Hypoxic Cancer Cells Promote Metastasis Of Normoxic Cancer Cells And Underlying Mechanisms In Colorectal Cancer

Tumor heterogeneity is an important feature of malignant tumors.Besides intratumor subpopulations negatively interact to lead to clonal evolution,the cell subpopulations also positively interact to enhance the tumor progression.Within a colorectal cancer tumor,due to differential access to nutrients and oxygen,there are hypoxic cancer cells and normoxic cancer cells owing to tumor architecture.Recent studies have shown that hypoxic cancer cells possess enhanced metastatic capacity;however,it is still unclear whether hypoxic cancer cells promote metastasis of normoxic cancer cells.Colorectal cancer cells(CRC)were cultured under hypoxia and Nutrient deprivation conditions to induce a hypoxic phenotype.We first demonstrate that,co-cultured with hypoxic CRC cells or treated with the conditioned medium(CM)derived from hypoxic CRC cells,normoxic CRC cells possess increased invasion and migration capacity in vitro,and confer enhanced metastatic capacity in vivo.Furthermore,we found that the conditioned medium of hypoxic CRC cells enriches for IL-8.CM of hypoxic CRC cells and IL-8 promote normoxic CRC cells metastasis by EMT.Interference of IL-8 in hypoxic CRC cells or use anti-IL-8 antibody decreases the invasion,migration and metastasis of normoxic CRC cells.Our findings illuminate that hypoxic CRC cell-derived IL-8 promotes metastatic capacity of normoxic CRC cells and provide new clues to reduce colorectal cancer cell metastasis.