A recent report (Cell 149, 1207–1220) uncovers a role for the stromal compartment in skin carcinogenesis.

Skin cancer often appears in the form of field cancerization, a constellation of alterations in the epithelial and mesenchymal tissues that surround a tumorigenic lesion, and is likely to emerge from broad exposure to carcinogens such as sunlight. However, it was not known whether stromal changes could drive this widespread transformation process.

Bing Hu et al. investigated the contribution of the stroma to tumorigenesis in mice by inactivating the tumor-suppressive Notch signaling pathway in mesenchymal cells. Interestingly, when they aged, these mice developed spontaneous, multifocal squamous carcinomas of diverse cellular origin, which were infiltrated by inflammatory cells. The formation of these lesions could be prevented by anti-inflammatory drug treatment.

In further studies, the authors confirmed that mouse and human skin fibroblasts with dysfunctional Notch signaling could foster the neoplastic transformation of epithelial cells by a mechanism that involved increased transcriptional activation by AP-1 factors.

Importantly, the stroma surrounding human preneoplastic skin lesions showed similar alterations in Notch signaling to those in the authors' mouse model, and these changes could be induced by exposure to ultraviolet A radiation. These new results expand the protumorigenic role of the stroma that has previously been observed in other tissues such as the mammary gland and draw attention to the role of mesenchymal components as cancer drivers.