Deciphering Cancer and Bone Interactions for Therapeutic Benefits.
Deciphering Cancer and Bone Interactions for Therapeutic Benefits.
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破译癌症和骨骼的相互作用以获得治疗效果。
DOI：
10.1002/jbm4.10137
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发表时间：
2019
期刊：
影响因子：
3.8
通讯作者：
Roodman,GDavid
中科院分区：
文献类型：
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作者：
Roodman,GDavid
骨是肿瘤转移最常见的部位之一，在美国有280,000例患者存在骨转移。它是乳腺癌和前列腺癌转移的首选部位。此外，许多其他类型的癌症转移到骨骼，包括甲状腺、肾脏和肺部。尽管骨转移在血液学恶性肿瘤患者中极为罕见，但多发性骨髓瘤是最常见的累及骨的癌症，高达90%的患者在其病程中累及骨。癌症对骨骼的影响对患者有着可怕的后果，包括即使在癌症缓解后仍会持续的剧烈骨痛，频繁的病理性骨折，脊髓压迫，可能危及生命的高钙血症，以及对患者生活质量和生存产生负面影响的全身肌肉无力。此外，一旦癌症涉及到骨骼，病人就很难治愈。因此，了解骨转移的机制，当癌症涉及骨骼时，正常骨重塑过程中发生的异常会增加肿瘤的生长和对化疗的耐药性，以及骨骼如何作为休眠肿瘤细胞的储存库，这些细胞可以被重新激活形成主动转移，并可以转移到远处的器官，这些都是重要的研究领域。在过去的几年中，我们对骨转移的机制，骨中不同细胞类型对转移过程的贡献以及骨转移的代谢后果的理解取得了很大进展。这种对骨转移过程的理解的增加导致了预防和治疗骨转移的新治疗靶点的确定，这可能会转化为临床。在这期《JBMR +癌症与骨》特刊中，我们邀请了该领域公认的专家来讨论一些令人兴奋的新结果，这些新结果扩展了我们对骨骼为何是转移的首选部位，肿瘤衍生因子如何破坏正常的骨重塑过程，以及肿瘤细胞和骨细胞如何建立有利于弥散性肿瘤细胞在骨上定植的转移前生态位的理解。这些散布在骨骼上的肿瘤细胞可以逃避治疗的影响，在被重新激活之前可以在休眠状态下存活很长一段时间。新的信息也提供了在多发性骨髓瘤中发生的长时间成骨细胞抑制的机制，这使得溶骨病变即使在没有活动性疾病的情况下也能持续存在。了解这一过程是非常重要的，因为目前的抗吸收治疗几乎没有骨合成代谢作用，可以修复骨髓瘤中的骨病变。最近的研究表明，表观遗传学机制在骨髓瘤诱导的成骨细胞分化抑制的建立和持续中起着重要作用。这些结果很重要，因为已经有药物可以缓解骨髓瘤动物模型和患者的成骨细胞抑制。此外，最近的研究已经确定骨细胞在骨转移，特别是骨髓瘤骨病中的重要作用。骨髓瘤细胞与骨细胞之间的双向Notch信号通路激活骨髓瘤细胞生长，诱导骨细胞凋亡，导致硬化蛋白和RANK配体生成增加，抑制成骨细胞分化，刺激骨破坏。此外，骨破坏过程可引起严重的全身肌肉无力，由于从骨中释放活性TGF-b。TGF-b可以刺激……
Bone is one of the most frequent sites for tumor metastasis with 280,000 patients in the US living with bone metastasis. It is the preferred site for metastasis caused by breast cancer and prostate cancer. In addition, many other types of cancer metastasize to bone, including thyroid, kidney, and lung. Although bone metastasis is extremely rare in patients with hematologic malignancies, multiple myeloma is the most frequent cancer to involve bone, with up to 90% of patients having bone involvement during the course of their disease. Bone involvement by cancer has horrific consequences for patients, including excruciating bone pain that can persist even after the cancer is in remission, frequent pathologic fractures, spinal cord compression, hypercalcemia that can be life threatening, and systemic muscle weakness that negatively impacts patientsL quality of life and survival. Further, once cancer involves bone, patients are rarely curable. Thus, understanding the mechanisms responsible for bone metastasis, the abnormalities that occur in the normal bone remodeling process that increase tumor growth and resistance to chemotherapy when cancer involves bone, and how bone serves as a reservoir for dormant tumor cells that can be reactivated to form active metastasis, which can go to distant organs, represent important areas of research. Much progress has been made over the last several years in our understanding of the mechanisms responsible for bone metastasis, the contribution of different cell types in bone to the metastatic process, and the metabolic consequences of bone metastasis. This increased understanding of the bone metastatic process has resulted in identification of new therapeutic targets for preventing and treating bone metastasis, which may be translatable to the clinic. In this special issue of JBMR Plus on Cancer and Bone, we invited recognized experts in thefield to discuss some of these exciting new results that expand our understanding of why bone is a preferential site for metastasis, how tumor-derived factors disrupt the normal bone remodeling process, and how tumor cells and bone cells establish a premetastatic niche that favors bone colonization by disseminated tumor cells. These disseminated tumor cells that colonize bone can evade the effects of treatment and survive for very prolonged periods of time in a dormant state before being reactivated. New information is also provided on the mechanisms responsible for the prolonged osteoblast suppression that occurs in multiple myeloma, which allows osteolytic lesions to persist even in the absence of active disease. Understanding this process is extremely important because current antiresorptive therapies have little bone anabolic effects that can repair bone lesions in myeloma. Recent studies have shown that epigenetic-based mechanisms play an important role in the establishment and persistence of myeloma-induced suppression of osteoblast differentiation. These results are important because agents are already available that can relieve osteoblast suppression in myeloma in animal models and possibly patients as well. Further, recent studies have identified an important role for osteocytes in bone metastasis and in particular in myeloma bone disease. Bidirectional Notch signaling between myeloma cells and osteocytes activates myeloma cell growth and induces osteocyte apoptosis, which results in increased sclerostin and RANK ligand production, to suppress osteoblast differentiation and stimulate bone destruction. Further, the bone-destructive process can induce profound systemic muscle weakness due to release of active TGF-b from bone. TGF-b can stimulate …