Fibroblast-Secreted CHI3L1 Enhances Tumor Growth and Angiogenesis

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. Breast tumors are characterized by an extensive desmoplastic stroma, abundantly populated by fibroblasts. 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).

During breast carcinogenesis, fibroblasts express various factors that facilitate tumor progression, but many of them remain unknown. We found that CHI3L1 is highly upregulated in CAFs isolated from invasive mammary tumors and from their pre-metastatic lungs, as compared with normal mammary and lung fibroblasts.
Although CHI3L1, a secreted glycoprotein, plays a pivotal role in exacerbating the inflammatory processes, promoting angiogenesis and remodeling of the ECM, its functional role in cancer-related inflammation is still largely unknown.

We found that CHI3L1 induced expression of pro-inflammatory and pro-tumorigenic pathways and enhanced cell migration in breast cancer cells. In vivo, supplementing tumor cells with CHI3L1 induced angiogenesis in matrigel plugs. Furthermore, orthotopic transplantation of breast cancer cells mixed with fibroblasts in which the expression of CHI3L1 was knocked-down resulted in attenuated tumor growth. Interestingly, CHI3L1 also increased macrophage migration and upregulation of M2-like gene signature. 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.