Stromal induction of WNT16B in response to DNA-damaging agents promotes tumor growth.
Major finding: Stromal induction of WNT16B in response to DNA-damaging agents promotes tumor growth.
Concept: Damaged normal cells can promote drug resistance and tumor progression in a paracrine manner.
Impact: Targeting proteins secreted in response to DNA damage may augment responses to chemotherapy.
Although cytotoxic agents are intended to selectively target tumor cells, normal cells are also affected. Radiation and chemotherapy are commonly administered in cycles to allow normal cells to recover, but gaps in treatment can also allow tumor cells to activate survival mechanisms that promote resistance to subsequent therapy. Sun and colleagues hypothesized that DNA damage responses in the noncancerous cells of the tumor microenvironment can also promote resistance to therapy and tumor progression. Both normal fibroblasts and smooth muscle cells in the tumor stroma of human prostate cancers treated with mitoxantrone and docetaxel indeed showed signs of DNA damage, indicated by increased histone H2AX phosphorylation. Cytotoxic agents activated a specific set of genes in primary prostate fibroblasts in addition to DNA damage response genes, including many encoding secreted proteins. One of the most highly upregulated genes was WNT16B, a poorly characterized WNT family member. Elevated amounts of WNT16 protein were found in conditioned media from prostate, breast, and ovarian fibroblasts after chemotherapy or radiation as well as the stroma of prostate, breast, and ovarian cancers treated with neoadjuvant chemotherapy. Conditioned medium from prostate fibroblasts stably expressing WNT16 significantly enhanced prostate cancer cell growth, migration, and invasion by activating canonical WNT signaling and inducing an epithelial-to-mesenchymal transition. Moreover, coimplantation of WNT16-expressing fibroblasts with prostate cancer cells significantly increased the size of tumors and attenuated the effects of mitoxantrone on tumor growth. Conversely, knockdown of WNT16 in prostate fibroblasts reduced tumor size and enhanced mitoxantrone efficacy. These results underscore the role of the tumor microenvironment in acquired resistance to chemotherapy and suggest that targeting stromal proteins such as WNT16B that are secreted following treatment with cytotoxic agents may improve responses to chemotherapy.