5 years ago

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

Pengfei Lin, Yang Gao, John P Lydon, Qinglei Li
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. This mouse model may be valuable for preclinical testing of new cancer therapies, particularly those targeting metastasis, one of the hallmarks of cancer and a major cause of death in endometrial cancer patients. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1002/path.4930

You might also like
Discover & Discuss Important Research

Keeping up-to-date with research can feel impossible, with papers being published faster than you'll ever be able to read them. That's where Researcher comes in: we're simplifying discovery and making important discussions happen. With over 19,000 sources, including peer-reviewed journals, preprints, blogs, universities, podcasts and Live events across 10 research areas, you'll never miss what's important to you. It's like social media, but better. Oh, and we should mention - it's free.

  • Download from Google Play
  • Download from App Store
  • Download from AppInChina

Researcher displays publicly available abstracts and doesn’t host any full article content. If the content is open access, we will direct clicks from the abstracts to the publisher website and display the PDF copy on our platform. Clicks to view the full text will be directed to the publisher website, where only users with subscriptions or access through their institution are able to view the full article.