Full Scientific Report for Gary Ren, Ph.D.
Mesenchymal Stromal Cell-Immune Cell Interactions in Cancer Therapeutic Resistance and Metastatic Relapse
Mesenchymal stem/stromal cells (MSCs) are multipotent stem cells with differentiation potentials for diverse types of tissue cells, including osteoblasts, adipocytes, chondrocytes and stromal fibroblasts. They exist in almost all tissues and are a key cell source for wound healing and regeneration. Upon tissue injury, MSCs and their lineages can rapidly sense and respond to the tissue damaging signals, such as inflammatory mediators and environmental toxic molecules, with a subsequent mobilization towards the sites of damage. At the wound sites, MSCs and their derivatives not only contribute to tissue regeneration, they also exert other functions such as immunoregulation which helps ameliorate injury-associated inflammation.
In mouse models of immunological injuries such as graft-versus-host disease (GvHD), MSCs were found to be highly responsive to the inflammatory milieu in tissue microenvironment where inflammatory cytokines quickly convert MSCs from an inert status to be intensely immunosuppressive by overexpressing regulatory molecules (Ren et al. Cell Stem Cell 2008; Ren et al. Stem Cells 2009; Ren et al. J Immunol 2010). Therefore, MSCs and their lineages effectively expedite the wound repair process through a negative feedback loop of immunoregulation (Ren et al. Trends Immunol 2012; Ren et al. Stem Cells Transl Med 2012)
Cancer is considered as an overhealing wound. Cancer cells always strategically take advantage of the wound healing-facilitating function of mesenchymal lineage cells. When arrived at the tumor sites following the tumor-wound cues, mesenchymal lineage cells behave similarly as they do during tissue repair: recruiting innate immune cells (to eliminate pathogens and secrete tissue growth factors) and suppressing T-cell immunity (to resolve the excessive adaptive immune responses). These mechanisms are well employed by tumors which render MSCs to be accomplices for tumor progression (Ren et al. Cell Stem Cell 2012; Ren et al. Oncogene 2014). Thus, the consequence of MSC-mediated tissue repair at the tumor sites is exacerbation, but not amelioration of cancer progression.
Conventional cancer treatments, such as chemotherapy and radiotherapy, always lead to host tissue damages in spite of their tumor-killing capabilities. These damages in turn boost the tissue repairing potentials of MSCs by upregulating growth factors and cytokines. As revealed by our recent studies, tumor cells again succeed in taking advantage of radiotherapy-induced tissue repairing mechanisms by MSCs and stromal fibroblasts for induction of radiotherapy resistance and post-therapy recurrence in melanoma and breast carcinoma models (Ren et al. manuscript submitted. 2016).
Altogether, MSCs and their derivatives are not innately functional. They are highly plastic and capable of quickly responding to tissue environmental stresses, such as inflammatory mediators, toxic chemicals and radicals etc, to gain their regulatory functions serving to achieve tissue homeostasis. Such beneficial features of mesenchymal lineage cells, unfortunately, are well exploited by “tumor wounds” leading to accelerated tumor progression, and therapy-induced resistance and metastatic relapse. Bearing the similarities of tumors to wounds in mind, our group dedicate to understanding how mesenchymal lineage cells exert tumor regulatory functions in response to environmental stresses including inflammation, cancer therapeutics and other physiological and pathological conditions.
Our studies will fully take advantage of the exceptional and unique research platform at the Jackson Laboratory: humanized mouse models (NSG™-SGM3) with over 450 patient-derived xenograft (PDX) tumors. Our findings will provide a much needed mechanistic understanding of mesenchymal stroma-immune cell-tumor interactions in clinically relevant settings. More importantly, they will directly lead to clinically applicable strategies to improve treatment efficacy and prevent metastatic relapse of diverse cancers by interfering with mesenchymal lineage cells.