As with many biological phenomena

As with many biological phenomena, immunomodulation is a double-edged sword, and many of these tolerogenic mechanisms appear to be manipulated by cancer Apremilast manufacturer to create an immunoprivileged niche to further their own growth (Rabinovich et al., 2007). One of the most prominent immunomodulatory leukocyte subpopulations in cancer consists of myeloid-derived suppressor cells (MDSCs) (Ostrand-Rosenberg and Sinha, 2009). Derived from myeloid precursors, MDSCs suppress immune response by a number of mechanisms, such as suppressing cytotoxic lymphocyte effector functions and targeting T cells by expressing the enzymes arginase 1 (ARG1) and inducible nitric oxide synthase (iNOS), both of which block the production of the T cell CD3-ζ chain by metabolizing L-arginine (Gabrilovich and Nagaraj, 2009; Gabrilovich et al., 2012). Human and mouse studies have revealed that chronic inflammation and proinflammatory mediators such granulocyte macrophage colony-stimulating factor (GM-CSF), IL-1β, IL-6, and prostaglandin E2 (PGE2) are involved in the induction of these suppressor leukocytes (Bunt et al., 2007; Serafini et al., 2004; Sinha et al., 2007; Young and Wright, 1992). Although it is clear that the tumor microenvironment is maintained by diverse cell types, the role of secreted factors other than cytokines and proinflammatory factors in the expansion of MDSCs has largely been unexplored, with the exception of vascular endothelial growth factor (Fricke et al., 2007; Shojaei et al., 2007). We report that MDSCs can be expanded by MSC-secreted hepatocyte growth factor (HGF), a potent mitogenic growth factor.


Recent reports have highlighted MDSCs as a prominent leukocyte subpopulation involved not only in tumor-associated immune suppression but also in regulation of the immune system at large (Almand et al., 2001; Gabrilovich and Nagaraj, 2009; Rodríguez and Ochoa, 2008). Previous data have shown that a number of proinflammatory mediators are important inducers of these cells, but there has been no report regarding the involvement of tumor-associated mitogenic growth factors in the process. Our data link HGF secreted by MSCs to the expansion of MDSCs. Our findings can help to explain the strong association of MDSCs with tumors, since it is well established that in the tumor microenvironment, HGF is highly secreted by both the cancer cells themselves and the supporting stromal cells, promoting cell survival and tumor growth (Cecchi et al., 2010; Mueller and Fusenig, 2004). While HGF has been implicated in immunoregulatory responses (Benkhoucha et al., 2010; Di Nicola et al., 2002), and the liver, which naturally secretes high levels of HGF, was reported to have some immunological functions (Sheth and Bankey, 2001), the specific molecular mechanisms underlying these observations have been largely unexplored and the reported effects have not been consistently replicated (Le Blanc et al., 2003). Our finding that high numbers of hepatic MDSCs in mice can be significantly altered by disruption of the HGF/c-Met pathway sheds some mechanistic light on this issue, and, overall, our data demonstrate that HGF mediates the expansion of functional MDSCs by engaging c-Met, its receptor, and increasing the phosphorylation of STAT3, one of its downstream molecules.
The immunomodulatory properties of MSCs have been highlighted as being therapeutic for autoimmune diseases and other immune-related diseases such as graft-versus-host disease (Abdi et al., 2008; Djouad et al., 2009; Keating, 2012; Le Blanc et al., 2008). As exciting as these findings are, some researchers have noted that the same immunomodulatory effects of MSCs can allow for the growth of tumors (Djouad et al., 2003). However, whether MSCs definitively enhance or inhibit tumor growth and cancer progression is still unresolved, since differences in the experimental design, cancer histologic cell type, and MSC isolation technique used can all affect the experimental outcome (Klopp et al., 2011; Yen and Yen, 2008). Moreover, to date, studies on MSC and cancer interactions have largely focused on the homing of MSCs to tumors, rather than the immunological aspects of MSCs (Elzaouk et al., 2006; Studeny et al., 2002; Xin et al., 2007). Although a considerable amount of data support MSC expansion of Tregs (Uccelli et al., 2008), and these immunosuppressive T lymphocytes are also found in tumors, MDSCs appear to play a more crucial role in maintaining the profound immune suppression of the tumor niche (Almand et al., 2001; Ostrand-Rosenberg and Sinha, 2009; Sinha et al., 2005; Young and Wright, 1992). Our data suggest that through HGF and the consequent expansion of MDSCs, MSCs may play a role in maintaining tumor growth.