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Objective: Hypoxic tumor cells are more resistant to standard chemotherapies. A number of studies indicated that improving oxygenation inside the tumor could serve as a potential strategy to target hypoxia-induced chemoresistance. In this study, we examined whether a hemoglobin-based oxygen carrier (OC89) could increase tumor oxygenation and thus enhance the efficiency of transarterial chemoembolization (TACE) in an orthotopic rat HCC model. Methods: Efficiency of the hemoglobin-based oxygen carrier (OC89) in improving tumor oxygenation was examined by OxyLab pO2. Sensitization of chemotherapy (cisplatin) in TACE by OC89 was evaluated in four different therapeutic regimens including cisplatin (1 mg/kg) + OC89 (0.2 g/kg), cisplatin (1 mg/kg) + OC89 (0.4 g/kg), cisplatin (3 mg/kg) + OC89 (0.2 g/kg), cisplatin (3 mg/kg) + OC89 (0.4 g/kg). For all the therapeutic regimens, a single delivery of OC89 via the tail vein was performed 1 h before TACE. Results: Compared with Ringer's buffer, systemic delivery of OC89 (0.4 g/kg) attenuated tumor hypoxia ( p < 0.05). Additionally, partial pressure of oxygen (pO2) fraction of low readings (0-10 mmHg) inside the tumor decreased from 74.1% to 24.6% after OC89 delivery, while pO2 fraction of high readings (15-25 mmHg) increased from 22.2% to 41.5%. When cisplatin was combined with OC89, regimen cisplatin (3 mg/kg) + OC89 (0.4 g/kg) resulted in a significant inhibition of tumor growth at Day 21 after therapy ( p < 0.05). Further investigation indicated that OC89 delivery influenced anti-apoptotic and pro-apoptotic balance of the UPR pathway in the tumor. Conclusions: Our data suggest that targeting tumor hypoxia with the hemoglobin-based O2 carrier serves as a promising approach to enhance the efficacy of cisplatin-based chemotherapy in HCC. [ABSTRACT FROM AUTHOR]

Background & Aims Liver graft injury and tumor recurrence are the major challenges of liver transplantation for the patients with hepatocellular carcinoma (HCC). Here, we aimed to explore the role and mechanism of liver graft injury mobilizing regulatory T cells (Tregs), which lead to late phase tumor recurrence after liver transplantation. Methods The correlation among tumor recurrence, liver graft injury and Tregs mobilization were studied in 257 liver transplant recipients with HCC and orthotopic rat liver transplantation models. The direct roles of CXCL10/CXCR3 signaling on Tregs mobilization and tumor recurrence were investigated in CXCL10 −/− and CXCR3 −/− mice models with hepatic IR injury. Results Clinically, patients received the graft with graft weight ratio (GWR) <60% had higher HCC recurrence after liver transplantation than the recipients with GWR ⩾60% graft. More circulating Tregs and higher intragraft TLR4/CXCL10/CXCR3 levels were detected in recipients with GWR <60% graft. These results were further validated in rat transplantation model. Foxp3 + cells and expressions of TLR4, CXCL10, TGFβ, CTLA-4 and CD274 were increased in rat liver tumor tissues from small-for-size graft group. In mouse model, the mobilization and recruitment of Tregs were decreased in TLR4 −/− , CXCL10 −/− and CXCR3 −/− mice compared to wild-type mice. Moreover, less CXCR3 + Tregs were recruited into liver in CXCL10 −/− mice after hepatic IR injury. The knockout of CXCL10 and depletion of Tregs inhibited tumor recurrence after hepatic IR injury. Conclusion CXCL10/CXCR3 signaling upregulated at liver graft injury directly induced the mobilization and intragraft recruitment of Tregs, which further promoted HCC recurrence after transplantation. Lay summary There were positive correlation among tumor recurrence, circulating Tregs and liver graft injury after human transplantation for HCC patients. The knockout of CXCL10 decreased hepatic recruitment of CXCR3 + Tregs and late phase tumor recurrence after hepatic IR injury. [ABSTRACT FROM AUTHOR]

Human hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide with a poor prognosis of limited survival. The role of regulatory B cell (Breg), a new important B cell subset, in HCC progression remains unclear. We firstly found that the percentage of B cells at tumor margin was significantly higher than that in tumor and non-tumor regions. Especially, increased intrahepatic B cells at tumor margin were positively associated with tumor invasive features and more tumor recurrence. Besides, HCC patients had a significantly higher percentage of circulating Bregs than healthy people. Increased circulating Bregs were correlated with advanced tumor staging, tumor multiplicity and venous infiltration. Next, we firstly revealed that human Bregs promoted HCC tumor growth independent of Tregs in SCID mice. The migration of Bregs from blood into tumor was also confirmed in mice. Finally, we further explored the molecular mechanism of Bregs promoting proliferation and migration of HCC cells in vitro . Bregs promoted HCC growth and invasiveness by directly interacting with liver cancer cells through the CD40/CD154 signaling pathway. [ABSTRACT FROM AUTHOR]