Tgfbr1 Haploinsufficiency Inhibits the Development of Murine Mutant Kras-Induced Pancreatic Precancer

Kevin Adrian,Eric C Cheon,Yanfei Xu,Sharbani Phukan,Akilesh Honasoge,Qinghua Zeng,Matthew J Strouch,Morgan R Barron,David J Bentrem,Maureen Sadim,Paul J Grippo,Boris Pasche

doi:10.1158/0008-5472.can-09-1705

Abstract

To dissect the role of constitutively altered Tgfbr1 signaling in pancreatic cancer development, we crossed Elastase-Kras(G12D) (EL-Kras) mice with Tgfbr1 haploinsufficient mice to generate EL-Kras/Tgfbr1(+/-) mice. Mice were euthanized at 6 to 9 months to compare the incidence, frequency, and size of precancerous lesions in the pancreas. Only 50% of all EL-Kras/Tgfbr1(+/-) mice developed preinvasive lesions compared with 100% of EL-Kras (wild-type Tgfbr1) mice. The frequency of precancerous lesions was 4-fold lower in haploinsufficient than in control mice. Paradoxically, the precancerous lesions of EL-Kras/Tgfbr1(+/-) mice were considerably larger than those in EL-Kras mice. Yet, the mitotic index of precancerous cells and the observable levels of fibrosis, lipoatrophy, and lymphocytic infiltration were reduced in EL-Kras/Tgfbr1(+/-) mice. We conclude that Tgfbr1 signaling promotes the development of precancerous lesions in mice. These findings suggest that individuals with constitutively decreased TGFBR1 expression may have a decreased risk of pancreatic cancer.

Highlights

Transforming growth factor-β (TGF-β) signaling plays dual roles in the etiology of pancreatic cancer (PC)
More information is available regarding the role of SMAD4, in which its loss occurs in about half of all PC [11] with reduced survival following surgery [3] and, in combination with mutant Kras expression, promotes PC in mice [4, 6]
The role of decreased TGFBR1 expression during the early stages of PC development is essentially unknown. In this in vivo study, we examined the role of constitutively decreased Tgfbr1 signaling on mutant Kras-induced precancer

Summary

Introduction

Transforming growth factor-β (TGF-β) signaling plays dual roles in the etiology of pancreatic cancer (PC). Our results show that EL-Kras/Tgfbr heterozygous null mice have a significantly reduced propensity of developing carcinoma in situ, lesions that do form are larger and more advanced This paradoxical response may be explained by the fact that loss of certain TGFBR1 function can inhibit the aggressive nature of cultured PC cells while suppressing tumor growth in vivo [8]. These findings highlight the central role of TGFBR1 and underscore the dichotomous nature of TGF-β signals with respect to pancreatic precancer development

Materials and Methods

Results

Discussion