乳腺癌是女性主要的恶性肿瘤。肿瘤细胞扩散后的归宿，很大程度上取决于肿瘤细胞所处的微环境。乳腺癌骨转移通常发生于原发肿瘤切除和辅助治疗多年后，表明特殊的骨微环境可能引起治疗耐药和肿瘤重新生长。
2018年11月12日，美国《细胞》旗下《癌细胞》发表中国上海交通大学医学院附属仁济医院、上海市肿瘤研究所、中日友好医院、美国贝勒医学院、休斯敦卫理公会医院研究所、德克萨斯大学的研究报告，发现成骨细胞微环境能够为乳腺癌骨转移细胞提供钙源，并且具有意想不到的治疗效果。
该研究发现，成骨细胞微环境可以促进癌细胞增殖和骨转移恶化，除了已经确定的哺乳动物雷帕霉素靶蛋白（mTOR）信号转导作用之外，从成骨细胞向癌细胞的钙流入对于早期骨转移癌细胞增殖至关重要。骨转移与其他转移相比，钙信号转导增强。癌细胞无法有效地从微环境吸收钙，但是可以依靠成骨细胞直接钙内流，增加癌细胞内的钙离子浓度。该研究利用临床前模型和临床数据分析，对其潜在机制进行了探讨，发现成骨细胞微环境通过细胞间隙连接成为癌细胞的钙储备库。钙信号转导与既往确定的mTOR信号转导一起促进骨转移恶化。该研究对抑制这两种信号转导通路的治疗药物进行靶向分析，确定达那色替（达努舍替）和三氧化二砷可以作为有效候选药物，通过抑制钙信号转导，抑制潜伏癌细胞的骨转移。达那色替目前正在进行临床开发，而三氧化二砷是美国食品药品管理局已经批准的白血病治疗药物，这些药物对骨微转移的优先作用可以立即用于消除骨髓潜伏癌细胞并且减少转移复发。
因此，该研究表明，通过达那色替或依维莫司联合三氧化二砷，可以有效抑制这些信号转导通路，这提供了利用临床已知药物消除骨微转移的可能性。
Cancer Cell. 2018 Nov 12;34(5):823-839.e7.
The Osteogenic Niche Is a Calcium Reservoir of Bone Micrometastases and Confers Unexpected Therapeutic Vulnerability.
Hai Wang, Lin Tian, Jun Liu, Amit Goldstein, Igor Bado, Weijie Zhang, Benjamin R. Arenkiel, Zonghai Li, Meng Yang, Shiyu Du, Hong Zhao, David R. Rowley, Stephen T.C. Wong, Zbigniew Gugala, Xiang H.-F. Zhang.
Baylor College of Medicine, Houston, TX, USA; Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; China-Japan Friendship Hospital, Beijing, China; Houston Methodist Research Institute, Houston, TX, USA; University of Texas Medical Branch, Galveston, TX, USA.
HIGHLIGHTS
Calcium signaling is enhanced in bone metastasis compared with other metastases
Cancer cells rely on direct calcium influx from osteogenic cells to increase [Ca 2+]
Gap junctions mediate Ca 2+ flow from osteogenic cells to cancer cells
As2O3 suppresses latent bone metastasis by inhibiting calcium signaling
The fate of disseminated tumor cells is largely determined by microenvironment (ME) niche. The osteogenic niche promotes cancer cell proliferation and bone metastasis progression. We investigated the underlying mechanisms using pre-clinical models and analyses of clinical data. We discovered that the osteogenic niche serves as a calcium (Ca) reservoir for cancer cells through gap junctions. Cancer cells cannot efficiently absorb Ca from ME, but depend on osteogenic cells to increase intracellular Ca concentration. The Ca signaling, together with previously identified mammalian target of rapamycin signaling, promotes bone metastasis progression. Interestingly, effective inhibition of these pathways can be achieved by danusertib, or a combination of everolimus and arsenic trioxide, which provide possibilities of eliminating bone micrometastases using clinically established drugs.
Breast cancer bone metastasis often occurs asynchronously, years after primary tumor resection and adjuvant therapies, suggesting mechanisms driving therapeutic resistance and tumor re-growth specifically in the bone ME. We discovered that Ca influx from the osteogenic niche to cancer cells is essential for proliferation of early-stage bone metastasis, in addition to the previously identified role of mTOR signaling. We performed target-driven search for therapeutic agents inhibiting both pathways and identified danusertib and arsenic trioxide as potent candidates. Danusertib is currently under clinical development. Arsenic trioxide is an FDA-approved drug for leukemia. The preferential efficacies of these drugs on BMM argue for immediate applications to eliminate latent cancer cells in the bone marrow and reduce metastasis recurrences.
KEYWORDS: micrometastasis; bone metastasis; microenvironment; the osteogenic niche; therapeutic responses; drug discovery or repositioning; breast cancer; prostate cancer; calcium signaling; gap junctions
DOI: 10.1016/j.ccell.2018.10.002
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