Cancer stem cells and the tumor microenvironment: interplay in tumor heterogeneity

Abstract

Tumor cells able to recapitulate tumor heterogeneity have been tracked, isolated and characterized in different tumor types, and are commonly named Cancer Stem Cells or Cancer Initiating Cells (CSC/CIC). CSC/CIC are disseminated in the tumor mass and are resistant to anti-cancer therapies and adverse conditions. They are able to divide into another stem cell and a “proliferating” cancer cell. They appear to be responsible for disease recurrence and metastatic dissemination even after apparent eradication of the primary tumor. The modulation of CSC/CIC activities by the tumor microenvironment (TUMIC) is still poorly known. CSC/CIC may mutually interact with the TUMIC in a special and unique manner depending on the TUMIC cells or proteins encountered. The TUMIC consists of extracellular matrix components as well as cellular players among which endothelial, stromal and immune cells, providing and responding to signals to/from the CSC/CIC. This interplay can contribute to the mechanisms through which CSC/CIC may reside in a dormant state in a tissue for years, later giving rise to tumor recurrence or metastasis in patients. Different TUMIC components, including the connective tissue, can differentially activate CIC/CSC in different areas of a tumor and contribute to the generation of cancer heterogeneity. Here, we review possible networking activities between the different components of the tumor microenvironment and CSC/CIC, with a focus on its role in tumor heterogeneity and progression. We also summarize novel therapeutic options that could target both CSC/CIC and the microenvironment to elude resistance mechanisms activated by CSC/CIC, responsible for disease recurrence and metastases.

Induction of Necroptosis in Cancer Stem Cells using a Nickel(II)‐Dithiocarbamate Phenanthroline Complex

“…[11] Upon surviving initial treatment, CSCs are able to reform tumour masses and generate motile-proficient cancer cells capableo fc olonizing secondary tumour sites. Potential CSC therapeutict argets, such as deregulated signalling pathways, [13] overactive organelles, [14] cell surfacem arkers, [15] and vulnerable microenvironments [16] have been identified, however,there is still no clinically approved agent that can selectively remove CSCs. Potential CSC therapeutict argets, such as deregulated signalling pathways, [13] overactive organelles, [14] cell surfacem arkers, [15] and vulnerable microenvironments [16] have been identified, however,there is still no clinically approved agent that can selectively remove CSCs.…”

Colon cancer therapy by focusing on colon cancer stem cells and their tumor microenvironment

“…Noncancer cells in TME consist of cancer-associated fibroblasts (CAFs), stromal myofibroblasts, endothelial cells, diverse immune cells, and tissue cells. These noncancer cells have been suggested that protects CSCs from anticancer therapies (Albini et al, 2015).…”

“…Noncancer cells in TME consist of cancer‐associated fibroblasts (CAFs), stromal myofibroblasts, endothelial cells, diverse immune cells, and tissue cells. These noncancer cells have been suggested that protects CSCs from anticancer therapies (Albini et al, ). Actually, various components of TME such as cytokines, transcription factors, extracellular vesicles, and free radicals can have a role in cross‐talks between different cells within this milieu (Najafi et al, ).…”

A Cancer Stem Cell Potent Cobalt(III)–Cyclam Complex Bearing Two Tolfenamic Acid Moieties

“…Given the implications of CSCs, to provide long-lasting durable responses, cancer therapies must have the ability to remove entire tumor populations, including CSCs. Although vulnerabilities in CSC defenses have been identified-such as overactive organelles [11,12], cell surface markers [13][14][15][16][17], dysregulated signaling pathways [18][19][20], and components of their microenvironment [21,22]-there is still no clinically approved agent (chemical or biological) that can effectively remove CSCs. The development of CSC-potent agents is in its infancy, and most of the drug candidates undergoing preclinical or clinical trials are completely organic in nature [7].…”

“…CSC depletion can be achieved by disrupting the microenvironments maintaining and supporting CSCs [21,22]. The CSC microenvironment is believed to be hypoxic, and the hypoxia-inducible factors (HIFs), HIF1α and HIF2α, are thought to be involved in CSC-associated self-renewal and and metastasis [29][30][31][32][33].…”