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。前列腺素等促炎介质可能以自分泌的方式对肿瘤细胞具有细胞自主性作用，然而，我们在缺乏宿主受体信号转导的基因敲除小鼠的肿瘤移植模型中的结果阐明了宿主间质PGE_2受体EP 3信号转导通过诱导促阴离子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美化作用。在野生型小鼠中，EP 3拮抗剂抑制肿瘤相关的血管生成，但在EP 3敲除小鼠中不抑制，这表明宿主EP 3受体信号传导在预防肿瘤相关的血管生成中是重要的。此外，骨髓移植实验表明，表达EP 3受体的骨髓细胞的募集对于体内血管生成是至关重要的。通过考克斯-2和诱导型PGE合酶mPGES-1的作用产生相关的PGE 2。令人印象深刻的P ...更多信息 植入肿瘤细胞的mPGES-1敲除小鼠的表型是减少的肿瘤生长和血管生成。肿瘤相关的淋巴管生成也被考克斯-2抑制剂抑制。因此，控制EP受体信号传导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）是降钙素/CGRP基因的初级转录本通过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学活性。在感觉神经去神经支配的部位，肿瘤生长显著减少。当给予CGRP拮抗剂CGRP 8 -37时，与载体输注相比，肿瘤生长受到抑制。在CGRP基因敲除小鼠中，与野生型小鼠相比，肿瘤生长和肿瘤相关的血管生成显著减少。在携带LLC的野生型小鼠中，背根神经节中的CGRP前体mRNA水平与未处理的小鼠相比增加。这种增加被取消的感觉神经去神经。此外，我们发现CGRP基因敲除小鼠的溃疡愈合显著延迟，血管生成和VEGF表达减少。在HUVEC与成纤维细胞共培养体系中，CGRP可促进内皮细胞管腔形成。这些结果表明，CGRP从刺激感觉神经在肿瘤的发展和溃疡愈合促进血管生成，CGRP可能成为一个新的治疗癌症或胃肠道粘膜损伤的目标。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