INSERM, U848, Villejuif, France.
Science. 2012 Sep 28;337(6102):1678-84. doi: 10.1126/science.1224922.
Cancer cells accommodate multiple genetic and epigenetic alterations that initially activate intrinsic (cell-autonomous) and extrinsic (immune-mediated) oncosuppressive mechanisms. Only once these barriers to oncogenesis have been overcome can malignant growth proceed unrestrained. Tetraploidization can contribute to oncogenesis because hyperploid cells are genomically unstable. We report that hyperploid cancer cells become immunogenic because of a constitutive endoplasmic reticulum stress response resulting in the aberrant cell surface exposure of calreticulin. Hyperploid, calreticulin-exposing cancer cells readily proliferated in immunodeficient mice and conserved their increased DNA content. In contrast, hyperploid cells injected into immunocompetent mice generated tumors only after a delay, and such tumors exhibited reduced DNA content, endoplasmic reticulum stress, and calreticulin exposure. Our results unveil an immunosurveillance system that imposes immunoselection against hyperploidy in carcinogen- and oncogene-induced cancers.
癌细胞适应多种遗传和表观遗传改变，最初激活内在（细胞自主）和外在（免疫介导）的肿瘤抑制机制。只有当这些致癌的障碍被克服后，恶性生长才能不受限制地进行。四倍体化可能有助于肿瘤发生，因为多倍体细胞在基因组上不稳定。我们报告说，由于内质网应激反应导致钙网蛋白在细胞表面异常暴露，多倍体细胞成为免疫原性的。多倍体、钙网蛋白暴露的癌细胞在免疫缺陷小鼠中容易增殖，并保持其增加的 DNA 含量。相比之下，注射到免疫功能正常的小鼠中的多倍体细胞在延迟后才形成肿瘤，而且这些肿瘤的 DNA 含量、内质网应激和钙网蛋白暴露减少。我们的结果揭示了一种免疫监视系统，该系统对致癌物和致癌基因诱导的癌症中的多倍体施加免疫选择。
