文章：

FLT1及其配体VEGFB和PlGF：抗血管生成治疗的药物靶点？

FLT1 and its ligands VEGFB and PlGF: drug targets for anti-angiogenic therapy?

原文发布日期：2008-12-01

DOI: 10.1038/nrc2524

类型: Review Article

开放获取: 否

要点：

1. Angiogenesis inhibitors that target vascular endothelial growth factor (VEGF) signalling pathways have proved successful for the clinical treatment of various types of cancer. However, a substantial fraction of tumours is resistant or escapes current anti-angiogenic therapies. Moreover, VEGFA is a trophic factor for healthy vessels, and therefore anti-angiogenic therapies cause side effects that although well managed, can also lead to life-threatening conditions in a subset of patients with cancer.
2. VEGFR2 (also known as FLK1) is the primary receptor that binds VEGFA, and therefore controls angiogenesis in both healthy and diseased tissues. By contrast, VEGFR1 (also known as FLT1) binds VEGFA, VEGFB and placental growth factor (PlGF). The expression of FLT1 and its two ligands, PlGF and VEGFB, is increased in various tumours, which correlates with disease progression and can predict poor prognosis, metastasis and recurrent disease in humans.
3. PlGF signals directly through FLT1 in various cell types, including endothelial cells, smooth-muscle cells, fibroblasts, angiogenesis-competent myeloid progenitors, macrophages and tumour cells, and thereby promotes tumour angiogenesis, lymphangiogenesis, tumour growth and the formation of the premetastatic niche. Therefore deletion of tyrosine-kinase activity in Flt1^TK−/− mice or treatment with FLT1- and PlGF-specific inhibitors, such as a monoclonal antibody against PlGF (αPlGF), impairs inflammation and pathological angiogenesis, and suppresses tumour growth and metastasis.
4. Myeloid cells confer resistance to therapies that target VEGF by secreting additional pro-angiogenic factors. αPlGF enhances the responsiveness to VEGF-targeted therapies by inhibiting macrophage recruitment. Therefore, owing to its complementary activities, αPlGF eliminates the source of angiogenic factors that contributes to anti-angiogenic escape of tumours.
5. Gene-deletion studies have revealed that PlGF is redundant for vascular development and physiological vessel maintenance in healthy adults, but contributes to the angiogenic and inflammatory switch in cancer. In support of the concept that PlGF is a disease-specific factor, αPlGF selectively inhibits pathological angiogenesis without affecting healthy vessels and thus does not cause the side effects that are typically observed during current anti-angiogenic therapies.
6. Genetic and pharmacological studies have thus identified FLT1 and PlGF as attractive therapeutic targets for anticancer therapy, which might provide an answer to some of the challenges and unmet needs that are faced by current anti-angiogenic therapies: how to increase efficacy, avoid resistance and minimize toxicity.

要点翻译：

1. 靶向血管内皮生长因子（VEGF）信号通路的血管生成抑制剂已被成功应用于多种癌症的临床治疗。然而，相当一部分肿瘤对当前抗血管生成疗法存在耐药性或产生逃逸现象。此外，VEGFA是健康血管的营养因子，因此抗血管生成治疗会引发副作用——尽管这些副作用已得到有效控制，但在部分癌症患者中仍可能导致危及生命的状况。
2. VEGFR2（亦称FLK1）作为结合VEGFA的主要受体，调控着健康组织与病变组织中的血管生成。相比之下，VEGFR1（又称FLT1）能结合VEGFA、VEGFB及胎盘生长因子（PlGF）。FLT1及其两种配体PlGF与VEGFB在多种肿瘤中表达上调，这与疾病进展相关，并可预测患者的不良预后、转移及疾病复发。
3. PlGF通过FLT1直接作用于多种细胞类型（包括内皮细胞、平滑肌细胞、成纤维细胞、具血管生成潜能的髓系祖细胞、巨噬细胞和肿瘤细胞），从而促进肿瘤血管生成、淋巴管生成、肿瘤生长及转移前微环境形成。因此，敲除Flt1TK−/−小鼠的酪氨酸激酶活性或使用FLT1与PlGF特异性抑制剂（如抗PlGF单克隆抗体αPlGF），可抑制炎症反应和病理性血管生成，并遏制肿瘤生长与转移。
4. 髓系细胞通过分泌其他促血管生成因子导致肿瘤对VEGF靶向治疗产生耐药性。αPlGF通过抑制巨噬细胞募集增强对VEGF靶向疗法的反应性。基于其互补作用机制，αPlGF能消除导致肿瘤抗血管生成逃逸的血管生成因子来源。
5. 基因敲除研究显示，PlGF在健康成体的血管发育和生理性血管维持过程中具有冗余性，但在癌症中参与血管生成与炎症转换。支持PlGF作为疾病特异性因子的概念是，αPlGF能选择性抑制病理性血管生成而不影响健康血管，因此不会引起当前抗血管生成疗法中常见的副作用。
6. 遗传学与药理学研究由此确认FLT1和PlGF可作为抗癌治疗的有吸引力的靶点，这或许能为当前抗血管生成疗法面临的挑战与未满足需求——如何提升疗效、避免耐药性及降低毒性——提供解决方案。

英文摘要：

Less than 5 years ago, it was still not clear whether anti-angiogenic drugs would prove successful in the clinic. After numerous patients with cancer or age-related macular degeneration have been treated with these drugs, they have now become part of the standard range of therapeutic tools. Despite this milestone, anti-angiogenic therapy still faces a number of clinical hurdles, such as improving efficacy, avoiding escape and resistance, and minimizing toxicity. Hopefully, other agents with complementary mechanisms, such as those that target placental growth factor, will offer novel opportunities for improved treatment.

摘要翻译： 

不到5年前，抗血管生成药物能否在临床上取得成功仍不明朗。在大量癌症或年龄相关性黄斑变性患者接受这些药物治疗后，它们现已成为标准治疗工具的一部分。尽管取得这一里程碑，抗血管生成疗法仍面临诸多临床障碍，如提高疗效、避免逃逸和耐药，以及最小化毒性。希望具有互补机制的其他药物，如靶向胎盘生长因子的药物，将为改善治疗提供新的机会。

原文链接：

FLT1 and its ligands VEGFB and PlGF: drug targets for anti-angiogenic therapy?