| Background and objectives:The colorectal carcinoma is one of the most common malignancy in digestive tract. The morbidity and mortality of colorectal carcinoma diagnosed tend to increase annually while the lifestyle and diet keep refreshing. Due to the delitescence and slowly development in the early stage, as well as the relative delayed metastasis, most of the initial symptoms of colorectal carcinoma are ignored. As long as the bowel obstruction, abdominal mass or distant metastasis are found, the advanced stage will be confirmed. Therefore, in order to obtain earlier diagnosis and prolong the survival, searching for some valuable pathological markers which indicate the disease progression and prognosis appears more and more imperative.Based on the modern molecular and cellular biological technique, we have realized the development of colorectal carcinoma is a multi-stage, multi-step, and complicated process and many kinds of tumor-associated molecules are involved. Caveolin-1, a novel molecule associated with carcinogenesis, is drawing more and more attention to the biological functions and effect to the carcinogenesis. Moreover, Caveolin-1 is a labeled protein adhering to the specific emboled microdomain located in the cellular membrane, 21-24kD, necessary for Caveolae to form the flask-shaped emboled domain. At present, a large number of evidences have shown that Caveolin-1 probably was an antioncogene, but the extensional mechanisms remain to be defined, in addition, reports regarding the expression of Caveolin-1 in colorectal carcinoma are quite unsufficient and the correlation with invasion and metastasis is still obscure. By means of determining and analyzing the variance of expression of Caveolin-1 in the level of protein and mRNA as well as the relationship with the clinicopathological parameters, we established a theoretical basis to detect the biological process of malignant transformation of colorectal carcinoma and the molecular mechanism of invasion, metastasis as well, thereby, a novel approach was paved to search for the valuable pathological parameters of colorectal carcinoma from clinic and the new targets of anti-tumor.As for the solid tumor, the nutrition supply and metabolic waste are transmitted by microvascular network, one of the preconditions of carcinogenesis. Angiogenesis consists of endothelial cell proliferation, migration and differentiation, anyway, the endothelial proliferation is the key step of angiogenesis, contributed by both vascular growth factors and extracellular matrix. VEGF is the main factor of endothelial cells, stimulating the angiogenesis in physiological and pathological state. VEGF specifically binds to the VEGF receptors, in this way, a series of signal pathways such as Ras-p42/44MAPK are activated, by then the endothelial proliferation is induced. More than the contribution of VEGF, the endothelial cells have to adhere to targeted extracellular matrix and transmit signals into cells by integrin-FAK passageway only to get survival and proliferation, otherwise, the programmed cell death will be intrigued. FAK is one of non-receptor tyrosine kinases which bridges the signal transduction between cells and extracellular matrix, playing a pivotal role in the signal transduction mediated by integrin. FAK is overexpressed in many kinds of malignancy of mankind, contributing to the formation of focal adhesion plaque, and regulating the cellular growth, differentiation, adhesion, movement as well as apoptosis. In this study, we devoted to researching the expression of VEGF and FAK proteins in the development of colorectal carcinoma, the relationships between expression and clinicopathological parameters and their correlations, to finding out the significant function and interactive mechanisms of them in the development of colorectal carcinoma and angiogenesis.The studies have found, Caveolin-1 is strongly associated with tumor angiogenesis. In this study, we mainly focused on the correlation of Caveolin-1 to the expression of VEGF and FAK proteins, meanwhile, we also strived to explore further how Caveolin-1 affect the vascular endothelial proliferation induced by VEGF and the vascular endothelial adhesion mediated by the pathway of integrin-FAK. In addition, the mechanism of effect of Caveolin-1 in tumor angiogenesis was also initially demonstrated. This provided the theoretic basis to the anti-tumor treatment targeting on Caveolin-1 to inhibit the angiogenesis.Materials and methods:1. The expression of Caveolin-1, VEGF and FAK proteins in 86 cases of colorectal carcinoma, 27 cases of colorectal adenoma and 35 cases of adjacent normal mucosa were detected by IHC.2. The expression of Caveolin-1 mRNA in 26 cases of fresh tumor samples resected with adjacent the normal mucosa correspondingly and 13 cases of colorectal adenoma