Mechanisms of Osteoblastic Bone Metastasis in Prostate Cancer: Role of Prostatic Acid Phosphatase

Abstract

Prostate cancer (PCa) preferentially metastasizes to bone, leading to complications including severe pain, fractures, spinal cord compression, bone marrow suppression, and a mortality of ∼70%. In spite of recent advances in chemo-, hormonal, and radiation therapies, bone-metastatic, castrate-resistant PCa is incurable. PCa is somewhat unique among the solid tumors in its tendency to produce osteoblastic lesions composed of hypermineralized bone with multiple layers of poorly organized type I collagen fibrils that have reduced mechanical strength. Many of the signaling pathways that control normal bone homeostasis are at play in pathologic PCa bone metastases, including the receptor activator of nuclear factor-κB/receptor activator of nuclear factor-κB ligand/osteoprotegerin system. A number of PCa-derived soluble factors have been shown to induce the dysfunctional osteoblastic phenotype. However, therapies directed at these osteoblastic-stimulating proteins have yielded disappointing clinical results to date. One of the soluble factors expressed by PCa cells, particularly in bone metastases, is prostatic acid phosphatase (PAP). Human PAP is a prostate epithelium-specific secretory protein that was the first tumor marker ever described. Biologically, PAP exhibits both phosphatase activity and ecto-5′-nucleotidase activity, generating extracellular phosphate and adenosine as the final products. Accumulating evidence indicates that PAP plays a causal role in the osteoblastic phenotype and aberrant bone mineralization seen in bone-metastatic, castrate-resistant PCa. Targeting PAP may represent a therapeutic approach to improve morbidity and mortality from PCa osteoblastic bone metastases.

Prostate cancer‐secreted CCN3 uses the GSK3β and β‐catenin pathways to enhance osteogenic factor levels in osteoblasts

“…The preference for prostate cancer to metastasize to bone contributes to a mortality rate of ~70% 29 . It is well documented that the interaction between cancer cells and the bone microenvironment results in a “vicious cycle” that increases both bone destruction and tumor growth 30,31 .…”

Bone, a Secondary Growth Site of Breast and Prostate Carcinomas: Role of Osteocytes

“…The osteoblastic phase leads to the formation of hypermineralized bone with multiple layers of poorly organized type I collagen fibrils of reduced mechanical strength. Secretory kinases and phosphatases are also involved in the formation of aberrant mineralization that makes phosphate and calcium available and regulates the function of proteins relevant for mineralization [ 18 ].…”

Значимість Окремих Маркерів При Різних Варіантах Перебігу Раку Передміхурової Залози

“…Як відомо, РПЗ належить до пухлин, що найбільш часто метастазують у кістки, що, за даними літератури, сягає 70% випадків [15]. Біохімічним показником діагностики метастазів у кістково-суглобовий апарат хворих на РПЗ є рівень Рис.…”