Haibe Yolla, Kreidieh Malek, El Hajj Hiba, Khalifeh Ibrahim, Mukherji Deborah, Temraz Sally, Shamseddine Ali
Division of Hematology/Oncology, Department of Internal Medicine, American University of Beirut-Medical Center, Beirut, Lebanon.
Department of Experimental Pathology, Immunology and Microbiology, American University of Beirut-Medical Center, Beirut, Lebanon.
Front Oncol. 2020 Feb 27;10:221. doi: 10.3389/fonc.2020.00221. eCollection 2020.
Tumor growth and metastasis rely on tumor vascular network for the adequate supply of oxygen and nutrients. Tumor angiogenesis relies on a highly complex program of growth factor signaling, endothelial cell (EC) proliferation, extracellular matrix (ECM) remodeling, and stromal cell interactions. Numerous pro-angiogenic drivers have been identified, the most important of which is the vascular endothelial growth factor (VEGF). The importance of pro-angiogenic inducers in tumor growth, invasion and extravasation make them an excellent therapeutic target in several types of cancers. Hence, the number of anti-angiogenic agents developed for cancer treatment has risen over the past decade, with at least eighty drugs being investigated in preclinical studies and phase I-III clinical trials. To date, the most common approaches to the inhibition of the VEGF axis include the blockade of VEGF receptors (VEGFRs) or ligands by neutralizing antibodies, as well as the inhibition of receptor tyrosine kinase (RTK) enzymes. Despite promising preclinical results, anti-angiogenic monotherapies led only to mild clinical benefits. The minimal benefits could be secondary to primary or acquired resistance, through the activation of alternative mechanisms that sustain tumor vascularization and growth. Mechanisms of resistance are categorized into VEGF-dependent alterations, non-VEGF pathways and stromal cell interactions. Thus, complementary approaches such as the combination of these inhibitors with agents targeting alternative mechanisms of blood vessel formation are urgently needed. This review provides an updated overview on the pathophysiology of angiogenesis during tumor growth. It also sheds light on the different pro-angiogenic and anti-angiogenic agents that have been developed to date. Finally, it highlights the preclinical evidence for mechanisms of angiogenic resistance and suggests novel therapeutic approaches that might be exploited with the ultimate aim of overcoming resistance and improving clinical outcomes for patients with cancer.
肿瘤的生长和转移依赖于肿瘤血管网络以充分供应氧气和营养物质。肿瘤血管生成依赖于生长因子信号传导、内皮细胞（EC）增殖、细胞外基质（ECM）重塑以及基质细胞相互作用等高度复杂的程序。已鉴定出许多促血管生成驱动因子，其中最重要的是血管内皮生长因子（VEGF）。促血管生成诱导剂在肿瘤生长、侵袭和外渗中的重要性使其成为几种癌症中极佳的治疗靶点。因此，在过去十年中，为癌症治疗开发的抗血管生成药物数量有所增加，至少有八十种药物正在进行临床前研究和I - III期临床试验。迄今为止，抑制VEGF轴的最常见方法包括用中和抗体阻断VEGF受体（VEGFRs）或配体，以及抑制受体酪氨酸激酶（RTK）酶。尽管临床前结果很有前景，但抗血管生成单一疗法仅带来轻微的临床益处。这种微小的益处可能继发于原发性或获得性耐药，这是通过激活维持肿瘤血管生成和生长的替代机制实现的。耐药机制分为VEGF依赖性改变、非VEGF途径和基质细胞相互作用。因此，迫切需要互补方法，例如将这些抑制剂与靶向血管形成替代机制的药物联合使用。本综述提供了肿瘤生长过程中血管生成病理生理学的最新概述。它还阐明了迄今为止已开发的不同促血管生成和抗血管生成药物。最后，它强调了血管生成耐药机制的临床前证据，并提出了可能被利用的新治疗方法，其最终目标是克服耐药性并改善癌症患者的临床结局。
