Concise Review: Cancer Cells, Cancer Stem Cells, and Mesenchymal Stem Cells: Influence in Cancer Development

Abstract

Tumors are composed of different types of cancer cells that contribute to tumor heterogeneity. Among these populations of cells, cancer stem cells (CSCs) play an important role in cancer initiation and progression. Like their stem cells counterpart, CSCs are also characterized by self-renewal and the capacity to differentiate. A particular population of CSCs is constituted by mesenchymal stem cells (MSCs) that differentiate into cells of mesodermal characteristics. Several studies have reported the potential pro-or anti-tumorigenic influence of MSCs on tumor initiation and progression. In fact, MSCs are recruited to the site of wound healing to repair damaged tissues, an event that is also associated with tumorigenesis. In other cases, resident or migrating MSCs can favor tumor angiogenesis and increase tumor aggressiveness. This interplay between MSCs and cancer cells is fundamental for cancerogenesis, progression, and metastasis. Therefore, an interesting topic is the relationship between cancer cells, CSCs, and MSCs, since contrasting reports about their respective influences have been reported. In this review, we discuss recent findings related to conflicting results on the influence of normal and CSCs in cancer development. The understanding of the role of MSCs in cancer is also important in cancer management. Stem Cells Translational Medicine 2017;6:2115-2125.

Keywords: Cancer progression; Drug resistance; Epithelial to mesenchymal transition; Mesenchymal stem cells; Microenvironment.

Figure 1

Model of CSCs theory: only CSCs are able to form and sustain tumor and are resistant to conventional therapies. CSCs are generated from normal stem cells or precursor/progenitor cells where epigenetic mutations are occurred. Abbreviation: CSC, cancer stem cell.

Figure 2

Tumor microenvironment consists not only of tumor cells and CSCs but are involved several types of cells and or processes, such as fibroblasts, migration of immune cells, angiogenesis, and matrix remodeling, MSCs thereby generating the so‐called tumor niche. Therefore, cancer cells and CSCs are intimately in contact with these cells, promoting tumourigenesis and cancer progression through several mechanisms among which tissue remodeling through matrix metalloproteinases, deposition of different extracellular matrix, liberation of pro‐angiogenic molecules, and secretion of soluble factors. Abbreviations: BMDC, bone‐marrow derived cells; CAF, cancer‐associated fibroblast; CSC, cancer stem cell; EPC, endothelial progenitor cells; MSC, mesenchymal stem cell.

Figure 3

MSCs secretome and tumor stemness. MSCs release several factors that can induce stemness and drug resistance or maintain the CSCs phenotype. MSCs produce BMP4 and 2 increasing CSCs number in ovarian cancer. CSCs, in turn, activate Hh pathway. MSCs can induce an increase of mir‐199 and mir‐214 leading to a repression of FoxP2 promoting metastasis and maintenance of CSCs phenotype. IL‐1α and IL‐1β secreted by cancer cells induce the production of PGE2, IL6, and IL8 by MSCs. This leads to a secretion of IL‐6, CXCL1, and CXCL8 by MSCs increasing stemness characteristics. MSCs are able to increase the number of breast cancer cells positive to ALDH by secretion of CXCR2 ligands inducing expression of Oct4 and Sox2. IL‐6 secreted by MSCs leads to an increase of CSCs expressing CD133 by JAK2‐STAT3 pathway. Irradiated breast cancer cells increase the release of TGFβ1, VEGF, and PDGF‐BB, which activate the migration of MSCs to cancer cells. Moreover, cocultures of MSCs with breast cancer cells increases the production of CXCR2 ligands including CXCL1, 5, 6, 7, and 8 that are able to increase the percentage of CSCs. Also, IL‐10, IL‐17b, and EGF, secreted by MSCs, are involved in increasing breast CSCs number. MSCs can also lead to an increase of CCL5 expression that, in turn, induce an increase of CSCs by upregulation of ZEB1, MMP9, and CD133 in prostate cancer. MSCs can also regulate the metabolism of CSCs through secretion of exosomes in breast cancer and cholangiosarcomas. Abbreviations: ALDH, aldehyde dehydrogenases; CSC, cancer stem cell; EGF, endothelial growth factor; HH, hedgehog; MSC, mesenchymal stem cell; PDGF‐BB, platelet‐derived growth factor BB; VEGF, vascular endothelial growth factor.

Figure 4

Model of a possible mechanism that enables cancer cells to migrate and form new tumors. Cancer cells produce CXCL16 that, in turn, induce the recruitment of MSCs in tumor site. CXCL16 binds its receptor, CXCR6 on MSCs. The latters are converted in CAFs producing high levels of CXCL12. CXCL12, in turn, induces cancer cells to undergo to an EMT that heightens CXCR4 expression in cancer cells. CXCR4 expression enables metastasis. Abbreviations: CAF, cancer‐associated fibroblast; EMT, epithelial‐to‐mesenchymal transition; MSC, mesenchymal stem cell.

Figure 5

Model of a mechanism inducing tumor angiogenesis and involving MSCs. These cells can produce a series of angiogenic factors such as angiopoietin‐1 and IL‐6 that induce the secretion of VEGF and other angiogenic molecules promoting tumor angiogenesis. Abbreviations: FGF, fibroblast growth factor; MSC, mesenchymal stem cell; PDGF, platelet‐derived growth factor; VEGF, vascular endothelial growth factor.