Concurrent PEDF deficiency and Kras mutation induce invasive pancreatic cancer and adipose-rich stroma in mice

Grippo, Paul J.; Fitchev, Philip; Bentrem, David J.; Melstrom, Laleh G.; Dangi-Garimella, Surabhi; Krantz, Seth B.; Heiferman, Michael J.; Chung, Chuhan; Adrian, Kevin; Cornwell, Mona; Flesche, Jan; Rao, Sambasiva; Talamonti, Mark S.; Munshi, Hidayatullah G.; Crawford, Susan E.

doi:10.1136/gutjnl-2011-300821

Cited by 64 publications

(77 citation statements)

References 47 publications

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“…Pancreatic tumors from older, obese patients are marked by the presence of adipocytes and these patients have worse outcomes [64–66]. Based on the observation that pancreatic cancers depend on glutamine metabolism for survival [67, 68], conditioned media from preadipocytes were also found to contain glutamine, which supported pancreatic cancer cell proliferation in glutamine-free growth media [69] (Fig.…”

Section: Intra-tumoral Metabolic Crosstalkmentioning

confidence: 99%

Metabolic Interactions in the Tumor Microenvironment

Lyssiotis

Kimmelman

2017

Trends in Cell Biology

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Tumors are dynamic pseudo-organs that contain numerous cell types interacting to create unique physiology. Within this network, the malignant cells encounter many challenges and rewire their metabolic properties accordingly. Such changes can be experienced and executed autonomously or through interaction with other cells in the tumor. The focus of this review is on the remodeling of the tumor microenvironment that leads to pathophysiologic interactions that are influenced and shaped by metabolism. They include symbiotic nutrient sharing, nutrient competition, and the role of metabolites as signaling molecules. Examples of such processes abound in normal organismal physiology, and such heterocelluar metabolic interactions are repurposed to support tumor metabolism and growth. The importance and ubiquity of these processes is just beginning to be realized, and insights into their role in tumor development and progression are being used to design new drug targets and cancer therapies.

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Section: Intra-tumoral Metabolic Crosstalkmentioning

confidence: 99%

Metabolic Interactions in the Tumor Microenvironment

Lyssiotis

Kimmelman

2017

Trends in Cell Biology

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“…The expression levels of lipid droplet-associated proteins, tail-interacting protein 47 (TIP47), and adipose differentiation-related protein (ADRP) were increased, while the expression of adipose triglyceride lipase, a key enzyme in lipolysis, was decreased in the pancreatic stroma of EL-Kras G12D /PEDF-deficient mice. Compared with the EL-Kras G12D /PEDF wild-type mice, ELKras G12D /PEDF-null mice had higher frequencies of cystic papillary neoplasms and invasive pancreatic ductal adenocarcinoma (11). Their study shed the light on the mechanism of intrapancreatic fatty infiltration.…”

mentioning

confidence: 99%

“…However, the mechanism of intrapancreatic fatty infiltration in obese patients remains to be determined. A recent study by Grippo and colleagues (11) showed that knockout of pigment epithelium-derived factor (PEDF) in ELKras G12D mice resulted in increased intrapancreatic fatty infiltration and peripancreatic fat with adipocyte hypertrophy. The expression levels of lipid droplet-associated proteins, tail-interacting protein 47 (TIP47), and adipose differentiation-related protein (ADRP) were increased, while the expression of adipose triglyceride lipase, a key enzyme in lipolysis, was decreased in the pancreatic stroma of EL-Kras G12D /PEDF-deficient mice.…”

