Effect Of Low Molecular Weight Heparin On Survival In Patients With Colorectal Cancer And Its Mechanisms

Low Molecular Weight Heparin Improves the Survival in Patients with Stage III Colorectal Cancer and Enhances the Susceptibility of Colon Cancer Cells to 5-FUPurpose:To study the effect of low molecular weight heparin (LMWH) on survival in patients with colorectal cancer and its underlying mechanism. Methods:Seven hundred twenty-five patients who had received an operation for colorectal adenocarcinoma were identified from the database. Of these,145 patients had been treated with LMWH after surgery, whereas 580 patients served as controls. Outcome was assessed in relation to 3-year disease free survival (DFS) and overall survival (OS). Furthermore, CXC chemokine receptor 4 (CXCR4), P-selectin(CD62P), vascular endothelial growth factor (VEGF) and basic Fibroblast Growth Factor (bFGF) were studied in colorectal cancer tissues by immunohistochemistry, to evaluate the correlation between these four protein expression and anti-cancer effect of LMWH. Besides, different concentrations of LMWH and 5-fluorouracil (5-FU) were respectively acted on the human colon carcinoma cell line SW620. The absorbance value was tested by colorimetry through the cell-counting kit 8 (CCK-8) method to evaluate the effect of LMWH,5-FU or the two drugs combined respectively after 48 hours. A subcutaneous tumor model of nude mice with SW620 cells was build, while LMWH and 5-FU were given to nude mice. Tumor volumes were measured in different groups. Results:There was no significant difference between LMWH group and CONTROL group in terms of 3-year DFS or OS. However, in a subgroup of patients with TNM-Ⅲ stage, LMWH treatment could improve the 3-year disease free survival (HR=0.527,95%CI 0.279-0.994) and overall survival (HR=0.440,95%CI 0.200-0.968), but not in subgroups of patients with stage Ⅰ, Ⅱ or Ⅳ. Furthermore, CXCR4 and CD62P were expressed in colorectal cancer tissues specifically and differentially. There was significant association between CXCR4 and CD62P expression and the anti-cancer effect of LMWH. Patients with CXCR4 or CD62P positively expressed, not negatively, had better disease free survival and overall sruvival after receiving LMWH treatment. Moreover, it was proved that LMWH alone could not inhibit the proliferation of SW620 cells, while it could enhance the inhibitory effect of 5-FU to SW620 cells. The proliferation rate was dose-dependent which was lower when 5-FU combined with LMWH than 5-FU alone. Although LMWH did not significantly inhibit the growth of subcutaneous colon tumors, it raised the inhibitory effect of 5-FU to them. Conclusions:LMWH improves the 3-year disease free survival and overall survival in patients with stage Ⅲ colorectal cancer, which was associated with the expression of CXCR4 and CD62P in cancer tissues; LMWH enhances the susceptibility of colon cancer cells to 5-FU.