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Pro-tumorigenic effects of transforming growth factor beta 1 in canine osteosarcoma.

ABSTRACT: Transforming growth factor beta 1 (TGF?1) is a pleiotropic cytokine that contributes to reparative skeletal remodeling by inducing osteoblast proliferation, migration, and angiogenesis. Organic bone matrix is the largest bodily reservoir for latent TGF?1, and active osteoblasts express cognate receptors for TGF?1 (TGF?RI and TGF?RII). During malignant osteolysis, TGF?1 is liberated from eroded bone matrix and promotes local progression of osteotropic solid tumors by its mitogenic and prosurvival activities.Canine osteosarcoma (OS) cells will possess TGF?1 signaling machinery. Blockade of TGF?1 signaling will attenuate pro-tumorigenic activities in OS cells. Naturally occurring primary OS samples will express cognate TGF?1 receptors; and in dogs with OS, focal malignant osteolysis will contribute to circulating TGF?1 concentrations.Thirty-three dogs with appendicular OS.Expression of TGF?1 and its cognate receptors, as well as the biologic effects of TGF?1 blockade, was characterized in OS cells. Ten spontaneous OS samples were characterized for TGF?RI/II expressions by immunohistochemistry. In 33 dogs with OS, plasma TGF?1 concentrations were quantified and correlated with bone resorption.Canine OS cells secrete TGF?1, express cognate receptors, and TGF?1 signaling blockade decreases proliferation, migration, and vascular endothelial growth factor secretion. Naturally occurring OS samples abundantly and uniformly express TGF?RI/II, and in OS-bearing dogs, circulating TGF?1 concentrations correlate with urine N-telopeptide excretion.Canine OS cells possess TGF?1 signaling machinery, potentially allowing for the establishment of an autocrine and paracrine pro-tumorigenic signaling loop. As such, TGF?1 inhibitors might impede localized OS progression in dogs.

SUBMITTER: Portela RF

PROVIDER: S-EPMC4895458 | biostudies-literature | 2014 May-Jun

REPOSITORIES: biostudies-literature

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Pro-tumorigenic effects of transforming growth factor beta 1 in canine osteosarcoma.

Portela R F RF Fadl-Alla B A BA Pondenis H C HC Byrum M L ML Garrett L D LD Wycislo K L KL Borst L B LB Fan T M TM

Journal of veterinary internal medicine 20140331 3

<h4>Background</h4>Transforming growth factor beta 1 (TGFβ1) is a pleiotropic cytokine that contributes to reparative skeletal remodeling by inducing osteoblast proliferation, migration, and angiogenesis. Organic bone matrix is the largest bodily reservoir for latent TGFβ1, and active osteoblasts express cognate receptors for TGFβ1 (TGFβRI and TGFβRII). During malignant osteolysis, TGFβ1 is liberated from eroded bone matrix and promotes local progression of osteotropic solid tumors by its mitoge ...[more]

PMID: 24684686

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Project description:Uncontrolled Transforming growth factor-beta (TGFβ) signaling promotes aggressive metastatic properties in late-stage breast cancers. However, how TGFβ-mediated cues are directed to induce late-stage tumorigenic events is poorly understood, particularly given that TGFβ has clear tumor suppressing activity in other contexts. Here we demonstrate that the transcriptional regulators TAZ and YAP (TAZ/YAP), key effectors of the Hippo pathway, are necessary to promote and maintain TGFβ-induced tumorigenic phenotypes in breast cancer cells. Interactions between TAZ/YAP, TGFβ-activated SMAD2/3, and TEAD transcription factors reveal convergent roles for these factors in the nucleus. Genome-wide expression analyses indicate that TAZ/YAP, TEADs and TGFβ-induced signals coordinate a specific pro-tumorigenic transcriptional program. Importantly, genes cooperatively regulated by TAZ/YAP, TEAD, and TGFβ, such as the novel targets NEGR1 and UCA1, are necessary for maintaining tumorigenic activity in metastatic breast cancer cells. Nuclear TAZ/YAP also cooperate with TGFβ signaling to promote phenotypic and transcriptional changes in non-tumorigenic cells to overcome TGFβ repressive effects. Our work thus identifies crosstalk between nuclear TAZ/YAP and TGFβ signaling in breast cancer cells, revealing novel insight into late-stage disease-driving mechanisms. Expression profiling was conducted following the repression of the transcriptional regulators TAZ and YAP (TAZ/YAP), the TEAD family of transcription factors (TEAD1/2/3/4), or the TGFb signaling pathway (with SB-431542, an inhibitor of the TBRI recpeptor) in human MDA-MB-231-LM2 breast cancer cells treated with TGFβ1. Human MDA-MB-231-LM2-4 breast cancer cells were transfected with control siRNA, or siRNAs targeting TAZ/YAP or all four TEADs and were treated 24 hours later with 500pM TGFβ1 or 5mM SB-431542 for an additional 24 hours. Total RNA was isolated and twelve microarrays in total were performed, with each condition carried out three times on separate days. The Boston University Microarray Core generated the data using the Affymetrix Human Gene 1.0 St Array.

Dataset Information

Pro-tumorigenic effects of transforming growth factor beta 1 in canine osteosarcoma.

Publications

Pro-tumorigenic effects of transforming growth factor beta 1 in canine osteosarcoma.

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