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)

Matrix metalloproteinases (MMP) are considered to play important roles in angiogenesis. In angiogenic processes, endothelial cells secrete MMP-2 or MMP-1 to dissolve the basement membrane or connective tissue around the vessels. MMP-7 (matrilysin) is secreted from the neovasculars induced by cancer and is a metastatic factor of colorectal cancer. The effect of matrilysin on angiogenesis is still unclear, however. We therefore examined the effect of MMP-7 on the proliferation of human umbilical vein endothelial cells (HUVECs) in vitro. Our results showed that recombinant MMP-7 (rMMP-7) accelerated the proliferation of endothelial cells dose-dependently, and did so for endothelial cells cultured not only on type IV collagen, but also on type I collagen. MMP-7 also upregulated MMP-1, -2 secretion, but did not stimulate vascular endothelial growth factor (VEGF) secretion. From this study, we conclude that MMP-7 directly induces angiogenesis, and that therefore MMP-7 would be a good target of cancer therapy.
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PMID:MMP-7 (matrilysin) accelerated growth of human umbilical vein endothelial cells. 1180 36

In serum, the major part of vascular endothelial growth factor derives from in vitro degranulation of granulocytes and platelets. Therefore, plasma may be preferred for vascular endothelial growth factor measurements. However, which specimen is the best predictor of survival is still debated. The present study analyzed the prognostic value of matched preoperative serum and plasma vascular endothelial growth factor concentrations in patients with colorectal cancer. To establish the reference range among healthy people, vascular endothelial growth factor was analyzed in 50 matched EDTA-plasma and serum samples from healthy blood donors. Preoperatively, in 524 patients with colorectal cancer, matched plasma and serum vascular endothelial growth factor concentrations were analyzed. In the colorectal cancer patients, the median plasma vascular endothelial growth factor concentration (44 pg ml(-1)) was significantly (P=0.01) higher than the median plasma vascular endothelial growth factor concentration (30 pg ml(-1)) in the healthy blood donors. In serum, no significant (P=0.30) difference in the median vascular endothelial growth factor concentration was found between colorectal cancer patients (268 pg ml(-1)) and healthy blood donors (220 pg ml(-1)). The preoperative vascular endothelial growth factor concentrations were dichotomized by the 95th percentile of the healthy blood donors (plasma=112 pg ml(-1), serum=533 pg ml(-1)). In univariate survival analyses, both high plasma vascular endothelial growth factor (>112 pg ml(-1)) and high serum vascular endothelial growth factor (>533 pg ml(-1)) predicted a reduced survival. In multivariate survival analyses, high serum vascular endothelial growth factor (>533 pg ml(-1)) independently predicted a reduced survival (HR=1.65, P=0.015), while high plasma vascular endothelial growth factor (>112 pg ml(-1)) did not (HR=1.27, P=0.23). This study indicates that preoperative serum vascular endothelial growth factor apparently is a better predictor of overall survival than the preoperative plasma vascular endothelial growth factor.
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PMID:Prognostic impact of matched preoperative plasma and serum VEGF in patients with primary colorectal carcinoma. 1286 38

The need for dependable prognostic markers in colorectal cancer, both in the advanced as well the as adjuvant setting, is greater than ever. The introduction of new chemotherapeutic agents in the clinic, with different mechanisms of action as well as different side-effect profiles, has made this even more important. Angiogenesis, the formation of new vessels, is essential for tumour growth and metastasis. The adverse impact of tumour angiogenesis in the context of colorectal cancer on relapse and prognosis has been evaluated in numerous retrospective studies. Most of these studies have tended to be relatively small in terms of patient numbers and sometimes have reached conflicting conclusions. A number of different angiogenic factors, including vascular endothelial growth factor (VEGF), thymidine phosphorylase (TP) and intratumoural microvessel density (IMD), have been assessed to varying extents. This article highlights some of the important developments in this rapidly expanding field.
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PMID:Prognostic role of angiogenesis in colorectal cancer. 1190 90

We examined the expression of tissue factor (TF) and vascular endothelial growth factor (VEGF) and the microvessel density (MVD) in 100 patients with colorectal cancer, and we investigated the relationship of the expression of TF or VEGF with angiogenesis. TF antigen was positive in 57.0% of all specimens. Incidence of TF expression was 41.2%, 45.5%, 52.6%, 84.6%, and 81.3% in tumors from patients in clinical stages I, II, IIIA, IIIB, and IV, respectively. TF expression was correlated with the Dukes' classification (P = 0.01) and the clinical stage of colorectal cancer (P = 0.02). VEGF antigen was positive in 64.0% of all specimens. Incidence of VEGF expression was 41.2%, 57.6%, 73.7%, 84.6%, and 75.0% in tumors from patients in clinical stages I, II, IIIA, IIIB, and IV, respectively. VEGF expression was correlated with the Dukes' classification (P = 0.01) but showed a weak association with the clinical stage (P = 0.08). MVD was significantly associated with the depth of invasion (P = 0.01), lymph node metastasis (P = 0.001), and liver metastasis (P = 0.02). The mean values of MVD were 7.5 +/- 2.8, 10.1 +/- 5.7, 14.6 +/- 5.8, 13.5 +/- 3.9, and 15.9 +/- 4.2 in tumors from patients in clinical stages I, II, IIIA, IIIB, and IV, respectively. A close relationship between VEGF and MVD (P < 0.001) and a significant correlation between TF expression and MVD were observed (P = 0.02). TF-positive carcinomas presented high MVD and VEGF expression (P < 0.001) more frequently than did TF-negative tumors. These results suggest that involvement of TF in the process of metastasis and progression of colorectal cancer may depend on increased angiogenesis.
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PMID:Expression of tissue factor and vascular endothelial growth factor is associated with angiogenesis in colorectal cancer. 1192 Oct 18

