Bone Morphogenetic Protein 7 Is Expressed in Prostate Cancer Metastases and Its Effects on Prostate Tumor Cells Depend on Cell Phenotype and the Tumor Microenvironment

Abstract Advanced prostate cancer cells preferentially metastasize to bone by acquiring a bone phenotype that allows metastatic cells to thrive in the skeletal environment. Identification of factors that promote the expression of ectopic bone genes—process known as osteomimicry—leading to tumor progression is crucial to prevent and treat metastatic prostate cancer and prolong life expectancy for patients. Here, we identify the extracelular matrix protein mindin in the secretome of prostate adenocarcinoma cells and show that mindin overexpression in human and mouse TRAMP-C1-induced prostate tumors correlates with upregulated levels of bone-related genes in the tumorigenic prostate tissues. Moreover, mindin silencing decreased osteomimicry in adenocarcinoma cells and in the prostate tumor mice model, as well as reduced tumor cell proliferation, migration and adhesion to bone cells. Inhibition of the extracellular signal-regulated kinase 1/2 (ERK 1/2) phosphorylation decreased the proliferative, migratory and pro-adhesion actions of mindin on prostate tumor cells. In addition, conditioned media obtained by crosstalk stimulation of either osteocytes or osteoblasts with the secretome of TRAMP-C1 cells promoted osteomimicry in prostate tumor cells; an effect inhibited by mindin silencing of TRAMP-C1 cells. In vivo, tibiae of primary tumor-bearing mice overexpressed the pro-angiogenic and pro-metastattic factor vascular endothelial growth factor receptor 2 (VEGFR2) in a mindin-dependent manner. Our findings indicate that mindin is a novel regulator of osteomimicry in prostate tumors and potentially mediates tumor-bone cell crosstalk, suggesting its promising role as a target to inhibit bone metastases.

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

The Journal of Cell Biology ◽

10.1083/jcb1956oia8 ◽

2011 ◽

Vol 195 (6) ◽

pp. i8-i8

Author(s):

Aya Kobayashi ◽

Hiroshi Okuda ◽

Fei Xing ◽

Puspa R. Pandey ◽

Misako Watabe ◽

...

Keyword(s):

Prostate Cancer ◽

Bone Morphogenetic Protein ◽

Bone Morphogenetic Protein 7 ◽

Morphogenetic Protein

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

Journal of Experimental Medicine ◽

10.1084/jem.201108402093c ◽

2012 ◽

Vol 209 (3) ◽

pp. 639-639 ◽

Cited By ~ 3

Author(s):

Aya Kobayashi ◽

Hiroshi Okuda ◽

Fei Xing ◽

Puspa R. Pandey ◽

Misako Watabe ◽

...

Keyword(s):

Prostate Cancer ◽

Bone Morphogenetic Protein ◽

Bone Morphogenetic Protein 7 ◽

Morphogenetic Protein

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A nonlinear model with competition between prostate tumor cells and its application to intermittent androgen suppression therapy of prostate cancer

Mathematical Biosciences ◽

10.1016/j.mbs.2008.03.001 ◽

2008 ◽

Vol 214 (1-2) ◽

pp. 134-139 ◽

Cited By ~ 36

Author(s):

Takashi Shimada ◽

Kazuyuki Aihara

Keyword(s):

Prostate Cancer ◽

Tumor Cells ◽

Nonlinear Model ◽

Prostate Tumor ◽

Intermittent Androgen Suppression ◽

Androgen Suppression ◽

Prostate Tumor Cells

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HGF/SF up-regulates the expression of bone morphogenetic protein 7 in prostate cancer cells

Urologic Oncology Seminars and Original Investigations ◽

10.1016/j.urolonc.2007.03.027 ◽

2008 ◽

Vol 26 (2) ◽

pp. 190-197 ◽

Cited By ~ 13

Author(s):

Lin Ye ◽

Jonathan M. Lewis-Russell ◽

Andrew J. Sanders ◽

Howard Kynaston ◽

Wen G. Jiang

Keyword(s):

Prostate Cancer ◽

Cancer Cells ◽

Bone Morphogenetic Protein ◽

Prostate Cancer Cells ◽

Bone Morphogenetic Protein 7 ◽

Morphogenetic Protein

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Unbiased Phenotype-Based Screen Identifies Therapeutic Agents Selective for Metastatic Prostate Cancer

Frontiers in Oncology ◽

10.3389/fonc.2020.594141 ◽

2021 ◽

Vol 10 ◽

Author(s):

Ivy Chung ◽

Kun Zhou ◽

Courtney Barrows ◽

Jacqueline Banyard ◽

Arianne Wilson ◽

...

