Fig. 3: Hypothesis on CSC generation, and CSC-targeting therapy through inhibition of mTOR pathway.
From: Targeted therapy of cancer stem cells: inhibition of mTOR in pre-clinical and clinical research
There have been several hypotheses on how the CSCs, which possess a crucial role in cancer development, are generated (purple box in left). Accumulation of mutations in normal stem cells are considered as an important cause of CSC generation [150, 151]. Also, cancer cells can be mutated into CSCs by chemotherapy during the process of metastasis [152]. The metastatic cancer cells can acquire the ability to differentiate into other types of cancer cells, resulting in generation of CSCs [150, 153]. In addition, when a small part of the cancer cells is stimulated and activated by radiotherapy and chemotherapy, it can be differentiated into cancer cells, which have ability to induce cancer recurrence [154]. And these cancer cells with recurrence ability can be activated into CSCs [155]. Through differentiation of the CSCs, CSC-derived cancer tissues are generated (middle of the scheme). Through treatment of mTOR inhibitor to the CSC-derived cancer tissues, CSC-targeting anti-cancer therapy is possible (pink box in right). By inhibition of mTOR signaling pathway, viability and ability of CSC decrease [89, 95, 97,98,99, 102, 109], radio/chemo-sensitivity of the CSCs increase [100], and number or size of tumor sphere decrease [87, 88, 90,91,92, 108, 111], resulting in apoptosis of the cancer tissues [86, 96, 112, 115].
