Wnt2 Expression in Cancer-Associated Fibroblasts Precedes Lymph Node Metastasis in Orthotopic Transplantation Mouse Model of Colorectal Cancer.

Abstract

Lymph node (LN) metastasis is one of the most common mechanisms underlying the spread of solid cancers. Mouse models of orthotopic tumor transplantation have been used to elucidate the metastatic mechanisms. Previous studies have mainly focused on metastasis in orthotopic models, and the correlation between histological findings of infiltrated cancer cells and tumor microenvironment has not been fully explored. Cancer-associated fibroblasts (CAFs) play a key role in metastasis, especially via secreting Wnt2, which plays a functional role in cancer progression. Here, we investigated the correlation between the incidence of LN metastases and histological findings in an orthotopic mouse model using 22 colorectal cancer cell lines. Lymphatic invasion was significantly associated with LN metastasis. Immunohistochemistry revealed that podoplanin and αSMA were highly expressed in the cancer stroma, thus suggesting that CAFs were also induced in the orthotopic implantation mouse model. Furthermore, Wnt2 positivity was mainly observed in the cancer stroma, and Wnt2 expression was significantly associated with the incidence of LN metastasis. Our results indicate that the orthotopic mouse model recapitulates cancer infiltration and the tumor microenvironment, including CAFs. The contribution of Wnt2 toward LN metastasis was also validated in an in vivo model. Thus, our findings provide new insights into the functional roles of CAFs and Wnt2 in metastasis.