Tumor expressed PTHrP facilitates prostate cancer‐induced osteoblastic lesions

Liao, Jinhui; Li, Xin; Koh, Amy J.; Berry, Janice E.; Thudi, Nanda K.; Rosol, Thomas J.; Pienta, Kenneth J.; McCauley, Laurie K.

doi:10.1002/ijc.23602

Cited by 94 publications

(82 citation statements)

References 54 publications

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“…In Pthrp-ablated animals, primary tumor hyperplasia was considerably delayed, and palpable tumors appeared much later and were smaller and fewer than in control mice. Our observations are in agreement with several clinical studies in which patients with tumors produc- ing high PTHrP levels presented higher rates of metastasis and increased or earlier mortality (40)(41)(42)(43). A recent report reached opposite conclusions, but relied on animal models with a very late-onset oncogenic system (neu based), which is more relevant to tumors arising in older animals (44), and used mice with a heterogeneous genetic background.…”

Section: Discussionsupporting

confidence: 88%

PTHrP drives breast tumor initiation, progression, and metastasis in mice and is a potential therapy target

Li¹,

Karaplis²,

Huang³

et al. 2011

J. Clin. Invest.

112

118

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Parathyroid hormone-related protein (PTHrP) is a secreted factor expressed in almost all normal fetal and adult tissues. It is involved in a wide range of developmental and physiological processes, including serum calcium regulation. PTHrP is also associated with the progression of skeletal metastases, and its dysregulated expression in advanced cancers causes malignancy-associated hypercalcemia. Although PTHrP is frequently expressed by breast tumors and other solid cancers, its effects on tumor progression are unclear. Here, we demonstrate in mice pleiotropic involvement of PTHrP in key steps of breast cancer -it influences the initiation and progression of primary tumors and metastases. Pthrp ablation in the mammary epithelium of the PyMT-MMTV breast cancer mouse model caused a delay in primary tumor initiation, inhibited tumor progression, and reduced metastasis to distal sites. Mechanistically, it reduced expression of molecular markers of cell proliferation (Ki67) and angiogenesis (factor VIII), antiapoptotic factor Bcl-2, cell-cycle progression regulator cyclin D1, and survival factor AKT1. PTHrP also influenced expression of the adhesion factor CXCR4, and coexpression of PTHrP and CXCR4 was crucial for metastatic spread. Importantly, PTHrP-specific neutralizing antibodies slowed the progression and metastasis of human breast cancer xenografts. Our data identify what we believe to be new functions for PTHrP in several key steps of breast cancer and suggest that PTHrP may constitute a novel target for therapeutic intervention.

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Section: Discussionsupporting

confidence: 88%

PTHrP drives breast tumor initiation, progression, and metastasis in mice and is a potential therapy target

Li¹,

Karaplis²,

Huang³

et al. 2011

J. Clin. Invest.

112

118

View full text Add to dashboard Cite

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“…Further experiments are needed to address the role of other factors produced by prostate cancer cells that effect osteoclast formation. For example, it has been demonstrated that PTHrP produced by prostate cancer cells can facilitate osteoclastogenesis and osteoblastogenesis [Li et al, 2007;Liao et al, 2008]. This study demonstrates that functional osteoclasts can be derived from CD11b+ cells derived from human PBMCs.…”

