Advances in Therapeutic Targeting of Cancer Stem Cells within the Tumor Microenvironment: An Updated Review

Abstract

Despite great strides being achieved in improving cancer patients’ outcomes through better therapies and combinatorial treatment, several hurdles still remain due to therapy resistance, cancer recurrence and metastasis. Drug resistance culminating in relapse continues to be associated with fatal disease. The cancer stem cell theory posits that tumors are driven by specialized cancer cells called cancer stem cells (CSCs). CSCs are a subpopulation of cancer cells known to be resistant to therapy and cause metastasis. Whilst the debate on whether CSCs are the origins of the primary tumor rages on, CSCs have been further characterized in many cancers with data illustrating that CSCs display great abilities to self-renew, resist therapies due to enhanced epithelial to mesenchymal (EMT) properties, enhanced expression of ATP-binding cassette (ABC) membrane transporters, activation of several survival signaling pathways and increased immune evasion as well as DNA repair mechanisms. CSCs also display great heterogeneity with the consequential lack of specific CSC markers presenting a great challenge to their targeting. In this updated review we revisit CSCs within the tumor microenvironment (TME) and present novel treatment strategies targeting CSCs. These promising strategies include targeting CSCs-specific properties using small molecule inhibitors, immunotherapy, microRNA mediated inhibitors, epigenetic methods as well as targeting CSC niche-microenvironmental factors and differentiation. Lastly, we present recent clinical trials undertaken to try to turn the tide against cancer by targeting CSC-associated drug resistance and metastasis.

Temozolomide Treatment Induces HMGB1 to Promote the Formation of Glioma Stem Cells via the TLR2/NEAT1/Wnt Pathway in Glioblastoma

“…At present, the origin of CSCs is not yet fully understood. Recent studies have shown that tumor microenvironment (TME), which is composed of immune cells, perivascular cells, fibroblasts and factors secreted by these cells, can provide extracellular signals for the generation and maintenance of CSCs (Dzobo et al, 2020 ). It was recently reported that chemotherapy could cause immunogenic cell death (ICD) of tumor cells, which release damage-associated molecular patterns (DAMPs) into TME (Inoue and Tani, 2014 ).…”

Cancer Stem Cell Marker CD44 Plays Multiple Key Roles in Human Cancers: Immune Suppression/Evasion, Drug Resistance, Epithelial–Mesenchymal Transition, and Metastasis

“…The main contributors to tumor heterogeneity are tumor cell evolution, stromal component contribution, and spatial differences occurring during tumor cell differentiation [11][12][13][14][15][16]. Based on the hierarchical organization of tumor cells, cancer stem cells are tumor-initiating cells capable of self-renewing and differentiating into non-tumorigenic cells [14,17,18]. Thus, cancer stem cells propel tumor formation, its progression, and the formation of secondary tumors [19][20][21].…”

Chronic intermittent hypoxia promoted lung cancer stem cell-like properties via enhancing Bach1 expression

“…Tumor resistance reduces the efficacy of current therapies resulting in relapse, progression, and subsequent patients' death [ 25 ]. CSCs referred to as tumor-initiating cells, are increasingly recognized as a key factor in tumor progression, metastasis, and drug resistance [ 13 , 15 ]. In this study, we established an orthotopic mouse model of primary lung cancer and cultured the mice under CIH conditions to mimic the process in the comorbidity of primary lung cancer and OSA.…”

“…Lung CSCs have been previously isolated based on the presence of cell surface markers, including CD133 and CD44 [ 13 , 14 ]. Hypoxia is increasingly recognized as owing the potential to exert a significant effect on the maintenance and evolution of CSCs [ 15 , 16 ]. In contrast to continuous hypoxia, CIH in patients with OSA is a unique physiological state with a phase of post-hypoxic re-oxygenation.…”