Causes and effects of heterogeneous perfusion in tumors
Causes and effects of heterogeneous perfusion in tumors
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DOI：
10.1038/sj.neo.7900037
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发表时间：
1999-08-01
期刊：
影响因子：
--
通讯作者：
Raghunand, Natarajan
中科院分区：
文献类型：
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作者：
Gillies, Robert J.;Schornack, Paul A.;Raghunand, Natarajan
实体瘤的一个特征是血流分布不均，在低血流区域有明显的缺氧和酸度。我们回顾了异质性肿瘤血流灌注的影响，并提出了其原因的概念性模型。低氧酸性区域对化疗和放射治疗有抵抗力，并可能刺激进展为更多的转移表型。在正常组织中，低氧和酸性诱导血管生成，这有望改善血流灌注。然而，侵袭性肿瘤可以有高的局部微血管密度，同时伴有明显的缺氧和酸中毒。对这一明显矛盾的可能解释是，调节血管网络生长和适应的机制受到了损害。根据最近关于血管网络结构适应的理论，四个相互关联的适应反应可以作为一个自我调节系统，在正常组织中产生一个成熟而有效的血液分配系统。有人认为，肿瘤的不均匀血流可能是由于这一系统的扰动造成的。血管生成可能通过增加平行的低阻力和高阻力血流通路之间的差异来增加肿瘤的灌注异质性。这一概念模型为未来的合理治疗提供了基础。例如，它表明选择性破坏肿瘤血管可能会增加灌注效率，改善治疗效果。
A characteristic of solid tumors is their heterogeneous distribution of blood flow, with significant hypoxia and acidity in low-flow regions. We review effects of heterogeneous tumor perfusion are reviewed and propose a conceptual model for its cause. Hypoxicacidic regions are resistant to chemo- and radiotherapy and may stimulate progression to a more metastatic phenotype. In normal tissues, hypoxia and acidity induce angiogenesis, which is expected to improve perfusion. However, aggressive tumors can have high local microvessel density simultaneously with significant regions of hypoxia and acidosis. A possible explanation for this apparent contradiction is that the mechanisms regulating growth and adaptation of vascular networks are impaired. According to a recent theory for structural adaptation of vascular networks, four interrelated adaptive responses can work as a self-regulating system to produce a mature and efficient blood distribution system in normal tissues. It is proposed that heterogeneous perfusion in tumors may result from perturbation of this system. Angiogenesis may increase perfusion heterogeneity in tumors by increasing the disparity between parallel low- and high-resistance flow pathways. This conceptual model provides a basis for future rational therapies. For example, it indicates that selective destruction of tumor vasculature may increase perfusion efficiency and improve therapeutic efficacy.