Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0699790 (colon cancer)
 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Two subtypes of thrombospondin (TSP-1 and TSP-2) have inhibitory roles in angiogenesis in vitro, although the biological significance of these TSP isoforms has not been determined in vivo. We examined TSP-1 and TSP-2 gene expression by reverse transcription polymerase chain reaction (RT-PCR) analysis in 61 colon cancers. Thirty-eight of these 61 colon cancers were positive for TSP-2 expression and showed hepatic metastasis at a significantly lower incidence than those without TSP-2 expression (P = 0.02). TSP-2 expression was significantly associated with M0 stage in these colon cancers (P = 0.03), whereas TSP-1 expression showed no apparent correlation with these factors. The colon cancer patients with TSP-2 expression showed a significantly low frequency of liver metastasis correlated with the cell-associated isoform of vascular endothelial growth factor (VEGF-189) (P = 0.0006). Vascularity was estimated by CD34 staining, and TSP-2(-)/VEGF-189(+) colon cancers showed significantly increased vessel counts and density in the stroma (P < 0.0001). TSP-2(-)/VEGF-189(+) colon cancer patients also showed significantly poorer prognosis compared with those with TSP-2(+)/VEGF-189(-) (P = 0.0014). These results suggest that colon cancer metastasis is critically determined by angiogenesis resulting from the balance between the angioinhibitory factor TSP-2 and angiogenic factor VEGF-189.
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PMID:Thrombospondin 2 expression is correlated with inhibition of angiogenesis and metastasis of colon cancer. 988 80

Administration of adenovirus (Ad) vectors to immunologically naive experimental animals almost invariably results in the induction of systemic anti-Ad neutralizing antibodies. To determine if the human systemic humoral host responses to Ad vectors follow a similar pattern, we evaluated the systemic (serum) anti-Ad serotype 5 (Ad5) neutralizing antibodies in humans after administration of first generation (E1(-) E3(-)) Ad5-based gene transfer vectors to different hosts. AdGVCFTR.10 (carrying the normal human cystic fibrosis [CF] transmembrane regulator cDNA) was sprayed (8 x 10(7) to 2 x 10(10) particle units [PU]) repetitively (every 3 months or every 2 weeks) to the airway epithelium of 15 individuals with CF. AdGVCD.10 (carrying the Escherichia coli cytosine deaminase gene) was administered (8 x 10(8) to 8 x 10(9) PU; once a week, twice) directly to liver metastasis of five individuals with colon cancer and by the intradermal route (8 x 10(7) to 8 x 10(9) PU, single administration) to six healthy individuals. AdGVVEGF121.10 (carrying the human vascular endothelial growth factor 121 cDNA) was administered (4 x 10(8) to 4 x 10(9.5) PU, single administration) directly to the myocardium of 11 individuals with ischemic heart disease. Ad vector administration to the airways of individuals with CF evoked no or minimal serum neutralizing antibodies, even with repetitive administration. In contrast, intratumor administration of an Ad vector to individuals with metastatic colon cancer resulted in a robust antibody response, with anti-Ad neutralizing antibody titers of 10(2) to >10(4). Healthy individuals responded to single intradermal Ad vector variably, from induction of no neutralizing anti-Ad antibodies to titers of 5 x 10(3). Likewise, individuals with ischemic heart disease had a variable response to single intramyocardial vector administration, ranging from minimal neutralizing antibody levels to titers of 10(4). Evaluation of the data from all trials showed no correlation between the peak serum neutralizing anti-Ad response and the dose of Ad vector administered (P > 0.1, all comparisons). In contrast, there was a striking correlation between the peak anti-Ad5 neutralizing antibody levels evoked by vector administration and the level of preexisting anti-Ad5 antibodies (P = 0.0001). Thus, unlike the case for experimental animals, administration of Ad vectors to humans does not invariably evoke a systemic anti-Ad neutralizing antibody response. In humans, the extent of the response is dictated by preexisting antibody titers and modified by route of administration but is not dose dependent. Since the extent of anti-Ad neutralizing antibodies will likely modify the efficacy of administration of Ad vectors, these observations are of fundamental importance in designing human gene therapy trials and in interpreting the efficacy of Ad vector-mediated gene transfer.
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PMID:Variability of human systemic humoral immune responses to adenovirus gene transfer vectors administered to different organs. 1040 Jul 71

