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首页> 外文学位 >A novel role for Semaphorin 4D in tumor metastasis.
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A novel role for Semaphorin 4D in tumor metastasis.

机译：Semaphorin 4D在肿瘤转移中的新作用。

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摘要

The semaphorin proteins were originally identified as axonal guidance factors expressed during neuronal development. In addition to this function, several semaphorins are now known to play diverse roles outside of the nervous system. Semaphorin 4D (Sema4D/CD100), a transmembrane molecule that shares structural homology with the scatter factors, exerts important biological effects on a variety of cells, including neural, epithelial and immune cells. Interaction between Sema4D and its receptor, Plexin-B1, has proven to be important in many facets of tumor progression such as tumor angiogenesis, regulation of tumor-associated macrophages and control of invasive growth.;Invasion and metastasis are key components of cancer progression. A distinct and largely forgotten path for tumor spread is perineural invasion (PNI), defined as the presence of cancer cells in the perineural space. PNI is frequently used by many human carcinomas, in particular by pancreatic, prostate, and oral squamous cell carcinoma (OSCC), and is associated with tumor recurrence and pain in patients with advanced disease. The work presented in this thesis shows that Sema4D and Plexin-B1 are involved in PNI in tumors and identifies Sema4D as a new player in the complex interaction between tumor cells, nerve cells and the tumor microenvironment.;We have previously found that Sema4D is able to promote angiogenesis in several in vitro assays and tumor growth and vascularity of head and neck squamous cell carcinoma xenografts in vivo, but the intracellular signaling pathways engaged and the mechanisms of regulation of this pro-angiogenic function remained unclear. Results presented in the second part of this thesis demonstrate that ligation of Plexin-B1 by Sema4D activates a RhoA-dependent pro-angiogenic phenotype in endothelial cells that signals through phosphatidylinositol 4-phosphate 5-kinase (PI(4)P5K) and generates lipid second messengers. We also discuss the essential role of hypoxia inducible factor (HIF) in endothelial cell migration and tumor vascularity.;In conclusion, deciphering the regulatory and signaling mechanisms of Sema4D could lead to the identification of new therapeutic targets for anti-angiogenic and anti-metastatic cancer therapy.
机译：信号量蛋白最初被确定为在神经元发育过程中表达的轴突指导因子。除此功能外，现在还已知几种信号量在神经系统外起着不同的作用。 Semaphorin 4D（Sema4D / CD100）是与散射因子具有结构同源性的跨膜分子，对包括神经细胞，上皮细胞和免疫细胞在内的多种细胞具有重要的生物学作用。 Sema4D及其受体Plexin-B1之间的相互作用已被证明在肿瘤进展的许多方面都很重要，例如肿瘤血管生成，肿瘤相关巨噬细胞的调控和侵袭性生长的控制。侵袭和转移是癌症进展的关键组成部分。神经扩散（PNI）是肿瘤扩散的一个明显且被很大程度上遗忘的途径，它被定义为神经细胞在癌细胞中的存在。 PNI常被许多人类癌所使用，尤其是胰腺癌，前列腺癌和口腔鳞状细胞癌（OSCC），并且与晚期疾病患者的肿瘤复发和疼痛有关。本论文的工作表明Sema4D和Plexin-B1参与了肿瘤中的PNI，并确定Sema4D是肿瘤细胞，神经细胞和肿瘤微环境之间复杂相互作用的新参与者。在几种体外测定中促进血管生成以及体内头颈鳞状细胞癌异种移植物的肿瘤生长和血管形成，但是尚不清楚细胞内信号传导途径和该促血管生成功能的调节机制。本论文第二部分介绍的结果表明，Sema4D连接Plexin-B1可激活内皮细胞中的RhoA依赖性促血管生成表型，该表型通过磷脂酰肌醇4-磷酸5激酶（PI（4）P5K）发出信号并产生脂质第二使者。我们还讨论了缺氧诱导因子（HIF）在内皮细胞迁移和肿瘤血管形成中的重要作用。总之，破译Sema4D的调节和信号传导机制可能导致鉴定抗血管生成和抗转移的新治疗靶标癌症治疗。

著录项

  • 作者

    Binmadi, Nada O.;

  • 作者单位

    University of Maryland, Baltimore.;

  • 授予单位 University of Maryland, Baltimore.;
  • 学科 Biology Molecular.;Health Sciences Pathology.;Health Sciences Oncology.
  • 学位 Ph.D.
  • 年度 2011
  • 页码 136 p.
  • 总页数 136
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 地球物理学;
  • 关键词

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