Abnormal blood and lymphatic vessels create a hostile tumor microenvironment characterized by hypoxia, low pH, and elevated interstitial fluid pressure. These abnormalities fuel tumor progression, immunosuppression, and treatment resistance. In 2001, we proposed a novel hypothesis that the judicious use of antiangiogenesis agents-originally developed to starve tumors-could transiently normalize tumor vessels and improve the outcome of anticancer drugs administered during the window of normalization. In addition to providing preclinical and clinical evidence in support of this hypothesis, we also revealed the underlying molecular mechanisms. In parallel, we demonstrated that desmoplasia could also impair vascular function by compressing vessels, and that normalizing the extracellular matrix could improve vascular function and treatment outcome in both preclinical and clinical settings. Here, we summarize the progress made in understanding and applying the normalization concept to cancer and outline opportunities and challenges ahead to improve patient outcomes using various normalizing strategies.

中文翻译：

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肿瘤血管正常化功能：进展，机遇和挑战。

血液和淋巴管异常会形成敌对的肿瘤微环境，其特征为缺氧，pH低和间质液压力升高。这些异常加剧了肿瘤的进展，免疫抑制和治疗抵抗力。在2001年，我们提出了一个新的假设，即合理地使用抗血管生成剂（最初是为了使肿瘤饿死）可以暂时使肿瘤血管正常化，并改善在正常化窗口内施用的抗癌药物的疗效。除了提供支持该假设的临床前和临床证据外，我们还揭示了潜在的分子机制。同时，我们证明了增生还可以通过压迫血管来损害血管功能，在临床前和临床环境中，使细胞外基质正常化可以改善血管功能和治疗效果。在这里，我们总结了在将归一化概念理解和应用到癌症方面取得的进展，并概述了使用各种归一化策略改善患者预后的机会和挑战。