Endogenous Hyperinsulinemia Contributes to Pancreatic Cancer Development

Zhang, Anni; Magrill, Jamie; Winter, Twan J. J. de; Hu, Xiaoke; Skovsø, Søs; Schaeffer, David F.; Kopp, Janel L.; Johnson, James D.

doi:10.1016/j.cmet.2019.07.003

Cited by 57 publications

(99 citation statements)

References 13 publications

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“…While insulin secretion was not measured in our study, hyperinsulinemia is a well-known risk factor for pancreatic cancer ( Andersen et al., 2017 ). Identifying the causative direction of this association is problematic; however, genetic reduction in insulin secretion capacity in the Kras G12D mouse model results in a slowing of pancreatic cancer initiation ( Zhang et al., 2019 ). Together with the efficacy of phosphatidylinositol 3-kinase (PI3K) inhibitors, suppressing insulin signaling, in pre-clinical models of pancreatic cancer ( Hopkins et al., 2018 ), this suggests that increased insulin secretion may be a primary mechanism by which obesity and dietary glucose influences pancreatic cancer.…”

Section: Discussionmentioning

confidence: 99%

Heterogeneous Effects of Calorie Content and Nutritional Components Underlie Dietary Influence on Pancreatic Cancer Susceptibility

Dooley¹,

Lagou²,

Goveia³

et al. 2020

Cell Reports

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Summary Pancreatic cancer is a rare but fatal form of cancer, the fourth highest in absolute mortality. Known risk factors include obesity, diet, and type 2 diabetes; however, the low incidence rate and interconnection of these factors confound the isolation of individual effects. Here, we use epidemiological analysis of prospective human cohorts and parallel tracking of pancreatic cancer in mice to dissect the effects of obesity, diet, and diabetes on pancreatic cancer. Through longitudinal monitoring and multi-omics analysis in mice, we found distinct effects of protein, sugar, and fat dietary components, with dietary sugars increasing Mad2l1 expression and tumor proliferation. Using epidemiological approaches in humans, we find that dietary sugars give a MAD2L1 genotype-dependent increased susceptibility to pancreatic cancer. The translation of these results to a clinical setting could aid in the identification of the at-risk population for screening and potentially harness dietary modification as a therapeutic measure.

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Section: Discussionmentioning

confidence: 99%

Heterogeneous Effects of Calorie Content and Nutritional Components Underlie Dietary Influence on Pancreatic Cancer Susceptibility

Dooley¹,

Lagou²,

Goveia³

et al. 2020

Cell Reports

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“…Given these islet adaptations, we postulated that enhanced insulin secretion may promote local pancreatic tumorigenesis in obese mice. Although aberrant insulin signaling is commonly proposed as a mechanism by which obesity drives tumorigenesis, direct in vivo evidence, especially in PDAC, is limited Zhang et al, 2019). As expected, ob/ob mice exhibited systemic hyperinsulinemia with increased fasting serum insulin (Figure S4A).…”

Section: Pancreatic Islet Cell Adaptations In Tumors Of Obese Micementioning

confidence: 55%

“…Apart from insulin Zhang et al, 2019), evidence for a protumorigenic role of pancreatic islet hormones in cancer development has been lacking until now.…”

Section: Discussionmentioning

confidence: 99%

Endocrine-exocrine signaling drives obesity-associated pancreatic ductal adenocarcinoma

Chung¹,

Singh

Lawres

et al. 2019

Preprint

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SUMMARYObesity is a major modifiable risk factor for pancreatic ductal adenocarcinoma (PDAC), yet how and when obesity contributes to PDAC progression is not well understood. Leveraging an autochthonous mouse model, we demonstrate a causal and reversible role for obesity in early PDAC progression, showing that obesity markedly enhances tumorigenesis, while genetic or dietary induction of weight loss intercepts cancer development. Bulk and single cell molecular analyses of human and murine samples define microenvironmental consequences of obesity that promote tumor development rather than new driver gene mutations. We observe increased inflammation and fibrosis and also provide evidence for significant pancreatic islet cell adaptation in obesity-associated tumors. Specifically, we identify aberrant islet beta cell expression of the peptide hormone cholecystokinin (CCK) in tumors as an adaptive response to obesity. Furthermore, beta cell CCK expression promotes oncogenic Kras-driven pancreatic ductal tumorigenesis. Our studies argue that PDAC progression is driven by local obesity-associated changes in the tumor microenvironment – rather than systemic effects – and implicate endocrine-exocrine signaling beyond insulin in PDAC development. Furthermore, our demonstration that these obesity-associated adaptations are reversible supports the use of anti-obesity strategies to intercept PDAC early during progression.

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“…As for the related hormones insulin-like growth factors 1 and 2 (IGF-I and IGF-II), intermittent fasting and protein-restriction, but not calorie restriction, were shown to reduce IGF-I levels [83]. Importantly, high levels of fasting blood insulin have been associated with increased risk of cancer in general [84], and more precisely, of breast [85], pancreas [86], and prostate [87,88] cancers. For colorectal carcinoma, there is conflicting evidence; while some studies detected increased risk of CRC in patients with high fasting blood insulin [89], other studies failed to detect this association [90][91][92].…”

Section: Fundamental Metabolic and Systemic Adaptations Induced By Enmentioning

confidence: 99%

Energy Restriction and Colorectal Cancer: A Call for Additional Research

et al. 2020

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Colorectal cancer has the second highest cancer-related mortality rate, with an estimated 881,000 deaths worldwide in 2018. The urgent need to reduce the incidence and mortality rate requires innovative strategies to improve prevention, early diagnosis, prognostic biomarkers, and treatment effectiveness. Caloric restriction (CR) is known as the most robust nutritional intervention that extends lifespan and delays the progression of age-related diseases, with remarkable results for cancer protection. Other forms of energy restriction, such as periodic fasting, intermittent fasting, or fasting-mimicking diets, with or without reduction of total calorie intake, recapitulate the effects of chronic CR and confer a wide range of beneficial effects towards health and survival, including anti-cancer properties. In this review, the known molecular, cellular, and organismal effects of energy restriction in oncology will be discussed. Energy-restriction-based strategies implemented in colorectal models and clinical trials will be also revised. While energy restriction constitutes a promising intervention for the prevention and treatment of several malignant neoplasms, further investigations are essential to dissect the interplay between fundamental aspects of energy intake, such as feeding patterns, fasting length, or diet composition, with all of them influencing health and disease or cancer effects. Currently, effectiveness, safety, and practicability of different forms of fasting to fight cancer, particularly colorectal cancer, should still be contemplated with caution.

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Endogenous Hyperinsulinemia Contributes to Pancreatic Cancer Development

Cited by 57 publications

References 13 publications

Heterogeneous Effects of Calorie Content and Nutritional Components Underlie Dietary Influence on Pancreatic Cancer Susceptibility

Heterogeneous Effects of Calorie Content and Nutritional Components Underlie Dietary Influence on Pancreatic Cancer Susceptibility

Endocrine-exocrine signaling drives obesity-associated pancreatic ductal adenocarcinoma

Energy Restriction and Colorectal Cancer: A Call for Additional Research

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