Loss of cIAP1 in Endothelial Cells Limits Metastatic Extravasation through Tumor-Derived Lymphotoxin Alpha

Simple Summary The ability of tumor cells to spread from one site to another within a patient is a critical factor in cancer survival. Tumor cell migration or metastasis is a complex process, which involves several stages. In this study, we specifically examine the stage in which the tumor cell must exit the blood stream. We find that the loss of cIAP1, a member of the inhibitors of apoptosis protein family (IAPs), alters the ability of tumor cells to exit the blood vessel or extravasate. Endothelial cell viability did not appear to be affected in the absence of cIAP1. Instead, we identified that the loss of cIAP1 hampers the response of endothelial cells to signals from the tumor cells to change shape and allow for migration through the endothelial barrier. In this study, we determined whether Smac mimetics play a role in metastasis, specifically in circulation, tumor extravasation and growth in a metastatic site. Reports suggest inducing the degradation of IAPs through use of Smac mimetics, alters the ability of the tumor cell to metastasize. However, a role for the immune or stromal compartment in affecting the ability of tumor cells to metastasize upon loss of IAPs has not been defined. To address this open question, we utilized syngeneic tumor models in a late-stage model of metastasis. Loss of cIAP1 in the endothelial compartment, rather than depletion of cIAP2 or absence of cIAP1 in the hematopoietic compartment, caused reduction of tumor load in the lung. Our results underline the involvement of the endothelium in hindering tumor cell extravasation upon loss of cIAP1, in contrast to the immune compartment. Endothelial specific depletion of cIAP1 did not lead to cell death but resulted in an unresponsive endothelium barrier to permeability factors causing a decrease in tumor cell extravasation. Surprisingly, lymphotoxin alpha (LTA), and not TNF, secreted by the tumor cells, was critical for the extravasation. Using TCGA, we found high LTA mRNA expression correlated with decreased survival in kidney carcinoma and associated with advanced disease stage. Our data suggest that Smac mimetics, targeting cIAP1/2, reduce metastasis to the lung by inhibiting tumor cell extravasation.

Automated summary

The loss of cIAP1 hampers tumor cell extravasation by affecting endothelial cell response to tumor cell signals, rather than causing endothelial cell death. Lymphotoxin alpha secreted by tumor cells plays a critical role in the extravasation process.Targeting cIAP1/2 with Smac mimetics reduces lung metastasis by inhibiting tumor cell extravasation.