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In vivo regulation of TGF-? by R-Ras2 revealed through loss of the RasGAP protein NF1.

ABSTRACT: Ras superfamily proteins participate in TGF-?-mediated developmental pathways that promote either tumor suppression or progression. However, the specific Ras proteins, which integrate in vivo with TGF-? signaling pathways, are unknown. As a general approach to this question, we activated all Ras proteins in vivo by genetic deletion of the RasGAP protein Nf1 and examined mice doubly deficient in a Ras protein to determine its requirement in formation of TGF-?-dependent neurofibromas that arise in Nf1-deficient mice. Animals lacking Nf1 and the Ras-related protein R-Ras2/TC21 displayed a delay in formation of neurofibromas but an acceleration in formation of brain tumors and sarcomas. Loss of R-Ras2 was associated with elevated expression of TGF-? in Nf1-deficient Schwann cell precursors, blockade of a Nf1/TGF?RII/AKT-dependent autocrine survival loop in tumor precursor cells, and decreased precursor cell numbers. Furthermore, the increase in size of sarcomas from xenografts doubly deficient in these genes was also found to be TGF-?-dependent, in this case resulting from cell nonautonomous effects on endothelial cells and myofibroblasts. Extending these findings in clinical specimens, we documented an increase in TGF-? ligands and an absence of TGF-? receptor II in malignant peripheral nerve sheath tumors, which correspond to tumors in the Nf1-deficient mouse model. Together, our findings reveal R-Ras2 as a critical regulator of TGF-? signaling in vivo.

SUBMITTER: Patmore DM

PROVIDER: S-EPMC4227504 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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In vivo regulation of TGF-β by R-Ras2 revealed through loss of the RasGAP protein NF1.

Patmore Deanna M DM Welch Sara S Fulkerson Patricia C PC Wu Jianqiang J Choi Kwangmin K Eaves David D Kordich Jennifer J JJ Collins Margaret H MH Cripe Timothy P TP Ratner Nancy N

Cancer research 20120823 20

Ras superfamily proteins participate in TGF-β-mediated developmental pathways that promote either tumor suppression or progression. However, the specific Ras proteins, which integrate in vivo with TGF-β signaling pathways, are unknown. As a general approach to this question, we activated all Ras proteins in vivo by genetic deletion of the RasGAP protein Nf1 and examined mice doubly deficient in a Ras protein to determine its requirement in formation of TGF-β-dependent neurofibromas that arise in ...[more]

PMID: 22918885

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Project description:Castration experiments in rodents show that the stromal vasculature is critical to the androgen-mediated prostate growth regulation. However, the role of angiogenesis inhibitors, such as thrombospondin-1 (TSP-1), in this process is unclear. TSP-1 is a multifunctional glycoprotein that can function as a potent angiogenesis inhibitor and an in vivo activator of latent transforming growth factor-beta (TGF-beta) in some tissues. On the basis of these observations, we hypothesized that TSP-1 regulated androgen withdrawal-induced prostate regression and that this process was mediated not only through antiangiogenic activity but also through TGF-beta activation. To test this, we evaluated angiogenic activity in human prostate epithelial and stromal cells treated with androgens and hypoxia in vitro. TSP-1 knockout mice were characterized to investigate the in vivo functions of TSP-1. In vitro, we found that androgens and hypoxia differentially regulated TSP-1 and angiogenic activity. Androgens stimulated normal epithelial cell, but inhibited normal stromal cell, angiogenic activity. Conversely, hypoxia stimulated stromal while inhibiting epithelial activity. Thus, in vivo, net angiogenic activity must reflect cellular interactions. And, we found that media conditioned by epithelial cells grown under normoxic conditions stimulated stromal cell angiogenic activity, and if epithelial cells were grown under hypoxic conditions, stromal activity was further increased. TSP-1 levels, however, were unchanged. In vivo, TSP-1 loss in a mouse model led to prostate epithelial hyperplasia by 3 months of age with only a modest stromal effect. Androgens suppressed TSP-1 as expression increased after castration both in normal mouse prostate and in human prostate cancer tissues. In addition, TSP-1 expression corresponded to increased TGF-beta activation in mouse tissues, specifically in the stromal compartment. These data show a critical role for TSP-1 in prostate epithelial and stromal growth regulation through angiogenic inhibition and activation of latent TGF-beta. Therefore, loss of TSP-1 during tumorigenesis would eliminate two barriers to cancer progression.

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In vivo regulation of TGF-? by R-Ras2 revealed through loss of the RasGAP protein NF1.

Publications

In vivo regulation of TGF-β by R-Ras2 revealed through loss of the RasGAP protein NF1.

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