Mechanisms of obesity-and diabetes mellitus-related pancreatic carcinogenesis:a comprehensive and systematic

Research on obesity-and diabetes mellitus(DM)-related carcinogenesis has expanded exponentially since these two diseases were recognized as important risk factors for cancers.The growing interest in this area is prominently actuated by the increasing obesity and DM prevalence,which is partially responsible for the slight but constant increase in pancreatic cancer(PC)occurrence.PC is a highly lethal malignancy characterized by its insidious symptoms,delayed diagnosis,and devastating prognosis.The intricate process of obesity and DM promoting pancreatic carcinogenesis involves their local impact on the pancreas and concurrent wholebody systemic changes that are suitable for cancer initiation.The main mechanisms involved in this process include the excessive accumulation of various nutrients and metabolites promoting carcinogenesis directly while also aggravating mutagenic and carcinogenic metabolic disorders by affecting multiple pathways.Detrimental alterations in gastrointestinal and sex hormone levels and microbiome dysfunction further compromise immunometabolic regulation and contribute to the establishment of an immunosuppressive tumor microenvironment(TME)for carcinogenesis,which can be exacerbated by several crucial pathophysiological processes and TME components,such as autophagy,endoplasmic reticulum stress,oxidative stress,epithelialmesenchymal transition,and exosome secretion.This review provides a comprehensive and critical analysis of the immunometabolic mechanisms of obesity-and DM-related pancreatic carcinogenesis and dissects how metabolic disorders impair anticancer immunity and influence pathophysiological processes to favor cancer initiation.

The evolving view of thermogenic fat and its implications in cancer and metabolic diseases

The incidence of metabolism-related diseases like obesity and type 2 diabetes mellitus has reached pandemic levels worldwide and increased gradually.Most of them are listed on the table of high-risk factors for malignancy,and metabolic disorders systematically or locally contribute to cancer progression and poor prognosis of patients.Importantly,adipose tissue is fundamental to the occurrence and development of these metabolic disorders.White adipose tissue stores excessive energy,while thermogenic fat including brown and beige adipose tissue dissipates energy to generate heat.In addition to thermogenesis,beige and brown adipocytes also function as dynamic secretory cells and a metabolic sink of nutrients,like glucose,fatty acids,and amino acids.Accordingly,strategies that activate and expand thermogenic adipose tissue offer therapeutic promise to combat overweight,diabetes,and other metabolic disorders through increasing energy expenditure and enhancing glucose tolerance.With a better understanding of its origins and biological functions and the advances in imaging techniques detecting thermogenesis,the roles of thermogenic adipose tissue in tumors have been revealed gradually.On the one hand,enhanced browning of subcutaneous fatty tissue results in weight loss and cancer-associated cachexia.On the other hand,locally activated thermogenic adipocytes in the tumor microenvironment accelerate cancer progression by offering fuel sources and is likely to develop resistance to chemotherapy.Here,we enumerate current knowledge about the significant advances made in the origin and physiological functions of thermogenic fat.In addition,we discuss the multiple roles of thermogenic adipocytes in different tumors.Ultimately,we summarize imaging technologies for identifying thermogenic adipose tissue and pharmacologic agents via modulating thermogenesis in preclinical experiments and clinical trials.

Lipid metabolism in pancreatic cancer:emerging roles and potential targets

Pancreatic cancer is one of the most serious health issues in developed and developing countries,with a 5-year overall survival rate currently<9%.Patients typically presentwith advanced disease due to vague symptoms or lack of screening for early cancer detection.Surgical resection represents the only chance for cure,but treatment options are limited for advanced diseases,such as distant metastatic or locally progressive tumors.Although adjuvant chemotherapy has improved long-term outcomes in advanced cancer patients,its response rate is low.So,exploring other new treatments is urgent.In recent years,increasing evidence has shown that lipid metabolism can support tumorigenesis and disease progression as well as treatment resistance through enhanced lipid synthesis,storage,and catabolism.Therefore,a better understanding of lipid metabolism networks may provide novel and promising strategies for early diagnosis,prognosis estimation,and targeted therapy for pancreatic cancer patients.In this review,we first enumerate and discuss current knowledge about the advances made in understanding the regulation of lipid metabolism in pancreatic cancer.In addition,we summarize preclinical studies and clinical trials with drugs targeting lipid metabolic systems in pancreatic cancer.Finally,we highlight the challenges and opportunities for targeting lipid metabolism pathways through precision therapies in pancreatic cancer.