Osteoblasts in prostate cancer metastasis to bone. [Review] [83 refs]
Department of Genitourinary Oncology, University of Texas, M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.Nature reviews. Cancer (Impact Factor: 37.4). 02/2005; 5(1):21-8. DOI: 10.1038/nrc1528
Metastasis to bone is common in lung, kidney, breast and prostate cancers. However, prostate cancer is unique in that bone is often the only clinically detectable site of metastasis, and the resulting tumours tend to be osteoblastic (bone forming) rather than osteolytic (bone lysing). The interaction between host cells and metastatic cancer cells is an important component of organ-specific cancer progression. How can this knowledge lead to the development of more effective therapies?
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- "Unlike bone marrow MSCs, which support myeloma disease progression   , evidence suggests that osteoblasts may suppress myeloma . Osteoblast-derived growth factors play a large role in stimulating the growth of prostate cancers within the bone , raising the question of why this does not occur in myeloma. It is not clear if myeloma cells respond differently to these same osteoblast-derived factors, or if myeloma cells, like prostate cancer cells, actually benefit from osteoblasts , but proliferate even more strongly when they activate osteoclastic activity rather than osteoblastic activity. "
ABSTRACT: Multiple myeloma is a B-cell malignancy characterized by the unrelenting proliferation of plasma cells. Multiple myeloma causes osteolytic lesions and fractures that do not heal due to decreased osteoblastic and increased osteoclastic activity. However, the exact relationship between osteoblasts and myeloma cells remains elusive. Understanding the interactions between these dynamic bone-forming cells and myeloma cells is crucial to understanding how osteolytic lesions form and persist, and how tumors grow within the bone marrow. This review provides a comprehensive overview of basic and translational research focused on the role of osteoblasts in multiple myeloma progression and their relationship to osteolytic lesions. Importantly, current challenges for in vitro studies exploring direct osteoblastic effects on myeloma cells, and gaps in understanding the role of the osteoblast in myeloma progression are delineated. Finally, successes and challenges in myeloma treatment with osteoanabolic therapy (i.e. any treatment that induces increased osteoblastic number or activity) are enumerated. Our goal is to illuminate novel mechanisms by which osteoblasts may contribute to multiple myeloma disease progression and osteolysis to better direct research efforts. Ultimately, we hope this may provide a roadmap for new approaches to the pathogenesis and treatment of multiple myeloma with a particular focus on the osteoblast. Copyright © 2015. Published by Elsevier Inc.Bone 02/2015; 75. DOI:10.1016/j.bone.2015.02.021 · 3.97 Impact Factor
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- "CaP metastasizes to the bone to predominantly produce an osteoblastic reaction (bone formation) by virtue of promoting proliferation and differentiation of mesenchymal progenitor cells into mature osteoblasts (Logothetis and Lin, 2005). Although S1P has been reported to regulate remodeling in normal bone physiology (Ishii et al., 2009, 2010; Pederson et al., 2008; Ryu et al., 2006), its role in the pathological context of bone metastasis has not been described to date. "
ABSTRACT: Sphingosine 1-phosphate (S1P) plays important roles in cell proliferation, differentiation or survival mainly through its surface G-protein-coupled receptors S1P(1-5). Bone represents the major site of metastasis for prostate cancer (CaP) cells, which rely on bone-derived factors to support their proliferation and resistance to therapeutics. In the present work we have found that conditioned medium (CM) from the MC3T3 osteoblastic cell line or primary murine and human osteoblast-like cells, as well as co-culture with MC3T3 stimulate proliferation of CaP lines in S1P-dependent manner. In addition, osteoblastic-derived S1P induces resistance of CaP cells to therapeutics including chemotherapy and radiotherapy. When S1P release from osteoblastic cells is decreased (inhibition of SphK1, knock-down of SphK1 or the S1P transporter, Spns2 by siRNA) or secreted SIP neutralized with anti-S1P antibody, the proliferative and survival effects of osteoblasts on CaP cells are abolished. Because of the paracrine nature of the signaling, we studied the role of the S1P receptors expressed on CaP cells in the communication with S1P secreted by osteoblasts. Strategies aimed at down-regulating S1P(1), S1P(2) or S1P(3) (siRNA, antagonists), established the exclusive role of the S1P/S1P(7) signaling between osteoblasts and CaP cells. Bone metastases from CaP are associated with osteoblastic differentiation resulting in abnormal bone formation. We show that the autocrine S1P/S1P(3) signaling is central during differentiation to mature osteoblasts by regulating Runx2 level, a key transcription factor involved in osteoblastic maturation. Importantly, differentiated osteoblasts exhibited enhanced secretion of SIP and further stimulated CaP cell proliferation in a S1P-dependent manner.Molecular Oncology 10/2014; 8(7). DOI:10.1016/j.molonc.2014.04.001 · 5.33 Impact Factor
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- "In this cancer, metastasis (i.e. tumor cells escaping from the primary tissue and eventually colonizing a distant site) reflects the most adverse phase, which commonly results in disruption of a complex set of biological processes, causing severe bone pain and spinal cord complications [2,3]. Due to the heterogeneity of the disease, there are currently no reliable morphologic features or genetic/genomic biomarkers that can effectively discriminate tissue-confined primary and/or metastatic tumors, thus less is known for the mechanisms underlying the development of metastatic disease. "
ABSTRACT: Background Prostate cancer is one of the most common malignant diseases and is characterized by heterogeneity in the clinical course. To date, there are no efficient morphologic features or genomic biomarkers that can characterize the phenotypes of the cancer, especially with regard to metastasis – the most adverse outcome. Searching for effective surrogate genes out of large quantities of gene expression data is a key to cancer phenotyping and/or understanding molecular mechanisms underlying prostate cancer development. Results Using the maximum relevance minimum redundancy (mRMR) method on microarray data from normal tissues, primary tumors and metastatic tumors, we identifed four genes that can optimally classify samples of different prostate cancer phases. Moreover, we constructed a molecular interaction network with existing bioinformatic resources and co-identifed eight genes on the shortest-paths among the mRMR-identified genes, which are potential co-acting factors of prostate cancer. Functional analyses show that molecular functions involved in cell communication, hormone-receptor mediated signaling, and transcription regulation play important roles in the development of prostate cancer. Conclusion We conclude that the surrogate genes we have selected compose an effective classifier of prostate cancer phases, which corresponds to a minimum characterization of cancer phenotypes on the molecular level. Along with their molecular interaction partners, it is fairly to assume that these genes may have important roles in prostate cancer development; particularly, the un-reported genes may bring new insights for the understanding of the molecular mechanisms. Thus our results may serve as a candidate gene set for further functional studies.Theoretical Biology and Medical Modelling 08/2014; 11(1):37. DOI:10.1186/1742-4682-11-37 · 0.95 Impact Factor