Review ArticleReviewsR

The Role of MSCs in the Tumor Microenvironment and Tumor Progression

SUNG YONG AHN
Anticancer Research June 2020, 40 (6) 3039-3047; DOI: https://doi.org/10.21873/anticanres.14284

Abstract

Over the past few decades, longevity without disease has become an important topic worldwide. However, as life expectancy increases, the number of patients with cancer is also increasing. Tumor progression is related to interactions between tumor cells and mesenchymal stem cells (MSCs) in the tumor microenvironment. MSCs are multipotent stromal cells known to be present in a variety of locations in the body, including bones, cartilage, fat, muscles, and dental pulp. MSCs migrate toward inflamed areas during pathological immune responses. MSCs also migrate toward tumor stroma and participate in tumor progression. MSCs can contribute to tumor progression by interacting with tumor cells via paracrine signaling and differentiate into diverse cell types. This also enables MSCs to make direct contact with tumor cells in tumor stroma. Interactions between tumor cells and MSCs enhance tumorigenic and metastatic potential, in addition to stimulating epithelial to mesenchymal transition. Herein, we reviewed the research associated with the tumor-enhancing role of MSCs in tumor progression, from primary tumor growth to distant tumor metastasis.

Mesenchymal stem cells (MSCs) are multipotent stromal cells (1, 2) with self-renewal abilities and the capacity to differentiate into osteoblasts, chondrocytes, and adipocytes (3, 4). MSCs usually express the lineage-specific markers CD73, CD90, and CD105 (2). MSCs generate anti-apoptotic factors, angiogenic factors, and growth factors, in addition to having chemo-attractive abilities (5). MSCs also have anti-inflammatory and immunomodulatory properties (6-8). Their immunomodulatory and immunosuppressive properties are a promising therapeutic tool for inhibiting inflammation and suppressing pathological immune responses (5). A variety of research has reported the effects of treatment for systemic sepsis using MSCs (Table I).

Over the past few years, clinical trials of MSC treatment have been conducted for various pathologies, such as sepsis (8, 9) and graft-versus-host disease (10), and diverse autoimmune diseases (11, 12), such as ulcerative colitis (1), rheumatoid arthritis (11), and acute respiratory distress syndrome (13). Several clinical trials have been conducted with MSC treatment for sepsis-related diseases (Table II).

Conversely, MSCs contribute to cancer progression and metastasis when used for cancer treatment (14-17). The tumor microenvironment comprises various cell types, including endothelial cells, cancer-associated fibroblasts (CAFs), neutrophils, macrophages, lymphocytes, cancer stem cells, pericytes, as well as MSCs. According to recent research, MSCs home to tumor sites and are implicated in tumor growth and progression (16-19). In addition, several studies have shown that MSCs can enhance the metastatic ability of tumor cells by strengthening tumor cell motility and invasiveness, as well as creating a metastatic niche at secondary tumor sites (16, 20-22). MSCs are recruited to injured, inflamed, and hypoxic tumor milieu (23). During tumorigenesis, a variety of growth factors, cytokines, and chemokines secreted by tumor cells recruit MSCs to surround the tumor, which is associated with enhancement of the neoplastic properties of tumor cells. Therefore, comprehensive knowledge of the interaction mechanisms between tumor cells and MSCs in the tumor microenvironment is required.

The Role of MSCs at the Primary Tumor Site

MSCs were shown to be involved in tumor growth and progression in a number of cancer types, such as of the prostate (17), colon (24), gastric (25), breast (16, 26), head and neck (15), and in glioma (27), and follicular lymphoma (14). Breast cancer cell motility, invasiveness, and metastasis were enhanced by chemokine (C-C motif) ligand 5 (CCL5 also called RANTES) secreted from MSCs (16). Similarly, when human bone marrow MSCs and breast cancer cells were injected together, tumor invasion and metastasis were induced (28). MSCs have been reported to promote gastric (29) and breast (26) cancer metastasis via stimulation of epithelial to mesenchymal transition (EMT). This research suggests that MSCs may induce tumor cell metastasis at the primary tumor site. MSCs reportedly are recruited to the tumor by soluble factors secreted by tumor cells during tumorigenesis (30). Several studies have shown that cancer cells secrete various growth factors, cytokines, and chemokines, such as transforming growth factor beta (TGFβ) and stromal cell-derived factor 1 alpha (SDF1α) (31), as well as interleukin1 beta (IL1β) (32). Breast cancer cells also secrete a large quantity of IL6, which activates and attracts MSCs to tumor under hypoxic conditions (23). A study has shown that MSCs secrete IL8, which promotes gastric cancer progression (25). MSCs also promote tumor growth and metastasis by means of paracrine effects and direct contact associated with expression of β-catenin and matrix metalloproteinase16 (MMP16) (29).

