Mechanisms of cancer stem cell senescence: Current understanding and future perspectives

Abstract

Cancer stem cells (CSCs) are a small population of heterogeneous tumor cells with the capacity of self‐renewal and aberrant differentiation for immortality and divergent lineages of cancer cells. In contrast to bulky tumor cells, CSCs remain less differentiated and resistant to therapy even when targeted with tissue‐specific antigenic markers. This makes CSCs responsible for not only tumor initiation, development, but also tumor recurrence. Emerging evidence suggests that CSCs can undergo cell senescence, a non‐proliferative state of cells in response to stress. While cell senescence attenuates tumor cell proliferation, it is commonly regarded as a tumor suppressive mechanism. However, mounting research indicates that CSC senescence also provides these cells with the capacity to evade cytotoxic effects from cancer therapy, exacerbating cancer relapse and metastasis. Recent studies demonstrate that senescence drives reprogramming of cancer cell toward stemness and promotes CSC generation. In this review, we highlight the origin, heterogeneity and senescence regulatory mechanisms of CSCs, the complex relationship between CSC senescence and tumor therapy, and the recent beneficial effects of senotherapy on eliminating senescent tumor cells.

Ciliated, Mitochondria-Rich Postmitotic Cells are Immune-privileged, and Mimic Immunosuppressive Microenvironment of Tumor-Initiating Stem Cells: From Molecular Anatomy to Molecular Pathway

“…Senescence is another common characteristic of PoMiCs and TiSCs. It is a mechanism by which TiSCs stop their cell cycle to provide efficient resistance against radiotherapy and anticancer agents [141]. It has been demonstrated that senescence in cancer cells is conducted by mitochondria.…”

Targeting cellular senescence to combat cancer and ageing

“…It is well‐known that crucial signaling components of senescence pathways, such as p16 INK4a , p21 cip1 , and p53, are also critical regulators of cancer stem‐cell‐like phenotypes [118]. A gain of stemness in cancer cells has profound effects on tumour progression and aggressiveness [119].…”

Cancer Stem Cells in Pancreatic Ductal Adenocarcinoma

“…However, the ability to re-establish the tumour diversity in an experimental animal model should not be equated with the capacity to induce the malignant tumour in the patient. Indeed, four possible sources of CSCs are proposed, including normal stem cells, mature cells, cancer cells and fusion cells [ 13 , 14 ]. Currently, cancer stem cells are considered a state rather than an entity [ 13 , 15 ], likely being in dynamic balance with the general malignant population.…”