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.

Keywords: Cancer initiating cells; cancer stem cells; connective tissue; heterogeneity; tumor microenvironment.

Figure 1.

Cancer Stem Cells or Cancer Initiating Cells (CSC/CIC) interact with the surrounding tumor microenvironment (TUMIC) by activating stem cell- and self renewal-associated pathways, such as Notch-1, PI3 Kinase and Hedgehog. Canonical anti-proliferative therapies mainly target bulk tumor cells, sparing aggressive CSC/CIC that are responsible for disease recurrence by activating resistance mechanisms including Vasculogenic Mimicry and Epithelial to Mesenchymal Transition. In addition, these cells may be able to: (1) survive hypoxia by increasing the production HIF1-α, VEGF; (2) increase angiogenesis by producing higher amount of pro-angiogenic factors; (3) induce immuno-tolerance by producing anti-inflammatory cytokines. Novel therapeutic treatments targeting both the CSC/CIC compartment and the TUMIC with the potential to eradicate the tumor, minimizing the risk of disease recurrence, are warranted.

Figure 2.

Mutated cells might be able to survive specific microenvironmental conditions, while the tumor microenvironments (TUMICs) perform clonal selection by releasing peculiar growth factors and cytokines. TUMIC1 may select transformed cells harboring only Mut1. The evolving microenvironment in which tumor cells live (TUMIC2) may induce a second favorable mutation, Mut2. Only cells harboring both Mut1 and 2 will survive and generate daughter cells through symmetric division. Finally, a third mutation (Mut3) induced by TUMIC3 will generate more aggressive cells harboring Mut1, Mut2 and Mut3. The process of clonal selection gives rise to tumor heterogeneity.