Parathyroid Hormone Related-Protein Promotes Epithelial-to-Mesenchymal Transition in Prostate Cancer

Ongkeko, Weg M.; Burton, Douglas W.; Kiang, Alan; Abhold, Eric L.; Kuo, Selena Z.; Rahimy, Elham; Yang, Meng; Hoffman, Robert M.; Wang‐Rodriguez, Jessica; Deftos, Leonard J.

doi:10.1371/journal.pone.0085803

Cited by 39 publications

(28 citation statements)

References 57 publications

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“…PTHrP is one of the well-known NEPCa derived peptides critical for tumor initiation, growth and metastasis (38). Previous studies showed that PTHrP promoted epithelial-to-mesenchymal transition that is closely connected with metastasis and stemness in PCa (66). It has also been shown that PTHrP enhanced PCa growth via both stabilizing AR and driving a CD11b+Gr1+ cell-mediated positive feedback loop(10, 38).…”

Section: Discussionmentioning

confidence: 98%

Neuroendocrine prostate cancer (NEPCa) increased the neighboring PCa chemoresistance via altering the PTHrP/p38/Hsp27/androgen receptor (AR)/p21 signals

Chen

Sun

et al. 2016

Oncogene

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Prostatic neuroendocrine cells (NE) are an integral part of prostate cancer (PCa) that are associated with PCa progression. As the current androgen-deprivation therapy (ADT) with anti-androgens may promote the neuroendocrine PCa (NEPCa) development, and few therapies can effectively suppress NEPCa, understanding the impact of NEPCa on PCa progression may help us to develop better therapies to battle PCa. Here we found NEPCa cells could increase the docetaxel-resistance of their neighboring PCa cells. Mechanism dissection revealed that through secretion of PTHrP, NEPCa cells could alter the p38/MAPK/Hsp27 signals in their neighboring PCa cells that resulted in increased androgen receptor (AR) activity via promoting AR nuclear translocation. The consequences of increased AR function might then increase docetaxel-resistance via increasing p21 expression. In vivo xenograft mice experiments also confirmed NEPCa could increase the docetaxel-resistance of neighboring PCa, and targeting this newly identified PTHrP/p38/Hsp27/AR/p21 signaling pathway with either p38 inhibitor (SB203580) or sh-PTHrP may result in improving/restoring the docetaxel sensitivity to better suppress PCa.

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Section: Discussionmentioning

confidence: 98%

Neuroendocrine prostate cancer (NEPCa) increased the neighboring PCa chemoresistance via altering the PTHrP/p38/Hsp27/androgen receptor (AR)/p21 signals

Chen

Sun

et al. 2016

Oncogene

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“…TAS-115 also acts on tumor cells PC3 and suppresses cell growth. Previous studies have shown that PC3 produces parathyroid hormone-related peptides (21) and that it is involved in cell migration of PC3 in vitro (22), but the roles of parathyroid hormone-related peptides in the growth and bone metastasis of PC3 in vivo are not known. The action of TAS-115 may be elicited by the suppression of FMS-regulated osteoclastogenesis and MET/VEGFR-dependent cancer cell proliferation in tumor microenvironments of bone tissues.…”

Section: Discussionmentioning

confidence: 99%

The MET/Vascular Endothelial Growth Factor Receptor (VEGFR)-targeted Tyrosine Kinase Inhibitor Also Attenuates FMS-dependent Osteoclast Differentiation and Bone Destruction Induced by Prostate Cancer

