Tumor-associated angiogenesis: mechanisms, clinical implications, and therapeutic strategies.
Tumor-associated angiogenesis: mechanisms, clinical implications, and therapeutic strategies.
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作者：
J. Pluda
令人信服的数据表明，血管生成和肿瘤相关的新生血管是肿瘤生长、侵袭和转移过程中的核心致病步骤。这些复杂的过程涉及多个步骤和途径，依赖于正、负调节因子之间的局部平衡，以及肿瘤、其血管系统和周围细胞外组织基质之间的相互作用。肿瘤处于休眠状态，细胞增殖率与凋亡率平衡，在没有获得性血管生成表型的情况下，肿瘤的大小不能超过几毫米。肿瘤转向血管生成表型的机制尚不清楚。正在设计治疗药物和策略，以中断或抑制肿瘤新生过程中涉及的一个或多个致病步骤，或直接靶向和破坏肿瘤血管系统。影响替代机制无法规避的最终靶点或途径的治疗可能显著提高疗效并扩大适用性。这些方法可能导致小的无血管肿瘤维持在休眠状态，或者可能与细胞毒性治疗相结合，它们可能会增强肿瘤的收缩，并维持肿瘤处于休眠状态。随着更强大的抗血管生成药物的开发，甚至这些休眠的微观病灶也可能被根除。抗血管生成药物和策略不同于通常的癌症治疗方法；因此，研究人员必须为临床开发的药物设计新的范例，这些药物可能对肿瘤只有静态作用，需要长期、慢性给药。需要对这些化合物在患者体内的生物活性进行评估。最终，抗血管生成疗法可能会提供一种新的癌症治疗方法，适合与标准疗法相结合。
Compelling data implicate angiogenesis and tumor-associated neovascularization as a central pathogenic step in the process of tumor growth, invasion, and metastasis. These complex processes involve multiple steps and pathways dependent on the local balance between positive and negative regulatory factors, as well as interactions among the tumor, its vasculature, and the surrounding extracellular tissue matrix. A tumor remains in a dormant state, the cellular proliferation rate balanced by the apoptotic rate, unable to grow in size beyond a few millimeters in the absence of the acquired angiogenic phenotype. The mechanism by which tumors switch to the angiogenic phenotype is unknown. Therapeutic agents and strategies are being devised either to interrupt or inhibit one or more of the pathogenic steps involved in the process of tumor neovascularization or to directly target and destroy the tumor vasculature. Therapies affecting an end target or pathway that cannot be circumvented by alternate mechanisms may significantly enhance efficacy and broaden applicability. These approaches may result in small, avascular tumors maintained in a dormant state or, perhaps in combination with cytotoxic therapies, they may potentiate shrinkage of tumors to, and maintain them, in a dormant state. As more powerful antiangiogenic agents are developed, perhaps even these dormant microscopic foci may be eradicated. Antiangiogenesis agents and strategies differ from the usual cancer therapeutic approaches; therefore, investigators must devise new paradigms for the clinical development of agents that may only have a static effect on tumors and require prolonged, chronic administration. Methods to assess the in vivo biologic activity of these compounds in patients are needed. Ultimately, antiangiogenic therapy may provide an additional novel cancer treatment suitable for combination with standard therapies.