**2. MSC and cancer: how they relate?**

#### **2.1. MSCs can induce epithelial-mesenchymal transition**

The epithelial-mesenchymal transition (EMT) is a process characterized by downregulation of proteins associated with cell adhesion present in epithelial cells such as E-cadherin, γ-catenin/plakoglobin, and zonula occludens-1. In turn, it triggers an upregulation of proteins related to the mesenchymal phenotype, such as N-cadherin, vimentin, fibronectin, and alpha smooth muscle actin [38, 39]. The EMT is present during organogenesis and wound healing. EMT has also been described during the development of epithelial tumors, which is associated with a more undifferentiated and metastatic phenotype (poor prognosis) [40]. There are accumulated evidence that suggests that a defective EMT promotes tumor invasion, metastasis, and chemoresistance to medications [41]. In many tumors, the presence of cytokines such as HGF, EGF, PDGF, and TGF-β produced and released by the stroma associated with the tumor, act by inducing EMT and favoring processes such as metastasis [42, 43]. Interestingly, it has been reported that these factors are secreted by MSCs [44] and that they can activate a number of transcription factors of genes that promote EMT, such as Snail, Slug, zinc finger E-box binding homeobox 1 (ZEB1), and Twist related protein-1 (TWIST) to transmit EMT promotion signals [45–47]. A recent study demonstrated the activation of specific genes to induce EMT in breast cancer cell lines when they were co-cultured with MSCs and a decrease in expression of genes related to epithelial differentiation [48]. MSCs also improve the ability to trigger the metastatic cascade in colon cancer cell lines through high expression of EMT-associated genes (ZEB1, ZEB2, Slug, Snail, and Twist-1), in a cell-cell-dependent manner. It should be noted that the decrease in the expression of the E-cadherin gene is related to EMT [48]. In breast cancer cell lines, it has been described that MSCs produce leptin which results in an increase in the expression of EMT genes and associated with metastasis (SERPINE1, MMP-2, and IL-6). On the other hand, in SCID/beige mice co-injected with MCF-7 breast cancer cells and with MSCs containing leptin shRNA, a decrease in the leptin levels produced by the MSCs was observed and consequently a reduction in the tumor volume MCF7 and less metastatic lesions in liver and lung [49]. Other authors have reported that MSCs can fuse with different cancer cells and unleash the classic characteristics of EMT [50–52].

SDF-1 by stimulating tumor growth through contribution of angiogenesis and the production

Multipotent Stromal Cells in a Tumor Microenvironment http://dx.doi.org/10.5772/intechopen.77345 67

*Immune response in tumor microenvironments*: In addition to protecting the host from external invaders, the immune system recognizes tumor antigens and eliminates malignant tumors [58]. Therefore, tumor growth, invasion, and metastasis are important aspects of the tumor's immune escape mechanism [59, 60]. During tumor initiation, TAMs and MSCs migrate to the tumor microenvironments. TAMs act as the main inflammatory component of the tumor microenvironment [61, 62]. In contrast, TAMs can show antitumor activities linked to the M1 phenotype via IFN-γ, TNF-α, TGF-β, PGE2, and IL-10 [72, 77–82]. Also, M1 TAMs secrete free oxygen radicals, nitrogen radicals, and pro-inflammatory interleukins (e.g., IL-1β, IL-6, IL-12, IL-23, and TNF-β) facilitating the killing of tumoral cells. The MSCs can be activated by the pro-inflammatory cytokines IFN-γ, TNF-α, or IL-1βn in tumor microenvironments [30, 52, 69, 83, 84]; additionally, the tumor cells and M2 produce immunomodulatory molecules, such as IDO, PGE2, IL-6, IL-10, HLA-G5, and NO [64, 65]. IDO is the critical rate-limiting enzyme of tryptophan catabolism through the kynurenine pathway, resulting in tryptophan depletion and halting the growth of various cells. In tumor microenvironments, MSCs can be activated by pro-inflammatory cytokines IFN-γ, TNF-α, or IL-1β [66, 67]. Within the immunomodulatory molecules secreted by MSCs, Prostaglandin E2 (PGE2) has a multifunctional role in pathological processes including the regulation of inflammation and cancer. The production of PGE2 by MSCs increases after stimulation with TNF-α or IFN-γ. In addition, PGE2 increases the level of expression of IL-10 and decreases the expression of TNF-α, IFN-γ, and IL-12 in cells of the developing immune system and of macrophages [68, 69]. PGE2 regulates the secretion of IFN-γ and IL-4 in Th1 and Th2 cells, respectively, and promotes proliferation of Treg cells [19]. It has been reported that IL-6 secreted by MSCs inhibits monocyte differentiation toward CD and decreases the activation capacity of CD to T cells [70, 71]. In addition, IL-6 secreted by MSCs resulted in a delay in apoptosis of lymphocytes and neutrophils [72, 73]. Another important molecule in the moderation of the immune response is nitric oxide (NO). NO is produced by inducible NO synthase (iNOS) through stimulation by inflammatory factors such as IL-1, IFN-γ, and TNF- α [72, 74] and also inhibits the functions of T cells [75]. In contrast to

**2.3. MSCs in tumor microenvironments can modulate the immune response**

of tumor stimulating growth factors [37, 61–63] (**Figure 2**).