MSC Differentiation

When MSCs surround a tumor, they can differentiate into more mature mesenchymal cells such as endothelial cells (33, 34), macrophages (35), and cancer-associated fibroblasts (CAFs) (36). Following differentiation, MSCs show outstanding phenotype changes, such as morphological elongation, diminished adhesion, reduced cytoskeletal fibers, and increased migration (37). CAFs are fibroblast-like cells with tumor-promoting function. According to several studies, CAFs are derived from bone marrow MSCs and fibroblasts, and transdifferentiate from epithelial and endothelial cells (38-40). TGFβ expression was shown to contribute to MSC differentiation into CAFs via increased expression of alpha smooth muscle actin (αSMA) and reduced expression of gelsolin (41). When TGFβ expression is accelerated, MSCs exhibit modified gene-expression profiles toward myofibroblast proteins, such as αSMA, fibroblast surface protein, and tenascin-C, in addition to growth-stimulating factors such as CCL5 and SDF1 (42, 43). Further mechanisms of differentiation of MSCs into CAFs are not yet fully understood. Nevertheless, TGFβ expression has been reported to promote morphologic changes in MSCs, regardless of the origin of the cells (40, 44-46). Under tumorigenic conditions, MSCs can differentiate into platelet-derived growth factor receptor-positive CAFs (47) or hematopoietic cells. The latter is mainly caused by reduced influx of Ca2+ (35, 47). Taken together, in tumor stroma, various tumor-promoting factors secreted by tumor cells induce both morphological and gene-expression changes in MSCs.

View this table:
Table I.

Preclinical studies of treatment for systemic sepsis using mesenchymal stem cells (MSCs).

MSCs and EMT

In tumor stroma, MSCs can induce cancer cell EMT. Directly co-culturing human breast or gastric cancer cells with MSCs was shown to increase the level of EMT markers, such as N-cadherin, TWIST, SNAIL, and vimentin, in addition to reducing the level of E-cadherin (26, 29). Similarly, the level of TGFβ secreted by tumor necrosis factor alpha (TNFα)- and interferon gamma (IFNγ)-treated human MSCs increased. When hepatocellular carcinoma cells were cultured in conditioned medium from TNFα- and IFNγ-treated human MSCs, their expression of EMT markers, migration, and invasion significantly increased both in vitro and in vivo (48). MSCs promoted cancer cell metastasis to the bones and lungs via EMT triggered by MSCs (49). Similarly, TGFβ1 secreted by MSCs enhanced EMT in MCF7 breast cancer cells; MSCs accelerated breast cancer cell metastasis by promoting the EMT process (50). MSCs were also found to modulate EMT and tumor progression during pancreatic cancer cell tumorigenesis (51).

MSCs and Metastasis

MSCs are involved in various stages of tumor progression (Figure 1). At the primary tumor site, MSCs induce tumor cells to have invasive and metastatic capacity. It has also been reported that both human and mouse MSCs enhance breast cancer metastasis (52). In tumor stroma, MSCs were reported to migrate and differentiate into CAFs. MSCs then induced colon cancer growth and metastasis by strengthening angiogenesis, motility, and invasiveness, and by suppressing cancer cell apoptosis (53). CAFs were also found to migrate from the primary tumor site to the lung metastatic site in mice (21). Similarly, hypoxia-inducible factors (HIFs) were found to relay paracrine signals between breast cancer cells, and MSCs promoted breast cancer metastasis (54).

