BaCKgRoUND aND aIMS: Cancer-associated fibroblasts (CAFs) are key players in multicellular, stromal-dependent alterations leading to HCC pathogenesis. However, the intricate crosstalk between CAFs and other components in the tumor microenvironment (TME) remains unclear. This study aimed to investigate the cellular crosstalk among CAFs, tumor cells, and tumor-associated neutrophils (TANs) during different stages of HCC pathogenesis. appRoaCH aND ReSUltS: In the HCC-TME, CAFderived cardiotrophin-like cytokine factor 1 (CLCF1) increased chemokine (C-X-C motif ) ligand 6 (CXCL6) and TGFβ secretion in tumor cells, which subsequently promoted tumor cell stemness in an autocrine manner and TAN infiltration and polarization in a paracrine manner. Moreover, CXCL6 and TGFβ secreted by HCC cells activated extracellular signal-regulated kinase (ERK) 1/2 signaling of CAFs to produce more CLCF1, thus forming a positive feedback loop to accelerate HCC progression. Inhibition of ERK1/2 or CLCF1/ciliary neurotrophic factor receptor signaling efficiently impaired CLCF1-mediated crosstalk among CAFs, tumor cells, and TANs both in vitro and in vivo. In clinical samples, up-regulation of the CLCF1−CXCL6/TGFβ axis exhibited a marked correlation with increased cancer stem cells, "N2"-polarized TANs, tumor stage, and poor prognosis. CoNClUSIoNS:This study reveals a cytokine-mediated cellular crosstalk and clinical network involving the CLCF1− CXCL6/TGFβ axis, which regulates the positive feedback loop among CAFs, tumor stemness, and TANs, HCC progression, and patient prognosis. These results may support the CLCF1 cascade as a potential prognostic biomarker and suggest that selective blockade of CLCF1/ciliary neurotrophic factor receptor or ERK1/2 signaling could provide an effective therapeutic target for patients with HCC. (Hepatology 2021;73:1717-1735. M ore than 80% of HCCs are characterized by extensive liver fibrosis caused by the activation, proliferation, and accumulation of fibroblasts. (1) A hallmark feature of the tumor microenvironment (TME) of HCC is the mass of cancer-associated fibroblasts (CAFs), which has been extensively reported to influence HCC progression. (1)

The presence of VM predicts poorer survival outcomes in cancer patients.

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Background High probability of metastasis limited the long-term survival of patients with hepatocellular carcinoma (HCC). Our previous study revealed that Galectin-3 was closely associated with poor prognosis in HCC patients. Methods The effects of Galectin-3 on tumour metastasis were investigated in vitro and in vivo, and the underlying biological and molecular mechanisms involved in this process were evaluated. Results Galectin-3 showed a close correlation with vascular invasion and poor survival in a large-scale study in HCC patients from multiple sets. Galectin-3 was significantly involved in diverse metastasis-related processes in HCC cells, such as angiogenesis and epithelial-to-mesenchymal transition (EMT). Mechanistically, Galectin-3 activated the PI3K-Akt-GSK-3β-β-catenin signalling cascade; the β-catenin/TCF4 transcriptional complex directly targeted IGFBP3 and vimentin to regulate angiogenesis and EMT, respectively. In animal models, Galectin-3 enhanced the tumorigenesis and metastasis of HCC cells via β-catenin signalling. Moreover, molecular deletion of Galectin-3-β-catenin signalling synergistically improved the antitumour effect of sorafenib. Conclusions The Galectin-3-β-catenin-IGFBP3/vimentin signalling cascade was determined as a central mechanism controlling HCC metastasis, providing possible biomarkers for predicating vascular metastasis and sorafenib resistance, as well as potential therapeutic targets for the treatment of HCC patients.

BackgroundPlatinum resistance is a major challenge in the clinical treatment of advanced ovarian cancer (OC). Accumulating evidence shows that the tumor-promotive M2 macrophage is linked to the limiting chemotherapy efficacy of multiple malignancies including OC. Circular RNAs (circRNAs) are a novel class of non-coding RNAs which function as the critical regulator in biological process of cancer. However, their impact on macrophage polarization and chemoresistance of OC remain unclear.MethodsPlatinum-resistant circRNAs were screened using circRNA deep sequencing and validated using in situ hybridization in OC tissues with or without platinum resistance. The role of circITGB6 in inducing cisplatin (CDDP) resistance was evaluated by clone formation, immunofluorescence and annexin V assays in vitro, and by intraperitoneal tumor model in vivo. The mechanism underlying circITGB6-mediated tumor-associated macrophage (TAM) polarization into M2 phenotype was investigated using RNA pull-down, luciferase reporter, electrophoretic mobility shift, RNA binding protein immunoprecipitation (RIP), ELISA and immunofluorescence assays.ResultsWe identified that a novel circRNA, circITGB6, robustly elevated in tumor tissues and serums from patients with OC with platinum resistance, was correlated with poor prognosis. circITGB6 overexpression promoted an M2 macrophage-dependent CDDP resistance in both vivo and vitro. Mechanistic research determined that circITGB6 directly interacted with IGF2BP2 and FGF9 mRNA to form a circITGB6/IGF2BP2/FGF9 RNA–protein ternary complex in the cytoplasm, thereby stabilizing FGF9 mRNA and inducing polarization of TAMs toward M2 phenotype. Importantly, blocking M2 macrophage polarization with an antisense oligonucleotide targeting circITGB6 markedly reversed the circITGB6-induced CDDP resistance of OC in vivo.ConclusionsThis study reveals a novel mechanism for platinum resistance in OC and demonstrates that circITGB6 may serve as a potential prognostic marker and a therapeutic target for patients with OC.

Adjuvant chemotherapy after surgery is the standard treatment modality for stage III and part of stage II or stage IV colorectal cancer (CRC) patients. However, the 5-year overall survival (OS) rate remains unsatisfactory. Thus, developing combination therapies is essential to improve the prognosis of patients with CRC. The present study aimed to determine the effect of a sequential combination of cytokine-induced killer cell (CIK) infusion and chemotherapy for patients with CRC. 122 patients with CRC treated with postoperative adjuvant chemotherapy were retrospectively included in this study. Among them, 62 patients received adjuvant chemotherapy only (control group), while the other 60 patients, with similar demographic and clinical characteristics, received adjuvant chemotherapy and sequential CIK cell immunotherapy (CIK group). Survival analysis showed significantly improved disease free survival (DFS) and OS rates in the CIK group compared with the control group (log-rank test, P = .0024; P = .008, respectively). Univariate and multivariate analyses indicated that sequential CIK cell treatment was an independent prognostic factor for patients' DFS and OS. Subgroup analyses showed that sequential CIK cell treatment significantly improved the DFS and OS of patients with high-risk T4 stage and insufficient chemotherapy duration. In conclusion, these data indicate that sequential adjuvant CIK cell treatment combined with chemotherapy is an effective therapeutic strategy to prevent disease recurrence and prolong survival of patients with CRC, particularly for patients with highrisk T4 stage and insufficient chemotherapy duration.

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