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confidence: 99%

Obesity, Intrapancreatic Fatty Infiltration, and Pancreatic Cancer

Wang

Maitra

2015

Clinical Cancer Research

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Obesity and intrapancreatic fatty infiltration are associated with increased risk of pancreatic cancer and its precursor lesions. The interplay among obesity, inflammation, and oncogenic Kras signaling promotes pancreatic tumorigenesis. Targeting the interaction between obesity-associated inflammation and Kras signaling may provide new strategies for prevention and therapy of pancreatic cancer. Clin Cancer Res; 21(15); 3369-71. Ó2015 AACR.See related article by Rebours et al., p. 3522 In this issue of Clinical Cancer Research, Rebours and colleagues (1) report that fatty infiltration in normal pancreas is associated with the body mass index (BMI), and the percentages of total fat area, visceral fat area, and subcutaneous fat area (SFA) in 110 patients who underwent pancreatic resection for well-differentiated pancreatic neuroendocrine tumors. They demonstrate that intralobular fibrosis and intralobular fatty infiltration of the pancreas are independently associated the presence of pancreatic intraepithelial neoplasia (PanIN), the precursor lesions of pancreatic ductal adenocarcinoma. The number of PanIN lesions increases with the severity of hepatic steatosis and the percentage of intrapancreatic fatty infiltration, but not with the percentage of SFA or BMI (1). This study provides a direct link between obesity, intrapancreatic fatty infiltration, and the risk of pancreatic cancer precursor lesions. Consistent with the findings from this study, prior reports have similarly underscored the deleterious association between intrapancreatic fatty infiltration with the increased risk of pancreatic ductal carcinoma (2). The association between obesity and the increased risk of pancreatic cancer has been well documented by both epidemiologic and experimental studies. In a large case-control study by Silverman and colleagues (3), obesity was associated with 50% to 60% increased risk of pancreatic cancer in both men and women. Compared with the group with the lowest quartile of BMI and caloric intake, the group with the highest quartile of BMI and caloric intake had a 180% higher risk of pancreatic cancer (3). In a pooled analysis of 2,170 cases and 2,209 control subjects from the Pancreatic Cancer Cohort Consortium (PanScan), the adjusted odds ratio (OR) for pancreatic cancer for the highest versus lowest quartile of BMI was 1.33[95% confidence interval (CI), 1.04-1.69] and 1.34 (95% CI, 1.05-1.70) in men and women, respectively (4). Overweight or obesity during early adulthood was associated not only with an increased risk of pancreatic cancer but also with the early onset of disease. In patients with pancreatic cancer, obesity was associated with poor survival (5). High-fat diet (HFD) has been shown to promote the growth and tumor cell turnover of human pancreatic cancer cells in an orthotopic xenograft study (6). These studies provided strong evidence that the obesity, particularly android obesity, and intrapancreatic fatty infiltration are associated with increased risk of pancreatic cancer and play an important r...

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“…The interactions between MMP-2 and PEDF were further demonstrated in a more recent study by [43] which identified that PEDF-deficient mice models with pancreatic tumours displayed increased levels of the proteins MMP-2 and/or MMP-9. Therefore, these findings indicate an inverse correlation between PEDF and MMP-2 during hypoxia and pancreatic cancer, which we hypothesize to occur via MT1-MMP and its activation of MMP-2, though further studies are warranted to confirm this hypothesis.…”

Section: The Regulatory Interactions Between Pedf Mt1-mmp and Mmp-2mentioning

confidence: 97%

Regulation of MT1-MMP and MMP-2 by the Serpin PEDF: a Promising New Target for Metastatic Cancer

Alcantara¹,

Dass²

2013

Cell Physiol Biochem

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The balance of endogenous angiogenic factors in the body is responsible for the homeostatic control of angiogenesis during normal physiological circumstances, with the disruption of this fragile balance leading to pathologic angiogenic events such as those involved in cancer progression. This review focuses regulation of the pro-angiogenic factors membrane type-1 matrix metalloproteinase (MT1-MMP) and matrix metalloproteinase-2 (MMP-2) by the anti-angiogenic factor pigment epithelium-derived factor (PEDF) in the contexts of angiogenesis, cancer cell proliferation and metastasis. Understanding the role of PEDF in the regulation of MT1-MMP and MMP-2 as it pertains to cancer control is important in order to understand whether and how such associations provide a novel target for cancer therapy.

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Concurrent PEDF deficiency and Kras mutation induce invasive pancreatic cancer and adipose-rich stroma in mice

Abstract: These data highlight the importance of lipid metabolism in the tumour microenvironment and identify PEDF as a critical negative regulator of both adiposity and tumour invasion in the pancreas.

Cited by 64 publications

References 47 publications

Metabolic Interactions in the Tumor Microenvironment

Metabolic Interactions in the Tumor Microenvironment

Obesity, Intrapancreatic Fatty Infiltration, and Pancreatic Cancer

Regulation of MT1-MMP and MMP-2 by the Serpin PEDF: a Promising New Target for Metastatic Cancer

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