文章：

癌症对骨骼：致命的吸引力

Cancer to bone: a fatal attraction

原文发布日期：2011-05-19

DOI: 10.1038/nrc3055

类型: Review Article

开放获取: 否

要点：

1. Bone metastases are a common complication of cancer and are generally incurable. They cause considerable pain, pathological bone fractures and hypercalcaemia. Up to 50% of patients prescribed anti-resorptive drugs to treat bone metastases develop new bone metastases, skeletal complications and disease progression, emphasizing the need for new therapies.
2. Tumour invasion into bone is associated with osteoclast and osteoblast recruitment. Osteoclasts secrete acid, collagenases and proteases that demineralize the bone matrix and degrade matricellular proteins. Macrophage colony stimulating factor and receptor activator of NF-κB ligand (RANKL) are important growth factors that support osteoclastogenesis, and they are primarily produced by osteoblasts. Osteoprotegerin is an endogenous decoy receptor of RANKL that inhibits osteoclastogenesis.
3. Bone marrow mesenchymal stem cells are directed along the osteoblast lineage through local factors, such as transforming growth factor-β (TGFβ), bone morphogenetic proteins (BMPs) and WNT proteins. These pathways lead to the expression of three key transcriptional regulators of osteoblast function, including RUNX2. The osteoblast-stimulating activity of metastatic tumour cells is thought to be due to the ability of these cells to express many of the factors that can drive osteoblast formation.
4. Osteoblasts and bone marrow stromal cells may attract metastatic tumour cells to bone and provide a niche through protein interactions that include integrins, such as α4β1–vascular cell adhesion molecule 1; chemokines, such as CXCL12–CXCR4; BMPs; Notch; nestin; and osteopontin. These mechanisms are similar to the physiological recruitment of haematopoietic stem cells.
5. The invasion and growth of metastatic tumour cells in the bone involves the modulation of a large number of genes and proteins that include matrix metalloproteinases, parathyroid hormone-related protein, TGFβ, interleukin-6, Jagged 1–Notch, GLI2, RUNX2, hypoxia-induced growth factor 1α, calcium and the calcium-sensing receptor.
6. Beyond the effects on osteoclasts and osteoblasts, tumours in the bone microenvironment recruit and modulate the function of platelets, myeloid cells, immune cells and nerve cells, and induce the formation of new blood vessels. These changes all help to ensure the growth and survival of metastatic tumour cells in bone and represent important therapeutic targets.
7. Drugs, such as bisphosphonates or RANKL antibodies, that target osteoclastogenesis decrease the incidence of skeletal complications and are the current standard of care for patients with bone metastases. These anti-resorptive agents might also have direct antitumour effects.
8. Advances in our understanding of the basic biology of bone remodelling, biomechanics and haematopoiesis, coupled with the advances in cancer genetics and tumour imaging should yield new therapeutic targets and insights into cancer metastasis in bone.

要点翻译：

1. 骨转移是癌症常见的并发症，通常无法治愈。它们会导致剧烈疼痛、病理性骨折和高钙血症。高达50%使用抗骨吸收药物治疗骨转移的患者会出现新的骨转移灶、骨骼并发症和疾病进展，这凸显了对新疗法的需求。
2. 肿瘤侵犯骨骼与破骨细胞和成骨细胞的募集相关。破骨细胞分泌酸、胶原酶和蛋白酶，使骨基质脱矿质并降解基质细胞蛋白。巨噬细胞集落刺激因子和NF-κB配体受体激活剂（RANKL）是支持破骨细胞生成的重要生长因子，主要由成骨细胞产生。骨保护素是RANKL的内源性诱饵受体，可抑制破骨细胞生成。
3. 骨髓间充质干细胞通过局部因子（如转化生长因子-β（TGFβ）、骨形态发生蛋白（BMP）和WNT蛋白）定向分化为成骨细胞系。这些通路导致成骨细胞功能的三个关键转录调节因子（包括RUNX2）的表达。转移性肿瘤细胞刺激成骨细胞的活性被认为是由于这些细胞能够表达许多驱动成骨细胞形成的因子。
4. 成骨细胞和骨髓基质细胞可能通过蛋白质相互作用（包括整合素，如α4β1–血管细胞黏附分子1；趋化因子，如CXCL12–CXCR4；BMP；Notch；巢蛋白；和骨桥蛋白）将转移性肿瘤细胞吸引至骨骼并提供生态位。这些机制与造血干细胞的生理募集相似。
5. 转移性肿瘤细胞在骨骼中的侵袭和生长涉及大量基因和蛋白质的调节，包括基质金属蛋白酶、甲状旁腺激素相关蛋白、TGFβ、白细胞介素-6、Jagged 1–Notch、GLI2、RUNX2、缺氧诱导生长因子1α、钙和钙敏感受体。
6. 除了对破骨细胞和成骨细胞的影响外，骨微环境中的肿瘤还会募集和调节血小板、髓系细胞、免疫细胞和神经细胞的功能，并诱导新血管的形成。这些变化都有助于确保转移性肿瘤细胞在骨骼中的生长和存活，并代表了重要的治疗靶点。
7. 针对破骨细胞生成的药物，如双膦酸盐或RANKL抗体，可降低骨骼并发症的发生率，是目前骨转移患者的标准治疗方法。这些抗骨吸收药物也可能具有直接的抗肿瘤作用。
8. 我们对骨重塑、生物力学和造血基础生物学理解的进展，加上癌症遗传学和肿瘤影像学的进步，应能产生新的治疗靶点并深化对癌症骨转移的认识。

英文摘要：

When cancer metastasizes to bone, considerable pain and deregulated bone remodelling occurs, greatly diminishing the possibility of cure. Metastasizing tumour cells mobilize and sculpt the bone microenvironment to enhance tumour growth and to promote bone invasion. Understanding the crucial components of the bone microenvironment that influence tumour localization, along with the tumour-derived factors that modulate cellular and protein matrix components of bone to favour tumour expansion and invasion, is central to the pathophysiology of bone metastases. Basic findings of tumour–bone interactions have uncovered numerous therapeutic opportunities that focus on the bone microenvironment to prevent and treat bone metastases.

摘要翻译： 

当癌症转移至骨骼时，会引发剧烈疼痛和骨重塑失调，极大降低治愈的可能性。转移的肿瘤细胞会动员并重塑骨骼微环境，以促进肿瘤生长和骨侵袭。理解骨骼微环境中影响肿瘤定位的关键成分，以及肿瘤衍生因子如何调节骨细胞与蛋白基质以利于肿瘤扩展和侵袭，是骨转移病理生理学的核心。肿瘤-骨相互作用的基础研究已揭示众多治疗靶点，聚焦于骨微环境以预防与治疗骨转移。

原文链接：

Cancer to bone: a fatal attraction