Roles of humoral and neural factors in angiogenesis and lymphangiogenesis in pathological conditions and their significance in molecular targeting therapy

血管生成也是癌症发生和转移的关键步骤。促炎症介质，如PGs，可能以自分泌的方式对肿瘤细胞产生自主性作用，然而，我们在缺乏宿主受体信号的敲除小鼠的肿瘤移植模型中的结果表明，宿主基质信号PGE_2受体EP3通过诱导促厌生生长因子在肿瘤相关血管生成中发挥关键作用，并对肿瘤细胞表现出美化作用。EP3拮抗剂抑制野生型小鼠的肿瘤相关血管生成，但在EP3基因敲除小鼠中不抑制，这表明宿主EP3受体信号在预防肿瘤相关血管生成中起重要作用。此外，骨髓移植实验表明，体内表达EP3受体的骨髓细胞的募集对血管生成至关重要。相关的PGE2是通过COX-2和可诱导的PGE合成酶mPGES-1的作用产生的。令人印象深刻的p…植入肿瘤细胞的mPGES-1基因敲除小鼠的更多表型是肿瘤生长和血管生成减少。COX-2抑制剂也抑制了肿瘤相关淋巴管的生成。因此，控制EP受体信号通路以及在肿瘤微环境中募集表达EP受体的细胞可能是治疗恶性肿瘤的新途径。降钙素基因相关肽(CGRP)是降钙素/CGRP基因初级转录产物的组织特异性选择性剪接产生的一种37个氨基酸的神经肽。降钙素基因相关肽广泛分布于中枢和外周神经系统，在哺乳动物体内具有广泛的生物活性。感觉神经失神经部位肿瘤生长明显减少。当给予CGRP拮抗剂CGRP8-37时，与赋形剂注射相比，肿瘤生长受到抑制。与野生型小鼠相比，CGRP基因敲除小鼠的肿瘤生长和肿瘤相关血管生成显著减少。LLC野生型小鼠背根神经节CGRP前体基因表达水平较未治疗组升高。这种增加被感觉神经去神经所抵消。此外，我们发现CGRP基因敲除小鼠的溃疡愈合明显延迟，血管生成和血管内皮生长因子表达减少。在人脐静脉内皮细胞和成纤维细胞共培养体系中，CGRP促进内皮细胞的管状形成。这些结果表明，在肿瘤发生和溃疡愈合过程中，感觉神经释放的CGRP促进血管生成，CGRP可能成为治疗癌症或胃肠道粘膜损伤的新靶点。较少

Angiogenesis is also a critical step for development and metastasis of cancers. Proinflammatory mediators, such as PGs may have cell-autonomous effects on tumor cells in autocrine fashion, however, our results from tumor implantation models in knockout mice which lack the host receptor signaling clarified that host stromal signaling of a PGE_2 receptor, EP3 has a crucial role in tumor-associated angiogenesis through the induction of proaniogenic growth factors, and exhibited the landscaping effects on tumor cells. An EP3 antagonist inhibited tumor-associated angiogenesis in wild type mice, but not in EP3 knockout mice, suggesting that host EP3 receptor signaling is important in prevention of tumor-associated angiogenesis. Further, bone marrow transplantation experiment revealed that recruitment of bone marrow cells which express EP3 receptor is critical for angiogenesis in vivo. Relevant PGE2 is generated through the actions of COX-2 and an inducible PGE synthase, mPGES-1. Impressive p … More henotypes of mPGES-1 knockout mice implanted with tumor cells are reduced tumor growth and angiogenesis. Tumor-associated lymphangiogenesis was also suppressed with a COX-2 inhibitor. Thus, control of EP receptor signaling as well as recruitment of EP receptor expressing cells in the tumor microenvironment is likely to be a novel therapeutic approach against malignant solid tumors.Calcitonin gene-related peptide (CGRP) is a 37-amino acid neuropeptide produced by tissue-specific alternative splicing of the primary transcript of the calcitonin/CGRP gene. CGRP is widely distributed in the central and peripheral nervous systems and exhibits numerous biological activities in mammals. Tumor growth was significantly reduced in the sites of sensory nerve denervation. When a CGRP antagonist, CGRP8-37 was given, tumor growth was suppressed compared with vehicle infusion. In CGRP knockout mice, the tumor growth and tumor-associated angiogenesis were significantly reduced compared with wild type mice. In LLC bearing wild type mice, CGRP precursor mRNA levels in dorsal root ganglion were increased compared with non-treated mice. This increase was abolished by sensory nerve denervations. Further, we found that ulcer healing was significantly delayed in CGRP knockout mice with reductions in angiogenesis and VEGF expression. In co-culture system using HUVEC and fiboblasts, CGRP increased tube formation of endothelial cells. These results suggested that CGRP release from sensory nerves stimulated during tumor development and ulcer healing facilitates angiogenesis, and that CGRP may become a target of new treatment for cancers or gastrointestinal mucosal injury. Less