was detected by RT-PCR.3. Statistical analysis: SPSS 11.0 software package was used for statistical analysis. Rates were compared by chi-square test or Fisher's exact test of probabilities. The correlation was analyzed with Spearman rank correlation. Measurement data were presented as mean±SD, group comparison was managed with ONE-Way ANOVA. The significance level wasα=0.05.Results:1. IHC showed: the positive chromatosis of Caveolin-1 protein in colorectal tissue were all located in the cellular membrane and kytoplasm. The positive expression rates of Caveolin-1 in normal colorectal tissue, adenoma and carcinoma were 85.71%(30/35), 55.56%(15/27) and 27.91%(24/86), respectively, showed significant difference(P<0.05), and statistical difference also were obtained from 2 inter-group comparisons(P<0.05). The expression of Caveolin-1 in colorectal carcinoma showed no more significant correlation to histopathologic type and clinical stage(P>0.05), but to tumor grade, invasion depth and regional lymph nodes metastasis(P<0.05).2. RT-PCR showed: The relative expression of Caveolin-1 mRNA in normal colorectal tissue, adenoma and carcinoma were 0.6852±0.1491, 0.5958±0.1631 and 0.2805±0.0957, respectively, and significant difference was obtained from three groups comparison(P<0.05). Furthermore, the significant difference lies in the two groups: between normal colorectal tissue and carcinoma, adenoma and carcinoma(P<0.05), no difference, however, between normal colorectal tissue and adenoma(P>0.05).3. IHC showed: the positive chromatosis of VEGF protein in colorectal tissue were mainly located in the kytoplasm. The positive expression rates of VEGF in normal colorectal tissue, adenoma and carcinoma were 8.57%(3/35), 29.63%(8/27) and 68.60%(59/86), respectively, showed significant difference (P<0.05), and statistical difference also were obtained from 2 inter-group comparisons(P<0.05). The expression of VEGF in colorectal carcinoma showed no more significant correlation to histopathologic type and tumor grade(P>0.05), but to invasion depth, regional lymph nodes metastasis and clinical stage(P<0.05).4. IHC showed: the positive chromatosis of FAK protein in colorectal tissue were mainly located in the kytoplasm. The positive expression rates of FAK in normal colorectal tissue, adenoma and carcinoma were 11.43%(4/35), 25.93%(7/27) and 79.07%(68/86), respectively, and significant difference was obtained from three groups comparison(P<0.05). The positive expression rate of FAK in carcinoma was dramatically higher than normal tissue and adenoma(P<<0.05), but no significant difference between the latter two groups(P>0.05). Regarding different histopathologic types, the expression of FAK had no statistical difference(P>0.05), however, the significant correlation was observed from the expression of FAK associated with tumor grade, invasion depth, regional lymph nodes metastasis and clinical stage(P<0.05).5. The negative correlation was observed between Caveolin-1 and VEGF proteins in colorectal carcinoma(P<0.05).6. The negative correlation was observed between Caveolin-1 and FAK proteins in colorectal carcinoma(P<0.05). 7. The positive correlation was observed between FAK and VEGF proteins incolorectal carcinoma(P<0.05).Conclusions:1. Caveolin-1 protein and mRNA present gradually degraded expression in normal colorectal, adenoma and carcinoma. The expression of Caveolin-1 protein in colorectal carcinoma is significantly correlated with tumor grade, invasion depth and regional lymph nodes metastasis. The down-expression of Caveolin-1 is an early event in colorectal tumorigenesis and development, probably associated with the tumor development.2. VEGF protein presents gradually elevated expression in normal colorectal, adenoma and carcinoma, correlated with invasion depth, regional lymph nodes metastasis and clinical stage significantly, regarded probably as a valuable parameter which is able to identify the colorectal carcinoma characterized by the potential of strong invasion and metastasis.3. The expression of FAK in colorectal carcinoma increased dramatically, significantly correlated with tumor grade, invasion depth, regional lymph nodes metastasis and clinical stage. As indicates the overexpression of FAK probably was involved in the tumorigenesis, development, invasion and metastasis.4. The expression of Caveolin-1 protein presents negative correlation to VEGF and FAK proteins in colorectal carcinoma, involved in the tumorigenesis, development and angiogenesis via mutual suppression with the latter two factors.5. The expression of VEGF and FAK proteins in colorectal carcinoma present positive correlation and synergism, together probably participating in the regulatory mechanism of angiogenesis in carcinogenesis and metastasis. |
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