Palliative and adjuvant treatment for colorectal cancer has been, until recently, largely dependent on 5-fluorouracil (5-FU)-based chemotherapy. Oral fluoropyrimidines have been evaluated in the advanced disease setting and they appear to be as effective as 5-FU, but are safer and more convenient for most patients. Irinotecan and oxaliplatin are new cytotoxic agents, which are active in 5-FU-resistant disease, but which may also be combined with 5-FU as initial therapy in advanced disease. Initial combination therapy leads to improved response rates and more prolonged progression-free survival compared with 5-FU monotherapy. Standard regimens for adjuvant therapy usually involve 6 months of chemotherapy using 5-FU and folinic acid. Recent trials of capecitabine, oxaliplatin and irinotecan in the adjuvant setting are ongoing, or have recently completed accrual, and may lead to a change in future clinical practice. Biological therapies are playing an increasing role in the management of colorectal cancer. Farnesyl transferase inhibition, inhibition of the epidermal growth factor receptor (EGFR) and the vascular endothelial growth factor (VEGF) are undergoing evaluation in advanced disease. In the adjuvant setting, both passive and active immunotherapeutic approaches have been studied. In addition, a large trial will evaluate the role of cyclo-oxygenase(COX)-2 inhibitors as adjuvant therapy. Further research is required in order to define the optimal sequence and combination of these different cytotoxic and biological therapies, in order to secure the best possible outcome for various subgroups of patients with both early and advanced stage colorectal cancer.
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PMID:Systemic treatment of colorectal cancer. 1197 25

p53 suppressor gene mutations are a well known step which occurs in the late stages of the complex tumourigenesis of colorectal cancer. A deregulation of p53 protein function may be associated with increased neovascularization and aggressive tumour growth. In vitro studies have shown that these genetic alterations cause a loss of wild-type p53-induced anti-angiogenetic control and could possibly induce expression of the neoangiogenic vascular endothelial growth factor (VEGF). Therefore, this in vivo study was performed to assess p53 mutations, i.e. hot spots in exons 4-9, in primary colorectal cancers and in corresponding liver metastases in order to test whether there is an association between p53 mutated tumours with increased microvessel density (MVD) and VEGF overexpression. Twenty-two tissue samples taken from primary colorectal cancers and the corresponding liver metastases were immediately snap-frozen in liquid nitrogen and fixed in formaldehyde. After DNA extraction exons 4-9 were amplified and directly sequenced. Cryostat sections were stained immunohistochemically using antibodies against VEGF, CD34, and p53 protein. A modified semiquantitative Weidner score and interactive computerized image analysis was used to assess MVD. Overexpression of immunohistochemically detected p53 protein was found in 7 of the 11 primary tumours and liver metastases (64%). Sequencing showed 3 out of 11 primary tumours (27%) and 5 out of 11 liver metastases (46%) to have p53 point or frameshift mutations; these samples tested immunohistochemically positive for p53 protein. Two p53 mutations in samples of liver metastases were not detectable in the corresponding primaries. We detected one frameshift mutation in exon 4 that has not yet been described in the literature. Tumour samples with p53 mutations and increased VEGF immunoreactivity were associated with higher MVD (p<0.01 and p<0.05, respectively). However, there was no association detected immunohistochemically between p53 and MVD as well as p53 mutations and VEGF overexpression. Our data demonstrate specific genetic alterations in the coding regions of p53 suppressor gene in both primary colorectal cancers and corresponding liver metastases, these alterations are associated with an increase in MVD, but not in VEGF overexpression. In addition, a novel frameshift mutation in both colorectal cancer and metastasis is described.
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PMID:Association of p53 mutations, microvessel density and neoangiogenesis in pairs of colorectal cancers and corresponding liver metastases. 1211 17

