P-166 Macrophage-Cancer Cell Fusion Potentiates Tumor Progression

Abstract

Inflammatory bowel disease (IBD) afflicts more than one million Americans and although great strides have been made in disease management, insufficient knowledge exists about the increased risk of cancer and the more aggressive nature of colitis associated cancer. Specifically, it is not known how cancer cells acquire altered behaviors that propagate tumor progression. We showed that circulating macrophages (MФs) spontaneously fuse with intestinal cancer cells. This fusion is enhanced in an inflammatory microenvironment and results in cells (fusion hybrids) that retain both MФ and epithelial cell gene expression. While the underlying physiologic function of cell fusion cancer cells is not clear, we hypothesize that it ultimately results in cancer cells that retain macrophage-like behaviors, making them more responsive to cytokine, migratory and more successful in seeding distant metastatic organs. Two models for cell fusion: (1) in vitro co-culture of intestinal colorectal cancer cells and MФs that result in spontaneous fusion, and (2) in vivo fusion with marked MФs were employed to generate fusion hybrids and explore their physiologic behavior and query their expression profiles. We have found that fusion between MФ and cancer cells result in fusion hybrids that have enhanced adhesive and proliferative function. Further, these fusion hybrids have demonstrated an increased ability to migrate towards various cytokines based upon their genetic profile. Finally, fusion hybrids seed and grow in the liver with increased ability relative to unfused cancer cells. Intriguingly, our data suggest that MФ-cancer cell fusion represents an under-appreciated mechanism for reprogramming of the cancer cell genome leading to acquisition of non-epithelial behaviors (e.g., differences in adhesion, migration and seeding in metastatic sites). Our study provides a potential paradigm-shifting mechanism underlying how cancer cells in a highly inflammatory microenvironment more readily gain aggressive metastatic properties associated with lethal disease. We postulate that identification of novel gene expression in these fusion hybrids have promise to provide new biomarkers that could predict risk for cancer and identify new therapeutic options for abating fusion-associated cancer cell behavior.