Regulation of Tumor and Metastatic Growth by Hypoxia and CTGF
缺氧和 CTGF 对肿瘤和转移性生长的调节
基本信息
- 批准号:8208641
- 负责人:
- 金额:$ 25.35万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2011
- 资助国家:美国
- 起止时间:2011-02-01 至 2013-01-31
- 项目状态:已结题
- 来源:
- 关键词:3-DimensionalAddressAdhesionsAdhesivesAffectAgarAntibodiesCancer cell lineCell AdhesionCell Adhesion InhibitionCell-Cell AdhesionCellsCharacteristicsClinicClinicalCollaborationsCombined Modality TherapyCytostaticsCytotoxic agentCytotoxinDataEffectivenessEmployee StrikesGrantGrowthHead and Neck NeoplasmsHumanHypoxiaImplantIndividualLeadMalignant - descriptorMalignant neoplasm of pancreasMediatingMolecularMusNeoplasm MetastasisPancreasPancreatitisPlasticsPrincipal InvestigatorProtocols documentationRegulationRoleStromal CellsTestingTumor-Derivedbasecell growthconnective tissue growth factoreffective therapyexpectationgemcitabinematrigelmutantneoplastic cellpancreatic cancer cellspancreatic neoplasmprogramssubcutaneoustumortumor growthtumor progression
项目摘要
During the last grant period, we have obtained evidence that the expression of connective tissue growth
factor (CTGF) is elevated in human pancreatic tumors, but not in normal pancreas or pancreatitis. Since
pancreatic tumors are highly hypoxia and CTGF is known to be hypoxia inducible, we have focused this
grant to understand the role of hypoxia and CTGF in pancreatic tumor progression. The basis for these
studies to investigate the importance of CTGF in pancreatic tumor progression derive from our
demonstration that targeted inhibition of CTGF with a monoclonal specific antibody results in significant
growth inhibition of two different pancreatic cancer cell lines implanted as subcutaneous tumors. In this
competitive renewal, Project 1 will focus on determining the mechanistic role of CTGF and its individual
domains on pancreatic tumor progression under normoxic and hypoxic conditions. Our preliminary data
suggests that CTGF is able to enhance the growth of pancreatic tumor cells. Induction of CTGF had no
effect on cell growth on plastic, but significantly enhanced spheroid growth in soft agar. Most striking was the
increase in cell adhesion induced by CTGF expression. These changes in cell adhesion that are necessary
for 3-D growth lead us to test the hypothesis that one of the major roles of CTGF in malignant progression is
to regulate cell-cell adhesion, and that inhibiting this activity will impact tumor growth and metastases. Thus,
the aims of this proposal are to 1) determine how CTGF affects cell adhesion of pancreatic tumor cells under
normoxic and hypoxic conditions using domain specific deletion mutants in cells that are manipulated to
express different levels of HIF-1 (Project 3), 2) determine how important CTGF is for 3-D growth and
invasion under normoxic and hypoxic conditions, 3) determine how inhibition of CTGF mediated adhesion
affects metastatic growth, 4) determine how inhibition of cell adhesion by CTGF affects subcutaneous and
orthotopic tumor growth of pancreatic tumor cells and in collaboration with Project 4 head and neck tumors,
5) determine the role of stromal and tumor cell CTGF on tumor growth, 6) determine how effective the
combination of CTGF Ab and the new hypoxic specific cytotoxin PR-104 are in controlling pancreatic tumor
growth compared to CTGF Ab and gemcitabine (Project 2). In summary, the proposed studies are
intended to address an important mechanism by which CTGF affects tumor progression in
pancreatic cancers and to determine how effective it is in combination therapy to bring it to the
clinic.
