Study Of Angiogenesis In Human Colorectal Carcinoma And Its Modulation By P53 Gene

Study of angiogenesis in human colorectal carcinoma and its modulation by p53 geneMany studies have shown that angiogenesis is required to supply oxygen and nutrition for growth and metastasis of colorectal carcinoma (CRC). In recent years, many stimulatory and inhibitory factors of tumor angiogenesis have been identified. Vascular endothelial growth factor (VEGF), or vascular permeability factor (VPF), is known to play a crucial role in neovascularization. Some studies have demonstrated that VEGF have not only paracrine effect upon the endothelial cell to promote angiogenesis, also an autocrine effect upon the tumor cell receptor itself. Ultimately, VEGF is expressed by growth status of tumor microvessel. Many in vitro studies have shown the important role played by p53 tumor suppressor gene in controlling tumor angiogenesis. There is few research, however, on the relationship of p53 gene, microvessel density (MVD), VEGF and its receptor in CRC. In this study, we observed the expression of the VEGF/KDR system in CRC and its relationship with the clinicopathologic features. We also examined MVD and p53 in CRC tissues to investigate the relations among p53, MVD and VEGF expression. They may provide the basis for target selection of anti-vascular therapy in CRC and serve as predictors for the recurrence, metastasis and prognosis.Methods:1. Surgical samples of 68 patients with CRC were studied using reverse transcription-polymerase chain reaction (RT-PCR). The relative level of VEGF mRNA expression was measured by determining a ratio of PCR products of VEGF to that of ~-actin gene.2.The expression of VEGF and KDR was studied by immunohistochemical SABC technique. 20 cases of normal colorectal tissuewere regarded as the control group.-4-3. The expression of VEGF p53 gene and MVD of different regions wasstudied by immunohistochemical method from 68 specimens obtained bysurgical resection of colorectal cancer.Results:l. Expression of VEGF mRNA in tumor tissues was fOund in 67.6%(46/68) of patients, whereas it was seen in 32.4 (22/68) of the nontumorouscolorectal tissues. The level of VEGF mRNA expression in tumors withserosal invasion, lymph node metastasis, distant metastasis or Dukes D stagewas higher than that without serosal invasion, lymph node metastasis, distantmetastasis or Dukes A, B or C stage (P<0.0l). There was no significantdifference in the expression of VEGF InRNA between lnye CRC(diameter>5cm) and small CRC (diameter55cm) (P>0.05) or histologicaltype (P>0.05).2. The expression of VEGF and KDR was negative in 20 cases ofcolorectal tissues. The positive rates of VEGF (55.9%, 38/68) and KDR(45.6%, 3l/68) in colorectal carcinoma were significantly higher than thoseofperitumoral tissue (l l .8%, 8/68, 8.8%, 6/68) (P<0.0l ). The expression ofVEGF and KDR positively correlated with depth of invasion, lymph-nodemetastasis, diStant metastasis, vessel invasion and Dukes stage, but therelationship to the histological types was not significant. VEGF expressionwas positively correlated with KDR expression.3. Both the positive rates of VEGF p53 and the arnount of MVD incolorectal cancer were significantly higher than those in peritumoral andnormal tissues. The expression of VEGF and p53 was positively correlatedwith the depth of invasion, lymph-node metastasis, distallt metastasis, vessel..invasion and Dukes stage, but the relationship to the histologic types was notsignificant. The MVD (34.61 l2.2: 3l 2f l2.6) in p53(+) or VEGF(+)tumors was significantly higher than that in negative tumors (l5.017.9:l2.7 l 6.3 ) (P<0.0l ), and MVD (36.5 i l l .9) in both p53(+) and VEGF(+)tumors was significantly higher than that in the other subgroups (P<0.0l ). Aclose correlation was present between MVD and VEGF positivity (P<0.0l ),- 5 -and p53 expression was correlated with both VEGF expression and MVD(P