Figure 2.

Proposed mechanism of the development of cancer stem cell (CSC) (purple) in HNSCC and its relation to sensitivity to DNA‐damaging agents, and tumor recurrence and metastasis. CSCs of HNSCC appear to originate from cancer cells that have undergone processes of multistage carcinogenesis (orange and green) at the advanced stage of tumor progression, since a majority of early stage tumors are cured by chemoradiation or irradiation alone (i.e., chemoradioselection) lacking the CSC phenotype. Thus, the origin of HNSCC is not likely CSC. However, this model does not exclude the possibility that CSCs of HNSCC originate from normal stem cells (white) that accumulated a series of abnormalities. CSCs can survive treatments with DNA‐damaging agents and propagate recurrent tumor. CSCs that have undergone epithelialߝ;mesenchymal transition (EMT) can migrate as “migrating CSCs” (jagged purple) and propagate metastatic tumors after they have, in turn, undergone mesenchymal epithelial transition (MET). Recurrent and metastatic tumors appear to be composed of relatively homogeneous cell population that that has two distinctive properties: insensitive to DNA‐damaging therapy and ability to rapidly expand gross tumor volume. For more details see text.