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展和转移的关键步骤。促炎介质，如PGs，可能以自分泌方式对肿瘤细胞具有细胞自主作用，然而，我们对缺乏宿主受体信号的敲除小鼠的肿瘤植入模型的研究结果表明，PGE_2受体EP3的宿主间质信号通过诱导促炎生长因子在肿瘤相关血管生成中起关键作用，并对肿瘤细胞表现出景观作用。EP3拮抗剂在野生型小鼠中抑制肿瘤相关血管生成，但在EP3敲除小鼠中没有，这表明宿主EP3受体信号传导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，募集表达EP3受体的骨髓细胞对体内血管生成至关重要。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。植入肿瘤细胞的mPGES-1基因敲除小鼠的更多表型显示肿瘤生长和血管生成减少。肿瘤相关淋巴管生成也被COX-2抑制剂抑制。因此，控制EP受体信号以及在肿瘤微环境中募集EP受体表达细胞可能是一种新的治疗恶性实体瘤的方法。降钙素基因相关肽（CGRP）是一种由降钙素/CGRP基因初级转录物的组织特异性选择性剪接产生的37个氨基酸的神经肽。CGRP广泛分布于中枢和外周神经系统，在哺乳动物中表现出多种生物活性。感觉神经去支配部位肿瘤生长明显减少。当给予CGRP拮抗剂CGRP8-37时，与载体输注相比，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明显减少。携带LLC野生型小鼠背根神经节CGRP前体mRNA水平较未处理小鼠升高。这种增加被感觉神经去神经所消除。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VEGF表达减少。在HUVEC和成纤维细胞共培养体系中，CGRP增加了内皮细胞的管状形成。这些结果提示，CGRP在肿瘤发展和溃疡愈合过程中刺激感觉神经释放，促进血管生成，CGRP可能成为癌症或胃肠道粘膜损伤新治疗的靶点。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