Division of Surgical Oncology, Department of Surgery; Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX, 75390-8593, USA.
Cancers (Basel). 2010 May 26;2(2):970-88. doi: 10.3390/cancers2020970.
Angiogenesis, the sprouting of the existing vascular network to form new vessels, is required for the growth of solid tumors. For this reason, the primary stimulant of angiogenesis, vascular endothelial growth factor-A (VEGF), is an attractive target for tumor therapy. In fact, there are currently numerous anti-VEGF therapies in clinical development for the treatment of various cancers, including breast cancer. VEGF signals through two primary VEGF receptors, VEGFR1 and VEGFR2. VEGFR2 is the primary angiogenic receptor, and VEGFR1 has been implicated in macrophage chemotaxis and tumor cell survival and invasion. It has only been appreciated recently that the VEGFRs are expressed not only on endothelial cells and tumor cells but also on many host immune cells. Therefore, to better understand the effects of anti-VEGF therapy it is important to consider the effects of VEGF on all cells in the tumor microenvironment, including immune cells. Bevacizumab (Avastin®, Genetech), which binds VEGF and inhibits interaction with VEGFR1 and VEGFR2, was approved for the treatment of metastatic HER2/NEU-negative breast cancer in 2008, however, the majority of human mammary tumors are either innately resistant or will acquire resistance to anti-VEGF therapy. This suggests that these tumors activate alternate angiogenesis pathways. Pleiotrophin (PTN) is an important angiogenic cytokine in breast cancer and is expressed at high levels in approximately 60% of human breast tumors. PTN functions as an angiogenic factor and promotes remodeling of the tumor microenvironment as well as epithelial-mesenchymal transition (EMT). In addition, PTN can have profound effects on macrophage phenotype. The present review focuses on the functions of VEGF and PTN on immune cell infiltration and function in breast cancer. Furthermore, we will discuss how anti-VEGF therapy modulates the immune cell profile.
血管生成是指现有血管网络的萌芽，以形成新的血管，这是实体瘤生长所必需的。出于这个原因，血管内皮生长因子-A（VEGF）作为血管生成的主要刺激物，是肿瘤治疗的一个有吸引力的靶点。事实上，目前有许多针对 VEGF 的治疗方法正在临床开发中，用于治疗各种癌症，包括乳腺癌。VEGF 通过两种主要的 VEGF 受体 VEGFR1 和 VEGFR2 发挥信号作用。VEGFR2 是主要的血管生成受体，而 VEGFR1 被认为与巨噬细胞趋化和肿瘤细胞的存活和侵袭有关。最近才意识到，VEGFR 不仅在血管内皮细胞和肿瘤细胞上表达，而且在许多宿主免疫细胞上也表达。因此，为了更好地了解抗 VEGF 治疗的效果，重要的是要考虑 VEGF 对肿瘤微环境中所有细胞的影响，包括免疫细胞。贝伐单抗（Avastin®，Genetech）与 VEGF 结合并抑制其与 VEGFR1 和 VEGFR2 的相互作用，于 2008 年被批准用于治疗转移性 HER2/NEU 阴性乳腺癌，然而，大多数人类乳腺肿瘤要么天生具有抗性，要么会对抗 VEGF 治疗产生抗性。这表明这些肿瘤激活了替代的血管生成途径。多效蛋白（PTN）是乳腺癌中的一种重要的血管生成细胞因子，约 60%的人类乳腺癌肿瘤中高表达。PTN 作为一种血管生成因子，促进肿瘤微环境的重塑以及上皮-间充质转化（EMT）。此外，PTN 可以对巨噬细胞表型产生深远的影响。本综述重点介绍 VEGF 和 PTN 对乳腺癌中免疫细胞浸润和功能的作用。此外，我们将讨论抗 VEGF 治疗如何调节免疫细胞谱。
