Fig. 1

Roles of MSCs in cancer progression and therapeutic resistance. MSCs are well known for homing to tumor sites, where they play crucial roles in cancer parthenogenesis and therapeutic resistance. Several factors are involved in the process, such as SDF-1α, MMP-2, CXCR1 and CCL8. Proliferation: mediators (i.e., PGE₂, lactate and TGF-β1) secreted by anti-inflammatory MSCs inhibited tumor cell death to further support tumor growth. Metastasis: MSCs are able to transform into CSCs or CAFs, which drives tumor heterogeneity. Moreover, several factors (i.e., CCL5, TGF-β and IFN-γ) produced by MSCs induced EMT, which contributed to metastasis. Apoptosis: several chemokines (i.e., VEGF, bFGF, PDGF and TGF-β) by MSCs recruited immune cells to tumor sites, thereby inducing anticancer immunity. In contrast, MSCs reduced cancer cell growth via paracrine inhibition of AKT and Wnt signaling pathways, which contribute to cancer cell proliferation. Immunosuppression: MSCs inhibited the anti-tumor immune response, including innate and adaptive immune responses. In adaptive immune responses, MSCs elicited Th2-polarized immune response, and indirectly triggered the development of Treg cells. Moreover, MSCs inhibited antigen triggered immunoglobulin release and slowed B cell proliferation. In innate immune responses, MSCs inhibited IFN-γ production in NK cells, and DCs maturation and function. Moreover, MSC induced a transition from inflammatory M1 macrophages to a pro-tumorigenic alternatively activated M2 state. In addition, trained neutrophils acquired immunosuppressive activity. Angiogenesis: MSCs secreted angiogenic factors (i.e., VEGF, HIF1α and βFGF) to promote angiogenesis, which contributes to cancer progression. Therapeutic resistance: paracrine or systematically secreting molecules (i.e., PIFAs, IL-6, EGF and IGF) by MSCs reduced tumor cell death, thereby inducing therapeutic resistance. In contrast, MSCs also suppress cancer pathogenesis and sensitize cancer cells to therapy by blocking the STAT3 pathway. MSCs support the CSC niche to further promote resistance to therapeutics, including CXCL7 and IL-6. In addition, several tumor suppressor genes in MSCs, such as RassF1A and HIC1, were methylated, thus indicating that MSCs transform into CSCs. Notably, tumor cells released IL-1, which induced MSCs to secrete several mediators (i.e., IL-6, IL-8 and CXCL1). These mediators together induce the formation of CSCs. Furthermore, MSCs significantly increased CXCL10 expression, which further promoted CSC proliferation when the CXCL10 receptor (CXCR3) was overexpressed on CSCs. As a result, they altogether increased tumor growth and enhanced therapeutic resistance