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.

Download full-text


Available from: Andrew Wilber,
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    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.
    Cell 11/2013; 155(4):750-64. DOI:10.1016/j.cell.2013.10.029 · 32.24 Impact Factor
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Bone metastasis is a frequent occurrence in late stage solid tumors, including breast cancers, prostate or lung. However, the causes for this proclivity have only recently been elucidated. Significant progress has been made in the past decade toward understanding the molecular underpinnings of bone metastasis, and much of this research reveals a crucial role of the host stroma in each step of the metastatic cascade. Tumor-stromal interactions are crucial in engineering a pre-metastatic niche, accommodating metastatic seeding, and establishing the vicious cycle of bone metastasis. Current treatments in bone metastasis focus on latter steps of the metastatic cascade, with most treatments targeting the process of bone remodeling; however, emerging research identifies many other candidates as promising targets. Host stromal cells including platelets and endothelial cells are important in the early steps of metastatic homing, attachment and extravasation while a variety of immune cells, parenchymal cells and mesenchymal cells of the bone marrow are important in the establishment of overt, immune-suppressed metastatic lesions. Many participants during these steps have been identified and functionally validated. Significant contributors include integrins, (αvβ3, α2β1, α4β1), TGFβ family members, bone resident proteins (BSP, OPG, SPARC, OPN), RANKL, and PTHrP. In this review, we will discuss the contribution of host stromal cells to pre-metastatic niche conditioning, seeding, dormancy, bone-remodeling, immune regulation, and chemotherapeutic shielding in bone metastasis. Research exploring these interactions between bone metastases and stromal cells has yielded many therapeutic targets, and we will discuss both the current and future therapeutic avenues in treating bone metastasis.
    Pharmacology [?] Therapeutics 10/2013; 141(2). DOI:10.1016/j.pharmthera.2013.10.006 · 9.72 Impact Factor
  • Source
    • "The positive influence of WISP1 on BMP-2 could therefore be part of the molecular underpinnings related to increased PC3-Luc metastasis in mice that have increased bone turnover induced by intermittent application of PTH [23]. BMP-7 has also been implicated to control prostate cancer growth and spread, however, its potential relationship to WISP1 remains to be clarified [44], [45]. One other factor that may be connected to WISP1 function is vitamin D3 an agent known to be beneficial to bone and in reducing cancer. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Prostate cancer (PC) is a leading cause of death in men however the factors that regulate its progression and eventual metastasis to bone remain unclear. Here we show that WISP1/CCN4 expression in prostate cancer tissues was up-regulated in early stages of the disease and, further, that it correlated with increased circulating levels of WISP1 in the sera of patients at early stages of the disease. WISP1 was also elevated in the mouse prostate cancer model TRAMP in the hypoplastic diseased tissue that develops prior to advanced carcinoma formation. When the ability of anti-WISP1 antibodies to reduce the spread of PC3-Luc cells to distant sites was tested it showed that twice weekly injections of anti-WISP1 antibodies reduced the number and overall size of distant tumors developed after intracardiac (IC) injection of PC3-Luc cells in mice. The ability of antibodies against WISP1 to inhibit growth of PC3-Luc cancer cells in mice was also evaluated and showed that twice weekly injections of anti-WISP1 antibodies reduced local tumor growth when examined in xenografts. To better understand the mechanism of action, the migration of PC3-Luc cells through membranes with or without a Matrigel™ barrier showed the cells were attracted to WISP1, and that this attraction was inhibited by treatment with anti-WISP1 antibodies. We also show the expression of WISP1 at the bone-tumor interface and in the stroma of early grade cancers suggested WISP1 expression is well placed to play roles in both fostering growth of the cancer and its spread to bone. In summary, the up-regulation of WISP1 in the early stages of cancer development coupled with its ability to inhibit spread and growth of prostate cancer cells makes it both a potential target and an accessible diagnostic marker for prostate cancer.
    PLoS ONE 08/2013; 8(8):e71709. DOI:10.1371/journal.pone.0071709 · 3.23 Impact Factor
Show more