CXCL1 Is Critical for Premetastatic Niche Formation and Metastasis in Colorectal Cancer

• Published in: Cancer research (Chicago, Ill.) Vol. 77; no. 13; pp. 3655 - 3665
• Main Authors: Wang, Dingzhi, Sun, Haiyan, Wei, Jie, Cen, Bo, DuBois, Raymond N
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research, Inc 01-07-2017
• Subjects: Adaptive immunity; Animals; Antagonists; Cell survival; Chemokine CXCL1 - biosynthesis; Chemokine CXCL1 - immunology; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - immunology; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; CXCR2 protein; HCT116 Cells; Heterografts; Humans; Immune response; Liver; Liver Neoplasms - immunology; Liver Neoplasms - metabolism; Liver Neoplasms - secondary; Macrophages; Male; Metastases; Metastasis; Mice; Mice, Inbred NOD; Mice, SCID; Microenvironments; Neoplasm Metastasis; Neoplastic Stem Cells - immunology; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Organs; Stem Cell Niche; Suppressor cells; Tumor Microenvironment
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-16-3199

Emerging evidence suggests that the primary tumor influences the development of supportive metastatic microenvironments, referred to as premetastatic niches, in certain distant organs before arrival of metastatic cells. However, the mechanisms underlying the contributions of the primary tumor to premetastatic niche formation are not fully understood. Here, we demonstrate that colorectal carcinoma cells secrete VEGFA, which stimulates tumor-associated macrophages to produce CXCL1 in the primary tumor. Elevation of CXCL1 in premetastatic liver tissue recruited CXCR2-positive myeloid-derived suppressor cells (MDSC) to form a premetastatic niche that ultimately promoted liver metastases. Importantly, premetastatic liver-infiltrating MDSCs induced tumor cell survival without involvement of innate or adaptive immune responses. Our study provides the first evidence that primary malignant cell-secreted VEGFA stimulates tumor-associated macrophages to produce CXCL1, which recruits CXCR2-positive MDSCs to form a premetastatic niche to promote liver metastases. Our findings not only shed light on how the tumor microenvironment contributes to premetastatic niche formation at distant sites, but they also provide comprehensive insights into how MDSCs are recruited to other organs where they contribute to metastatic spread of disease. Moreover, our work also provides a rationale for development of CXCR2 antagonists to inhibit or prevent metastatic spread of disease.
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