Watanabe¹,

Hirata²,

Tominari

et al. 2016

Journal of Biological Chemistry

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The tyrosine kinase inhibitor TAS-115 that blocks VEGF receptor and hepatocyte growth factor receptor MET signaling exhibits antitumor properties in xenografts of human gastric carcinoma. In this study, we have evaluated the efficacy of TAS-115 in preventing prostate cancer metastasis to the bone and bone destruction using the PC3 cell line. When PC3 cells were injected into proximal tibiae in nude mouse, severe trabecular and cortical bone destruction and subsequent tumor growths were detected. Oral administration of TAS-115 almost completely inhibited both PC3-induced bone loss and PC3 cell proliferation by suppressing osteoclastic bone resorption. In an ex vivo bone organ culture, PC3 cells induced osteoclastic bone resorption when co-cultured with calvarial bone, but TAS-115 effectively suppressed the PC3-induced bone destruction. We found that macrophage colony-stimulating factor-dependent macrophage differentiation and subsequent receptor activator of NF-B ligand-induced osteoclast formation were largely suppressed by adding TAS-115. The phosphorylation of the macrophage colony-stimulating factor receptor FMS and osteoclast related kinases such as ERK and Akt were also suppressed by the presence of TAS-115. Gene expression profiling showed that FMS expression was only seen in macrophage and in the osteoclast cell lineage. Our study indicates that tyrosine kinase signaling in host pre-osteoclasts/osteoclasts is critical for bone destruction induced by tumor cells and that targeting of MET/VEGF receptor/FMS activity makes it a promising therapeutic candidate for the treatment of prostate cancer patients with bone metastasis.VEGF signaling through the tyrosine kinase receptor VEGF receptor (VEGFR) 3 is a pivotal factor for tumor angiogenesis that regulates tumor progression. However, VEGFR-targeted inhibitor monotherapies showed limited effects on various carcinomas, and even combination therapies with chemotherapeutic agents are unsatisfactory (1, 2). The tyrosine kinase MET is a receptor for hepatocyte growth factor (HGF), and HGF-MET signaling is also involved in tumor progression, metastasis, angiogenesis, and resistance to chemotherapy in various cancers, indicating that MET kinase inhibitors could have major therapeutic potential. Inhibition of both VEGFR and MET signaling pathways has been reported to suppress tumor growth and angiogenesis synergistically (3), suggesting the possibility that the dual inhibition of VEGFR and MET signals may have potential effects on the prevention of tumor growth. Recently, Fujita et al. (4) developed a novel VEGFR/MET-targeted tyrosine kinase inhibitor, TAS-115, and showed its antitumor properties in MET-amplified human cancer-bearing mice. In this study, we have investigated the effect of TAS-115 on prostate cancer cell metastasis to bone and a process associated with osteoclast activation.Bone remodeling is regulated by osteoclastic bone resorption and new bone formation. Osteoclasts, which are the primary bone-resorbing cells, are differentiated from macrophages b...

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“…Acquisition of invasive ability and mesenchymal phenotype by cancer cells from primary tumors is a requirement for bone metastasis formation [21]. In this contest, several growth factors such as transforming growth factor-β1 (TGF-β1) [22,23], connective tissue growth factor (CTGF) [24], interleukin 11 (IL-11) [25] and parathyroid hormone-related protein (PTHrP) [26], which are critical inducers of skeletal metastases by osteotropic tumors, may play a prominent role in EMT of NETs. Moreover, both the receptor activator of NF-κB (RANK) and C-X-C chemokine receptor type 4 (CXCR4) are involved in the promotion of EMT [27,28,29].…”

Section: Introductionmentioning

confidence: 99%

Reviewing the Osteotropism in Neuroendocrine Tumors: The Role of Epithelial-Mesenchymal Transition

Cives

Rizzo²,

Simone³

et al. 2015

Neuroendocrinology

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Background: Neuroendocrine tumors (NETs) metastasize to the bone. However, the incidence, clinical features, management and pathogenesis of bone involvement in NET patients have been poorly investigated. Methods: We reviewed all published reports of histologically confirmed bone metastatic NETs and explored clinical, radiological, prognostic and therapeutic characteristics in a population of 152 patients. We then evaluated immunohistochemical expression of a panel of eight epithelial-mesenchymal transition (EMT)-related factors including SNAIL, TGF-β1, CTGF, IL-11, PTHrP, EpCAM, CXCR4 and RANK in an independent cohort of 44 archival primary NETs. Biomarker expression was correlated with clinicopathological variables, including skeletal involvement, and tested for survival prediction. Results: We found that 55% of NET patients with bone metastases were male, with a median age of 55 years at diagnosis. Metastases were restricted to the skeleton in 34% of the NET population, and axial and osteoblastic lesions were prevalent. NETs differently expressed proteins involved in EMT activation. High CXCR4 (p < 0.0001) and low TGF-β1 levels (p = 0.0015) were significantly associated with increased risk of skeletal metastases, suggesting that EMT is implicated in NET osteotropism. By applying an algorithm measuring distinct immunohistochemical predictors of osteotropism on primary tumors, we were able to identify NET patients with bone metastases with a sensitivity and specificity of 91 and 100%, respectively (p < 0.0001). Patients whose primary tumors expressed CTGF (p = 0.0007) as well as the truncated form of EpCAM (p = 0.06) showed shorter survival. Conclusion: Although underestimated, bone metastases are a prominent feature of NETs, and the tumor expression of EMT markers at diagnosis may predict concurrent or subsequent skeleton colonization.

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Parathyroid Hormone Related-Protein Promotes Epithelial-to-Mesenchymal Transition in Prostate Cancer

Cited by 39 publications

References 57 publications

Neuroendocrine prostate cancer (NEPCa) increased the neighboring PCa chemoresistance via altering the PTHrP/p38/Hsp27/androgen receptor (AR)/p21 signals

Neuroendocrine prostate cancer (NEPCa) increased the neighboring PCa chemoresistance via altering the PTHrP/p38/Hsp27/androgen receptor (AR)/p21 signals

The MET/Vascular Endothelial Growth Factor Receptor (VEGFR)-targeted Tyrosine Kinase Inhibitor Also Attenuates FMS-dependent Osteoclast Differentiation and Bone Destruction Induced by Prostate Cancer

Reviewing the Osteotropism in Neuroendocrine Tumors: The Role of Epithelial-Mesenchymal Transition

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