Chitinase 3-like 1 Mediates Tumor-Promoting Interactions between Fibroblasts and Macrophages in the Microenvironment of Breast Tumors

Cancer-Associated Fibroblasts (CAFs) are an activated sub-population of stromal fibroblasts, which have different characteristics in different tumor types and tissue locales. CAFs were shown to facilitate tumor growth by supporting tumor cell growth, enhancing angiogenesis and remodeling the extracellular matrix (ECM). In some tumor types, including breast cancer, fibroblasts are the most abundant cell type, and their abundance correlates with worse prognosis. Breast cancer continues to be one of the leading causes of cancer related death in women, and the requirement for better therapies is an unmet clinical need.

During breast carcinogenesis, fibroblasts are reprogrammed to express various factors that facilitate tumor progression, but many of them remain unknown. We found that Chi3L1, also known as YKL-40 in humans, is highly upregulated in CAFs isolated from invasive mammary tumors as compared with normal fibroblasts. Chi3L1 is a secreted heparin-binding glycoprotein, induced specifically during the course of inflammation. Although Chi3L1 plays a pivotal role in exacerbating the inflammatory processes and in promoting angiogenesis and remodeling of the extracellular matrix, its functional role in cancer-related inflammation is still largely unknown. We found that Chi3L1 plays a role in the communication between CAFs and macrophages: Chi3L1 increased macrophage migration and upregulation of a pro-tumorigenic gene signature in macrophages. Furthermore, orthotopic transplantation of breast cancer cells mixed with fibroblasts in which the expression of Chi3L1 was knocked-down resulted in attenuated tumor growth. Taken together, our findings implicate fibroblast-derived Chi3L1 as a key player in the crosstalk between tumor cells and their microenvironment, and deepen our understanding of the contribution of CAFs to tumor progression and metastasis.