Stem cell programs in cancer initiation, progression, and therapy resistance

Abstract

Over the past few decades, substantial evidence has convincingly revealed the existence of cancer stem cells (CSCs) as a minor subpopulation in cancers, contributing to an aberrantly high degree of cellular heterogeneity within the tumor. CSCs are functionally defined by their abilities of self-renewal and differentiation, often in response to cues from their microenvironment. Biological phenotypes of CSCs are regulated by the integrated transcriptional, post-transcriptional, metabolic, and epigenetic regulatory networks. CSCs contribute to tumor progression, therapeutic resistance, and disease recurrence through their sustained proliferation, invasion into normal tissue, promotion of angiogenesis, evasion of the immune system, and resistance to conventional anticancer therapies. Therefore, elucidation of the molecular mechanisms that drive cancer stem cell maintenance, plasticity, and therapeutic resistance will enhance our ability to improve the effectiveness of targeted therapies for CSCs. In this review, we highlight the key features and mechanisms that regulate CSC function in tumor initiation, progression, and therapy resistance. We discuss factors for CSC therapeutic resistance, such as quiescence, induction of epithelial-to-mesenchymal transition (EMT), and resistance to DNA damage-induced cell death. We evaluate therapeutic approaches for eliminating therapy-resistant CSC subpopulations, including anticancer drugs that target key CSC signaling pathways and cell surface markers, viral therapies, the awakening of quiescent CSCs, and immunotherapy. We also assess the impact of new technologies, such as single-cell sequencing and CRISPR-Cas9 screening, on the investigation of the biological properties of CSCs. Moreover, challenges remain to be addressed in the coming years, including experimental approaches for investigating CSCs and obstacles in therapeutic targeting of CSCs.

Thrombospondin 4/integrin α2/HSF1 axis promotes proliferation and cancer stem-like traits of gallbladder cancer by enhancing reciprocal crosstalk between cancer-associated fibroblasts and tumor cells

“…Growing evidence suggests that tumor metastasis is not only determined by epigenetic or genetic networks in cancer cells but is also influenced by the tumor microenvironments [ 4 , 5 ]. Cancer-associated fibroblasts (CAFs), the main component of tumor stroma in tumor microenvironments, can build-up the cross-talk with cancer cells to facilitate tumor growth, metastasis, immunosuppression, and chemoresistance as well as the creation of a niche for maintaining cancer stemness [ 6 – 9 ]. In human lung cancer, the tumor microenvironment harbors abundant CAFs that secrete IGF-II, a signaling molecule that binds to IGF1R on lung CSCs to activate Akt/Nanog cascades, which play crucial roles in maintaining lung cancer stemness [ 10 ].…”

Bioinformatics Analysis Reveals an Association Between Cancer Cell Stemness, Gene Mutations, and the Immune Microenvironment in Stomach Adenocarcinoma

“…The intrinsic characteristics of CSCs include self-renewal and multipotent properties, as well as proliferative potential, which give certain cellular subpopulations the ability to initiate, develop, and progress cancer (Huang et al, 2020). Dormant CSCs may be activated by a series of gene mutation accumulations and undergo a significant number of DNA sequence alterations (Sengupta and Cancelas, 2010).…”

Loss of neuropilin1 inhibits liver cancer stem cells population and blocks metastasis in hepatocellular carcinoma via epithelial-mesenchymal transition

“…A lot of convincing evidences have revealed that the existence of cancer stem cells (CSCs) is responsible for HCC metastasis, recurrence and heterogeneity [16]. Here, we identified the knockdown of NRP1 suppresses the population of CSCs representative surface markers (CD133 + /EpCAM + /CD13 + ), inhibits the migration of HCC cells and the recurrence and prognosis of HCC patients.…”