U.O. Diagnostica Ematochimica, Dipartimento di Patologia e Medicina di Laboratorio, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy.
Semin Thromb Hemost. 2010 Jul;36(5):558-69. doi: 10.1055/s-0030-1255450. Epub 2010 Jul 14.
Angiogenesis plays a pivotal role in many serious and life-threatening disorders (e.g., cancer, atherosclerosis, diabetes, arthritis, psoriasis, nephropathy, and retinopathy) and is regulated by a delicate equilibrium between a variety of pro- and anti-angiogenic factors. Although recombinant platelet factor 4 (PF4) was originally developed and evaluated as a clinical alternative to protamine for heparin neutralization, the current scientific evidence supports a role for this protein and derivative peptides in inhibiting tumor growth and spread, by suppression of tumor-induced neovascularization in many different types of solid tumors. As a heparin-binding tetramer, recombinant PF4 interferes with several steps of endothelial cell proliferation, migration, and angiogenesis, regulates apoptotic death through activation of distinct signal transduction pathways, inhibits growth factor receptor binding, amplifies the inflammatory response of natural killer cells through regulation of cytokines production, and induces and maintains a nonspecific immune response to cancer cells. These biological evidences paved the way for the development and marketing of novel PF4-based angiostatic agents characterized by reduced toxicity and improved bioavailability, thus raising the possibility of an alternative approach for preventing and treating growth and metastasis of tumors. Some PF4-derived molecules such as carboxyl-terminal fragments of recombinant human PF4 and modified and chimeric peptides have already been developed that exhibit stronger anti-angiogenic properties than the parent molecule and may serve as leads for further therapeutic developments. Newer means of delivering of this anti-angiogenic agent are also being attempted, including PF4-bearing polymeric microspheres, vector-mediated PF4 transduction, transgene transfection into oncolytic viruses, and molecular targeting therapy against PF4 and rHuPF4 conjugates. These delivery systems aim to produce high concentrations of the therapeutic agent in a local area for a sustained period, thereby avoiding the typical problems encountered with long-term administration of recombinant proteins.
血管生成在许多严重的危及生命的疾病（如癌症、动脉粥样硬化、糖尿病、关节炎、银屑病、肾病和视网膜病变）中起着关键作用，并且受到多种促血管生成和抗血管生成因子之间的微妙平衡调节。虽然重组血小板因子 4（PF4）最初是作为肝素中和的替代物开发和评估的，但目前的科学证据支持这种蛋白质及其衍生肽在抑制肿瘤生长和扩散方面的作用，通过抑制许多不同类型的实体肿瘤中的肿瘤诱导的新血管生成。作为一种肝素结合的四聚体，重组 PF4 干扰内皮细胞增殖、迁移和血管生成的几个步骤，通过激活不同的信号转导途径调节细胞凋亡死亡，抑制生长因子受体结合，通过调节细胞因子产生放大自然杀伤细胞的炎症反应，并诱导和维持对癌细胞的非特异性免疫反应。这些生物学证据为开发和销售新型基于 PF4 的血管生成抑制剂铺平了道路，这些抑制剂具有降低的毒性和提高的生物利用度，从而为预防和治疗肿瘤的生长和转移提供了另一种方法的可能性。已经开发了一些 PF4 衍生的分子，如重组人 PF4 的羧基末端片段和修饰的和嵌合肽，它们表现出比母体分子更强的抗血管生成特性，并且可以作为进一步治疗开发的先导。也正在尝试新的方法来递送这种抗血管生成剂，包括携带 PF4 的聚合物微球、载体介导的 PF4 转导、转染到溶瘤病毒中的转基因转染，以及针对 PF4 和 rHuPF4 缀合物的分子靶向治疗。这些递送系统旨在在局部区域产生高浓度的治疗剂并持续一段时间，从而避免长期给予重组蛋白时遇到的典型问题。
