Hepatic Thermal Injury Promotes Colorectal Cancer Engraftment in C57/black 6 Mice

Abstract

Background:Treatment of liver metastases (primarily colorectal cancer) is limited by high recurrence rates and tumor progression. Surgical approaches to management of these metastases typically utilize heat energy: including electrocautery; argon beam coagulation; thermal ablation of surgical margins for hemostasis; and preemptive thermal ablation to prevent bleeding or effect tumor destruction. Based on high rates of local recurrence, these studies assess whether local effects of hepatic thermal injury (HTI) might contribute to poor outcomes by promoting a hepatic microenvironment favorable for tumor engraftment or progression due to induction of pro-cancer cytokines and deleterious immune infiltrates at the site of thermal injury. Approach and Results:To test this hypothesis, an immunocompetent mouse model was developed wherein HTI was combined with concomitant intrasplenic injection of cells from a well characterized MC38 colon carcinoma cell line. In this model, HTI resulted in a significant increase in engraftment and progression of MC38 tumors at the site of thermal injury. Further, there were local increases in expression of mRNA for Hif1a, Arg1, and Vegfaand activation changes in recruited macrophages at the HTI site but not in untreated liver tissue. Inhibition of HIF1α following HTI significantly reduced discreet hepatic tumor development (p=0.03). Conclusions:Taken together, these findings demonstrate that HTI creates a favorable local environment that is associated with pro-tumorigenic activation of macrophages and circulating tumors implanting. Discrete targeting of HIF1α and/or its up and downstream pathways and/or inhibiting macrophages offer potential strategies for improving the outcome of surgical management of hepatic metastases where HTI is utilized.