苯并吡喃异黄酮化合物barbigerone干扰VEGF-D/VEGFR3信号通路抑制肿瘤淋巴管形成和转移的分子机制研究

Metastases are responsible for the majority of cancer deaths in chemotherapy.Cancer cells spread through two important routes, including lymphatic or blood vessels. Comparing with hematogenous metastasis , lymphatic metastasis owns more advantages, however, related study received little attention until recently. We have isolated barbigerone (BA) from seeds of M. pachycarpa Benth. As a naturally occurring compound, besides apoptosis induction, it exhibits anti-angiogenesis activity in our reports. Further studies continued. In vivo, BA suppressed metastasis of B16 and VEGF-D/LL2 cells xenografts, with significant inhibition to lymphogenesis. Moreover, BA could inhibit migration and the formation of capillary-like structures of HLEC cells, decreased expression of VEGFR3 and the downstream protein kinases.It demonstrates that BA inhibits tumor lymphogenesis and matastases via regulating VEGF-D/VEGF3.In this study, we would focus on three parts: (1) We hope to demonstrate the specific machanisms of BA inhibiting the formation of lymphogenesis, and find the molecular networks of VEGFR3-FAK in lymphogenesis. (2) We will elucidate the molecular mechanisms in BA-mediated cancer cells migrarion and invasion. (3) VEGF-D/SKOV3 cells xenograft model was used to evaluate the inhibition of BA on tumor lymphogenesis and metastases in vivo.

肿瘤转移是化疗失败的主要原因之一。血管和淋巴管是肿瘤转移的两大通道，其中淋巴管转移有更多优势，但是该研究最近才被重视,相关药物开发有重要意义。Barbigerone (BA)是我们从厚果鸡血藤中获得的中药活性成分，该化合物诱导细胞凋亡和抗血管生成活性为我们首先报道。进一步研究，BA能显著抑制B16肿瘤转移和VEGF-D/LL2肿瘤淋巴管形成和转移；并能抑制细胞迁移和成管能力，降低VEGFR3及部分下游激酶的表达。揭示BA可能通过调节VEGF-D、VEGFR3相关信号通路抑制肿瘤淋巴管形成和转移。本课题重点研究以下三个方面：（1）揭示BA抑制淋巴管形成的具体作用机制，阐明FAK与VEGFR3的关系及其对淋巴管形成的调节作用；（2）研究BA抑制肿瘤细胞转移侵袭能力的分子调节机制；（3）建立人源VEGF-D/SKOV3移植瘤模型考察BA的药效。旨在为开发BA用于肿瘤治疗提供理论基础和研究新方向。

血管和淋巴管转移是肿瘤耐性性产生的两大机制，其中淋巴管转移的肿瘤更具有耐药性，但是相关的研究最近才被重视,该领域的药物研发具有重要意义。我们课题组在国家自然科学基金委的支持下完成了天然小分子抗肿瘤淋巴管转移的相关机制及药效研究，BA能显著抑制B16肿瘤转移和VEGF-D/LL2肿瘤淋巴管形成和转移；并能抑制细胞迁移和成管能力，降低VEGFR3及部分下游激酶的表达。揭示BA可能通过调节VEGF-D、VEGFR3相关信号通路抑制肿瘤淋巴管形成和转移。本课题主要进行了以下三个方面的研究：（1）揭示BA抑制淋巴管形成的具体作用机制，阐明FAK与VEGFR3的关系及其对淋巴管形成的调节作用；（2）研究BA抑制肿瘤细胞转移侵袭能力的分子调节机制；（3）建立人源VEGF-D/SKOV3移植瘤模型考察BA的药效。旨在为开发BA用于肿瘤治疗提供理论基础和研究新方向。