In:
Molecular Cancer Research, American Association for Cancer Research (AACR), Vol. 12, No. 12_Supplement ( 2014-12-01), p. B16-B16
Abstract:
Patients with chronic pancreatitis are at increased risk of developing pancreatic cancer. However, the key inflammatory action mediating pancreatic tumorigenesis has not been clearly determined. Here, we initially identified evaluated levels of activated glucocorticoid receptors (GR) were observed in patients of chronic pancreatitis and pancreatic ductal adenocarcinomas (PDAC). Utilizing mice that conditionally expressed KrasG12D in acinar cell compartment with or without loss of GR, we demonstrated that activation of GR was required for generation of metaplastic ductal lesion and development of pancreatic intraepithelial neoplasia (PanIN) in mice with experimental pancreatitis. Administration of dexamethason, a potent synthetic glucocoticoid, was sufficient to induce development of advanced PanINs and metastatic PDACs in KrasG12D mice that harbour single-allele deletion of p53. We further revealed that nongenomic activation of GR was a key action that led to evaluating c-Src signaling and triggering a pathological threshold of Ras activity necessary for neoplastic transformation. In contrast, treatment of dasatinib, a Src kinase inhibitor, could suppressed development of PanIN and PDAC induced by dexamethasone. Importantly, cre-lox based lineage-tracing mice was applied and identified that GR activation directly transformed GFP-tagged KrasG12D-expressing acinar cells to tumorigenic cells that posse features of cancer initiating cells. The findings explained why chronic inflammation increase pancreatic cancer risk and raised concerns on the use of glucocorticoids on patients of chronic pancreatitis Citation Format: Chia-Ning Shen, Chien-Chang Su, Chi-Chih Hsieh, Wen-Ying Liao, Wan-Yu Mao, Chia-Rui Shen, Michael Hsiao. Activated glucocorticoid signaling in pancreatitis contributes to acinar-to-ductal metaplasia and KrasG12D-driven tumorigenesis. [abstract]. In: Proceedings of the AACR Special Conference on RAS Oncogenes: From Biology to Therapy; Feb 24-27, 2014; Lake Buena Vista, FL. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(12 Suppl):Abstract nr B16. doi: 10.1158/1557-3125.RASONC14-B16
Type of Medium:
Online Resource
ISSN:
1541-7786
,
1557-3125
DOI:
10.1158/1557-3125.RASONC14-B16
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2014
detail.hit.zdb_id:
2097884-4
SSG:
12
Permalink