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原发肿瘤切除后，全身血液循环仍然残存着无法被检测到的播散性肿瘤细胞，给癌症治疗带来了重大挑战。这些持续休眠的播散性肿瘤细胞，成为癌症将来复发转移的孽种，将其从休眠状态唤醒的具体机制尚不明确。由于癌症休眠机制为预防转移提供了独特的治疗机会，故有必要全面了解休眠肿瘤细胞库的分布、组成及其动态变化。 2021年6月2日，全球自然科学三大旗舰期刊之首、英国《自然》正刊在线发表瑞士巴塞尔大学、巴塞尔大学医院、巴塞尔州立医院的研究报告，发现自然杀伤细胞可引起乳腺癌休眠，而肝脏星状细胞可抑制自然杀伤细胞所致乳腺癌休眠。 自然杀伤细胞又称天然杀伤细胞或大颗粒淋巴细胞，不需预先接触抗原，就可杀伤病毒感染细胞或肿瘤细胞，是人体抗病毒、抗肿瘤的重要免疫机制。肝脏星状细胞又称肝窦周围细胞、伊东细胞，由日本群马大学伊东俊夫教授于1956年发现，位于肝窦血管与肝脏细胞之间的窦周间隙，正常状态处于静止期，主要储存脂肪和维生素A，受到炎症刺激后，可引起肝脏纤维化。 该研究首先发现，不同的组织特定微环境可抑制或允许乳腺癌发生肝转移，通常与不良预后密切相关。 随后，该研究将人类三阴性乳腺癌MDA-MB-231转移细胞和休眠细胞、小鼠三阴性乳腺癌转移细胞4T1和休眠细胞4T07分别注入小鼠体内建立肿瘤模型，发现三阴性乳腺癌休眠细胞周围的自然杀伤细胞显著较多。肿瘤切除术后，利用白细胞介素15进行免疫治疗，可确保自然杀伤细胞大量增殖，并通过γ干扰素→乳腺癌细胞表面γ干扰素受体信号传导，维持乳腺癌细胞休眠，从而防止肝转移，并延长生存时间。 肝脏共培养物蛋白质组学研究表明，被激活的肝脏星状细胞可分泌大量趋化因子12，通过自然杀伤细胞表面的趋化因子受体4，抑制自然杀伤细胞增殖，乳腺癌细胞继而退出休眠状态。 此外，肝转移患者与未转移患者相比，趋化因子12表达水平、被激活的肝脏星状细胞丰度显著较高。 因此，该研究结果表明，自然杀伤细胞与肝星状细胞之间的相互作用，是三阴性乳腺癌细胞休眠的主要开关，针对自然杀伤细胞、白细胞介素15及其受体、γ干扰素及其受体、肝星状细胞、趋化因子12以及趋化因子受体4的靶向药物，有望成功防治三阴性乳腺癌细胞转移生长的新方法。 对此，法国马赛大学发表同期报道：自然杀伤细胞让肿瘤进入休眠。 Nature. 2021 Jun 2. Online ahead of print. Hepatic stellate cells suppress NK cell-sustained breast cancer dormancy. Ana Luísa Correia, Joao C. Guimaraes, Priska Auf der Maur, Duvini De Silva, Marcel P. Trefny, Ryoko Okamoto, Sandro Bruno, Alexander Schmidt, Kirsten Mertz, Katrin Volkmann, Luigi Terracciano, Alfred Zippelius, Marcus Vetter, Christian Kurzeder, Walter Paul Weber, Mohamed Bentires-Alj. University of Basel, Basel, Switzerland; Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland; University Hospital Basel, Basel, Switzerland; Institute of Pathology Liestal, Cantonal Hospital Basel-Land, Liestal, Switzerland. The persistence of undetectable disseminated tumour cells (DTCs) after primary tumour resection poses a major challenge to effective cancer treatment. These enduring dormant DTCs are seeds of future metastases, and the mechanisms that switch them from dormancy to outgrowth require definition. Because cancer dormancy provides a unique therapeutic window for preventing metastatic disease, a comprehensive understanding of the distribution, composition and dynamics of reservoirs of dormant DTCs is imperative. Here we show that different tissue-specific microenvironments restrain or allow the progression of breast cancer in the liver—a frequent site of metastasis that is often associated with a poor prognosis. Using mouse models, we show that there is a selective increase in natural killer (NK) cells in the dormant milieu. Adjuvant interleukin-15-based immunotherapy ensures an abundant pool of NK cells that sustains dormancy through interferon-γ signalling, thereby preventing hepatic metastases and prolonging survival. Exit from dormancy follows a marked contraction of the NK cell compartment and the concurrent accumulation of activated hepatic stellate cells (aHSCs). Our proteomics studies on liver co-cultures implicate the aHSC-secreted chemokine CXCL12 in the induction of NK cell quiescence through its cognate receptor CXCR4. CXCL12 expression and aHSC abundance are closely correlated in patients with liver metastases. Our data identify the interplay between NK cells and aHSCs as a master switch of cancer dormancy, and suggest that therapies aimed at normalizing the NK cell pool might succeed in preventing metastatic outgrowth. DOI: 10.1038/s41586-021-03614-z Nature. 2021 Jun 2. Online ahead of print. Natural killer cells lull tumours into dormancy. Noella Lopes, Eric Vivier. Aix Marseille University, Marseille, France. Natural killer cells can drive spreading cancer cells to enter a state of dormancy. That finding, together with the discovery of a pathway that hinders this antitumour function, could spur the development of new treatments. DOI: 10.1038/d41586-021-01381-5
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