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Review
, 37 (1), 319

Pancreatic Cancer Associated With Obesity and Diabetes: An Alternative Approach for Its Targeting

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Review

Pancreatic Cancer Associated With Obesity and Diabetes: An Alternative Approach for Its Targeting

Ramesh Pothuraju et al. J Exp Clin Cancer Res.

Abstract

Background: Pancreatic cancer (PC) is among foremost causes of cancer related deaths worldwide due to generic symptoms, lack of effective screening strategies and resistance to chemo- and radiotherapies. The risk factors associated with PC include several metabolic disorders such as obesity, insulin resistance and type 2 diabetes mellitus (T2DM). Studies have shown that obesity and T2DM are associated with PC pathogenesis; however, their role in PC initiation and development remains obscure.

Main body: Several biochemical and physiological factors associated with obesity and/or T2DM including adipokines, inflammatory mediators, and altered microbiome are involved in PC progression and metastasis albeit by different molecular mechanisms. Deep understanding of these factors and causal relationship between factors and altered signaling pathways will facilitate deconvolution of disease complexity as well as lead to development of novel therapies. In the present review, we focuses on the interplay between adipocytokines, gut microbiota, adrenomedullin, hyaluronan, vanin and matrix metalloproteinase affected by metabolic alteration and pancreatic tumor progression.

Conclusions: Metabolic diseases, such as obesity and T2DM, contribute PC development through altered metabolic pathways. Delineating key players in oncogenic development in pancreas due to metabolic disorder could be a beneficial strategy to combat cancers associated with metabolic diseases in particular, PC.

Keywords: Adiponectin; Diabetes; Gut microbiota; Inflammation; Insulin resistance; Leptin; Obesity; Pancreatic cancer.

Conflict of interest statement

Ethics approval and consent to participate

Not applicable

Consent for publication

All authors read and approved the final manuscript.

Competing interests

SKB is one of the co-founders of Sanguine Diagnostics and Therapeutics, Inc. WMJ is Chief Scientific Officer of Sanguine Diagnostics and Therapeutics, Inc. Other authors declare no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
A schematic representation of obesity- and diabetes-associated pancreatic cancer. High fat/caloric intake results in accumulation of excess fat, which further leads to development of obesity. a. In obesity, adipose tissue releases free fatty acids (FFAs), which enter circulation and accumulate in the non-adipose tissues such as muscle, liver and pancreas that leads to insulin resistance and diabetes. b. Along with FFAs, adipokines, altered gut microbiota and inflammatory markers contribute to pancreatic cancer development through unknown mechanisms.
Fig. 2
Fig. 2
Adipocytokines mediate pancreatic cancer tumorigenesis by different signaling mechanisms. a. Adiponectin secreted from adipose tissue binds to its receptor (AdipoR) to activate AKT, MAPK and AMPK pathways, which block the apoptosis of pancreatic cancer cells. b. Similarly, leptin binding to its receptor (OBR) results in activation of the JAK2/STAT3 pathway, which leads to matrix metalloproteinase-13 activation and eventual pancreatic cancer metastasis. In addition, OBR also regulates its own expression through hypoxia inducible factor-1, resulting in cancer cell survival via an unknown mechanism. Moreover, leptin also triggers Notch receptor signaling, which results in activation of its downstream molecules (survivin and Hey2), thereby increasing cancer cell proliferation.
Fig. 3
Fig. 3
Altered gut microbiota is responsible for pancreatic cancer progression. a. High-fat diet intake alters the gut microbiota composition. Altered gut microbiota secrete lipopolysaccharides (LPS), which enters circulation by damaging intestinal tight junction proteins. Circulatory LPS then binds to the toll like receptor on immune cells to recruit MyD88 or TRIF adaptor molecules. These molecules further activate MAPK and NF-κB pathways to activate  several inflammatory cytokines, leading to cancer cell proliferation. b. Short-chain fatty acids (SCFAs) are released from resistant starch by the gut microbiota that enters the circulation. Afterward, SCFAs bind to G-protein-coupled receptors to activate the MAPK signaling pathway, triggering cancer cell proliferation.

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