF-1R system in human colon cancer cells. We found that the colon cancer cell lines Caco2, HT29, SW837, and SW480 express high levels of the IGF-1R receptor, and that both SW837 and SW480 cells display constitutive activation of this receptor. Treatment of SW837 cells with 20 microg/ml of EGCG (the IC50 concentration for growth inhibition) caused within 6 h a decrease in the phosphorylated (i.e., activated) form of the IGF-1R protein. At 12 h, there was a decrease in the levels of both IGF-1 protein and mRNA and within 3-6 h there was an increase in the levels of both IGFBP-3 protein and mRNA. The increased expression of the latter protein was sustained for at least 48 h. When SW837 cells were treated with EGCG for a longer time, i.e., 96 h, a very low concentration (1.0 microg/ml) of EGCG also caused inhibition of activation of IGF-1R, a decrease in the IGF-1 protein, and an increase in the IGFBP-3 protein. EGCG also caused a decrease in the levels of mRNAs that encode MMPs-7 and -9, proteins that proteolyze IGFBP-3. In addition, treatment with EGCG caused a transient increase in the expression of TGF-beta2, an inducer of IGFBP-3 expression. These findings expand the roles of EGCG as an inhibitor of critical RTKs involved in cell proliferation, providing further evidence that EGCG and related compounds may be useful in the chemoprevention or treatment of colorectal cancer.
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PMID:EGCG inhibits activation of the insulin-like growth factor-1 receptor in human colon cancer cells. 1605 20

Cancer cells transcriptionally activate many genes that are important for uncontrolled proliferation and cell death. Deregulated transcriptional machinery in tumor cells usually consists of increased expression/activity of transcription factors. Ideally, cancer-specific killing can be achieved by delivering a therapeutic gene under the control of the DNA elements that can be activated by transcription factors that are overexpressed and/or constitutively activated in cancer cells. Additionally, tumor-specific translation of tumor-killing genes has been also exploited in cancer gene therapy. Based on these rationales, cancer-specific expression of a therapeutic gene has emerged as a potentially successful approach for cancer gene therapy. To achieve tumor-specific expression, cancer-specific vectors are generally composed of promoters, enhancers, and/or 5'-UTR that are responsive to tumor-specific transcription factors. A number of cancer-specific promoters have been reported, such as those of probasin, human telomerase reverse transcriptase, survivin, ceruloplasmin, HER-2, osteocalcin, and carcinoembryonic antigen. Evidences suggest that the enhancer element targeted by beta-catenin can be useful to target colon cancer cells. The 5'-UTR of the basic fibroblast growth factor-2 has been reported to provide tumor specificity. Moreover, a variety of therapeutic genes demonstrated direct antitumor effects such as those encoding proapoptotic proteins p53, E1A, p202, PEA3, BAX, Bik, and prodrug metabolizing enzymes, namely thymidine kinase and cytosine deaminase. As cancerous cells of different origins vary significantly in their genetic, transcriptional/translational, and cellular profiles, the success of a cancer gene therapy will not be promised unless it is carefully designed based on the biology of a specific tumor type. Thus, tremendous research efforts have been focused on the development of non-viral vectors that selectively target various tumors resulting in minimal toxicity in the normal tissues. Significant progresses were also made in the exploitation of various novel apoptotic, cytotoxic genes as therapeutic tools that suppress the growth of different tumors. Together, these recent advances provide rationales for future clinical testing of transcriptionally targeted non-viral vectors in cancer patients.
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PMID:Cancer-specific gene therapy. 1609 14

Increased expression of COX-2 appears to play an important role in the development of colorectal cancer. The level of COX-2 expression is regulated by various factors including activation of members of the EGFR family of RTKs. We previously reported that in HT29 human colon cancer cells EGCG, the major biologically active component of green tea, inhibits activation of two members of this family, EGFR and HER2, and multiple downstream signaling pathways. In this study we examined the effects of EGCG on the HER3 RTK and on COX-2 expression in the SW837 human colon cancer cell line that expresses a high level and constitutive activation of HER3 and also expresses a high level of COX-2. Treatment of these cells with 20 microg/ml of EGCG (the IC50 concentration for growth inhibition) caused, within 6 hours, a decrease in the phosphorylated (i.e. activated) forms of not only EGFR and HER2, but also HER3. At 6 to 12 hours there was a decrease in the phosphorylated forms of the downstream signaling proteins ERK and Akt. Within 6 to 12 hours there was a decrease in cellular levels of both COX-2 protein and mRNA, and within 48 hours the cells displayed apoptosis. Reporter assays indicated that EGCG inhibited the transcriptional activities of the COX-2, AP-1, and NF-kappaB promoters. EGCG also caused a decrease in production of PGE2, a major product of COX-2. With a longer incubation time, 96 hours, a very low dose (1.0 microg/ml) of EGCG also caused inhibition of cell growth, inhibition of activation of EGFR, HER2, and HER3, a decrease in the levels of COX-2 and Bcl-xL proteins, and apoptosis. These results provide the first evidence that a low concentration of EGCG can inhibit activation of, at least, three members of the EGFR family of RTKs, and also inhibit COX-2 expression in colon cancer cells. These findings extend our previous evidence that EGCG may be useful in the chemoprevention and/or treatment of colorectal cancer.
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PMID:EGCG inhibits activation of HER3 and expression of cyclooxygenase-2 in human colon cancer cells. 1641 3

