Activated hepatic stellate cells secrete periostin to induce stem cell-like phenotype of residual hepatocellular carcinoma cells after heat treatment

Abstract

Some evidences show that residual tumor after thermal ablation will progress rapidly. However, its mechanisms remain unclear. Here, we assessed whether activated HSCs could regulate stem cell-like property of residual tumor after incomplete thermal ablation to promote tumor progression. Human HCC cell lines were exposed to sublethal heat treatment to simulate the peripheral zone of thermal ablation. After residual HCC cells were cultured with conditional medium (CM) from activated HSCs, parameters of the stem cell-like phenotypes were analyzed. Nude mice bearing heat-exposed residual HCC cells and HSCs were subjected to metformin treatment to thwarter tumor progression. CM from activated primary HSCs or LX-2 cells significantly induced the stem cell-like phenotypes of residual HCC cells after heat treatment. These effects were significantly abrogated by neutralizing periostin (POSTN) in the CM. POSTN regulated the stemness of heat-exposed residual HCC cells via activation of integrin β1/AKT/GSK-3β/β-catenin/TCF4/Nanog signaling pathway. Metformin significantly inhibited in vivo progression of heat-exposed residual HCC via suppressing POSTN secretion and decreasing cancer stem cell marker expression. Our data propose a new mechanism of activated HSCs promoting the stemness traits of residual HCC cells after incomplete thermal ablation and suggest metformin as a potential drug to reverse this process.

RETRACTED ARTICLE: Periostin secreted by cancer-associated fibroblasts promotes cancer stemness in head and neck cancer by activating protein tyrosine kinase 7

“…Many studies have reported that POSTN secreted by CAFs promoted tumor progression and the CSC-like phenotype 24 , 25 , 35 , 36 , and PTK7 has been shown to be a CSC marker in some tumors 7 , 8 . We efficiently knocked down PTK7 expression in the HN6 and SCC-25 cells and overexpressed PTK7 expression in CAL 27 cells with GFP-tagged lentivirus (Supplementary Figure 4A ).…”

Contributions of Fibroblasts, Extracellular Matrix, Stiffness, and Mechanosensing to Hepatocarcinogenesis

“…[64][65][66][67] Higher expression of Laminin-332 in HCC than in normal or peritumoral tissue, association with metastatic phenotype 68 Periostin Periostin interacts with integrins αvβ3, αvβ5, and α6β4, resulting in the activation Akt/PKB and FAK-mediated signaling pathways as well as increased EGFR activation. [69][70][71] Periostin induces stemness in HCC 78 Periostin is upregulated in multiple cancers including HCC and associated with poor outcomes 72,75,76 Growth factors HGF Binds to its receptor Met, resulting in the activation of multiple kinase pathways such as Erk, Akt, and NF-κB 185,255 Promotes hepatocyte proliferation and survival; in HCC, HGF increases tumor migration, neoangiogenesis, proliferation, 180,183,256,257 and chemoresistance. 17 73 Periostin is upregulated in multiple cancers including HCC and associated with poor outcomes.…”

“…72,75,76 Mechanistically, periostin appears to promote HCC development by inducing angiogenesis 77 and stemness of heat-exposed residual HCC cells. 78 Hyaluronic acid (HA) is a non-sulfated glycosaminoglycan which, like other ECM components, exerts multiple functions that include besides its role as mechanical and lubricating component of ECM also the promotion of wound healing, inflammation and epithelial cell behavior. HA bioactivity is via an Erk/AP-1/ SP1.…”

Activated hepatic stellate cells promote progression of post-heat residual hepatocellular carcinoma from autophagic survival to proliferation

“…As we described previously [19,20], HCC cells were exposed to sublethal heat stress (IT50, 47 C for 10 min) to simulate the incomplete RFA. Cell growth curves of heat-treated residual HCC cells showed an obvious latency growth and slower proliferation compared with control cells treated by 37 C for 10 min (Figure 1(A)).…”