Spry2对非小细胞肺癌血管形成的影响及其在肺癌中表达调控的研究

The growth, survival and metastasis of solid tumors are dependent on the extensive tumor angiogenesis. Inhibition of angiogenesis can inhibit tumor growth and metastasis, and may be a potential therapeutical method for future use. Growth factors, such as VEGF, FGF and PDGF induce tumor angiogenesis by promoting proliferation, migration and tube formation of endothelial cells through RTK(Receptor Tyrosine Kinases) signaling pathway. Spry2 is a general inhibitor of receptor tyrosine kinase signaling, whose expression was downregulated in many kinds of solid tumors, such as breast cancers, prostate cancers and non-small cell lung cancers, but the function and the molecular mechanisms of Spry2 in tumor progression are still largelly unknown. We supposed that the downregulation of Spry2 in non-small cell lung cancer led to the overactivation of RTK singaling pathway and promoted tumor angiogenesis. In this study, we will go deep insight into i)the effects of Spry2 on tumor angiogenesis in votro and in vivo and the underlined melocular mechanisms; ii)the underlined mechanisms responsible for the decreased expression of Spry2 gene mRNA in non-small cell lung cancers; ⅲ) the relevance between Spry2 expression and the blood vessel density，metastasis and prognosis of non-small cell lung cancers.

实体肿瘤的生长、存活及转移依赖于持续和广泛的肿瘤血管生成，因而控制肿瘤血管生成能抑制实体肿瘤的生长和转移，并可能成为肿瘤临床治疗措施之一。VEGF、FGF、PDGF等生长因子通过受体酪氨酸激酶信号通路诱导血管形成相关因子表达，促进血管内皮细胞增殖、迁移及血管形成，包括肿瘤中的血管形成。Spry2是受体酪氨酸激酶信号通路抑制因子，其表达在乳腺癌、前列腺癌及非小细胞肺癌等多种实体肿瘤中表达下调，但它在肿瘤发生发展过程中的作用及分子机制并未被深入研究。我们推测在非小细胞肺癌的发生发展过程中，Spry2失表达导致肿瘤细胞内受体酪氨酸激酶信号通路过度活化，诱导肿瘤新生血管形成，促进肿瘤的生长及转移。本研究将从肿瘤血管形成的体外、体内实验探讨Spry2基因对肿瘤血管形成的影响，并从转录或转录后水平揭示Spry2基因在非小细胞肺癌中低表达的调控机制以及Spry2低表达与血管丰度、肿瘤转移和预后的关系。