Becattini Barbara, Breasson Ludovic, Sardi Claudia, Zani Fabio, Solinas Giovanni
The Wallenberg Laboratory, Department of Molecular and Clinical Medicine at Institute of Medicine, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.
The Francis Crick Institute, London, UK.
JHEP Rep. 2021 Sep 2;3(6):100359. doi: 10.1016/j.jhepr.2021.100359. eCollection 2021 Dec.
BACKGROUND & AIMS: Phosphatidylinositides-3 kinases (PI3Ks) are promising drug targets for cancer therapy, but blockage of PI3K-AKT signalling causes hyperglycaemia, hyperinsulinaemia, and liver damage in patients, and hepatocellular carcinoma (HCC) in mice. There are 4 PI3Ks: PI3Kα, PI3Kβ, PI3Kδ, and PI3Kγ. The role of PI3Kγ in HCC is unknown.
We performed histopathological, metabolic, and molecular phenotyping of mice with genetic ablation of PI3Kγ using models where HCC was initiated by the carcinogen diethylnitrosamine (DEN) and promoted by dietary or genetic obesity (ob/ob). The role of PI3Kγ in leucocytes was investigated in mice lacking PI3Kγ in haematopoietic and endothelial cells.
Loss of PI3Kγ had no effects on the development of DEN-induced HCC in lean mice. However, in mice injected with DEN and placed on an obesogenic diet, PI3Kγ ablation reduced tumour growth, which was associated with reduced insulinaemia, steatosis, and expression of inflammatory cytokines. ob/ob mice lacking PI3Kγ, and mice with diet-induced obesity lacking PI3Kγ in leucocytes and endothelial cells did not display improved insulin sensitivity, steatosis, metabolic inflammation, or reduced tumour growth. However, these mice showed a reduced number of tumours, reduced liver infiltration by neutrophils, and reduced hepatocyte proliferation acutely induced by DEN.
Loss of PI3Kγ reduces tumour development in obesity-promoted HCC through multiple cell types and mechanisms that include improved insulinaemia, steatosis, and metabolic inflammation as well as the regulation of acute neutrophil infiltration and compensatory hepatocyte proliferation. PI3Kγ-selective inhibition may represent a novel therapeutic approach to reduce HCC initiation and slow HCC progression.
Class-1 phosphatidylinositides-3 kinases (PI3Ks) are critical targets in cancer therapy, but complete inhibition of all isoforms causes liver damage, hyperglycaemia, and insulinaemia. Here we show that selective ablation of the PI3Kγ isoform dampens tumour initiation and growth in a mouse model of carcinogen-initiated and obesity-promoted hepatocellular carcinoma (HCC). The effect of PI3Kγ ablation on reduced tumour growth was explained by reduced tumour cell proliferation, which was associated with reduced insulin levels, liver lipids, and reduced expression of tumour-promoting cytokines. PI3Kγ ablation in leucocytes of obese mice had no effects on tumour size. However, it reduced tumour number in association with reduced carcinogen-induced neutrophil infiltration and hepatocyte proliferation in livers of obese mice. Inhibition of PI3Kγ may thus reduce HCC initiation and growth in obese subjects by a mechanism involving reduced metabolic stress and insulinaemia and reduced carcinogen-induced neutrophil infiltration to the fatty liver.
磷脂酰肌醇-3激酶（PI3Ks）是癌症治疗中很有前景的药物靶点，但阻断PI3K-AKT信号通路会导致患者出现高血糖、高胰岛素血症和肝损伤，以及小鼠发生肝细胞癌（HCC）。PI3K有4种：PI3Kα、PI3Kβ、PI3Kδ和PI3Kγ。PI3Kγ在HCC中的作用尚不清楚。
我们使用致癌物二乙基亚硝胺（DEN）启动并由饮食或基因肥胖（ob/ob）促进HCC发生的模型，对PI3Kγ基因敲除小鼠进行了组织病理学、代谢和分子表型分析。在造血细胞和内皮细胞中缺乏PI3Kγ的小鼠中研究了PI3Kγ在白细胞中的作用。
PI3Kγ缺失对瘦小鼠DEN诱导的HCC发生没有影响。然而，在注射了DEN并给予致肥胖饮食的小鼠中，PI3Kγ基因敲除可减少肿瘤生长，这与胰岛素血症降低、脂肪变性和炎性细胞因子表达减少有关。缺乏PI3Kγ的ob/ob小鼠，以及白细胞和内皮细胞中缺乏PI3Kγ的饮食诱导肥胖小鼠，并未表现出胰岛素敏感性改善、脂肪变性、代谢炎症减轻或肿瘤生长减缓。然而，这些小鼠的肿瘤数量减少，肝脏中中性粒细胞浸润减少，DEN急性诱导的肝细胞增殖减少。
PI3Kγ缺失通过多种细胞类型和机制减少肥胖促进的HCC中的肿瘤发生，这些机制包括改善胰岛素血症、脂肪变性和代谢炎症，以及调节急性中性粒细胞浸润和代偿性肝细胞增殖。PI3Kγ选择性抑制可能代表一种减少HCC起始和减缓HCC进展的新型治疗方法。
1类磷脂酰肌醇-3激酶（PI3Ks）是癌症治疗中的关键靶点，但完全抑制所有亚型会导致肝损伤、高血糖和胰岛素血症。在此我们表明，在致癌物启动和肥胖促进的肝细胞癌（HCC）小鼠模型中，PI3Kγ亚型的选择性缺失可抑制肿瘤起始和生长。PI3Kγ缺失对肿瘤生长减少的影响可通过肿瘤细胞增殖减少来解释，这与胰岛素水平降低、肝脏脂质减少和促肿瘤细胞因子表达减少有关。肥胖小鼠白细胞中的PI3Kγ缺失对肿瘤大小没有影响。然而，它与肥胖小鼠肝脏中致癌物诱导的中性粒细胞浸润和肝细胞增殖减少相关，从而减少了肿瘤数量。因此，抑制PI3Kγ可能通过减少代谢应激和胰岛素血症以及减少致癌物诱导的中性粒细胞向脂肪肝的浸润，来减少肥胖受试者中HCC的起始和生长。
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