在上一次授权期内,我们获得了结缔组织生长的表达
结缔组织生长因子(CTGF)在人胰腺肿瘤中升高,但在正常胰腺或胰腺炎中不升高。自.以来
胰腺肿瘤是高度低氧的,CTGF是众所周知的低氧诱导的,我们已经关注了这一点
了解缺氧和CTGF在胰腺肿瘤进展中的作用。这些的基础是
研究CTGF在胰腺肿瘤进展中的作用
证明用一种单抗特异性抗体靶向抑制CTGF可显著
两种不同胰腺癌细胞皮下移植瘤的生长抑制作用。在这
竞争性更新,项目1将侧重于确定CTGF及其个人的机械作用
常氧和低氧条件下胰腺肿瘤进展的区域。我们的初步数据
提示CTGF具有促进胰腺癌细胞生长的作用。CTGF的诱导没有
对塑料上的细胞生长有影响,但显著促进软琼脂中的球体生长。最引人注目的是
CTGF表达诱导的细胞黏附增加。这些细胞黏附的变化是必要的
导致我们检验了CTGF在恶性进展中的主要作用之一的假设
来调节细胞间的黏附,抑制这种活性会影响肿瘤的生长和转移。因此,
本研究的目的是:1)研究CTGF对胰腺癌细胞黏附的影响。
在细胞中使用区域特异性缺失突变体的常氧和低氧条件,这些突变体被操纵以
表达不同水平的HIF-1(项目3),2)确定CTGF对3D生长和
常氧和低氧条件下的侵袭,3)抑制CTGF介导的黏附
影响转移生长,4)确定CTGF抑制细胞黏附如何影响皮下和
胰腺肿瘤细胞的原位肿瘤生长,并与项目4头颈部肿瘤合作,
5)确定间质和肿瘤细胞CTGF在肿瘤生长中的作用,6)确定
CTGF单抗与新型缺氧特异性细胞毒素PR-104联合应用控制胰腺肿瘤
与CTGF单抗和吉西他滨相比的生长(项目2)。总括而言,建议进行的研究包括
旨在阐明CTGF影响肿瘤进展的一个重要机制。
并确定在联合治疗中将胰腺癌带到
诊所。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Amato J. Giaccia其他文献
Benzamides substitués et leurs utilisations
苯甲酰胺替代品和用途
- DOI:
- 发表时间:
2011 - 期刊:
- 影响因子:0
- 作者:
M. Bonnet;Denise A. Chan;Amato J. Giaccia;Michael Patrick Hay;Edwin W. Lai;Olga V. Razorenova;Connie Sun;Ray Tabibiazar;Po - 通讯作者:
Po
88: Lysyl Oxidase Is Essential for Hypoxia-Induced Metastasis
- DOI:
10.1016/j.ijrobp.2006.07.118 - 发表时间:
2006-11-01 - 期刊:
- 影响因子:
- 作者:
Janine Erler;Quynh Le;Amato J. Giaccia - 通讯作者:
Amato J. Giaccia
Lysyl oxidase is essential for hypoxia-induced metastasis
赖氨酰氧化酶对于缺氧诱导的转移是必不可少的
- DOI:
10.1038/nature04695 - 发表时间:
2006-04-27 - 期刊:
- 影响因子:48.500
- 作者:
Janine T. Erler;Kevin L. Bennewith;Monica Nicolau;Nadja Dornhöfer;Christina Kong;Quynh-Thu Le;Jen-Tsan Ashley Chi;Stefanie S. Jeffrey;Amato J. Giaccia - 通讯作者:
Amato J. Giaccia
Hypoxic gene expression and metastasis
- DOI:
10.1023/b:canc.0000031768.89246.d7 - 发表时间:
2004-08-01 - 期刊:
- 影响因子:8.700
- 作者:
Quynh-Thu Le;Nicholas C. Denko;Amato J. Giaccia - 通讯作者:
Amato J. Giaccia
Therapeutic targeting of the functionally elusive TAM receptor family
对功能上难以捉摸的 TAM 受体家族的治疗靶向
- DOI:
10.1038/s41573-023-00846-8 - 发表时间:
2023-12-13 - 期刊:
- 影响因子:101.800
- 作者:
Yu Rebecca Miao;Erinn B. Rankin;Amato J. Giaccia - 通讯作者:
Amato J. Giaccia
Amato J. Giaccia的其他文献
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{{ truncateString('Amato J. Giaccia', 18)}}的其他基金
Project 1: Inhibition of Complement C5aR1 Radioprotects Normal Tissue and Radiosensitizes Tumors
项目 1:抑制补体 C5aR1 辐射保护正常组织并使肿瘤辐射增敏
- 批准号:
10707880 - 财政年份:2022
- 资助金额:
$ 25.35万 - 项目类别:
Project 1: Inhibition of Complement C5aR1 Radioprotects Normal Tissue and Radiosensitizes Tumors
项目 1:抑制补体 C5aR1 辐射保护正常组织并使肿瘤辐射增敏
- 批准号:
10334199 - 财政年份:2022
- 资助金额:
$ 25.35万 - 项目类别:
Preclinical Testing of a Novel Therapy Targeting AXL in Advanced Kidney Cancer
针对晚期肾癌 AXL 的新疗法的临床前测试
- 批准号:
8949353 - 财政年份:2016
- 资助金额:
$ 25.35万 - 项目类别:
The Impact of Mitochondrial Repression and Lipid Accumulation by HIF on Tumor Growth
HIF 抑制线粒体和脂质积累对肿瘤生长的影响
- 批准号:
10212325 - 财政年份:2015
- 资助金额:
$ 25.35万 - 项目类别:
The Impact of Mitochondrial Repression and Lipid Accumulation by HIF on Tumor Growth
HIF 抑制线粒体和脂质积累对肿瘤生长的影响
- 批准号:
9976465 - 财政年份:2015
- 资助金额:
$ 25.35万 - 项目类别:
HIF-1alpha, a Survival and Differentiation Factor for Cartilage
HIF-1alpha,软骨的存活和分化因子
- 批准号:
8609400 - 财政年份:2013
- 资助金额:
$ 25.35万 - 项目类别:
Regulation of Tumor and Metastatic Growth by Hypoxia and CTGF
缺氧和 CTGF 对肿瘤和转移性生长的调节
- 批准号:
8492949 - 财政年份:2011
- 资助金额:
$ 25.35万 - 项目类别:
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