View this table:
Table II.

Clinical trials using mesenchymal stem cells (MSCs) for sepsis-related diseases.

The Role of MSCs in Enhancement of Distant Metastasis

When human MSCs and breast cancer cells were injected into mice, lung metastasis of breast cancer cells was stimulated by the increased interactions between CCL5 from MSCs and chemokine (C-C motif) receptor 5 (CCR5) from breast cancer cells (16). According to further research, CCL5 secreted by human MSCs promoted lung metastasis of osteosarcoma (55) and breast cancer cells (56). Furthermore, human MSCs isolated from metastatic sites (the liver and lung) expressed various CAF markers, such as αSMA, SDF1α, and MMP2 and MMP9 (56). Consequently, tumor-derived osteopontin (OPN) enhanced tumor growth and progression via the transformation of MSCs to CAFs (56). In several studies, increased OPN expression was associated with prostate cancer progression, in addition to being a landmark of distant metastasis enhancement (57-60). Increased OPN expression in breast cancer cells was also associated with osteolysis and bone metastasis (61, 62).

The Role of MSCs in the Tumor Microenvironment

MSCs contribute to tumor cell growth and metastasis in the tumor microenvironment (Table III). MSCs are implicated in multiple phases of cancer pathogenesis. A large number of bone marrow-derived MSCs were recruited to the tumor stroma during tumor development (63).

Stemness. The multilineage potential of MSCs accelerates tumor development. For instance, MSCs modulated the self-renewal ability of breast cancer stem cells via cytokine networks, including IL6 and chemokine (C-X-C motif) ligand7 (CXCL7) (64). Human ovarian carcinoma-associated MSCs stimulated tumorigenesis by altering bone morphogenetic protein production (65). In addition to bone morphogenetic protein signaling, a variety of signaling pathways involving TGFβ, WNT (66) and IL6/Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) (67, 68) enhanced the stemness of tumor cells. MSCs stimulated by carcinoma cells can create a carcinoma stem-cell niche, inducing carcinogenesis via production of large amounts of prostaglandin E2 (69).

Migration. EMT is an essential process in cancer cell migration, and can also facilitate carcinogenesis (70). EMT promotes cancer cell migration by inducing cancer cells to detach from the primary tumor site, and stimulates the subsequent metastasis of cancer cells (70, 71). In the tumor microenvironment, MSCs reinforce the metastatic potential of tumor cells by inducing tumor cell EMT after being recruited to the tumor site. When MSCs and breast cancer cells were cultured together, SNAIL family members SNAIL (SNAI1) and SLUG (SNAI2) (72), and vimentin expression increased but the expression of E-cadherin decreased (73). MSCs may also affect cancer cells via diverse mechanisms such as the CXCL1/CXCL5-chemokine (C-X-C motif) receptor 2 (CXCR2) (74), CCL5 and IL6 (75), and estrogen receptor (ER) and CXCR4 pathways (76) in breast cancer. MSCs also expedite prostate cancer cell invasion and migration by enhancing MMP2 and MMP9 expression (77).

Angiogenesis. Vascular endothelial growth factor (VEGF) expression by MSCs was found to contribute to pancreatic cancer angiogenesis (78). MSCs expedite tumor development in vivo by strengthening the neovascularization surrounding tumors (18). MSCs activate angiogenesis by secreting several soluble factors, such as macrophage colony-stimulating factor, leukemia inhibitory factor, macrophage inflammatory protein 2, VEGF (18), TNFα, and IFNγ (79).

