Quiroz-Munoz Mariana, Izadmehr Sudeh, Arumugam Dushyanthy, Wong Beatrice, Kirschenbaum Alexander, Levine Alice C
Division of Endocrinology, Diabetes and Bone Disease, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York.
Division of Hematology and Medical Oncology, Tisch Cancer Institute, New York, New York.
J Endocr Soc. 2019 Feb 1;3(3):655-664. doi: 10.1210/js.2018-00425. eCollection 2019 Mar 1.
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-B/receptor activator of nuclear factor-B 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.
前列腺癌（PCa）优先转移至骨骼，导致包括剧痛、骨折、脊髓压迫、骨髓抑制等并发症，死亡率约为70%。尽管在化疗、激素治疗和放射治疗方面取得了最新进展，但骨转移性、去势抵抗性PCa仍无法治愈。PCa在实体瘤中 somewhat 独特，其倾向于产生由过度矿化的骨组成的成骨细胞病变，这些骨具有多层组织紊乱的I型胶原纤维，机械强度降低。许多控制正常骨稳态的信号通路在病理性PCa骨转移中起作用，包括核因子-κB受体激活剂/核因子-κB配体受体激活剂/骨保护素系统。已证明许多源自PCa的可溶性因子可诱导功能失调的成骨细胞表型。然而，迄今为止，针对这些刺激成骨细胞的蛋白质的治疗产生了令人失望的临床结果。PCa细胞表达的可溶性因子之一，特别是在骨转移中，是前列腺酸性磷酸酶（PAP）。人PAP是一种前列腺上皮特异性分泌蛋白，是有史以来描述的第一个肿瘤标志物。从生物学上讲，PAP兼具磷酸酶活性和胞外5'-核苷酸酶活性，最终产生细胞外磷酸盐和腺苷。越来越多的证据表明，PAP在骨转移性、去势抵抗性PCa中出现的成骨细胞表型和异常骨矿化中起因果作用。靶向PAP可能代表一种改善PCa成骨细胞骨转移发病率和死亡率的治疗方法。
