Expressions Of Fascin, E-cadherin, CXCR4 And CXCR12 In Colorectal Carcinoma And Their Relationship With Lymphatic Metastasis

Objective: Colorectal cancer (CRC) is one of the most common human malignancies. The incidence of CRC is increasing for the past several decades and now its incidence ranks the third among all the malignant tumors in the world. Although multimodality treatment measures including surgical resection, radiotherapy, chemotherapy and immunotherapy, etc were widely used, the prognosis of CRC was still not good enough. The mean 5-year survival rate was about 50%. Most of patients died of local recurrence and distant metastases. It is reported that more than 60% cancer patients already existed metastasis at the time of initial diagnosis. Invasion and metastasis are the main causes of death for the patients with malignant tumors. The same as other malignant tumors, recurrence and metastasis were the most critical factors influencing outcome of treatment and quality of life for the patients with colorectal cancer. Thus, it would be very of great significance searching for better markers for the early diagnosis, prediction of recurrence, metastasis and prognosis of colorectal cancer.Tumor invasion and metastasis are the result of very complicated processes involving multiple intracellular and extra cellular factors. Changes in differentiation status, cell-cell and cell-matrix adhesion properties as well as organization of the actin cytoskeleton may enable epithelial cell to gain the migration ability.Fascin is an actin-bundling cytoskeleton protein. Its function involves in the cell adhesion and motility. It could induce the aggregate of actin into bundles, increase the formation of membrane protrusions and thus increases cell motility in normal and transformed cells. Fascin expression in normal epithelial tissue was low or absent, but is upregulated in several epithelial neoplasms with invasive phenotype. The mechanism of fascin on invasive growth and metastasis of malignant tumors is by formation of actin-related structure, mediating cells displacement and interactions of cells or by the formation of cytoplasmic microfilament bundles.E-cadherin plays very important role in the inhibition of tumor infiltration and metastasis. And changes in its adhesion properties may lead to reorganization of cytoskeleton, resulting in tumor infiltration and metastisis. E-cadherin was closely related with fascin in the transformed cells.The chemokines are a group of cytokines with chemotaxis function. Combination of Chemokine sdf-1 and CXCR4 could result in the polymerization of actin and the formation of cell pseudopod protrusion, induce tumor chemotactic migration and invasion reaction. Up to now, few studies on the significance of fascin expression on lymph node metastasis in CRC were seen. Works on the possible relationship between the expression of fascin, CXCR4, CXCL12 and E-cadherin in colorectal cancers have not been found in the literature.To furthe explore the possible mechanism of lymph node metastasis in the colorectal cancer and to find sensitive indicators for the monitoring of regional lymph node metastasis, the expressions of fascin, E-cadherin, CXCR4 and CXCL12 in normal colorectal mucosa, primary carcinoma and lymph node metastatic foci of the colorectal carcinoma was studied with immunohistochemical staining method.Methods: The expressions of fascin, E-cadherin, CXCR4 and CXCL12 was studied in 20 cases of normal colorectal mucosa, 126 cases of primary CRC (including 69 cases without lymph node metastasis and 57 cases with lymph node metastasis) and 57 cases of lymph node metastasis carcinoma tissue of CRC with EliVisionTM plus two step methods. The relationship between the expression of fascin, E-cadherin, CXCR4 and CXCL12 in CRC and their clinical pathological significance was also analyzed.Results:1 Expression of fascin in different groups: Immunohistochemical staining results showed the positive expression rate of fascin in 126 cases primary tumor was significantly higher than that in 20 cases normal colorectal mucosa tissue (47.63 vs 15.00%, P<0.05). The positive expression of fascin in lymph node metastatic carcinoma was significantly higher than that in their corresponding primary carcinoma tissue (75.44% vs 57.89%, P<0.05). Fascin expression in CRC was closely correlated with lymph node metastasis, differentiation, duke's stage and histological type in colorectal cancer (P<0.05). The positive expression rate of fascin in poor differentiated cases of CRC was significantly higher than that in well and moderately differentiated cases (P<0.05).2 Expression of E-cadherin in different groups: Immunohistochemically, the positive expression rate of E-cadherin in CRC was significantly lower than that in normal control(18.25% vs 80%, P<0.05). That in lymph node metastatic carcinoma showed slightly higher positive expression of E-cad than that in their corresponding primary carcinoma tissue , but significant deference was found ( 8.77% vs 7.02%,P>0.05). The positive expression of fascin was closely related with lymph node metastasis and that in CRC with lymph node metastasis was significantly lower than that without( P<0.05. E-cadherin expression was decreased as the grade of the tumor differentiation decreased. The positive expression rate in poor differentiated CRC was significantly lower than that in well/moderate differentiated CRC (P<0.05). No correlation were found between the positive expression of E-cadherin protein and other clinicopathological features (P >0.05). 3 Expression of CXCR4 in different groups: Immunohistochemical results showed the positive expression rates of CXCR4 in CRC and normal colorectal mucosa tissue was 58.73% and 35% respectively. CXCR4 expression in CRC was significantly increased( P<0.05). The positive expression of CXCR 4 in lymph node metastatic carcinoma was significantly higher than that in their corresponding primary carcinoma tissue (49.12% vs 82.46%,P<0.05).The positive expression rate of CXCR4 in CRC with lymph node metastasis was significantly higher than that without (P<0.05).No significant relationships between the positive expression of CXCR4 protein and other clinicopathological features was found (P >0.05).4 Expression of CXCL12 in different groups: The positive expression rates of CXCL12 in CRC was significantly higher than that in normal colorectal mucosa tissue (83.33% vs 35%,P<0.05) .Statistical difference in the expression of CXCL12 between lymph node metastatic carcinoma and their corresponding primary carcinoma tissue was seen , with the former significantly higher than that of the latter(94.74% vs 82.46%, P<0.05). No significant relationships between the positive expression of CXCL12 protein and clinical pathological features was found (P >0.05).5 Relationship between the expression of fascin, CXCR4 and CXCL12 in CRC: The expression of fascin and E-cadherin was reversely correlated in CRC (r=-0.204, P=0.022). Positive correlation between fascin and CXCR4 expression and between fascin and CXCL12 expression could be found (r=0.186, P=0.037<0.05; r=0.213, P=0.017<0.05 respectively).Conclusions:1 The expression of fascin, CXCR4 and CXCL12 in CRC was significant higher than that in normal colorectal mucosa tissue and that in metastatic carcinoma tissue of CRC was dramatically higher than that in their corresponding primary carcinoma, while E-cad showed a reverse expression pattern with the above three markers.2 The expressions of fascin, E-cadherin, CXCR4 and CXCL12 in CRC were all significantly correlated with and lymph node metastasis and differentiation of tumor.3 The results in this study showed that fascin, E-cadherin, CXCR4 and CXCL12 may play important roles in carcinogenesis, progression and metastasis of colorectal carcinoma.