Search results were manually curated, evaluated for relevance, and recorded. Publications referenced were selected based on the quality scientific methodology and relevance. Preclinical models that faithfully reproduce PCa bone lesions are essential to gaining a functional understanding of bone-PCa interactions. Existing xenograft models of PCa bone metastases have been developed through a variety of injection approaches to study the processes of bone targeting i. The model systems that study bone targeting have been less successful than the intraosseous model that recapitulates the final phase of PCa disease progression.
The intraosseous technique has proven to be a reproducible approach for studying tumor-bone interactions and factors governing the bone reaction.
Treating Prostate Cancer Spread to Bones
Table 1 summarizes the distinguishing features of human PCa xenograft models using intraosseous injection of bone metastases [ 14—20 ]. Of the available cell lines and xenograft models, the one that most closely reproduces bmCRPC in patients is intratibial inoculation of the VCaP cell line into immunocompromised mice. Many of the factors that control bone homeostasis are at play in pathologic PCa bone metastases. Key players in the osteolytic phase of PCa bone metastases.
Prostate cancer tumor cells interact with all of the components of bone including osteoblasts, osteoclasts, osteocytes, and bone matrix though paracrine green arrow , autocrine blue arrow , and inhibitory red line mechanisms. A variety of other cancer-derived and bone cell—derived secretory factors contribute to the initial and ongoing osteolytic phase of PCa bone metastases.
Prostate cancer bone metastases: Treatment and survival rate
PDGF, platelet-derived growth factor. Key players in the osteoblastic phase of prostate cancer bone metastases. In the osteoblastic phase, PCa cells continue to interact with all of the components of bone, although paracrine green arrow and autocrine blue arrow mechanisms as noted. ET-1, endothelin However, therapies directed at these OB-stimulating factors have yielded disappointing clinical results to date.
Mortality from PCa can be directly linked to these OB lesions, both in terms of the stimulatory effect of activated osteoblasts on PCa growth in bone as well as the destructive effect of hypermineralized bone on the bone marrow. The precise physiologic function of PAP has not been delineated, although given the very high levels in seminal fluid, it is thought to play a role in male reproduction. PAP is a phosphotyrosyl-protein phosphatase [ 35 ] with multiple phosphomonoester substrates that functions at an optimum pH range of 4.
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There are two different isoforms of PAP that result from alternate splicing of the same gene product: i a secreted isoform and ii a transmembrane isoform [ 37 ]. The secreted enzyme PAP is a glycoprotein, nonspecific tyrosine phosphatase, constituted in its active form as a kDa dimer composed of two subunits of 50 kDa [ 38 ]. A possible causal role for PAP in OB bone metastases was postulated when it was demonstrated that PAP stimulated collagen synthesis and alkaline phosphatase content of isolated bone cells [ 43 ].
Our group demonstrated that PAP is highly expressed in human PCa bone metastases, even after castration therapy, and stimulates preosteoblast proliferation and differentiation [ 44 ].
These findings suggest that PAP secreted by PCa cells in bone has both autocrine and paracrine effects that coordinately result in OB lesions [ 45 ]. The PAP gene, acid phosphatase prostate, is expressed in various tissues, including the testes and oviducts of chickens. Eggshell formation occurs in the specialized shell gland region of the chicken oviduct.
The process of shell mineralization in hens is very similar to that of bone mineralization in humans, occurring in stages that include the formation of calcium carbonate depositions, its aggregation as crystals, and its organization by organic matrix. Comparison of gene expression in the shell glands from juvenile and laying hens demonstrated genes for which there was no a priori expectation of differential gene expression including the PAP gene acid phosphatase prostate [ 46 ]. In addition, quantitative proteomics to study key stages of shell mineralization revealed that PAP protein expression was overabundant throughout the process of shell formation [ 47 ].
Similarly, PAP induced calcium deposit formation in a human osteoblast cell line [ 48 ], suggesting that PAP directly stimulates bone mineralization. Bone formation involves the synthesis of collagenous organic matrix by osteoblasts followed by mineralization of the matrix [ 49 ] through formation of hydroxyapatite-based mineral calcium and phosphate. The SIBLING proteins include osteopontin, bone sialoprotein, dentin matrix protein 1, dentin sialophosphoprotein, and matrix extracellular phosphoglycoprotein [ 50 ].
Inactivation of a secretory kinase e. Adenosine has been reported to increase bone formation via G-protein coupled receptors on osteoblasts and osteoclasts, specifically adenosine receptor types 2A and 2B [ 53 , 54 ]. Taken together, there are at least three possible mechanisms whereby increased PAP in the OB niche might lead to aberrantly mineralized bone: i increased generation of extracellular adenosine that stimulates bone formation via adenosine receptor types 2A and 2B; ii increased availability of local phosphate; and iii dephosphorylation of key sites on SIBLING proteins.
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All of these would serve to increase formation of hydroxyapatite, inducing bone formation [ 55 ] and mineralization [ 56 ], and additionally restricting bone resorption [ 57 ]. A variety of PCa and bone cell—derived factors have been demonstrated to play a role in the destructive crosstalk in advanced lesions, but targeting them has not led to improvements in overall survival. Accumulating evidence demonstrates that PAP plays a causal role in OB bone metastases by increasing bone formation and mineralization.
Oxford University Press is a department of the University of Oxford. It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide. Sign In or Create an Account. Sign In. Advanced Search. Article Navigation. Close mobile search navigation Article Navigation. Volume 3. Article Contents. Prostate Cancer Osteoblastic Bone Metastases. Summary and Conclusions. References and Notes. Oxford Academic. Google Scholar. Sudeh Izadmehr.
Dushyanthy Arumugam. Beatrice Wong. Alexander Kirschenbaum.
Stage IV Prostate Cancer
Alice C Levine. E-mail: alice.
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Anaemia and thrombocytopenia in patients with prostate cancer and bone metastases. Basic mechanisms responsible for osteolytic and osteoblastic bone metastases. The use of bisphosphonates in men with hormone-refractory prostate cancer: a systematic review of randomized trials. Full guideline Public Health England.