Section: Discussionmentioning

confidence: 75%

Prostate Cancer Promotes Cd11b Positive Cells to Differentiate Into Osteoclasts

Mizutani¹,

Sud²,

Pienta³

2009

Journal of Urology

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Bone is the preferred site of prostate cancer metastasis, contributing to the morbidity and mortality of this disease. A key step in the successful establishment of prostate cancer bone metastases is activation of osteoclasts with subsequent bone resorption causing the release of several growth factors from the bone matrix. CD11b+ cells in bone marrow are enriched for osteoclast precursors. Conditioned media from prostate cancer PC-3 cells induces CD11b+ cells from human peripheral blood to differentiate into functional osteoclasts with subsequent bone resorption. Analysis of PC-3 conditioned media revealed high amounts of IL-6 and IL-8. CD11b+ cells were cultured with M-CSF and RANKL, IL-6, IL-8 and CCL2, alone or in combination. All of these conditions induced osteoclast fusion, but cells cultured with M-CSF, IL-6, IL-8 and CCL2 were capable of limited bone resorption. Co-incubation with IL-6 and IL-8 and the RANK inhibitor, RANK-Fc, failed to inhibit osteoclast fusion and bone resorption, suggesting a potential RANKL-independent mechanism of functional osteoclast formation. This study demonstrates that functional osteoclasts can be derived from CD11b+ cells derived from human PBMCs. Prostate cancer cells secrete factors, including IL-6 and IL-8, that play an important role in osteoclast fusion by a RANKLindependent mechanism. KeywordsOsteoclast; CD11b; Prostate Cancer; RANKL; IL-6; IL-8; CCL2Prostate cancer is the most commonly diagnosed malignancy in US men [Walczak and Carducci, 2007]. Advanced prostate cancer is first treated through chemical or surgical castration because a large percentage of the cancer cells are androgen dependent. The large majority of patients, however, relapse within a few years of treatment because of the emergence of a castration resistant clone of cancer cells. Castration independent prostate cancer is an incurable disease with little effective therapy and there is a great need for novel therapeutic strategies that target the molecular basis of castration-independent, chemoresistant prostate cancer [Isaacs, 2005]. Previous studies have demonstrated that 83%-90% of men had evidence of bone metastasis when they died of prostate cancer Kingsley et al., 2007;Loberg et al., 2005]. Bone is the preferred metastasis site of advanced prostate cancer, and in many patients, the only clinically evident site of metastasis at the time of death . There is a great need of novel therapeutic strategies that target the molecular basis of advanced prostate cancer -bone interactions. A NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript key step in the successful establishment of prostate cancer bone metastases is osteoclast formation and bone resorption followed by the release of several growth factors from the bone matrix that promotes tumor growth . The mechanisms by which prostate cancer cells promote osteoclast formation and bone resorption remain unclear.Previous reports suggested that RANKL, Interleukin-6 (IL-6), Interleukin-8 (IL-8) and C-C chemokine ligand 2 (MC...

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“…PTHrP raises calcium levels in serum and is the principal agent of hypercalcemia of malignancy (18). PTHrP also promotes the metastasis of prostate cancer cells to bone (19,20). Thus, we suggest that the production of PTHrP by local prostate tumors is a plausible mechanism that could underlie the association between higher serum calcium and decreased prostate cancer survival.…”

Section: Discussionmentioning

confidence: 78%

A Prospective Study of Total and Ionized Serum Calcium and Time to Fatal Prostate Cancer

Schwartz

Skinner

2012

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Background: Higher levels of total and ionized serum calcium have been shown to predict fatal prostate cancer in prospective studies. Because the follow-up time in these studies was relatively short, these associations could reflect the effect of clinically significant but occult prostate tumors on serum calcium levels. If this were true, prostate cancer mortality rates among men with higher levels of serum calcium should be higher during the early follow-up period and should decline thereafter.Methods: We tested this hypothesis by estimating the relative risk of death from prostate cancer in the National Health and Nutrition Examination Survey III for incremental increases in total and ionized serum calcium using Cox proportional hazards regression with time-dependent effects.Results: Forty-nine (49) fatal prostate cancers occurred over 204 months of follow-up and 1,069,327 person-months of observation. Men with higher total serum calcium and higher serum ionized calcium had increased risks of fatal prostate cancer during the first 96 months of follow-up [Relative Hazard (RH) ¼ 1.50 per 0.1 mmol/L total serum calcium, 95% confidence interval (CI) ¼ 1.04-2.17; RH ¼ 1.72 per 0.05 mmol/L ionized calcium, 95% CI ¼ 1.11-2.66]. Evidence of an association between total and ionized serum calcium and prostate cancer deaths was not significant after 96 months.Conclusions: Our analyses support the hypothesis that the elevated risk for fatal prostate cancer observed in men with high serum calcium is because of the presence of extant, but occult prostate cancer.Impact: These findings have implications for the potential use of serum calcium in the detection of clinically significant prostate cancer. Cancer Epidemiol Biomarkers Prev; 21(10); 1768-73. Ó2012 AACR.

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Tumor expressed PTHrP facilitates prostate cancer‐induced osteoblastic lesions

Cited by 94 publications

References 54 publications

PTHrP drives breast tumor initiation, progression, and metastasis in mice and is a potential therapy target

PTHrP drives breast tumor initiation, progression, and metastasis in mice and is a potential therapy target

Prostate Cancer Promotes Cd11b Positive Cells to Differentiate Into Osteoclasts

A Prospective Study of Total and Ionized Serum Calcium and Time to Fatal Prostate Cancer

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