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Title: In vitro model of metastasis to bone marrow mediates prostate cancer castration resistant growth through paracrine and extracellular matrix factors
Authors: Lescarbeau, R.M.Seib, F.P.Prewitz, M.Werner, C.Kaplan, D.L.
Publishers Version: https://doi.org/10.1371/journal.pone.0040372
Issue Date: 2012
Published in: PLoS ONE Vol. 7 (2012), No. 8
Publisher: San Francisco, CA : Public Library of Science
Abstract: The spread of prostate cancer cells to the bone marrow microenvironment and castration resistant growth are key steps in disease progression and significant sources of morbidity. However, the biological significance of mesenchymal stem cells (MSCs) and bone marrow derived extracellular matrix (BM-ECM) in this process is not fully understood. We therefore established an in vitro engineered bone marrow tissue model that incorporates hMSCs and BM-ECM to facilitate mechanistic studies of prostate cancer cell survival in androgen-depleted media in response to paracrine factors and BM-ECM. hMSC-derived paracrine factors increased LNCaP cell survival, which was in part attributed to IGFR and IL6 signaling. In addition, BM-ECM increased LNCaP and MDA-PCa-2b cell survival in androgen-depleted conditions, and induced chemoresistance and morphological changes in LNCaPs. To determine the effect of BM-ECM on cell signaling, the phosphorylation status of 46 kinases was examined. Increases in the phosphorylation of MAPK pathway-related proteins as well as sustained Akt phosphorylation were observed in BM-ECM cultures when compared to cultures grown on plasma-treated polystyrene. Blocking MEK1/2 or the PI3K pathway led to a significant reduction in LNCaP survival when cultured on BM-ECM in androgen-depleted conditions. The clinical relevance of these observations was determined by analyzing Erk phosphorylation in human bone metastatic prostate cancer versus non-metastatic prostate cancer, and increased phosphorylation was seen in the metastatic samples. Here we describe an engineered bone marrow model that mimics many features observed in patients and provides a platform for mechanistic in vitro studies.
Keywords: interleukin 6; mitogen activated protein kinase; phosphatidylinositol 3 kinase; scleroprotein; vitronectin receptor; article; bone marrow; bone marrow metastasis; cancer cell; cancer growth; cell adhesion; cell differentiation; cell survival; cell viability; controlled study; extracellular matrix; human; human cell; immunohistochemistry; mesenchymal stem cell; osteoblast; prostate cancer; protein expression; protein phosphorylation; protein secretion; Androgens; Apoptosis; Bone Marrow Neoplasms; Cell Line, Tumor; Cell Survival; Extracellular Matrix; Humans; Male; MAP Kinase Signaling System; Mesenchymal Stromal Cells; Models, Biological; Neoplasm Metastasis; Paracrine Communication; Phosphorylation; Prostatic Neoplasms
DDC: 610
License: CC BY 3.0 Unported
Link to License: https://creativecommons.org/licenses/by/3.0/
Appears in Collections:Medizin



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