**Figure 2.** Figure illustrating the epithelial-mesenchymal transition.

#### **2.2. MSCs can induce transition to tumor-associated fibroblast**

*MSC to fibroblasts associated with tumors*: The tumors consist of cancer cells and different stromal cells that form the tumor cell medium [53]. The tumor stroma consists of an extracellular matrix scaffold (MEC) populated by stromal cells that include fibroblasts, immune cells, and endothelial cells. Fibroblasts can be activated in the tumor stroma and activated fibroblasts (also called myofibroblasts) are called carcinoma-associated fibroblasts (CAF) or tumorassociated fibroblasts (TAF). CAF/TAF are abundant in most invasive tumors and are mainly composed of cells expressing smooth muscle actin α (α-SMA) [54]. These cells can secrete SDF-1 with the consequent promotion of tumor growth and angiogenesis [55], which binds to CXCR4 expressed by tumor cells [55]. Recently, it was reported that MSCs could differentiate into CAFs/TAFs [24, 56, 57]. In fact, MSCs can differentiate into CAF/TAF and increase the production of α-SMA, tenascin-C and fibroblast surface protein (FSP), CCL5/RANTES, and

**Figure 2.** Figure illustrating the epithelial-mesenchymal transition.

**2. MSC and cancer: how they relate?**

66 Stromal Cells - Structure, Function, and Therapeutic Implications

characteristics of EMT [50–52].

**2.2. MSCs can induce transition to tumor-associated fibroblast**

*MSC to fibroblasts associated with tumors*: The tumors consist of cancer cells and different stromal cells that form the tumor cell medium [53]. The tumor stroma consists of an extracellular matrix scaffold (MEC) populated by stromal cells that include fibroblasts, immune cells, and endothelial cells. Fibroblasts can be activated in the tumor stroma and activated fibroblasts (also called myofibroblasts) are called carcinoma-associated fibroblasts (CAF) or tumorassociated fibroblasts (TAF). CAF/TAF are abundant in most invasive tumors and are mainly composed of cells expressing smooth muscle actin α (α-SMA) [54]. These cells can secrete SDF-1 with the consequent promotion of tumor growth and angiogenesis [55], which binds to CXCR4 expressed by tumor cells [55]. Recently, it was reported that MSCs could differentiate into CAFs/TAFs [24, 56, 57]. In fact, MSCs can differentiate into CAF/TAF and increase the production of α-SMA, tenascin-C and fibroblast surface protein (FSP), CCL5/RANTES, and

**2.1. MSCs can induce epithelial-mesenchymal transition**

The epithelial-mesenchymal transition (EMT) is a process characterized by downregulation of proteins associated with cell adhesion present in epithelial cells such as E-cadherin, γ-catenin/plakoglobin, and zonula occludens-1. In turn, it triggers an upregulation of proteins related to the mesenchymal phenotype, such as N-cadherin, vimentin, fibronectin, and alpha smooth muscle actin [38, 39]. The EMT is present during organogenesis and wound healing. EMT has also been described during the development of epithelial tumors, which is associated with a more undifferentiated and metastatic phenotype (poor prognosis) [40]. There are accumulated evidence that suggests that a defective EMT promotes tumor invasion, metastasis, and chemoresistance to medications [41]. In many tumors, the presence of cytokines such as HGF, EGF, PDGF, and TGF-β produced and released by the stroma associated with the tumor, act by inducing EMT and favoring processes such as metastasis [42, 43]. Interestingly, it has been reported that these factors are secreted by MSCs [44] and that they can activate a number of transcription factors of genes that promote EMT, such as Snail, Slug, zinc finger E-box binding homeobox 1 (ZEB1), and Twist related protein-1 (TWIST) to transmit EMT promotion signals [45–47]. A recent study demonstrated the activation of specific genes to induce EMT in breast cancer cell lines when they were co-cultured with MSCs and a decrease in expression of genes related to epithelial differentiation [48]. MSCs also improve the ability to trigger the metastatic cascade in colon cancer cell lines through high expression of EMT-associated genes (ZEB1, ZEB2, Slug, Snail, and Twist-1), in a cell-cell-dependent manner. It should be noted that the decrease in the expression of the E-cadherin gene is related to EMT [48]. In breast cancer cell lines, it has been described that MSCs produce leptin which results in an increase in the expression of EMT genes and associated with metastasis (SERPINE1, MMP-2, and IL-6). On the other hand, in SCID/beige mice co-injected with MCF-7 breast cancer cells and with MSCs containing leptin shRNA, a decrease in the leptin levels produced by the MSCs was observed and consequently a reduction in the tumor volume MCF7 and less metastatic lesions in liver and lung [49]. Other authors have reported that MSCs can fuse with different cancer cells and unleash the classic

SDF-1 by stimulating tumor growth through contribution of angiogenesis and the production of tumor stimulating growth factors [37, 61–63] (**Figure 2**).
