**1. Introduction: Properties of the MSC**

Mesenchymal stem cells (MSCs) are a promising source for cell therapy in regenerative medicine. The therapeutic properties of MSCs are related to their potentials for transdifferentiation, immunomodulation, and trophic factor secretion. Investigators have isolated MSCs from many

> © 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

different tissues, including bone marrow, adipose tissue, umbilical cord blood, peripheral blood, dermis, liver, skin, and skeletal muscle [1–4]. Previously it has been reported that MSCs from different sources (adipose tissue, bone marrow, kidney, muscle, etc.) share characteristics properties (i.e., expression of cell surface antigens, immunomodulatory capability, and tropism toward tumor) [5–8]. On the other hand, it has been reported that MSCs isolated from different sources can be found into tumor microenvironments, and depending on the level of commitment to a certain lineage by MSCs, they can be transdifferentiated faster to certain cell types depending on the source [9]. The MSCs from different source express a distinct set of genes, which is a reflection of its commitment related to their potential of differentiation (including adipocytes, osteocytes, chondrocytes, hepatocytes, fibroblasts, and pericytes) [10, 11]. MSCs can be expanded until five passages preserving their therapeutic potential for use in clinical applications [12, 13]. Additionally, the transdifferentiation of MSCs has rarely been observed in animal models [14]. Regarding the immunomodulator potential, it has been reported that MSCs can secrete various immunomodulators, such as nitric oxide (NO), prostaglandin (PGE2), indoleamine 2,3-dioxygenase (IDO), interleukin (IL)-6, IL-10, and HLA-G [12, 13]. Regarding the immunomodulatory potential of MSCs, there are molecules that can moderate the immune response such as nitric oxide (NO), prostaglandin (PGE2), indoleamine 2,3-dioxygenase (IDO), interleukin (IL)-6, IL-10, and histocompatibility antigen class I, G (HLA-G). These soluble factors modify the function of immune cells and induce T regulatory cells activation ([14]). In addition, MSCs can suppress immune cell activation via cell-to-cell contact. MSCs can also inhibit the proliferation of effector T cells by activating programmed cell death pathways such as apoptosis by the interaction of programmed death signal molecules type 1 (PD-1) with their related ligands PD-L1 and PD-L2. On the other hand, it has been reported that MSCs can induce T cell anergy by inhibiting the expression of CD80 and CD86 in antigen-presenting cells [15–17]. Among the wide range of factors that MSCs secrete, are modulators that can regulate inflammation, apoptosis, angiogenesis, fibrosis, and tissue regeneration [18]. In addition, previous studies reported that MSCs produce trophic factors that promote cell survival (SDF-1, HGF, IGF-1), cell proliferation (EGF, HGF, NGF, TGF-α), and angiogenesis (VEGF) [19, 20]. Faced with the signal of damaged tissue, MSCs can migrate to the site of injury (homing) by sensing chemoattractant gradients of cytokines secreted by the extracellular stromal matrix (MEC) and spreading through the peripheral blood to all the organisms [21–24]. At the site of injury, MSCs are stimulated and activated by local damage and repair factors, such as hypoxia, the cytokine environment, and Toll-like receptor ligands. This cascade of stimuli as a whole promotes the production and the release of abundant growth factors that converge to increase tissue regeneration [28, 29]. In contrast to the use of MSCs in regenerative medicine, recent data suggest that MSCs may increase tumorigenesis or inhibit tumorigenesis [25, 26]. In the tumor microenvironment, the tumor tries to avoid recognition by the immune system while secreting inflammatory mediators to establish and maintain a constant state of inflammation [27]. In addition, the correlation between normal cells, cancer cells, and the matrix within the tumor microenvironments has gained increasing attention, especially because these interactions contribute to certain hallmarks of cancer, such as immunomodulation, angiogenesis, invasion and metastasis, and apoptotic resistance [28–30]. Regarding, if the MSCs promote or suppress tumor development, in several studies shown that MSCs perform homing the tumor microenvironment and then promote the formation of

tumor blood vessels, improving the fibrovascular network and suppressing immune responses, modulating thus the tumor response to antitumor therapy [31–35]. Unlike its tumor-promoting abilities, MSCs can also suppress tumor growth by inhibiting proliferation-related signaling pathways, such as AKT, PI3K, and Wnt, by the secretion of proapoptotic molecules such as Dikkopf type 1 (Dkk1) inhibiting the progression of the cell cycle; in turn, they can negatively regulate the X-linked inhibitor of the apoptosis protein (XIAP) and suppression of angiogenesis [31, 36, 37] (**Figure 1**). In this chapter, we will analyze how MSCs can contribute to tumorigenesis, including (i) transition to tumor-associated fibroblasts; (ii) suppression of the immune response; (iii) promotion of angiogenesis; (iv) stimulation of epithelial-mesenchymal transition (EMT); (v) through contribution to the tumor microenvironment; (vi) inhibition of tumor cell apoptosis; through contribution to the tumor microenvironment; (vi) inhibition of tumor cell

**Figure 1.** MSC effects in clinical use. The therapeutic potential of MSCs relies on several unique properties as: (i) the capacity to differentiate into various cell lineage, (ii) the ability to secrete paracrine factors initiating healing and regeneration in the surrounding cells, (iii) the ability to reduce inflammation and regulate immune response and to