Expression of vascular endothelial growth factor (VEGF), an important angiogenic factor in colon cancer, is tightly regulated by factors in the microenvironment. However, specific factors indigenous to the organ microenvironment of colon cancer growth that regulate VEGF expression in human colon cancer are not well defined. We investigated interleukin-1beta (IL-1beta) induction of VEGF expression in colon cancer cells and the mechanism by which this occurs. HT29 human colon cancer cells were treated with IL-1beta for various periods. Induction of VEGF mRNA by IL-1beta peaked at 24 h (> fivefold) and returned to baseline by 48 h. SW620 human colon cancer cells also reached a peak induction of VEGF mRNA 24 h after treatment with IL-1beta. VEGF was induced at a dose range between 1 and 20 ng ml(-1) of IL-1beta. IL-1beta induction of VEGF was also confirmed at the protein level. To examine the mechanism for VEGF induction by IL-1beta, we transiently transfected VEGF promoter-reporter constructs into HT29 cells. IL-1beta increased the activity of the VEGF promoter-reporter construct. Pretreatment of HT29 cells with dactinomycin abrogated the induction of VEGF mRNA by IL-1beta. The half-life of VEGF mRNA was not prolonged by treatment with IL-1beta. These findings suggest that IL-1beta regulates VEGF expression in human colon cancer cells by increasing transcription of the VEGF gene.
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PMID:Regulation of vascular endothelial growth factor expression in human colon cancer by interleukin-1beta. 1040 90

We demonstrated in this study that inhibition of intra-hepatic growth of colon cancer by TAC-101 is mediated by inhibition of angiogenesis. In vitro experiments showed that TAC-101 inhibited the proliferation of murine hepatic sinusoidal endothelial (HSE) cells induced by coculture with murine colon 26-L5 (L5) cells. HSE cell proliferation was also enhanced by conditioned medium of L5 cells (CM-L5), and this enhancement of proliferation was abrogated by anti-vascular endothelial growth factor antibody. CM-L5 also induced in vitro tube formation of HSE cells on Matri-gel, and this activity of CM-L5 was abrogated by TAC-101 in a concentration-dependent manner. On the other hand, p.o. administration of TAC-101 inhibited tumor-induced angiogenesis in vivo and decreased the weights of L5 tumors in the mouse liver. Reverse transcriptase-PCR analysis using in vivo tumor tissue suggested that repression of vascular endothelial growth factor expression by TAC-101 was associated with the antiangiogenic activity. TAC-101 alone and 5-fluorouracil (5-FU)/D,L-leucovorin (LV) significantly inhibited the intrahepatic growth of L5 tumors (P = 0.002 and 0.001, respectively), whereas 5-FU alone did not (P = 0.088). When TAC-101 was administered with 5-FU/LV, marked enhancement of antitumor activity was observed (95% inhibition; P<0.001). This enhanced antitumor effect was also observed in experiments using Co-3 human colon adenocarcinoma. Concurrent treatment with TAC-101 and 5-FU/LV and sequential treatment with 5-FU/LV followed by TAC-101 resulted in significant augmentation of antitumor activity against Co-3 (overall P = 0.007 and 0.015, respectively). These findings indicate that TAC-101 inhibits tumor angiogenesis and suggest that it may be effective against hepatic metastasis of colon cancer.
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PMID:Inhibition of angiogenesis and intrahepatic growth of colon cancer by TAC-101. 1049 97

Increased vascular endothelial growth factor (VEGF) expression is associated with colon cancer metastases. We hypothesized that inhibition of VEGF receptor activity could inhibit colon cancer liver metastases. BALB/c mice underwent splenic injection with CT-26 colon cancer cells to generate metastases. Mice received daily i.p. injections of vehicle, tyrosine kinase inhibitor for Flk-1/KDR (SU5416) or tyrosine kinase inhibitor for VEGF, basic fibroblast growth factor, and platelet-derived growth factor receptors (SU6668). SU5416 and SU6668 respectively inhibited metastases (48.1% and 55.3%), microvessel formation (42.0% and 36.2%), and cell proliferation (24.4% and 27.3%) and increased tumor cell (by 2.6- and 4.3-fold) and endothelial cell (by 18.6- and 81.4-fold) apoptosis (P<0.001). VEGF receptor inhibitors increased endothelial cell apoptosis, suggesting that VEGF may serve as an endothelial survival factor.
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PMID:Antiangiogenic therapy targeting the tyrosine kinase receptor for vascular endothelial growth factor receptor inhibits the growth of colon cancer liver metastasis and induces tumor and endothelial cell apoptosis. 1055 7

