Almog Nava, Henke Vanessa, Flores Ludmila, Hlatky Lynn, Kung Andrew L, Wright Renee D, Berger Raanan, Hutchinson Lloyd, Naumov George N, Bender Elise, Akslen Lars A, Achilles Eike-Gert, Folkman Judah
Vascular Biology Program and Department of Surgery, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts 02115, USA.
FASEB J. 2006 May;20(7):947-9. doi: 10.1096/fj.05-3946fje. Epub 2006 Apr 25.
The disease state of cancer appears late in tumor development. Before being diagnosed, a tumor can remain for prolonged periods of time in a dormant state. Dormant human cancer is commonly defined as a microscopic tumor that does not expand in size and remains asymptomatic. Dormant tumors represent an early stage in tumor development and may therefore be a potential target for nontoxic, antiangiogenic therapy that could prevent tumor recurrence. Here, we characterize an experimental model that recapitulates the clinical dormancy of human tumors in mice. We demonstrate that these microscopic dormant cancers switch to the angiogenic phenotype at a predictable time. We further show that while angiogenic liposarcomas expand rapidly after inoculation of tumor cells in mice, nonangiogenic dormant liposarcomas remain microscopic up to one-third of the normal severe combined immune deficiency (SCID) mouse life span, although they contain proliferating tumor cells. Nonangiogenic dormant tumors follow a similar growth pattern in subcutaneous (s.c.) and orthotopic environments. Throughout the dormancy period, development of intratumoral vessels is impaired. In nonangogenic dormant tumors, small clusters of endothelial cells without lumens are observed early after tumor cell inoculation, but the nonangiogenic tumor cannot sustain these vessels, and they disappear within weeks. There is a concomitant decrease in microvessel density, and the nonangiogenic dormant tumor remains harmless to the host. In contrast, microvessel density in tumors increases rapidly after the angiogenic switch and correlates with rapid expansion of tumor mass. Both tumor types cultured in vitro contain fully transformed cells, but only cells from the nonangiogenic human liposarcoma secrete relatively high levels of the angiogenesis inhibitors thrombospondin-1 and TIMP-1. This model suggests that as improved blood or urine molecular biomarkers are developed, the microscopic, nonangiogenic, dormant phase of human cancer may be vulnerable to antiangiogenic therapy years before symptoms, or before anatomical location of a tumor can be detected, by conventional methods.
癌症的疾病状态在肿瘤发展后期才出现。在被诊断之前，肿瘤可能会在休眠状态下持续很长时间。休眠的人类癌症通常被定义为一种微观肿瘤，其大小不会扩大且无症状。休眠肿瘤代表肿瘤发展的早期阶段，因此可能是无毒抗血管生成疗法的潜在靶点，这种疗法可以预防肿瘤复发。在此，我们描述了一种在小鼠中重现人类肿瘤临床休眠的实验模型。我们证明这些微观休眠癌在可预测的时间转变为血管生成表型。我们进一步表明，虽然血管生成性脂肪肉瘤在小鼠接种肿瘤细胞后迅速生长，但非血管生成性休眠脂肪肉瘤在高达正常严重联合免疫缺陷（SCID）小鼠寿命三分之一的时间内仍保持微观状态，尽管它们含有增殖的肿瘤细胞。非血管生成性休眠肿瘤在皮下（s.c.）和原位环境中遵循相似的生长模式。在整个休眠期，肿瘤内血管的发育受到损害。在非血管生成性休眠肿瘤中，在接种肿瘤细胞后早期可观察到无管腔的小簇内皮细胞，但非血管生成性肿瘤无法维持这些血管，它们在数周内消失。微血管密度随之降低，非血管生成性休眠肿瘤对宿主仍然无害。相比之下，在血管生成转变后肿瘤中的微血管密度迅速增加，并与肿瘤块的快速生长相关。两种在体外培养的肿瘤类型都含有完全转化的细胞，但只有来自非血管生成性人类脂肪肉瘤的细胞分泌相对高水平的血管生成抑制剂血小板反应蛋白-1和基质金属蛋白酶组织抑制剂-1。该模型表明，随着血液或尿液分子生物标志物的改进，人类癌症的微观、非血管生成性休眠期在出现症状之前，或在通过传统方法检测到肿瘤的解剖位置之前数年，可能对抗血管生成疗法敏感。