Immunomodulation. Recent research has demonstrated the effects of MSC-based immunotherapy in allogeneic cell and tissue transplantation (80-82). It has been reported that MSCs have immunosuppressive or immunomodulatory properties (5). Cytokines secreted by MSCs, such as TGFβ (83), IL10 (80), nitric oxide (84), prostaglandin E2 (10), and indoleamine 2,3-dioxygenase (85), are implicated in immunomodulation. According to previous research, the immunomodulatory properties of MSCs enable escape from host immune rejection (86, 87). The immunomodulatory properties of MSCs allow for the treatment of various inflammatory diseases (86). Furthermore, the sustainment of the effects of MSCs is related to the rate of their immune detection (86, 88). The rates of immune detection and removal of MSCs are determined by a balance between the relative expression of immunogenic and immunomodulatory (immunosuppressive) factors of MSCs (Figure 2). Moreover, MSC-related immunomodulation has been diversely reported in tumor growth and progression. MSCs were shown to support breast cancer cells by enhancing regulatory T-cell activity (89). In melanoma, the immunomodulatory function of MSCs was induced by TNFα and IFNγ. These cytokines promoted the expression of nitric oxide synthases by MSCs (90). The inflammatory cytokine IL1α was found to induce the immunomodulatory properties of MSCs, enabling prostate cancer cells to avoid immunosurveillance (91).

Figure 1.
Figure 1.

Interactions between mesenchymal stem cells (MSCs) and tumor cells during tumor progression. MSCs promote tumor progression from primary tumor sites to sites of metastasis by regulating various interactions between MSCs and tumor cells. MSCs have been shown to stimulate epithelial to mesenchymal transition (EMT) of tumor cells via direct cell to cell contact and transforming growth factor beta (TGFβ) secretion (48, 77). In addition, osteopontin (OPN) secreted by tumor cells induces chemokine (C-C motif) ligand 5 (CCL5) secretion of MSCs and promotes metastasis of breast cancer cells through interactions with chemokine (C-C motif) receptor 5 (CCR5) of breast cancer cells (56). Tumor cells secrete various growth factors, cytokines, and chemokines, such as stromal cell-derived factor 1 alpha (SDF1α) (31) and interleukin 6 (IL6), which activates and attracts MSCs to the hypoxic tumor conditions (23). MSCs also affect tumor cells via SDF1α (42, 43) and IL6 secretion (64, 75).

Figure 2.
Figure 2.

Immunomodulatory properties of mesenchymal stem cells (MSCs) enable immune evasion. Immunogenic MSCs express high levels of major histocompatibility complex (MHC) class I (in yellow) and II (in red) proteins, whereas immunomodulatory MSCs express low levels of MHC class I and II.

View this table:
Table III.

Correlation between mesenchymal stem cells (MSCs) and tumor cells in the tumor microenvironment.

Conclusion

MSCs are implicated in various stages of tumor progression. In summary, they are recruited to a tumor by soluble factors secreted by tumor cells during carcinogenesis. When MSCs surround the tumor, they can differentiate into more mature mesenchymal cells and promote tumor progression. In tumor stroma, MSCs stimulate EMT of cancer cells. Similarly, MSCs increase cancer cell motility and can induce metastatic colonization of cancer cells at distant metastatic sites. A variety of tumor-promoting factors secreted by tumor cells induce both phenotypic changes and modify the gene expression of MSCs. MSCs also promote tumor cell stemness, and angiogenesis, and can regulate immune responses through their immunosuppressive or immunomodulatory properties in the tumor microenvironment. Consequently, MSCs enhance tumor progression by regulating the tumor microenvironment. MSCs can therefore serve as an indicator of tumor progression. Several studies have shown that MSCs contribute to the growth and metastasis of tumor cells. MSCs are also involved in various stages of cancer pathogenesis. This suggests the potential of MSCs as a therapeutic target for the clinical treatment of patients with cancer.

Acknowledgements

The Author expresses their thanks to Nari Jeon and Hee Chun Jeon for help with English proofreading and illustration, respectively.

Footnotes

  • This article is freely accessible online.

  • Conflicts of Interest

    The Author declares no conflicts of interest.

  • Funding

    This research was supported by the National Research Foundation of Korea (NRF) grant, funded by the Korean government (2017R1A6A3A11029376 to S.Y.A.).

  • Received April 6, 2020.
  • Revision received April 20, 2020.
  • Accepted April 21, 2020.

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The Role of MSCs in the Tumor Microenvironment and Tumor Progression
SUNG YONG AHN
Anticancer Research Jun 2020, 40 (6) 3039-3047; DOI: 10.21873/anticanres.14284
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