既往研究发现，转移至肺部的乳腺癌细胞可以长时间处于休眠状态，但是限制其扩散的机制尚不明确。
　　2024年10月7日，全球自然科学三大旗舰期刊之一、美国《细胞》正刊在线发表美国纽约西奈山伊坎医学院和爱因斯坦医学院、英国爱丁堡大学、澳大利亚西澳大学、西班牙国家癌症中心的研究报告，首次发现来源于胚胎时期并且驻留于肺泡组织的巨噬细胞通过诱导休眠可以持续抑制肺泡内乳腺癌继续转移。
　　该研究通过配体与受体映射和体内成像，发现肺泡巨噬细胞可表达转化生长因子β2，并且通过转化生长因子β受体III，与癌细胞持续相互作用，让癌细胞处于休眠状态。耗尽肺泡巨噬细胞或者癌细胞转化生长因子β2受体缺失，可以唤醒转移癌细胞。侵袭性乳腺癌细胞要么被肺泡巨噬细胞抑制，要么通过避免相互作用和下调转化生长因子β2受体逃避该抑制作用。恢复侵袭性乳腺癌细胞转化生长因子β受体III，可以恢复转化生长因子β2引发巨噬细胞产生癌症生长抑制作用。

　　因此，该研究结果表明，肺泡巨噬细胞可以充当乳腺癌转移免疫屏障，诱导并且维持播散至肺部的乳腺癌细胞处于休眠状态，转化生长因子β2信号传导下调，可使癌细胞能够克服巨噬细胞产生癌症生长抑制作用。该研究结果为催眠乳腺癌细胞、避免乳腺癌转移奠定了基础。

Cell. 2024 Oct 7. IF: 45.5
Lung-resident alveolar macrophages regulate the timing of breast cancer metastasis.
Erica Dalla, Michael Papanicolaou, Matthew D. Park, Nicole Barth, Rui Hou, Deisy Segura-Villalobos, Luis Valencia Salazar, Dan Sun, Alistair R.R. Forrest, Maria Casanova-Acebes, David Entenberg, Miriam Merad, Julio A. Aguirre-Ghiso.
Icahn School of Medicine at Mount Sinai, New York, NY, USA; Albert Einstein College of Medicine, Bronx, New York, NY, USA; University of Edinburgh, Edinburgh, UK; The University of Western Australia, Nedlands, WA, Australia; Spanish National Cancer Centre, Madrid, Spain.
HIGHLIGHTS
  • Embryo-derived alveolar macrophages (AMs) induce disseminated cancer cell dormancy
  • Disseminated cancer cells (DCCs) interact frequently with AMs in the lung alveolus
  • DCC dormancy is due to persistent AM-DCC interactions via TGF-β2-TGF-βRIII signaling
  • Loss of AMs or TGF-βRIII in DCCs eliminates an innate immune barrier to metastasis
Breast disseminated cancer cells (DCCs) can remain dormant in the lungs for extended periods, but the mechanisms limiting their expansion are not well understood. Research indicates that tissue-resident alveolar macrophages suppress breast cancer metastasis in lung alveoli by inducing dormancy. Through ligand-receptor mapping and intravital imaging, it was found that alveolar macrophages express transforming growth factor (TGF)-β2. This expression, along with persistent macrophage-cancer cell interactions via the TGF-βRIII receptor, maintains cancer cells in a dormant state. Depleting alveolar macrophages or losing the TGF-β2 receptor in cancer cells triggers metastatic awakening. Aggressive breast cancer cells are either suppressed by alveolar macrophages or evade this suppression by avoiding interaction and downregulating the TGF-β2 receptor. Restoring TGF-βRIII in aggressive cells reinstates TGF-β2-mediated macrophage growth suppression. Thus, alveolar macrophages act as a metastasis immune barrier, and downregulation of TGF-β2 signaling allows cancer cells to overcome macrophage-mediated growth suppression.
KEYWORDS: breast cancer, lung metastasis, dormancy, reawakening, homeostasis, alveolar macrophage, intravital imaging, TGFβ2, TGFβR3
DOI: 10.1016/j.cell.2024.09.016