Interleukin (IL)-8, heme oxygenase-1 (HO-1), and vascular endothelial growth factor (VEGF) appear to be critically involved in immune responses associated with inflammation, infection and tumor growth. Regulation of these mediators was studied in the human colon carcinoma cell line DLD-1. Here we report that pyrrolidine dithiocarbamate (PDTC) not only augmented tumor necrosis factor-alpha-induced release of IL-8, but also mediated IL-8 expression as a single stimulus. Mutational analysis of the IL-8 promotor and electrophoretic mobility shift analysis revealed that activation of the transcription factor activator protein-1 (AP-1) and a constitutive nuclear factor-kappaB (NF-kappaB) binding activity in DLD-1 cells were mandatory for PDTC-induced IL-8 expression. Besides IL-8, PDTC also upregulated the expression of HO-1 and VEGF in these cells. Induction of IL-8 by PDTC was not restricted to DLD-1 cells, but was observed in Caco-2 colon carcinoma cells and in peripheral blood mononuclear cells. PDTC is currently advocated for use as a chemotherapeutic drug in the treatment of certain malignancies, among them colorectal cancer. Induction of IL-8, HO-1 and VEGF may affect therapeutic applications of this agent.
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PMID:Expression of interleukin-8, heme oxygenase-1 and vascular endothelial growth factor in DLD-1 colon carcinoma cells exposed to pyrrolidine dithiocarbamate. 1215 44

Recent trials have established the IFL combination (fluorouracil [5-FU], leucovorin, and irinotecan [CPT-11, Camptosar]) as a new standard first-line therapy for patients with metastatic colorectal cancer. Median survival for such patients treated with IFL still ranges from approximately 14 to 18 months, however, underscoring the need for new agents with novel mechanisms of action. Angiogenesis has become an attractive target for anticancer drug development, based on its important roles in tumor growth, invasion, and metastasis. A potent stimulus of angiogenesis is vascular endothelial growth factor (VEGF); two agents developed to inhibit VEGF activity, bevacizumab (Avastin) and SU5416, are in advanced clinical trials. Based on encouraging results in phase I and II trials with bevacizumab, a randomized trial of IFL with or without this monoclonal antibody is under way. Similarly, a randomized trial of 5-FU and leucovorin with or without the tyrosine kinase inhibitor SU5416 has recently completed accrual and results are pending. SU5416 is also being tested in a phase I/II trial combined with IFL. This article briefly reviews preclinical and clinical data leading to the current trials of these two agents in patients with colorectal cancer.
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PMID:Targeting vascular endothelial growth factor in colorectal cancer. 1219 27

We wished to demonstrate vascular endothelial growth factor (VEGF) transcript polymorphism in human colon cancer. RNA was extracted from 25 primary human colorectal adenocarcinomas followed by VEGF transcript amplification, fragment elution, subcloning, positive selection via insert analysis and sequencing. Four distinct splice variants were consistently expressed in cancer, including VEGF121, VEGF165, VEGF189 and the newly identified truncated splice variant VEGF145. Six novel mutations were characterized, all of which occurred within the conserved expression site of the gene and which consequently were present in all splice forms. Five cancers exhibited single nucleotide changes and 1 cancer a 2-nucleotide deletion. A silent mutation was observed in exon 1 at position +70 relative to the amplification start site, a 1- and 2-base deletion with frameshift and protein truncation in exon 3 at positions +172 and +171/172, respectively, a transition mutation in exon 3 at position +248 and 2 transition mutations in exon 4 at positions +398 and +403. All of these sense mutations should alter protein conformation. To our knowledge, this is the first report of VEGF145 in solid malignancy. Its biologic activity remains to be determined. We have demonstrated a variety of sporadic mutations within human colorectal cancer VEGF mRNA. Mutant angiogenic VEGF may provide a genomic basis for the diversity of tumor-host response and may prove to be important in antisense oligonucleotide targeting, since all the different VEGF isoforms would have to be neutralized to prevent angiogenesis.
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PMID:VEGF isoforms and mutations in human colorectal cancer. 1220 85

Insulin-like growth factor-I (IGF-I) has potent mitogenic and anti-apoptotic effects that give it a critical role in the regulation of rapidly renewing epithelial cell populations such as those found in the colon. Recent evidence has implicated circulating IGF-I levels as an important determinant of colorectal cancer risk, but the role, if any, of its autocrine/paracrine expression remains unexplored. Therefore, we investigated the local expression of IGF-I and IGF-I type I receptor (IGF-IR) in 50 paired normal colon and carcinoma samples. IGF-IR mRNA was present in all samples, whereas IGF-I mRNA was detected in only 30 normal (60%) and 27 tumour (54%) biopsies. Samples that did not express IGF-I mRNA had no IGF-I peptide detectable by immunocytochemistry. The absence of local IGF-1 expression was associated with significantly reduced mRNA levels specifying the proliferating cell nuclear antigen and c-myc, as well as Cox-2, and vascular endothelial growth factor - gene products that regulate angiogenesis. The biological relevance of this finding is suggested by the significant association between local IGF-I mRNA levels and microvessel density in the colorectal cancers.
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PMID:Local expression of insulin-like growth factor-I affects angiogenesis in colorectal cancer. 1221 93


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