Genetic Regulation of Angiogenesis in Colonic Polyps

结肠息肉血管生成的遗传调控

基本信息

批准号：
8053719
负责人：
DANIEL C CHUNG
金额：
$ 24.33万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-04-01 至 2013-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8053719
关键词：
Address Adenomatous Polyps Angiogenesis Inhibitors Angiogenic Factor Benign Binding Blood Vessels Colon Carcinoma Colonic Neoplasms Colonic Polyps Complex Cues Environmental Risk Factor Epithelial Cells Epithelium Equilibrium Funding Gene Expression Genetic Glycogen Synthase Kinase 3 Hypoxia In Vitro Interleukin-8 Maintenance Mediating Metabolic Mutate Mutation Neoplasms Oncogenic Pathologic Processes Pathway interactions Patients Pattern Phenotype Physiological Processes Play Premalignant Process Recruitment Activity Regulation Resistance Resistance development Role Signal Pathway Signal Transduction Staging TCF7L2 gene Thrombospondin 1 VEGFA gene Vascular Endothelial Growth Factors Vascular blood supply angiogenesis c-myc Genes chemokine design environmental change hypoxia inducible factor 1 in vivo mutant novel promoter response therapeutic target tumor tumor xenograft

项目摘要

DESCRIPTION (provided by applicant): Angiogenesis is an essential feature of both physiological and pathological processes, and multiple genetic and environmental factors converge to regulate the formation of new blood vessels. In the well-described progression from normal colonic epithelium to colon cancer, angiogenesis begins early at the stage of the benign adenomatous polyp. Genetic alterations in the K-ras and Wnt pathways that occur at this premalignant stage can regulate the expression of vascular endothelial growth factor (VEGF). As tumors enlarge, hypoxia invariably develops as the metabolic demands outstrip the blood supply. Preliminary studies have revealed that K-ras can interact with and respond to the tumor microenvironment. K-ras cooperates with hypoxia to recruit novel angiogenic pathways that do not require hypoxia-inducible factor-1 (HIF-1). These include the induction of additional angiogenic factors such as interleukin-8 (IL-8) and the novel activation of c-myc to upregulate VEGF. Moreover, K-ras is responsive to local shifts in the balance between pro- and anti-angiogenic factors so that these alternative pathways can be activated in a compensatory manner when classical pathways such as HIF-1 are blocked. This ability of colon tumors to recruit alternative angiogenic factors may explain the resistance that can develop when only a single agent is used for anti-angiogenic therapy. Collectively, these findings suggest that maintenance of the angiogenic phenotype is a dynamic process that is highly responsive to local environmental cues, and there is an important role for K-ras in this process. To address the hypothesis that alterations in K-ras that typically occur in early colonic neoplasia interact with the microenvironment to regulate multiple angiogenic pathways, the following specific aims are proposed: (I) to define the role of K-ras in the induction of IL-8 in colonic epithelial cells, (II) to define the role of K-ras in the hypoxic regulation of VEGF by c-myc in colonic epithelial cells, and (III) to determine whether K-ras induces the expression of alternative angiogenic factors following inhibition of both VEGF and IL-8. A better understanding of the complete spectrum of angiogenic pathways activated in the colonic epithelium is a prerequisite for the rational design and application of targeted anti- angiogenic approaches.

描述（由申请人提供）：血管生成是生理和病理过程的重要特征，多个遗传和环境因素会融合以调节新血管的形成。在从正常结肠上皮到结肠癌的良好描述的进展中，血管生成始于良性腺瘤息肉的阶段。在此前阶段发生的K-RAS和WNT途径中的遗传改变可以调节血管内皮生长因子（VEGF）的表达。随着肿瘤的增大，由于代谢需要超过血液供应，低氧总是会出现。初步研究表明，K-Ras可以与肿瘤微环境相互作用并反应。 K-RAS与缺氧合作，招募不需要缺氧诱导因子1（HIF-1）的新型血管生成途径。这些包括诱导其他血管生成因子，例如白介素8（IL-8）以及C-MYC上调VEGF的新型激活。此外，K-RAS对促和抗血管生成因子之间平衡的局部变化有反应，因此当封闭经典途径（例如HIF-1）时，可以以补偿方式激活这些替代途径。结肠肿瘤募集替代性血管生成因子的这种能力可能解释了只有单一药物用于抗血管生成疗法时可以发展的耐药性。总的来说，这些发现表明，维持血管生成表型是一个动态过程，对局部环境提示的反应高度敏感，并且在此过程中K-RAS具有重要作用。为了解决以下假设：在早期结肠肿瘤中通常发生的K-RAS的改变与微环境相互作用以调节多个血管生成途径，提出了以下具体目的：（i）定义K-RAS在IL诱导IL中的作用-8在结肠上皮细胞中，（ii）定义k-ras在结肠上皮细胞中c-myc对VEGF的低氧调节中的作用，（iii）确定k-ras是否诱导替代性血管生成因子的表达抑制VEGF和IL-8。更好地理解在结肠上皮中激活的血管生成途径的完整频谱是靶向抗血管生成方法的合理设计和应用的先决条件。

项目成果

期刊论文数量（14）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

c-Myc is regulated by HIF-2α in chronic hypoxia and influences sensitivity to 5-FU in colon cancer.

DOI：
10.18632/oncotarget.12911
发表时间：
2016-11-29
期刊：
Oncotarget
影响因子：
0
作者：
Wang L;Xue M;Chung DC
通讯作者：
Chung DC

Hypoxia activates the K-ras proto-oncogene to stimulate angiogenesis and inhibit apoptosis in colon cancer cells.

DOI：
10.1371/journal.pone.0010966
发表时间：
2010-06-04
期刊：
PloS one
影响因子：
3.7
作者：
Zeng M;Kikuchi H;Pino MS;Chung DC
通讯作者：
Chung DC

Oncogenic KRAS and BRAF differentially regulate hypoxia-inducible factor-1alpha and -2alpha in colon cancer.

DOI：
10.1158/0008-5472.can-09-2213
发表时间：
2009-11-01
期刊：
Cancer research
影响因子：
11.2
作者：
Kikuchi H;Pino MS;Zeng M;Shirasawa S;Chung DC
通讯作者：
Chung DC

Transplanting normal vascular proangiogenic cells to tumor-bearing mice triggers vascular remodeling and reduces hypoxia in tumors.

DOI：
10.1158/0008-5472.can-10-0412
发表时间：
2010-08-01
期刊：
Cancer research
影响因子：
11.2
作者：
Sasajima J;Mizukami Y;Sugiyama Y;Nakamura K;Kawamoto T;Koizumi K;Fujii R;Motomura W;Sato K;Suzuki Y;Tanno S;Fujiya M;Sasaki K;Shimizu N;Karasaki H;Kono T;Kawabe J;Ii M;Yoshiara H;Kamiyama N;Ashida T;Bardeesy N;Chung DC;Kohgo Y
通讯作者：
Kohgo Y

HIF-1alpha and HIF-2alpha have divergent roles in colon cancer.

HIF-1α 和 HIF-2α 在结肠癌中具有不同的作用。

DOI：
10.1002/ijc.24032
发表时间：
2009-02-15
期刊：
INTERNATIONAL JOURNAL OF CANCER
影响因子：
6.4
作者：
Imamura, Takaaki;Kikuchi, Hirotoshi;Herraiz, Maria-Teresa;Park, Do-Youn;Mizukami, Yusuke;Mino-Kenduson, Mari;Lynch, Maureen P.;Rueda, Bo R.;Benita, Yair;Xavier, Ramnik J.;Chung, Daniel C.
通讯作者：
Chung, Daniel C.