Hypoxic Colorectal Cancer Cells Promote Metastasis Of Normoxic Cancer Cells Depending On IL-8/p65 Signaling Pathway

Within a tumor tissue,there are several sub-populations of tumor cells,with different tumor biological characteristics,which play different roles in development and progression of tumor,which is called the tumor heterogeneity.There are diverse inter-cellular interactions among different tumor cell sub-populations,including competition and cooperation.Hypoxic tumor cells have increased metastatic capacity.However,it is not clear whether hypoxic colorectal cancer cells promote the metastasis of normoxic cancer cells.On the basis of the previous studies,in a variety of hypoxic models in vitro and in vivo,this study further confirmed that hypoxic tumor cells in colorectal cancer transfer IL-8through the paracrine pathway to enhance the migration,invasion ability in vitro and the lung metastasis potential of normoxic tumor cells in vivo.In addition,we found that hypoxic tumor cell-derived IL-8 increased the phosphorylation of p65 to promote the epithelial-mesenchymal transition of normoxic tumor cells and thereby enhance their invasion,migration capacity and pulmonary metastatic potential.Inhibition or knockdown of p65 in normoxic tumor cells weakened the effect of IL-8 on promoting epithelial-mesenchymal transition and enhancing invasion,migration capacity and pulmonary metastatic potential.In this study,we further studied the mechanism of hypoxic tumor cells-derived IL-8 in promoting the metastasis of normoxic tumor cells in colorectal cancer,and provided a new idea for reducing the metastasis of colorectal cancer cells from the perspective of tumor heterogeneity.More importantly,we utilized Bevacizumab to induce hypoxia of CRC xenograft tumors through intratumoral injection,and successfully obtained hypoxic and normoxic tumors,separated in position but interacted in function,in one mouse.This provides a new approach for future study of the interaction between normoxic and hypoxic tumors in vivo.