Figure 8. Model of the development of human urothelial carcinoma, progressing from SHH-positive basal stem cells to distinct molecular subtypes.

Clonal loss of SHH expression caused by DNA methylation leads to the suppression of the stromal Hh response, which in turn facilitates the initiation and progression of tumors at early stages, ultimately resulting in the formation of the SHH-negative, basal subtype of invasive carcinoma. Decreased methylation of the SHH gene suppresses tumor growth by inducing subtype conversion from basal to luminal-like urothelial carcinoma through increased activity of Hh/BMP signaling feedback between cancer cells and the tumor stroma. See text.