Cyclooxygenase enzymes play an important role in carcinogenesis, and increased expression of cyclooxygenase enzymes has been reported in cancers arising at a number of different sites. Most, if not all of these actions are thought to be mediated by prostaglandin E2 (PGE2). The actions of PGE2 are mediated via four main prostanoid receptors, designated EP1, EP2, EP3 and EP4, based on their different pharmacological properties and secondary messenger pathways. Recently, expression of EP1 has been reported in rat mammary gland and the inhibition of this receptor has been documented to have chemopreventive effect in this animal model. EP1 has also been shown to decrease the incidence of colon cancer in mouse models. In this study, we analysed the expression of EP1 in normal and malignant breast tissues. Expression of EP1 was analysed in breast (benign and cancer) cell lines by reverse-transcriptase polymerase chain reaction and by western blot analyses. Expression was also analysed by immunohistochemistry in normal breast tissues and in 89 cases of breast cancer. Semiquantitative analysis of the staining was performed. The data were compared with and correlated with other prognostic factors like tumour size, tumour grade, lymph node status, oestrogen receptor, progesterone receptor (PR), HER2/neu and cyclooxygenase-2. EP1 expression was demonstrated in human breast cancer by immunohistochemistry. Expression of EP1 was seen both in the cytoplasm and/or in the nuclear membrane in majority of cases. Nuclear EP1 expression correlated with PR (P=0.032) and inversely with node positivity (P=0.025). However, EP1 expression did not correlate with expression of cyclooxygenase-2 (P=0.059). Expression of EP1 is frequently seen in human breast cancers. Nuclear expression of EP1 correlates with good prognosis markers like node negative status and PR expression.
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PMID:Prostanoid receptor EP1 expression in breast cancer. 1790 15

Curcumin (diferuloylmethane), which has been shown to inhibit growth of transformed cells, has no discernible toxicity and achieves high levels in colonic mucosa. 5-fluorouracil (5-FU) or 5-FU plus oxaliplatin (FOLFOX) remains the backbone of colorectal cancer chemotherapeutics, but with limited success. The present investigation was, therefore, undertaken to examine whether curcumin in combination with conventional chemotherapeutic agent(s)/regimen will be a superior therapeutic strategy for colorectal cancer. Indeed, results of our in vitro studies demonstrated that curcumin together with FOLFOX produced a significantly greater inhibition (p < 0.01) of growth and stimulated apoptosis (p < 0.001) of colon cancer HCT-116 and HT-29 cells than that caused by curcumin, 5-FU, curcumin + 5-FU or FOLFOX. These changes were associated with decreased expression and activation (tyrosine phosphorylation) of EGFR, HER-2, HER-3 (72-100%) and IGF-1R (67%) as well as their downstream effectors such as Akt and cycloxygenase-2 (51-97%). Furthermore, while these agents produced a 2-3-fold increase in the expression of IGF-binding protein-3 (IGFBP-3), curcumin together with FOLFOX caused a 5-fold increase in the same, when compared to controls. This in turn led to increased sequestration of IGF by IGFBP-3 rendering IGF-1 unavailable for binding to and activation of IGF-1R. We conclude that the superior effects of the combination therapy of curcumin and FOLFOX are due to attenuation of EGFRs and IGF-1R signaling pathways. We also suggest that inclusion of curcumin to the conventional chemotherapeutic agent(s)/regimen could be an effective therapeutic strategy for colorectal cancer.
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PMID:Curcumin enhances the effects of 5-fluorouracil and oxaliplatin in mediating growth inhibition of colon cancer cells by modulating EGFR and IGF-1R. 1791 58

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