Cancer stem cells and their niche in the progression of squamous cell carcinoma

Most cancers harbor a small population of highly tumorigenic cells known as cancer stem cells (CSCs). Because of their stem cell‐like properties and resistance to conventional therapies, CSCs are considered to be a rational target for curable cancer treatment. However, despite recent advances in CSC research, CSC‐targeted therapies are not as successful as was initially hoped. The proliferative, invasive, and drug‐resistant properties of CSCs are regulated by the tumor microenvironment associated with them, the so‐called CSC niche. Thus, targeting tumor‐promoting cellular crosstalk between CSCs and their niches is an attractive avenue for developing durable therapies. Using mouse models of squamous cell carcinoma (SCC), we have demonstrated that tumor cells responding to transforming growth factor β (TGF‐β) function as drug‐resistant CSCs. The gene expression signature of TGF‐β–responding tumor cells has accelerated the identification of novel pathways that drive invasive tumor progression. Moreover, by focusing on the cytokine milieu and macrophages in the proximity of TGF‐β–responding tumor cells, we recently uncovered the molecular basis of a CSC–niche interaction that emerges during early tumor development. This review article summarizes the specialized tumor microenvironment associated with CSCs and discusses mechanisms by which malignant properties of CSCs are maintained and promoted.