دورية أكاديمية
Concurrent PEDF deficiency and Kras mutation induce invasive pancreatic cancer and adipose-rich stroma in mice.
| العنوان: | Concurrent PEDF deficiency and Kras mutation induce invasive pancreatic cancer and adipose-rich stroma in mice. |
|---|---|
| المؤلفون: | Grippo PJ; Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. p-grippo@northwestern.edu, Fitchev PS, Bentrem DJ, Melstrom LG, Dangi-Garimella S, Krantz SB, Heiferman MJ, Chung C, Adrian K, Cornwell ML, Flesche JB, Rao SM, Talamonti MS, Munshi HG, Crawford SE |
| المصدر: | Gut [Gut] 2012 Oct; Vol. 61 (10), pp. 1454-64. Date of Electronic Publication: 2012 Jan 10. |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: British Medical Assn Country of Publication: England NLM ID: 2985108R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1468-3288 (Electronic) Linking ISSN: 00175749 NLM ISO Abbreviation: Gut Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: London, British Medical Assn. |
| مواضيع طبية MeSH: | Adipocytes, White/*pathology , Biomarkers, Tumor/*deficiency , Carcinoma, Pancreatic Ductal/*metabolism , Nerve Growth Factors/*deficiency , Pancreatic Neoplasms/*metabolism , Proto-Oncogene Proteins p21(ras)/*genetics , Serpins/*deficiency, Adipocytes, White/metabolism ; Adiposity ; Animals ; Biomarkers, Tumor/metabolism ; Blotting, Western ; Carcinoma, Pancreatic Ductal/genetics ; Carcinoma, Pancreatic Ductal/pathology ; Cell Line, Tumor ; Eye Proteins ; Genetic Markers ; Humans ; Matrix Metalloproteinase 2/metabolism ; Matrix Metalloproteinase 9/metabolism ; Mice ; Mice, Knockout ; Mutation ; Neoplasm Invasiveness ; Pancreas/metabolism ; Pancreas/pathology ; Pancreatic Neoplasms/genetics ; Pancreatic Neoplasms/pathology ; Real-Time Polymerase Chain Reaction ; Stromal Cells/metabolism ; Stromal Cells/pathology |
| مستخلص: | Background and Aims: Pigment epithelium-derived factor (PEDF), a non-inhibitory SERPIN with potent antiangiogenic activity, has been recently implicated in metabolism and adipogenesis, both of which are known to influence pancreatic cancer progression. Increased pancreatic fat in human pancreatic tumour correlates with greater tumour dissemination while PEDF deficiency in mice promotes pancreatic hyperplasia and visceral obesity. Oncogenic Ras, the most common mutation in pancreatic ductal adenocarcinoma (PDAC), has similarly been shown to promote adipogenesis and premalignant lesions. Methods: In order to determine whether concurrent loss of PEDF is sufficient to promote adipogenesis and tumorigenesis in the pancreas, the authors ablated PEDF in an EL-Kras(G12D) mouse model of non-invasive cystic papillary neoplasms. Results: EL-Kras(G12D)/PEDF deficient mice developed invasive PDAC associated with enhanced matrix metalloproteinase (MMP)-2 and MMP-9 expression and increased peripancreatic fat with adipocyte hypertrophy and intrapancreatic adipocyte infiltration (pancreatic steatosis). In support of increased adipogenesis, the stroma of the pancreas of EL-Kras(G12D)/PEDF deficient mice demonstrated higher tissue levels of two lipid droplet associated proteins, tail-interacting protein 47 (TIP47, perilipin 3) and adipose differentiation-related protein (ADRP, Pperilipin 2), while adipose triglyceride lipase, a key factor in lipolysis, was decreased. In patients with PDAC, both tissue and serum levels of PEDF were decreased, stromal TIP47 expression was higher and the tissue VEGF to PEDF ratio was increased (p<0.05). Conclusions: 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. |
| معلومات مُعتمدة: | R01-CA126888 United States CA NCI NIH HHS; R01-CA64239 United States CA NCI NIH HHS |
| المشرفين على المادة: | 0 (Biomarkers, Tumor) 0 (Eye Proteins) 0 (Genetic Markers) 0 (Nerve Growth Factors) 0 (Serpins) 0 (pigment epithelium-derived factor) EC 3.4.24.24 (Matrix Metalloproteinase 2) EC 3.4.24.35 (Matrix Metalloproteinase 9) EC 3.6.5.2 (Hras protein, mouse) EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras)) |
| تواريخ الأحداث: | Date Created: 20120112 Date Completed: 20121119 Latest Revision: 20191210 |
| رمز التحديث: | 20231215 |
| DOI: | 10.1136/gutjnl-2011-300821 |
| PMID: | 22234980 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 1468-3288 |
|---|---|
| DOI: | 10.1136/gutjnl-2011-300821 |