Rogers Michael S, Novak Katherine, Zurakowski David, Cryan Lorna M, Blois Anna, Lifshits Eugene, Bø Trond H, Oyan Anne M, Bender Elise R, Lampa Michael, Kang Soo-Young, Naxerova Kamila, Kalland Karl-Henning, Straume Oddbjorn, Akslen Lars A, Watnick Randolph S, Folkman Judah, Naumov George N
Authors' Affiliations: Departments of Surgery and 2Anesthesia; 3the Vascular Biology Program, Boston Children's Hospital; 4Harvard Medical School, Boston, Massachusetts; 5Department of Microbiology, Haukeland University Hospital; 6Section for Microbiology, The Gade Institute; 7Centre for Cancer Biomarkers CCBIO, Department of Clinical Medicine; and 8Section of Oncology, Institute of Internal Medicine, University of Bergen, Bergen, Norway.
Mol Cancer Res. 2014 May;12(5):754-64. doi: 10.1158/1541-7786.MCR-13-0532-T. Epub 2014 Feb 26.
The angiogenic switch, a rate-limiting step in tumor progression, has already occurred by the time most human tumors are detectable. However, despite significant study of the mechanisms controlling this switch, the kinetics and reversibility of the process have not been explored. The stability of the angiogenic phenotype was examined using an established human liposarcoma xenograft model. Nonangiogenic cells inoculated into immunocompromised mice formed microscopic tumors that remained dormant for approximately 125 days (vs. <40 days for angiogenic cells) whereupon the vast majority (>95%) initiated angiogenic growth with second-order kinetics. These original, clonally derived angiogenic tumor cells were passaged through four in vivo cycles. At each cycle, a new set of single-cell clones was established from the most angiogenic clone and characterized for in vivo for tumorigenic activity. A total of 132 single-cell clones were tested in the second, third, and fourth in vivo passage. Strikingly, at each passage, a portion of the single-cell clones formed microscopic, dormant tumors. Following dormancy, like the original cell line, these revertant tumors spontaneously switched to the angiogenic phenotype. Finally, revertant clones were transcriptionally profiled and their angiogenic output determined. Collectively, these data demonstrate that the angiogenic phenotype in tumors is malleable and can spontaneously revert to the nonangiogenic phenotype in a population of human tumor cells.
Leveraging the rate of reversion to the nonangiogenic phenotype and tumor dormancy may be a novel anticancer strategy.
血管生成开关是肿瘤进展中的限速步骤，在大多数人类肿瘤可检测到时就已经发生。然而，尽管对控制这一开关的机制进行了大量研究，但该过程的动力学和可逆性尚未得到探索。使用已建立的人脂肪肉瘤异种移植模型研究血管生成表型的稳定性。接种到免疫缺陷小鼠体内的非血管生成细胞形成了微小肿瘤，这些肿瘤保持休眠状态约125天（血管生成细胞则小于40天），随后绝大多数（>95%）以二级动力学启动血管生成生长。这些原始的、克隆衍生的血管生成肿瘤细胞经过四个体内周期传代。在每个周期，从血管生成性最强的克隆中建立一组新的单细胞克隆，并对其体内致瘤活性进行表征。在第二、第三和第四次体内传代中总共测试了132个单细胞克隆。令人惊讶的是，在每次传代时，一部分单细胞克隆形成了微小的休眠肿瘤。休眠后，与原始细胞系一样，这些回复性肿瘤会自发转变为血管生成表型。最后，对回复性克隆进行转录谱分析并确定其血管生成输出。总体而言，这些数据表明肿瘤中的血管生成表型具有可塑性，并且在一群人类肿瘤细胞中可以自发地恢复为非血管生成表型。
利用向非血管生成表型的回复率和肿瘤休眠可能是一种新的抗癌策略。