Keyword(s):

Prostate Cancer ◽

Cancer Cells ◽

Tumor Cells ◽

Metastatic Prostate Cancer ◽

Prostate Tumor ◽

Prostate Cancer Cells ◽

Normal Prostate ◽

Prostate Tumor Cells ◽

Benign Prostate

In American men, prostate cancer is the second leading cause of cancer-related death. Dissemination of prostate cancer cells to distant organs significantly worsens patients’ prognosis, and currently there are no effective treatment options that can cure advanced-stage prostate cancer. In an effort to identify compounds selective for metastatic prostate cancer cells over benign prostate cancer cells or normal prostate epithelial cells, we applied a phenotype-based in vitro drug screening method utilizing multiple prostate cancer cell lines to test 1,120 different compounds from a commercial drug library. Top drug candidates were then examined in multiple mouse xenograft models including subcutaneous tumor growth, experimental lung metastasis, and experimental bone metastasis assays. A subset of compounds including fenbendazole, fluspirilene, clofazimine, niclosamide, and suloctidil showed preferential cytotoxicity and apoptosis towards metastatic prostate cancer cells in vitro and in vivo. The bioavailability of the most discerning agents, especially fenbendazole and albendazole, was improved by formulating as micelles or nanoparticles. The enhanced forms of fenbendazole and albendazole significantly prolonged survival in mice bearing metastases, and albendazole-treated mice displayed significantly longer median survival times than paclitaxel-treated mice. Importantly, these drugs effectively targeted taxane-resistant tumors and bone metastases – two common clinical conditions in patients with aggressive prostate cancer. In summary, we find that metastatic prostate tumor cells differ from benign prostate tumor cells in their sensitivity to certain drug classes. Taken together, our results strongly suggest that albendazole, an anthelmintic medication, may represent a potential adjuvant or neoadjuvant to standard therapy in the treatment of disseminated prostate cancer.

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Bone Morphogenetic Protein 7 Protects Prostate Cancer Cells from Stress-Induced Apoptosis via Both Smad and c-Jun NH2-Terminal Kinase Pathways

Cancer Research ◽

10.1158/0008-5472.can-05-4456 ◽

2006 ◽

Vol 66 (8) ◽

pp. 4285-4290 ◽

Cited By ~ 40

Author(s):

Shangxin Yang ◽

Minyoung Lim ◽

Linda K. Pham ◽

Stephen E. Kendall ◽

A. Hari Reddi ◽

...

Keyword(s):

Prostate Cancer ◽

Cancer Cells ◽

Bone Morphogenetic Protein ◽

Prostate Cancer Cells ◽

Bone Morphogenetic Protein 7 ◽

Morphogenetic Protein ◽

Induced Apoptosis

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Bone Marrow-Derived Mesenchymal Stem Cells Migrate toward Hormone-Insensitive Prostate Tumor Cells Expressing TGF-β via N-Cadherin

Biomedicines ◽

10.3390/biomedicines9111572 ◽

2021 ◽

Vol 9 (11) ◽

pp. 1572

Author(s):

Jinok Noh ◽

Jinyeong Yu ◽

Wootak Kim ◽

Aran Park ◽

Ki-Sook Park

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Mesenchymal Stem Cells ◽

Tumor Microenvironment ◽

Tumor Cells ◽

Transforming Growth Factor ◽

Prostate Tumor ◽

Prostate Tumors ◽

Migration Assay ◽

Prostate Tumor Cells

The prostate tumor microenvironment plays important roles in the metastasis and hormone-insensitive re-growth of tumor cells. Bone marrow-derived mesenchymal stem cells (BM-MSCs) are recruited into prostate tumors to facilitate tumor microenvironment formation. However, the specific intrinsic molecules mediating BM-MSCs’ migration to prostate tumors are unknown. BM-MSCs’ migration toward a conditioned medium (CM) of hormone-insensitive (PC3 and DU145) or hormone-sensitive (LNCaP) prostate tumor cells was investigated using a three-dimensional cell migration assay and a transwell migration assay. PC3 and DU145 expressed transforming growth factor-β (TGF-β), but LNCaP did not. Regardless of TGF-β expression, BM-MSCs migrated toward the CM of PC3, DU145, or LNCaP. The CM of PC3 or DU145 expressing TGF-β increased the phosphorylation of Smad2/3 in BM-MSCs. Inactivation of TGF-β signaling in BM-MSCs using TGF-β type 1 receptor (TGFBR1) inhibitors, SB505124, or SB431542 did not allow BM-MSCs to migrate toward the CM. The CM of PC3 or DU145 enhanced N-cadherin expression on BM-MSCs, but the LNCaP CM did not. SB505124, SB431542, and TGFBR1 knockdown prevented an increase in N-cadherin expression. N-cadherin knockdown inhibited the collective migration of BM-MSCs toward the PC3 CM. We identified N-cadherin as a mediator of BM-MSCs’ migration toward hormone-insensitive prostate tumor cells expressing TGF-β and introduced a novel strategy for controlling and re-engineering the prostate tumor microenvironment.

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