4. Cancer Stem Cells (CSCs)
One of the reasons for cancer progression and treatment failure is cancer heterogeneity [220]. Different cancer cell types in the tumor contribute to tumor heterogeneity, and among these cells, cancer stem cells (CSCs) are highly involved in the initiation and progression of cancer as well as have self-renewal and differentiation abilities [221]. Stem cells in cancers can be divided into two categories based on their function:
(1) Resident cancer stem cells that can initiate the tumor,
(2) Migratory stem cells that metastasize and form tumors in another location [221].
Due to these capabilities, CSCs play a key role in tumor initiation, drug resistance, metastasis, and cancer recurrence [222]. During successful chemotherapy, although a significant portion of tumor cells undergo apoptosis, a subset of CSCs may survive and cause cancer recurrence [223, 224].
There is a wide range of mechanisms and factors that contribute to CSCs to promote chemoresistance, including:
(1) Tumor microenvironment (Autophagy, Inflammation, Adipocyte-released factors, CAFs, Mesenchymal stem cells (MSCs), Extracellular matrix (ECM), Hypoxia, Endothelial cells (ECs), Immune cells), (2) EMT induction or activation of EMT-transcription factors,
(3) Self-renewal ability (high telomerase activity),
(4) High expression of CSCs markers (such as CD133, ALDH1, CD44, CD24+),
(5) Quiescence / Dormancy / low proliferation rate,
(6) Stemness genes (such as Bmi1 and Musashi (MSI)),
(7) Epigenetic mechanisms (DNA methylation, Histone modifications),
(8) Signaling pathways (such as Hedgehog pathways, Notch pathways, and Wnt pathways),
(9) Resistant to DNA damage-induced cell death (Promoting the DNA repair capability, Enhancing ROS scavenging, Activating the anti-apoptotic signaling pathways), (10) Metabolism alteration,
(11) Higher expression of multi-drug resistance (MDR) or detoxification proteins (Aldehyde dehydrogenase (ALDH), Drug-transporter proteins (ABCG1, ABCB1)),
(12) Non-coding RNAs (ncRNAs) [220, 225-230].
There is extensive evidence indicating that ncRNAs, including lncRNAs and miRNAs, play a key role in regulating CSC capabilities such as asymmetric cell division, cancer recurrence, tumor initiation, self-renewal, and drug resistance [220, 231-236]. Moreover, according to multiple studies, ncRNAs control the cancer progression and growth and division of cancer stem cells by regulating downstream signaling pathways and transcription factors [226, 237-240].