The expression of vascular endothelial growth factor (VEGF), a highly potent angiogenic molecule, is thought to be correlated with the development of colon cancer; however, direct evidence for a role of VEGF in metastasis is lacking. This study was designed to more directly establish the role of VEGF in the growth and metastasis of human colon cancer using a genetically engineered cancer cell line. A stable VEGF gene-transfected human colon cancer cell line, LoVo, was made by genetic manipulation using eukaryotic expression constructs designed to express the complete VEGF121 cDNA in the sense orientation. Transfected clones were screened for VEGF121 mRNA expression by Northern blot analysis and for VEGF121 protein expression by Western blot analysis. Consequently, we obtained S17 cells that expressed a high level of both VEGF mRNA and VEGF protein. A vector-transfected clone (V7 cell) was used as a control. The experiment with the dorsal air sac method revealed that S17 cells elicited a stronger directional out-growth of capillaries than V7 cells. S17 cells formed faster-growing tumors than did V7 cells when xenografted s.c. into nude mice, although there was no significant difference in their in vitro proliferation. Tumors derived from S17 cells had more vascularity, as assessed by counting capillary vessels after staining with factor VIII, than did tumors derived from V7 cells (P < 0.05). With regard to the metastatic potential, S17 cells exhibited a higher capacity for both hepatic metastasis after the splenic portal inoculation and peritoneal dissemination after i.p. injection than did V7 cells. However, S17 cells showed no apparent metastasis, despite their rapid growth after orthotopic implantation. In conclusion, the present study showed clearly that VEGF plays an important role in cancer growth due to stimulation of angiogenesis by accelerating cell growth after reaching the target organs.
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PMID:Enhancement of angiogenesis, tumor growth, and metastasis by transfection of vascular endothelial growth factor into LoVo human colon cancer cell line. 1069 May 48

Because the crucial role of angiogenesis has been demonstrated in tumor growth and metastasis, the present study was undertaken to characterize the relative expression of vascular endothelial growth factors VEGF (vascular endothelial growth factor), VEGF-B, VEGF-C, and their receptors KDR (kinase insert domain-containing receptor), FLT-1 (fms-like tyrosine kinase), and FLT-4 in human colonic cancers, in relation to the Astler-Coller pathological classification, and to prognosis. VEGF and VEGF-B gene expression was quantified by Northern blot in 72 tumor samples matched with control tissues. VEGF gene expression was 1.4 times higher in adenocarcinomas than in control tissues (p = 0.02), but did not increase further between Astler-Coller tumor stages A and D, and did not correlate with disease recurrence for patients at stages B2 or C. In adenomas, VEGF mRNA levels were not significantly different from those in the paired control colonic mucosa. The expression pattern of VEGF isoforms, mainly identified by RT-PCR (reverse-transcriptase-coupled polymerase chain reaction) as VEGF121 and VEGF165 and to a lesser extent VEGF189, was comparable in tumor and control tissues. VEGF-B mRNA levels were unchanged during the neoplastic progression of colonic mucosa. In contrast to KDR and FLT-4, the expression of VEGF-C and FLT-1 genes increased in some pathological tissues. These results provide evidence that the early and sustained increase in VEGF transcripts and the expression of multiple angiogenic factors and receptors contribute to the development of colon cancer, and thus constitute a putative target for anti-angiogenic drug therapy.
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PMID:Vegf, Vegf-B, Vegf-C and their receptors KDR, FLT-1 and FLT-4 during the neoplastic progression of human colonic mucosa. 1073 43

