Role of angiogenesis in human tumor dormancy - Animal models of the angiogenic switch
Role of angiogenesis in human tumor dormancy - Animal models of the angiogenic switch
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DOI：
10.4161/cc.5.16.3018
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发表时间：
2006-08-15
期刊：
影响因子：
4.3
通讯作者：
Folkman, Judah
中科院分区：
文献类型：
--
作者：
Naumov, George N.;Akslen, Lars A.;Folkman, Judah
肿瘤进展取决于连续事件，包括向血管生成表型的转变（即血管的初始募集）。微观肿瘤未能完成这一过程中的一个或多个早期步骤可能会导致癌症的临床表现延迟。微小的人类癌症可以在人的一生中保持无症状、不可检测和隐匿的状态。临床和实验证据表明，人类肿瘤可以作为处于休眠状态（即肿瘤块不扩张）的微小病变持续很长一段时间。因为众所周知，超过 1-2 毫米大小的肿瘤生长依赖于血管生成，因此我们假设大肿瘤的出现归因于在其他微观休眠肿瘤中向血管生成表型的转变。尽管在临床上很重要，但人类肿瘤休眠的生物学却知之甚少。本文将总结动物模型的发展，这些模型概括了临床观察到的休眠肿瘤转变为血管生成表型的时间和比例。还总结了血管生成开关中涉及的分子机制以及从异质人类肿瘤细胞系或手术标本中分离血管生成和非血管生成肿瘤细胞群的不同策略。几种成像技术已用于定性和定量检测小鼠的显微肿瘤，并讨论了它们的优点和局限性。这里使用的动物模型允许对血管生成开关进行进一步研究。这些模型还允许开发基于血管生成的血液和尿液生物标志物组，这些生物标志物可以量化并用于在血管生成转换之前或期间检测微小肿瘤。如果从这些动物模型中获得的信息可以转化为临床，那么未来就有可能在癌症出现症状和可检测之前数年，将癌症的治疗从对解剖部位的依赖中解放出来。
Tumor progression depends on sequential events, including a switch to the angiogenic phenotype (i.e.,initial recruitment of blood vessels). Failure of a microscopic tumor to complete one or more early steps in this process may lead to delayed clinical manifestation of the cancer. Microscopic human cancers can remain in an asymptomatic, nondetectable, and occult state for the life of a person. Clinical and experimental evidence suggest that human tumors can persist for long periods of time as microscopic lesions that are in a state of dormancy (i.e., not expanding in tumor mass). Because it is well established that tumor growth beyond the size of 1-2 mm is angiogenesis-dependent, we hypothesized that presentation of large tumors is attributed to a switch to the angiogenic phenotype in otherwise microscopic, dormant tumors. Although clinically important, the biology of human tumor dormancy is poorly understood. The development of animal models which recapitulate the clinically observed timing and proportion of dormant tumors which switch to the angiogenic phenotype are reviewed here. The contributing molecular mechanisms involved in the angiogenic switch and different strategies for isolation of both angiogenic and non-angiogenic tumor cell populations from otherwise heterogeneous human tumor cell lines or surgical specimens are also summarized. Several imaging techniques have been utilized for the qualitative and quantitative detection of microscopic tumors in mice and their strengths and limitations are discussed. The animal models employed here permitted further studies of the angiogenic switch. These models also allowed development of an angiogenesis-based panel of blood and urine biomarkers that can be quantified and used to detect microscopic tumors before or during the angiogenic switch. If the information obtained from these animal models is translatable to the clinic, it may be possible in the future to liberate the management of cancer from a dependency on anatomical site years before it becomes symptomatic and detectable.