Tnf-Receptor 2 Plays A Critical Role In Liver Metastasis By Regulating Sinusoidal Endothelial Vcam-1 Expression, Ly6g+Leukocyte Recruitment And Transendothelial Migration

The hepatic microenvironment can play an important role in promoting liver metastasis. We and others have shown that when metastatic carcinoma cells enter the liver, a rapid inflammatory response mediated by TNF-α is triggered, enabling tumor transendothelial migration and metastasis. TNF-α binds to the cell surface through two receptors; the p55/p60 TNFR1 and the p75/p80 TNFR2. To elucidate the roles of these receptors in the inflammatory cascade and in liver colonization by tumor cells, we used mice with tnfr1, tnfr2 and combined tnfr1/tnfr2 gene deficiencies and investigated parameters of the host response and the outcome of metastasis in these mice using the highly metastatic mouse colon carcinoma MC-38 and lung carcinoma H-59 cells. We found that experimental liver metastasis following intrasplenic/portal inoculation of the tumor cells was markedly reduced in TNFR2 −/− and even further in TNFR1 −/− /TNFR2 −/- female mice as compared to wild-type controls but no reduction was observed in TNFR1 −/− mice. To identify the underlying mechanism(s), we investigated changes in the liver microenvironment following tumor inoculation using a combination of immunohistochemistry, confocal microscopy, qRT-PCR, and cytokine/chemokines profiling. We found that while in wild-type and TNFR1 −/- mice, VCAM-1 expression on the sinusoidal endothelium was significantly upregulated within 16 hr post tumor injection, it was unchanged in TNFR2 −/− and double negative female mice. In addition, qRT-PCR analysis revealed that the production of the neutrophil chemokine CXCL1, while upregulated in control mice, was suppressed in TNFR2 −/− mice. These changes were associated with a parallel decrease in Ly6G + neutrophil recruitment into extravascular, pro-metastatic niches 16-48 hr post tumor inoculation. Interestingly, these reductions were not observed in male TNFR2 −/− mice and correspondingly, their metastatic burden was not reduced relative to control mice. Taken together, the results suggest that TNFR2 plays a critical and gender-specific role in Ly6G + cell recruitment into the tumor-microenvironment by regulating sinusoidal endothelial VCAM-1 expression and chemokine production. In turn, the recruitment of these cells into extravascular pro-metastatic niches appears to promote liver metastasis. Supported by grant MOP-80201 from the Canadian Institute for Health Research. (to PB) and by a McGill Integrated Cancer Research Training Program fellowship (to BH). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1508. doi:1538-7445.AM2012-1508