Abstract IA30: CXCL1 is critical for pre-metastatic niche formation and metastasis in colorectal cancer

Abstract

Abstract Emerging evidence suggests that once a primary tumor forms it can then influence the development of a supportive metastatic microenvironment, referred to as pre-metastatic niches, in certain distant organs before arrival of metastatic cells. However, the mechanisms underlying the contributions of the primary tumor to pre-metastatic niche formation are not fully understood. Here we demonstrate that colorectal carcinoma cells secrete VEGF-A that stimulates tumor-associated macrophages to produce CXCL1 in the primary tumor. Elevation of CXCL1 in pre-metastatic liver tissue recruits CXCR2-positive myeloid-derived suppressor cells (MDSCs) to form a pre-metastatic niche that ultimately promotes liver metastases. Importantly, we found that pre-metastatic liver-infiltrating MDSCs induce tumor cell survival without involvement of the innate or adaptive immune responses. Our study provides the first evidence we know of showing that primary malignant cell-secreted VEGF-A stimulates tumor-associated macrophages to produce CXCL1 that recruits CXCR2-positive MDSCs to form a pre-metastatic niche which promotes liver metastases. Our findings not only reveal a novel mechanism by which the interactions of malignant cells with their stromal counterparts in the primary tumor contribute to the formation of a pre-metastatic niche that favors tumor cell survival, but also provides a rational for development of CXCR2 antagonists to inhibit or prevent metastatic spread of disease. Citation Format: Raymond N. DuBois. CXCL1 is critical for pre-metastatic niche formation and metastasis in colorectal cancer [abstract]. In: Proceedings of the AACR International Conference: New Frontiers in Cancer Research; 2017 Jan 18-22; Cape Town, South Africa. Philadelphia (PA): AACR; Cancer Res 2017;77(22 Suppl):Abstract nr IA30.