Impact of the Tumor Microenvironment on Tumor Heterogeneity and Consequences for Cancer Cell Plasticity and Stemness
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Biochemistry and Tumor Biology Lab, Department of Obstetrics and Gynecology, Hannover Medical School, 30625 Hannover, Germany
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First Department of Medicine, University Hospital Schleswig-Holstein, Campus Lübeck, 23538 Lübeck, Germany
3
Department of General Surgery, Visceral, Thoracic, Transplantation and Pediatric Surgery, University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany
*
Author to whom correspondence should be addressed.
Cancers 2020, 12(12), 3716; https://doi.org/10.3390/cancers12123716
Received: 16 November 2020
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Revised: 8 December 2020
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Accepted: 8 December 2020
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Published: 11 December 2020
(This article belongs to the Special Issue Stemness and Differentiation in Cancer)
Simple Summary
The cancer cells in solid tumors are embedded in a complex connective tissue matrix composed of various other cell types, i.e., mesenchymal stroma/stem-like cells (MSCs) and tumor-associated macrophages (TAMs). This tumor microenvironment (TME) is considered the major cause of tumor heterogeneity, which in turn accounts for treatment failure in current cancer therapies. Physical and chemical signals from the TME as well as factors secreted by MSCs and TAMs can induce epigenetic alterations in the cancer cells that alter their phenotypic plasticity, eventually resulting in the generation of cancer stem cells (CSCs). Phenotype switching of CSCs involves processes such as epithelial-mesenchymal transition, transdifferentiation, retrodifferentiation, or spontaneous cell fusion of cancer cells with stromal cells, particularly MSCs. Principally, phenotype plasticity of cancer (stem) cells may be targeted pharmacologically to reduce tumor heterogeneity and hence resistance to therapy.
Tumor heterogeneity is considered the major cause of treatment failure in current cancer therapies. This feature of solid tumors is not only the result of clonal outgrowth of cells with genetic mutations, but also of epigenetic alterations induced by physical and chemical signals from the tumor microenvironment (TME). Besides fibroblasts, endothelial and immune cells, mesenchymal stroma/stem-like cells (MSCs) and tumor-associated macrophages (TAMs) intimately crosstalk with cancer cells and can exhibit both anti- and pro-tumorigenic effects. MSCs can alter cancer cellular phenotypes to increase cancer cell plasticity, eventually resulting in the generation of cancer stem cells (CSCs). The shift between different phenotypic states (phenotype switching) of CSCs is controlled via both genetic programs, such as epithelial-mesenchymal transdifferentiation or retrodifferentiation, and epigenetic alterations triggered by signals from the TME, like hypoxia, spatial heterogeneity or stromal cell-derived chemokines. Finally, we highlight the role of spontaneous cancer cell fusion with various types of stromal cells. i.e., MSCs in shaping CSC plasticity. A better understanding of cell plasticity and phenotype shifting in CSCs is a prerequisite for exploiting this phenomenon to reduce tumor heterogeneity, thereby improving the chance for therapy success.
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Keywords:
cancer cell fusion; mesenchymal stroma/stem-like cells; post-hybrid selection process; retrodifferentiation; activated and silenced cancer stem cell niche; tumor plasticity; epithelial-mesenchymal transition; cancer stem cells
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MDPI and ACS Style
Hass, R.; von der Ohe, J.; Ungefroren, H. Impact of the Tumor Microenvironment on Tumor Heterogeneity and Consequences for Cancer Cell Plasticity and Stemness. Cancers 2020, 12, 3716. https://doi.org/10.3390/cancers12123716
AMA Style
Hass R, von der Ohe J, Ungefroren H. Impact of the Tumor Microenvironment on Tumor Heterogeneity and Consequences for Cancer Cell Plasticity and Stemness. Cancers. 2020; 12(12):3716. https://doi.org/10.3390/cancers12123716
Chicago/Turabian StyleHass, Ralf, Juliane von der Ohe, and Hendrik Ungefroren. 2020. "Impact of the Tumor Microenvironment on Tumor Heterogeneity and Consequences for Cancer Cell Plasticity and Stemness" Cancers 12, no. 12: 3716. https://doi.org/10.3390/cancers12123716
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