Multipotent mesenchymal stromal cells play critical roles in hepatocellular carcinoma initiation, progression and therapy

Abstract

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, with high morbidity, relapse and mortality rates. Multipotent mesenchymal stromal cells (MSCs) can be recruited to and become integral components of the HCC microenvironment and can influence tumor progression. This review discusses MSC migration to liver fibrosis and the HCC microenvironment, MSC involvement in HCC initiation and progression and the widespread application of MSCs in HCC-targeted therapy, thus clarifying the critical roles of MSCs in HCC.

Keywords: Carcinogenesis; Chemotaxis; Hepatocellular carcinoma (HCC); Mesenchymal stromal cells (MSCs); Neoplasm metastasis; Tumor-targeted therapy.

Fig. 1

Complex interactions between HCC cells and stromal cells influence HCC progression. The main types of stromal cells in the HCC microenvironment are fibrogenesis cells (HSCs, fibroblasts), vascular system cells (ECs), immune cells (CD8⁺ T cells, Tregs, macrophages) and bone marrow-derived cells (MDSCs). HCC cells can “educate” these cells by different mechanisms. They can activate HSCs through secreting SHH and creating an acidic HCC microenvironment, and the latter can promote HCC drug resistance and metastasis by HGF, OPN, laminin-5 and laminin-332. HCC cells activate the conversion of liver and lung fibroblasts to CAFs by secreting TIMP-1 and exosomal miR-1247-3p, respectively, thus CAFs promote HCC growth through the IL-6/STAT3 pathway and secrete CCL2, CCL5, CCL7, CXCL6, TGF-β and SDF1 to facilitate HCC metastasis and vasculogenic mimicry. Hepatoma cells recruit MDSCs, Tregs and macrophages by secreting CCL5, CCL26, HIF-1, CCL28, CCL20, IL-6 and IL-8 and inhibit CD8⁺ T cells through the upregulated expression of amphiregulin, B7-H3 and PD-L1 to inhibit antitumor immunity. They can also promote EC proliferation to enhance angiogenesis

Fig. 2

Chemotaxis mechanisms that mediate MSC migration to the liver fibrosis and HCC microenvironment. MSCs can migrate to the liver fibrosis and HCC microenvironment, and this capacity has made MSCs ideal carriers for targeted therapies. MSCs migration to the liver fibrosis microenvironment can be mediated by the chemokine SDF-1α/CXCR4 and CCL25/CCR9 axes and the growth factor HGF via activation of c-MET. In addition to the chemokines and inflammatory growth factors known to exert potent cellular chemotactic effects, the sphingolipid metabolite S1P is one of the most important candidates for the induction of MSC mobilization via SIP3R. CB1 can also mediate homing of MSCs triggered by chronic liver injury. MSCs can be recruited into the HCC microenvironment by AMF and several chemokines, including IL-8, CCL2, CXCL1/2/3, CCL20 and CCL15/CCR, and SDF-1/CXCR4. TGF-β/TGF-βR are also involved in this process. Thyroid hormones can increase hMSC migration to HCC stroma via integrin αvβ3

Fig. 3

MSC-based HCC-targeted therapies. MSC-based HCC-targeted therapies primarily include genetically engineered MSCs and oncolytic virus-infected MSCs. MSCs engineered with cytokine genes, such as IFN-β, IFN-α2b, TRAIL and IL-12, inhibit HCC proliferation, growth, metastasis and induce apoptosis. MSCs packaging adenovirus expressing anti-CD3scfv can activate CTL and inhibit HCC. Using the NIS gene to modify MSCs provided a novel mechanism for evaluation of MSCs as gene delivery vehicles for tumor therapy and improved the effect of local radiotherapy. MSCs transfected with the suicide gene HSV-TK can transform the prodrug ganciclovir into a cytotoxic drug that kills hepatoma cells. MSCs engineered with PEDF, HNF4α and apoptin genes can inhibit angiogenesis, growth, metastasis and proliferation. Oncolytic viruses used to infect MSCs include measles virus and oncolytic adenovirus, and they presented obvious tumor inhibition in the HCC microenvironment