Yoneda Toshiyuki
Dept. of Biochemistry, Osaka University Graduate School of Dentistry.
Gan To Kagaku Ryoho. 2011 Jun;38(6):877-84.
Bone, as well as the lung and liver, is among the sites of predilection for cancer metastasis. The bone stores large amounts of growth factors such as insulin-like growth factors and transforming growth factor-b, and provides fertile soil for metastatic cancer cells by continuously releasing these bone-stored growth factors, which are a consequence of osteoclastic bone resorption. Metastatic cancer cells in turn produce osteoclast-stimulating cytokines such as parathyroid hormone-related protein( PTH-rP), prostaglandin E2.(PGE2), and various interleukins(ILs). These cancer-produced osteoclast-stimulating cytokines bind to their cognitive receptors and promote the expression of ligands for the receptor activators of nuclear factor kB (RANKL)in osteoblasts. RANKL then binds to its receptor RANK, expressed in pre-osteoclasts, stimulates mature osteoclast formation, and subsequently, osteoclastic bone resorption. This vicious cycle between metastatic cancer cells and osteoclasts is critical to the development and progression of bone metastases. In addition, it is likely that metastatic cancer cells are influenced by bone environments(or niche)and acquire additional capacities such as an epithelial-mesenchymal transition(EMT), allowing them to be resistant to chemotherapy or apoptosis, to survive in a dormant state, or to aggressively spread to distant organs including lung and liver. Thus, the bone can serve as transit port. Disrupting this cycle by inhibiting osteoclastic bone resorption, antagonizing bone-derived growth factors, and neutralizing RANKL or PTH-rP, should be a promising therapeutic intervention for bone metastases. Bisphosphonates(BP)are specific inhibitors of osteoclasts, and have been shown to significantly reduce skeletal-related events(SRE)associated with bone metastasis. Denosumab is a neutralizing monoclonal antibody to RANKL and has recently been found to inhibit SRE more effectively than BP. Further understanding of the crosstalk communication between metastatic cancer cells and bone at the molecular level should lead us to design novel, more effective and specific treatments for cancer patients with bone metastases.
骨骼以及肺和肝脏一样，是癌症转移的好发部位。骨骼储存大量生长因子，如胰岛素样生长因子和转化生长因子-β，并通过持续释放这些储存在骨骼中的生长因子为转移性癌细胞提供肥沃的土壤，这是破骨细胞骨吸收的结果。转移性癌细胞反过来又产生刺激破骨细胞的细胞因子，如甲状旁腺激素相关蛋白（PTH-rP）、前列腺素E2（PGE2）和各种白细胞介素（ILs）。这些由癌细胞产生的刺激破骨细胞的细胞因子与其相应受体结合，促进成骨细胞中核因子κB受体激活剂配体（RANKL）的表达。RANKL随后与其在前破骨细胞中表达的受体RANK结合，刺激成熟破骨细胞的形成，随后导致破骨细胞骨吸收。转移性癌细胞与破骨细胞之间的这种恶性循环对于骨转移的发生和发展至关重要。此外，转移性癌细胞很可能受到骨环境（或微环境）的影响，并获得诸如上皮-间质转化（EMT）等额外能力，使其对化疗或凋亡具有抗性，能够以休眠状态存活，或积极扩散到包括肺和肝脏在内的远处器官。因此，骨骼可作为转运端口。通过抑制破骨细胞骨吸收、拮抗骨源性生长因子以及中和RANKL或PTH-rP来破坏这个循环，应该是一种有前景的骨转移治疗干预措施。双膦酸盐（BP）是破骨细胞的特异性抑制剂，已被证明能显著减少与骨转移相关的骨相关事件（SRE）。地诺单抗是一种针对RANKL的中和单克隆抗体，最近发现它比BP更有效地抑制SRE。在分子水平上进一步了解转移性癌细胞与骨骼之间的相互作用，应该能引导我们为骨转移癌患者设计出新颖、更有效和更具特异性的治疗方法。