Multipotent Stromal Cells in a Tumor Microenvironment http://dx.doi.org/10.5772/intechopen.77345 65

apoptosis, and (vii) promotion of tumor metastasis.

migrate to the exact site of injury.

different tissues, including bone marrow, adipose tissue, umbilical cord blood, peripheral blood, dermis, liver, skin, and skeletal muscle [1–4]. Previously it has been reported that MSCs from different sources (adipose tissue, bone marrow, kidney, muscle, etc.) share characteristics properties (i.e., expression of cell surface antigens, immunomodulatory capability, and tropism toward tumor) [5–8]. On the other hand, it has been reported that MSCs isolated from different sources can be found into tumor microenvironments, and depending on the level of commitment to a certain lineage by MSCs, they can be transdifferentiated faster to certain cell types depending on the source [9]. The MSCs from different source express a distinct set of genes, which is a reflection of its commitment related to their potential of differentiation (including adipocytes, osteocytes, chondrocytes, hepatocytes, fibroblasts, and pericytes) [10, 11]. MSCs can be expanded until five passages preserving their therapeutic potential for use in clinical applications [12, 13]. Additionally, the transdifferentiation of MSCs has rarely been observed in animal models [14]. Regarding the immunomodulator potential, it has been reported that MSCs can secrete various immunomodulators, such as nitric oxide (NO), prostaglandin (PGE2), indoleamine 2,3-dioxygenase (IDO), interleukin (IL)-6, IL-10, and HLA-G [12, 13]. Regarding the immunomodulatory potential of MSCs, there are molecules that can moderate the immune response such as nitric oxide (NO), prostaglandin (PGE2), indoleamine 2,3-dioxygenase (IDO), interleukin (IL)-6, IL-10, and histocompatibility antigen class I, G (HLA-G). These soluble factors modify the function of immune cells and induce T regulatory cells activation ([14]). In addition, MSCs can suppress immune cell activation via cell-to-cell contact. MSCs can also inhibit the proliferation of effector T cells by activating programmed cell death pathways such as apoptosis by the interaction of programmed death signal molecules type 1 (PD-1) with their related ligands PD-L1 and PD-L2. On the other hand, it has been reported that MSCs can induce T cell anergy by inhibiting the expression of CD80 and CD86 in antigen-presenting cells [15–17]. Among the wide range of factors that MSCs secrete, are modulators that can regulate inflammation, apoptosis, angiogenesis, fibrosis, and tissue regeneration [18]. In addition, previous studies reported that MSCs produce trophic factors that promote cell survival (SDF-1, HGF, IGF-1), cell proliferation (EGF, HGF, NGF, TGF-α), and angiogenesis (VEGF) [19, 20]. Faced with the signal of damaged tissue, MSCs can migrate to the site of injury (homing) by sensing chemoattractant gradients of cytokines secreted by the extracellular stromal matrix (MEC) and spreading through the peripheral blood to all the organisms [21–24]. At the site of injury, MSCs are stimulated and activated by local damage and repair factors, such as hypoxia, the cytokine environment, and Toll-like receptor ligands. This cascade of stimuli as a whole promotes the production and the release of abundant growth factors that converge to increase tissue regeneration [28, 29]. In contrast to the use of MSCs in regenerative medicine, recent data suggest that MSCs may increase tumorigenesis or inhibit tumorigenesis [25, 26]. In the tumor microenvironment, the tumor tries to avoid recognition by the immune system while secreting inflammatory mediators to establish and maintain a constant state of inflammation [27]. In addition, the correlation between normal cells, cancer cells, and the matrix within the tumor microenvironments has gained increasing attention, especially because these interactions contribute to certain hallmarks of cancer, such as immunomodulation, angiogenesis, invasion and metastasis, and apoptotic resistance [28–30]. Regarding, if the MSCs promote or suppress tumor development, in several studies shown that MSCs perform homing the tumor microenvironment and then promote the formation of

64 Stromal Cells - Structure, Function, and Therapeutic Implications

**Figure 1.** MSC effects in clinical use. The therapeutic potential of MSCs relies on several unique properties as: (i) the capacity to differentiate into various cell lineage, (ii) the ability to secrete paracrine factors initiating healing and regeneration in the surrounding cells, (iii) the ability to reduce inflammation and regulate immune response and to migrate to the exact site of injury.

tumor blood vessels, improving the fibrovascular network and suppressing immune responses, modulating thus the tumor response to antitumor therapy [31–35]. Unlike its tumor-promoting abilities, MSCs can also suppress tumor growth by inhibiting proliferation-related signaling pathways, such as AKT, PI3K, and Wnt, by the secretion of proapoptotic molecules such as Dikkopf type 1 (Dkk1) inhibiting the progression of the cell cycle; in turn, they can negatively regulate the X-linked inhibitor of the apoptosis protein (XIAP) and suppression of angiogenesis [31, 36, 37] (**Figure 1**). In this chapter, we will analyze how MSCs can contribute to tumorigenesis, including (i) transition to tumor-associated fibroblasts; (ii) suppression of the immune response; (iii) promotion of angiogenesis; (iv) stimulation of epithelial-mesenchymal transition (EMT); (v) through contribution to the tumor microenvironment; (vi) inhibition of tumor cell apoptosis; through contribution to the tumor microenvironment; (vi) inhibition of tumor cell apoptosis, and (vii) promotion of tumor metastasis.
