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Expression profiling of stroma cells from prostate cancer co-cultures, with or without TGF-beta signaling

ABSTRACT: Prostate stroma-specific TGF-beta signaling induces morphological changes in LNCaP cells. We have previously shown that stromal TGF-beta signaling regulates prostate tumor growth. To further delineate the underlying mechanisms, we generated LNCaP cells overexpressing an HA-tagged constitutively activate TGF-beta1 ligand (LNCaP-HA-TGF-β1(a)) and control LNCaP cells (LNCaP-Ctrl), and performed in vitro co-cultures of LNCaP-HA-TGF-β1(a) and LNCaP-Ctrl cells on top of the confluent HPS-19I cells, a human prostate stromal cell line. Since LNCaP cells are defective in TGF-beta receptor I (TbetaRI / ALK-5) that is essential for mediating TGF-beta signaling, only HPS19I cells are able to respond to TGF-beta ligand in these co-cultures. This provides a unique opportunity to study how prostate stromal cell-specific TGF-beta signaling regulates PCa biology. To identify the prostate epithelia-specific gene that was regulated by prostate stromal TGF-beta signaling, we also treated HPS19I cells using conditioned media collected from LNCaP- HA-TGF-β1(a) cells and LNCaP-Ctrl cells cultured in RPMI1640 supplemented with 0.2% FBS. After 6 days of treatment, we extracted total RNA from these HPS19I cells and performed microarray.

ORGANISM(S): Homo sapiens

PROVIDER: GSE51622 | GEO | 2014/11/12

SECONDARY ACCESSION(S): PRJNA224106

REPOSITORIES: GEO

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Project description:Venkatraman2012 - Interplay between PLS and TSP1 in TGF-β1 activation The interplay between PLS (Plasmin) and TSP1 (Thrombospondin-1) in TGF-β1 (Transforming growth factor-β1)is shown using mathematical modelling and in vitro experimentents. This model is described in the article: Plasmin triggers a switch-like decrease in thrombospondin-dependent activation of TGF-β1. Venkatraman L, Chia SM, Narmada BC, White JK, Bhowmick SS, Forbes Dewey C Jr, So PT, Tucker-Kellogg L, Yu H. Biophys J. 2012 Sep 5;103(5):1060-8. Abstract: Transforming growth factor-β1 (TGF-β1) is a potent regulator of extracellular matrix production, wound healing, differentiation, and immune response, and is implicated in the progression of fibrotic diseases and cancer. Extracellular activation of TGF-β1 from its latent form provides spatiotemporal control over TGF-β1 signaling, but the current understanding of TGF-β1 activation does not emphasize cross talk between activators. Plasmin (PLS) and thrombospondin-1 (TSP1) have been studied individually as activators of TGF-β1, and in this work we used a systems-level approach with mathematical modeling and in vitro experiments to study the interplay between PLS and TSP1 in TGF-β1 activation. Simulations and steady-state analysis predicted a switch-like bistable transition between two levels of active TGF-β1, with an inverse correlation between PLS and TSP1. In particular, the model predicted that increasing PLS breaks a TSP1-TGF-β1 positive feedback loop and causes an unexpected net decrease in TGF-β1 activation. To test these predictions in vitro, we treated rat hepatocytes and hepatic stellate cells with PLS, which caused proteolytic cleavage of TSP1 and decreased activation of TGF-β1. The TGF-β1 activation levels showed a cooperative dose response, and a test of hysteresis in the cocultured cells validated that TGF-β1 activation is bistable. We conclude that switch-like behavior arises from natural competition between two distinct modes of TGF-β1 activation: a TSP1-mediated mode of high activation and a PLS-mediated mode of low activation. This switch suggests an explanation for the unexpected effects of the plasminogen activation system on TGF-β1 in fibrotic diseases in vivo, as well as novel prognostic and therapeutic approaches for diseases with TGF-β dysregulation. This model is hosted on BioModels Database and identified by: MODEL1303130000 . To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models . To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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Expression profiling of stroma cells from prostate cancer co-cultures, with or without TGF-beta signaling

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