Conditional abrogation of transforming growth factor ‐β receptor 1 in PTEN‐inactivated endometrium promotes endometrial cancer progression in mice

Abstract Although a putative role for transforming growth factor‐β (TGFB) signalling in the pathogenesis of human endometrial cancer has long been proposed, the precise function of TGFB signalling in the development and progression of endometrial cancer remains elusive. Depletion of phosphatase and tensin homologue (PTEN) in the mouse uterus causes endometrial cancer. To identify the potential role of TGFB signalling in endometrial cancer, we simultaneously deleted TGFB receptor 1 (Tgfbr1) and Pten in the mouse uterus by using Cre‐recombinase driven by the progesterone receptor (termed Ptend/d;Tgfbr1d/d). We found that Ptend/d;Tgfbr1d/d mice developed severe endometrial lesions that progressed more rapidly than those resulting from conditional deletion of Pten alone, suggesting that TGFB signalling synergizes with PTEN to suppress endometrial cancer progression. Remarkably, Ptend/d;Tgfbr1d/d mice developed distant pulmonary metastases, leading to a significantly reduced lifespan. The development of metastasis and accelerated tumour progression in Ptend/d;Tgfbr1d/d mice are associated with increased production of proinflammatory chemokines, enhanced cancer cell motility, as shown by myometrial invasion and disruption, and an altered tumour microenvironment characterized by recruitment of tumour‐associated macrophages. Thus, conditional deletion of Tgfbr1 in PTEN‐inactivated endometrium leads to a disease that recapitulates invasive and lethal human endometrial cancer....
Source: The Journal of Pathology - Category: Pathology Authors: Tags: Original Paper Source Type: research