Bone morphogenetic protein 7 in dormancy and metastasis of prostate cancer stem-like cells in bone

Department of Medical Microbiology, Immunology, and Cell Biology, Southern Illinois University School of Medicine, Springfield, IL 19626, USA.
Journal of Experimental Medicine (Impact Factor: 12.52). 11/2011; 208(13):2641-55. DOI: 10.1084/jem.20110840
Source: PubMed


Metastatic disease is the major cause of cancer deaths, and recurrent tumors at distant organs are a critical issue. However, how metastatic tumor cells become dormant and how and why tumors recur in target organs are not well understood. In this study, we demonstrate that BMP7 (bone morphogenetic protein 7) secreted from bone stromal cells induces senescence in prostate cancer stem-like cells (CSCs) by activating p38 mitogen-activated protein kinase and increasing expression of the cell cycle inhibitor, p21, and the metastasis suppressor gene, NDRG1 (N-myc downstream-regulated gene 1). This effect of BMP7 depended on BMPR2 (BMP receptor 2), and BMPR2 expression inversely correlated with recurrence and bone metastasis in prostate cancer patients. Importantly, this BMP7-induced senescence in CSCs was reversible upon withdrawal of BMP7. Furthermore, treatment of mice with BMP7 significantly suppressed the growth of CSCs in bone, whereas the withdrawal of BMP7 restarted growth of these cells. These results suggest that the BMP7-BMPR2-p38-NDRG1 axis plays a critical role in dormancy and recurrence of prostate CSCs in bone and suggest a potential therapeutic utility of BMP7 for recurrent metastatic disease.

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    • "Research is beginning to identify multiple mechanisms for dormancy and escape. For example , stress signaling through the p38(SAPK) pathway and ER-stress signaling may coordinate the induction of growth arrest and drug resistance[Ranganathan et al. 2006;El Touny et al. 2013], but these are likely downstream signaling events from more proximal dormancy target(s) such as BMP7, that is secreted by the bone marrow stroma[Kobayashi et al. 2011]. More recently, epigenetic reprogramming by such agents as HDAC inhibitors has been shown to induce dormancy-like growth arrest and present a potential therapeutic strategy[Landreville et al. 2012]. "
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    ABSTRACT: In spite of decades of research, cancer survival has increased only modestly. This is because most research is based on models of primary tumors. Slow recognition has begun that disseminated, dormant cancer cells (micrometastatic cells) that are generally resistant to chemotherapy are the culprits in recurrence, and until these are targeted effectively we can expect only slow progress in increasing overall survival from cancer. This paper reviews efforts to understand the mechanisms by which cancer cells can become dormant, and thereby identify potential targets and drugs either on the market or in clinical trials that purport to prevent metastasis. This review targets the most recent literature because several excellent reviews have covered the literature from more than two years ago. The paper also describes recent work in the authors’ laboratories to develop a screening-based approach that does not require understanding of mechanisms of action or the molecular target. Success of this approach shows that targeting micrometastatic cells is definitely feasible.
    No preview · Article · Jan 2016
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    • "Treatment with BMP or genetic activation of BMP signaling inhibits the ability of breast cancer cells to manifest cancer stem cell traits in vitro and to initiate tumorigenesis upon transplantation in vivo (Gao et al., 2012b). Prostate cancer cells may also be sensitive to the inhibitory action of BMP because systemic treatment with BMP blocks the outgrowth of intratibially injected prostate carcinoma cells (Kobayashi et al., 2011). These findings suggest that paracrine BMP signaling induces metastasis-initiating cells to enter into dormancy by inhibiting their capacity for self-renewal. "
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    ABSTRACT: Many cancer patients suffer from metastatic relapse several years after they have undergone radical surgery. Early cancer cell dissemination followed by a protracted period of dormancy potentially explains this prevalent clinical behavior. Increasing evidence suggests that the metastasis-initiating cells are cancer stem cells or revert to this functional state upon infiltrating a target organ. Their entry into dormancy and subsequent reactivation are governed by intrinsic programs and by contextual cues, which resemble those regulating the self-renewal capability of adult stem cells. In addition, metastatic cells undergoing reactivation are nursed by specialized extracellular matrix niches, which support positive signals, such as Wnt and Notch, and attenuate negative signals, such as BMP. In spite of significant remaining uncertainties, these findings provide a framework to understand the logic of metastatic dormancy and reactivation and open new avenues for therapeutic intervention.
    Preview · Article · Nov 2013 · Cell
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    • "Bone morphogenic protein 7 (BMP7) secreted from endothelial cells effects a reversible cell cycle block in prostate cancer stem cells through p38 induction. Constant exposure of BMP7 leads to senescence and death (Kobayashi et al., 2011). Alternatively, upon induction of angiogenesis, TGFβ1 from sprouting vascular tips is linked to an exit from dormancy and proliferation (Ghajar et al., 2013). "
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