MSCs are multipotent progenitor cells capable of proliferation and commonly isolated from bone marrow, amniotic fluid, placenta, cord blood, skeletal muscle, and adipose tissues. Under specific culture conditions, MSCs can be induced to differentiate into different mesodermal and myogenic lineages. Moreover, MSCs can modulate immune response and are therefore used to control autoimmune disorders. Since MSCs can be cultured ex vivo and successfully used for autologous transplantation, they have potential application in regenerative medicine.

Several in vitro as well as in vivo studies have reported that MSCs exhibit tumor-directed migration and stromal incorporation (Loebinger et al. 2009). Studies performed with MSCs and cancer cell lines have demonstrated that MSCs show significant tumor tropism (Kidd et al. 2009). This phenomenon occurs due to tumor-derived cytokines, chemokines, and inflammatory mediators which results in tumor-directed MSC migration and subsequent incorporation in the tumor microenvironment. Tumor-educated MSCs further induced inflammation by recruiting PBMCs (peripheral blood monocytes) that drives tumor growth. This proinflammatory response is mediated by tumor-derived IL-1-β through the FAK/MAPK signaling while TGF-β inhibited this phenotype of MSCs. In the stroma of both primary tumor as well as metastatic sites, MSCs can differentiate into cancer-associated fibroblasts (CAFs) (Koh and Kang 2012). Previously it has been shown that MSCs are capable of enhancing angiogenesis of breast and prostate cancer (Zhang et al. 2013). Studies performed by Spaeth et al. provide evidence that MSCs have the capacity to differentiate into CAFs and induce expression of HGF, IL-6, and VEGF which drive tumor growth and angiogenesis (Spaeth et al. 2009). The presence of MSCs, CAFs, and other dysregulated stromal cells within tumor is associated with poor clinical outcome and enhanced metastatic potential (Quail and Joyce 2013). The mechanism by which tumor cells interact with the stromal cells and how that interaction controls tumor progression are not well defined. McAllister et al. have shown that OPN secreted in instigating primary tumor controls the migration of aggressive cancer cells towards distant nonmalignant tumors through bone marrow cell activation (McAllister et al. 2008). Mi et al. have shown that OPN regulates CCL5-mesenchymal stromal cell-mediated breast cancer metastasis (Mi et al. 2011, Fig. 6.2). Using in vitro and in vivo models, they have shown that tumor-derived OPN binds to integrin and AP-1 transactivation leading to induced CCL5 expression by the MSCs. Upon activation by tumor-derived OPN, MSCs have been shown to metastasize to distant tissues where they differentiate into CAFs and express fibroblast-specific markers: α-SMA, FSP-1, CXCL-12, and tenascin-c. These CAFs have been shown to produce MMP-2 and MMP-9 that mediate cancer progression by remodeling the tissue architecture (Mi et al. 2011).

Major part of tumor stroma consists of fibroblasts and these are imperative for promotion of primary tumors to higher grades and overall cancer spread (Wels et al. 2008). Under normal physiological conditions, fibroblast shows inhibitory role in cell proliferation whereas in tumor context these are activated by the factors secreted by cancerous cells or stromal cells and thereby support the cell proliferation (Wels et al. 2008; Tchou and Conejo-Garcia 2012). Myofibroblast-specific gene expression is the hallmark of CAFs (Cirri and Chiarugi 2011). Several studies have shown that CAFs play multifaceted role in tumor progression and angiogenesis and metastasis by regulating factors linked to proliferation, apoptosis, invasion, and immune evasion (Wels et al. 2008; Tchou and Conejo-Garcia 2012; Cirri and Chiarugi 2011).

Senescent fibroblasts, reminiscent of myofibroblasts, promote the preneoplastic cell growth via OPN (Pazolli et al. 2009). OPN is required for the transactivation of fibroblasts to myofibroblasts by TGF-β and deletion of OPN prevents the activation of fibroblasts (Lenga et al. 2008). Tumor-derived OPN promote breast tumor progression by inducing the transformation of MSC into CAFs with upregulation of CCL5 and myofibroblastic marker α-SMA (Fig. 6.2). Blockade of OPN-mediated CCL5 expression using RGD, a competitive ligand inhibitor of integrin binding, CD44-blocking Ab, or OPN-R3 APT abated tumor growth and metastasis by diminishing CAFs generation (Mi et al. 2011). Recent data have shown that tumor-derived PDGF-CC recruits stromal fibroblasts into tumor and activates to CAFs by engaging with PDGFR-α. In addition, CAFs-dependent melanoma growth is mediated through CAF-derived OPN (Anderberg et al. 2009, Fig. 6.2).

Infiltration of mononuclear inflammatory cells proximal to neoplastic tissues is one of the hallmarks of cancer-associated chronic inflammation. Macrophages, dendritic cells, and neutrophils are mainly observed at sites of inflammation. In tumors, cancer cells secrete chemokines which are classified as inflammatory or inducible (Mantovani et al. 2002). Constitutive expression of NF-κB is correlated with increased production of CXCL1 that results in inflammation within the tumor (Yang and Richmond 2001). Studies have shown that infiltration of macrophages in higher frequency is associated with poor prognosis of cancer. Macrophages exhibit two polarized states: M1 phenotype, in which they can invade the site of inflammation by responding to cytokines and chemokines released by neoplastic cells where they adopt the M2 phenotype that helps in tumor progression and metastasis (Mantovani et al. 2002). Recent studies have shown that macrophages overexpress OPN upon co-culturing with breast cancer cells (Solinas et al. 2010). Antagonizing OPN with neutralizing antibody interferes with macrophage function in the tumor microenvironment (Giachelli et al. 1998).

At the site of injury or infection, proinflammatory mediators and growth factors like TNF-α, IL-1, and PDGF increase expression of OPN by activating protein kinase C (Denhardt et al. 2001). In different cancers, OPN-expressing macrophages are more in number near the edge of tumor and in areas of tumor necrosis suggesting their role in invasion and metastasis (Brown et al. 1994). In colorectal cancer, immunohistochemical analyses have shown increased expression of OPN in TAMs (Rao et al. 2013a). Recently Kale et al. have shown that OPN expressing macrophages help in enhancing melanoma growth and angiogenesis through ERK/p38 pathway leading to COX-2 and PGE2 production (Kale et al. 2014, Figs. 6.2 and 6.3). In adenocarcinoma specimens overexpression of OPN in infiltrating tumor-associated macrophages correlates with poor prognosis (Hsu et al. 2010). OPN secreted from macrophages reinstates the metastatic potential of hepatoma cells treated with OPN siRNA (Cheng et al. 2007). Thus, targeting macrophage derived OPN may help in regressing tumor growth.