Targeting the perivascular niche sensitizes disseminated tumour cells to chemotherapy
Targeting the perivascular niche sensitizes disseminated tumour cells to chemotherapy
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DOI：
10.1038/s41556-018-0267-0
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发表时间：
2019-02-01
影响因子：
21.3
通讯作者：
Ghajar, Cyrus M.
中科院分区：
文献类型：
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作者：
Carlson, Patrick;Dasgupta, Arko;Ghajar, Cyrus M.
骨髓中存在播散性肿瘤细胞（DTC）可预测局部乳腺癌患者的无转移生存率。尽管全身给予辅助化疗，DTC仍持续存在于远处组织中。许多人认为这是因为大多数DTC是静止的。在这里，我们挑战这一概念，并提供证据表明，DTC的微环境保护他们免受化疗，独立于细胞周期状态。我们发现，化疗耐药DTC占据血管周围的壁龛（PVN）的远端组织，在那里他们的治疗血管内皮细胞的保护。抑制整合素介导的DTC和PVN之间的相互作用（部分由内皮源性血管性血友病因子和血管细胞粘附分子1驱动），可使DTC对化疗敏感。重要的是，在不诱导DTC增殖或加重化疗相关毒性的情况下实现化学增敏，并最终导致预防骨转移。这表明，预先使用整合素抑制剂进行辅助治疗是根除DTC和预防转移的可行临床策略。
The presence of disseminated tumour cells (DTCs) in bone marrow is predictive of poor metastasis-free survival of patients with breast cancer with localized disease. DTCs persist in distant tissues despite systemic administration of adjuvant chemotherapy. Many assume that this is because the majority of DTCs are quiescent. Here, we challenge this notion and provide evidence that the microenvironment of DTCs protects them from chemotherapy, independent of cell cycle status. We show that chemoresistant DTCs occupy the perivascular niche (PVN) of distant tissues, where they are protected from therapy by vascular endothelium. Inhibiting integrin-mediated interactions between DTCs and the PVN, driven partly by endothelial-derived von Willebrand factor and vascular cell adhesion molecule 1, sensitizes DTCs to chemotherapy. Importantly, chemosensitization is achieved without inducing DTC proliferation or exacerbating chemotherapy-associated toxicities, and ultimately results in prevention of bone metastasis. This suggests that prefacing adjuvant therapy with integrin inhibitors is a viable clinical strategy to eradicate DTCs and prevent metastasis.