Mutation of c-K-ras oncogene is an important step in progression of colon cancer. We used a hammerhead ribozyme (KrasRz) against mutated K-ras gene transcripts (codon 12, GTT) to inactivate mutant K-ras function in the colon cancer cell line SW480, harbouring a mutant K-ras gene. The beta-actin promoter-driven KrasRz sequence (pHbeta/KrasRz) was introduced into these cells (SW480/KrasRz), and we evaluated its effects on growth of the colon cancer. The gene expression of angiogenesis-related molecules (vascular endothelial growth factor and thrombospondin) was also estimated in SW480/KrasRz. KrasRz specifically and efficiently cleaved the mutant K-ras mRNA but not wild-type mRNA in vitro. SW480/KrasRz showed decreased growth rate under tissue culture conditions (P< 0.01, Dunnett's test). The xenotransplantability of SW480/KrasRz (XeSW480/KrasRz) was significantly decreased in nude mice (P< 0.05, Fisher's exact test). Tumour volume of the xenografts XeSW480/KrasRz was significantly smaller than that of XeSW480/DisKrasRz (P< 0.01, Dunnett's test). Gene expression of VEGF was suppressed in SW480/KrasRz, while TSP1 gene expression was enhanced. The SW480/KrasRz cells showed apoptosis-related features including nuclear condensation and DNA fragmentation. These results suggested that the hammerhead ribozyme-mediated inactivation of the mutated K-ras mRNA induced growth suppression, apoptosis and alteration of angiogenic factor expression.
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PMID:Ribozyme-mediated inactivation of mutant K-ras oncogene in a colon cancer cell line. 1095 90

We previously demonstrated that cyclooxygenase-2 (COX-2) was predominantly expressed in macrophages of sporadic human colonic adenomas; however, the role of COX-2-expressing cells during colon carcinogenesis has not yet been elucidated. In the present study, we showed the effect of PGE, on vascular endothelial growth factor (VEGF) production by PMA-differentiated U937 cells, a human macrophage model (H-Mac), and by human colon cancer cells T84. PGE1 dramatically induced VEGF production by H-Mac, but not that by T84. PGE1 significantly increased intracellular cAMP formation by H-Mac, but only modestly increased that by T84. 8-bromo-cAMP and cholera toxin also increased VEGF production by H-Mac. In contrast, neither of these agents modulated VEGF production by T84. EP2 and EP4 (PGE specific receptors) mRNA was expressed in both cells. PG dramatically increased VEGF production by activated macrophages, but not by cancer cells, through a specific PGE receptor-mediated process. These findings suggest that PGs produced by COX-2-expressing macrophages induce VEGF production by macrophages, but not by cancer cells, in an autocrine fashion.
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PMID:Effect of prostaglandin E1 on vascular endothelial growth factor production by human macrophages and colon cancer cells. 1096 22

Angiogenesis plays a key role in tumor growth and metastasis. The transforming growth factor alpha (TGF-alpha)-epidermal growth factor receptor (EGFR) autocrine pathway controls in part the production of angiogenic factors such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) in cancer cells. In this study, we have evaluated the antiangiogenic and antitumor activity of monoclonal antibody (MAb) C225, an anti-EGFR chimeric human-mouse MAb, alone and in combination with a human VEGF antisense (AS) 21-mer phosphorothioate oligonucleotide (VEGF-AS) in human GEO colon cancer cells. MAb C225 treatment determined a dose-dependent inhibition of VEGF, bFGF, and TGF-alpha production by GEO cells in vitro. Treatment with VEGF-AS caused a selective inhibition in VEGF expression by GEO cells in vitro. Treatment of immunodeficient mice bearing established, palpable GEO xenografts for 3 weeks with VEGF-AS or with MAb C225 determined a cytostatic reversible inhibition of tumor growth. In contrast, a prolonged inhibition of tumor growth was observed in all mice treated with the two agents, in combination with a significant improvement in mice survival compared with controls (P < .001), to MAb C225 (P < .001), or to VEGF-AS (P < .001) treated mice. All mice died within 4, 6, and 8 weeks after tumor cell injection in the control, VEGF-AS and MAb C225 groups, respectively. In contrast, 50% of mice treated with the combination of VEGF-AS and MAb C225 were alive at 13 weeks. Ten % of mice treated with VEGF-AS plus MAb C225 were alive at 20 weeks and had no histological evidence of GEO tumors. Immunohistochemical analysis of GEO tumor xenografts demonstrated a significant reduction of VEGF expression after treatment with VEGF-AS with a parallel reduction in microvessel count. MAb C225 treatment determined a reduction in the expression of VEGF, bFGF, and TGF-alpha with a reduction in microvessel count. Finally, a significant potentiation in inhibition of VEGF expression and little or no microvessels were observed in GEO tumors after the combined treatment with the two agents.
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PMID:Antiangiogenic and antitumor activity of anti-epidermal growth factor receptor C225 monoclonal antibody in combination with vascular endothelial growth factor antisense oligonucleotide in human GEO colon cancer cells. 1099 68


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