Prostate cancer bone metastases promote both osteolytic and osteoblastic activity

Keller, Evan T.; Brown, Johnny E.

doi:10.1002/jcb.10662

Cited by 251 publications

(225 citation statements)

References 132 publications

Supporting

Mentioning

215

Contrasting

Unclassified

Order By: Relevance

“…Despite the overall osteoblastic nature of prostate cancer bone metastases, a number of studies suggest that the up-regulation of osteolytic bone resorption also occurs and is essential for initiation of bone metastases (35,36). Multiple signaling pathways regulate osteoclastogenesis (19), but Src is known to be one of the key components of this process.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Hsp90 activates osteoclast c-Src signaling and promotes growth of prostate carcinoma cells in bone

Yano

Tsutsumi

Soga

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Hsp90 inhibitors are being evaluated extensively in patients with advanced cancers. However, the impact of Hsp90 inhibition on signaling pathways in normal tissues and the effect that this may have on the antitumor activity of these molecularly targeted drugs have not been rigorously examined. Breast and prostate carcinomas are among those cancers that respond to Hsp90 inhibitors in animal xenograft models and in early studies in patients. Because these cancers frequently metastasize to bone, it is important to determine the impact of Hsp90 inhibitors in the bone environment. In the current study, we show that, in contrast to its activity against prostate cancer cells in vitro and its inhibition of s.c. prostate cancer xenografts, the Hsp90 inhibitor 17-AAG stimulates the intraosseous growth of PC-3M prostate carcinoma cells. This activity is mediated not by a direct effect on the tumor but by Hsp90-dependent stimulation of osteoclast maturation. Hsp90 inhibition transiently activates osteoclast Src kinase and promotes Srcdependent Akt activation. Both kinases are key drivers of osteoclast maturation, and three agents that block osteoclastogenesis, the Src inhibitor dasatinib, the bisphosphonate alendronate, and the osteoclast-specific apoptosis-inducer reveromycin A, markedly reduced 17-AAG-stimulated tumor growth in bone. These data emphasize the importance of understanding the complex role played by Hsp90 in regulating signal transduction pathways in normal tissues as well as in cancer cells, and they demonstrate that drug-dependent modulation of the local tumor environment may profoundly affect the antitumor efficacy of Hsp90-directed therapy.cancer ͉ geldanamycin ͉ heat shock protein 90 ͉ osteoclastogenesis

show abstract

Section: Discussionmentioning

confidence: 99%

Inhibition of Hsp90 activates osteoclast c-Src signaling and promotes growth of prostate carcinoma cells in bone

Yano

Tsutsumi

Soga

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…The underlying osteolysis by the activation of osteoclasts further impacts the integrity of the mineral matrix resulting in bone pain and a higher risk for pathological fractures. 20,21 …”

Section: Clinical Predisposing Factors For Bone Loss and Osteoporosismentioning

confidence: 99%

Androgen-deprivation therapy and bone loss in prostate cancer patients: a clinical review

Bienz¹,

Saad²

2015

BoneKEy Reports

View full text Add to dashboard Cite

Androgen-deprivation therapy (ADT) has become a standard of care in the management of advanced prostate cancer or as an adjunct therapy. However, ADT is associated with a well-known deleterious effect on bone health, resulting in a decrease in bone-mass density (BMD) and increased risk for fracture. With the longer life expectancy of prostate cancer patients, improvement of the quality of life has become increasingly important. Therefore, adequate screening, prevention and treatment of BMD loss is paramount. Zoledronic acid and denosumab have shown promising results in recent studies, which has led to the Food and Drug Administration approval of these treatment options in various settings throughout the course of the disease, including the prevention of ADT-associated bone loss. This review focuses on the various parameters that impact BMD loss in men initiating ADT, on the specific effect of ADT on bone health and on various lifestyle modifications and treatment options such as bisphosphonates, osteoclast-targeted therapy and selective estrogen-receptor modulators that have shown promising results in recent studies.

show abstract

“…skeletal compartment predominates [2] leading to substantial bone pain and mortalities. Although the nature of bone metastatic prostate cancer lesions have been described as osteoblastic, these lesions develop concomitantly with notable amounts of bone resorption [3]. While the topic of intense investigation, factors contributing to the stimulation of such bone remodeling phenotypes still remain largely unidentified.…”

Section: Introductionmentioning

confidence: 99%

Intraosseous injection of RM1 murine prostate cancer cells promotes rapid osteolysis and periosteal bone deposition

McCabe

Madajka

Vasanji

et al. 2008

Clin Exp Metastasis

View full text Add to dashboard Cite

The molecular mechanisms associated with prostate cancer (PCa) progression within bone remain a topic of intense investigation. With the availability of transgenic mouse strains, a model of PCa for use in immune competent/transgenic mice would be highly beneficial. This study was designed to explore the utility of RM1 mouse PCa cells in investigations of tumor:bone interactions. The efficacies of several implantation techniques were examined for reliably producing intra-bone RM1 tumor growth and bone lesion formation in immune competent mice. Longitudinal monitoring of bone remodeling and lesion phenotypes was conducted by microcomputed tomography (μCT) and histological analyses. Our results indicate that direct intrabone injections of RM1 cells are necessary for tumor growth within bone and direct implantation promotes the rapid development of osteolytic bone lesions with periosteal bone deposition post-cortical breach. In vitro, RM1 cells promote the proliferation of osteoblast (MC3T3-E1) and osteoclast (Raw264.7) progenitors in a dose dependent manner. Conditioned culture media from RM1 cells appears to promote earlier expression of genes/ proteins associated with osteoblastic differentiation. While clearly stimulating osteoclast function in vivo, RM1 cells had little effect on differentiation and tartate resistant acid phosphatase (TRAP) expression by Raw264.7 cells. These data, coupled with in vivo μCT images, indicate the ability of RM1 cells to induce mixed, yet predominentally osteolytic, responses in bone and illustrate the potential of RM1 cells as a model of investigating prostate tumor:stroma interactions in immune competent/transgenic mice on a C57BL/6 background.

show abstract

Prostate cancer bone metastases promote both osteolytic and osteoblastic activity

Cited by 251 publications

References 132 publications

Inhibition of Hsp90 activates osteoclast c-Src signaling and promotes growth of prostate carcinoma cells in bone

Inhibition of Hsp90 activates osteoclast c-Src signaling and promotes growth of prostate carcinoma cells in bone

Androgen-deprivation therapy and bone loss in prostate cancer patients: a clinical review

Intraosseous injection of RM1 murine prostate cancer cells promotes rapid osteolysis and periosteal bone deposition

Contact Info

Product

Resources

About