The Study Of The Relationship Between αvβ3Integrin Expression And Vasculogenic Mimicry And Related Molecular Mechanism In Colorectal Carcinoma

ObjectiveFirst, to study the incidence of vasculogenic mimicry (VM) and its clinical significance in human colorectal cancer(CRC). Second, to elucidate the relationship between expression of αvβ3integrin, microvessel density(MVD) and their clinical significance in human colorectal cancer. Third, to explore the relationship between presence of VM, MVD and αvβ3integrin, FAK, VEGF and MMP-2expression and correlation of αvβ3integrin expression on FAK, VEGF and MMP-2expression in human colorectal cancer. Finally, to investigate the possible molecular mechanism of avP3integrin participating in the process of tumor angiogenesis.Methods227human colorectal cancer patients undergoing surgery with complete clinical pathology date between2000to2004were collected from the Department of Pathology, Tianjin Cancer Institute and Hospital, Tianjin Medical University, China. Tissue sections (5μm) were prepared well. The distribution and clinical pathological significance of VM was observed by CD31and PAS double staining. Immunohisochemical staining was used to observe the expression of avP3integrin, FAK, VEGF, MMP-2. The collected data were deal with statistics analysis.Results1. The distribution and clinical pathological significance of VM in human colorectal cancerUsing CD31/PAS double-staining, VM was observed in CRC. VM was identified in41(18.1%) of the227CRC specimens. The frequency of VM was found to be closely associated with PTNM stages, grades of differentiation, metastasis in CRC (.P=0.000; P<0.019; P=0.007). No association was found between the frequency of VM and age, gender and diameter of tumors (P=0.442; P=0.491; P=1.000). Furthermore, Kaplan-Meier survival analysis showed that the total survival time for patients in the VM-present group was significantly shorter than for those in the VM-absent group (P=0.003). The average survival time for VM-present patients was40.8months, whereas the average survival time for VM-absent patients was62.4months.2. The expression of avP3integrin in CRC and its clinical pathological significanceThe staining for avP3integrin was confined to the cytoplasm and cytomembrane of CRC cells. The positive rate of αvβ3integrin was found to be closely related to metastasis in CRC (P=0.018). However, the staining for αvβ3integrin had no significant association with gender, age, diameter of tumors and PTNM stages (P=0.880; P=0.789; P=0.473; P=0.162). The total survival period of patients with αvβ3integrin expression was found to be significantly shorter than that of patients without avP3integrin expression (P=0.001). The average survival period for αvβ3integrin patients was45.8months, whereas that for αvβ3integrin-negative patients was56.5months.3. Association of MVD with Clinicopathological FactorsNo correlation was found between the high MVD and patient characteristics, such as age, gender, diameter of tumors and grades of differentiation (P=0.273; P=0.958; P=0.242; P=0.907). The mean MVD score was higher in advanced-stage carcinomas (TNM stages Ⅲ and Ⅳ) than in early-stage carcinomas (TNM stages Ⅰ and Ⅱ)(P=0.043). It was also significantly higher in the group with metastasis than in the group without metastasis and recurrence. Kaplan-Meier survival analysis showed that the survival rate in the group with MVD>28was significantly different from that in the MVD≤28group (the mean MVD was27.3±8.8). The average survival time for MVD>28patients was45.2months, whereas the average survival time for MVD≤28patients was57.4months.4. Relationship between presence of VM and expression of αvβ3integrin, FAK, VEGF and MMP-2FAK, VEGF and MMP-2were expressed in the cytoplasm of CRC cells. The positive rate of avP3integrin in VM-present group was significantly higher than that in VM-absent group (P=0.000). The VM-present group also had a higher rate of FAK, VEGF and MMP-2expression than the VM-negative group (P=0.010; P=0.005; P=0.015).5. Relationship between MVD and expression of avP3integrin, FAK, VEGF and MMP-2The αvβ3integrin-positive group had higher MVD than the αvβ3integrin-negative group(P=0.000). The FAK-positive group had high MVD than the FAK-negative group(P=0.001). The VEGF-positive group had high MVD than the VEGF-negative group(P=0.000). The VEGF-positive group had high MVD than the VEGF-negative group(P=0.000).6. Correlation of αvβ3integrin, FAK, VEGF and MMP-2in CRC There was a significantly positive correlation between the expression of αvβ3integrin and FAK (r=0.181, P=0.005), as well as the αvβ3integrin expression and VEGF (r=0.177, P=0.007) in CRC. There was also a significantly positive correlation between expression of αvβ3integrin and MMP-2(r=0.313, P<0.001).Conclusion1. There was VM in colorectal carcinoma. The patients with VM differentiate poorly, metastasis earlier and had a poor prognosis.2. The positive rates of αvβ3integrin were56.8%(129/227) in colorectal carcinoma and the patients with αvβ3integrin expression metastasis earlier and had a poor prognosis.3. The MVD was in close correlation with metastasis. MVD was a prognostic factor in colorectal carcinoma.4. In colorectal carcinoma, avP3integrin, FAK, VEGF and MMP-2contribute to forming the VM structure. αvβ3integrin is possible to participate in the formation of VM through the interaction with FAK,VEGF and MMP-2.5. In colorectal carcinoma, avP3integrin, FAK, VEGF and MMP-2contribute to building the vesseles of tumours. αvβ3integrin is possible to participate in the formation of vesseles through the interaction with FAK,VEGF and MMP-2.