IL-8, GRO and MCP-1 produced by hepatocellular carcinoma microenvironment determine the migratory capacity of human bone marrow-derived mesenchymal stromal cells without affecting tumor aggressiveness

Abstract

New therapies are needed for advanced hepatocellular carcinoma (HCC) and the use of mesenchymal stromal cells (MSCs) carrying therapeutic genes is a promising strategy. HCC produce cytokines recruiting MSCs to the tumor milieu and modifying its biological properties. Our aim was to study changes generated on human MSCs exposed to conditioned media (CM) derived from human HCC fresh samples and xenografts. All CM shared similar cytokines expression pattern including CXCL1-2-3/GRO, CCL2/MCP-1 and CXCL8/IL-8 being the latter with the highest concentration. Neutralizing and knockdown experiments of CCL2/MCP-1, CXCL8/IL-8, CXCR1 and CXCR2 reduced in vitro MSC migration of ≥20%. Simultaneous CXCR1 and CXCR2 neutralization resulted in 50% of MSC migration inhibition. MSC stimulated with CM (sMSC) from HuH7 or HC-PT-5 showed a 2-fold increase of migration towards the CM compared with unstimulated MSC (usMSC). Gene expression profile of sMSC showed ~500 genes differentially expressed compared with usMSC, being 46 genes related with cell migration and invasion. sMSC increased fibroblasts and endothelial cells chemotaxis. Finally, sMSC with HuH7 CM and then inoculated in HCC tumor bearing-mice did not modify tumor growth. In this work we characterized factors produced by HCC responsible for the changes in MSC chemotactic capacity with would have an impact on therapeutic use of MSCs for human HCC.

Novel Combination of Mesenchymal Stem Cell-Conditioned Medium with Sorafenib Have Synergistic Antitumor Effect of Hepatocellular Carcinoma Cells

“…MSCs can be used to suppress the development of HCC. Their multipotency, immunoregulatory, pro-regenerative effects (Hsu et al, 2017) and their chemotactic properties to home to tumor invaded regions make them a good candidate for cancer therapy (Bayo et al, 2017). MSCs inhibit tumor growth by increasing inflammatory infiltration (Ohlsson et al, 2003), inhibiting angiogenesis (Otsu et al, 2009), suppressing the signaling of Wnt (Qiao et al, 2008a;Qiao et al, 2008b) and AKT (Khakoo et al, 2006), and inducing cell cycle arrest and apoptosis 4 (Cousin et al, 2009;Dasari et al, 2010;Lu et al, 2008).…”

The Role of the Tumor Microenvironment in the Development and Progression of Hepatocellular Carcinoma

“…The first reports indicated that MSCs inhibited HCC growth in vitro and in vivo (75,76). However, other results demonstrated either a pro-tumorigenic effect (77,78) or a null effect of MSCs on HCC growth (35,36,(79)(80)(81)(82). The inhibition of tumor growth was associated with Wnt, NF-κB, and PI3-K/Akt signaling pathways (75,83), whereas enhancement of microvessel density was observed in the case of tumor progression (77,78).…”

“…Consequently, MSCs can be recruited to these tumor sites and activated to have repair and immunomodulation functions. Several factors such as interleukin (IL)-8, monocyte chemoattractant protein-1, growth-regulated oncogene, and autocrine motility factor, produced by the HCC, are known to attract and recruit MSCs (35,36). It is known that MSCs can secrete several growth factors, cytokines, chemokines, and ECM components (37).…”

Understanding the inflammation-cancer transformation in the development of primary liver cancer

“…When liver tissue or cells stimulate with stimulants like alcohol and fatty acid, liver tissue synthesizes various types of cytokines to defend that [20][21][22][23][24][25] . The well-studied cytokines include tumor necrosis factor-α (TNF-α) [26,27] , interleukin family (IL-6, IL-1β) [7,28,29] , chemokines (VCAM-1, ICAM-1 and MCP-1) [30][31][32][33] , etc. TNF-α and IL-6 are two multifunctional cytokines in chronic hepatic inflammation.…”