Integrin-mediated mechanisms of prostate cancer progression
Integrin-mediated mechanisms of prostate cancer progression
批准号:
10197842
负责人:
Lucia R. Languino
金额:
$35.69万
依托单位国家:
美国
项目类别:
财政年份:
2018
资助国家:
美国
项目状态:
已结题
起止时间:
2018-07-15 至 2023-06-30
关键词:
AdhesionsAffectAndrogen ReceptorCancer PatientCastrationCell CommunicationCell surfaceCellsChemicalsDataDown-RegulationExperimental DesignsFamilyFocal AdhesionsImmunoblottingIn VitroInfiltrationInjectionsIntegrin alphaVIntegrin alphaVbeta3IntegrinsInvestigationLabelLigandsMAPK8 geneMalignant NeoplasmsMalignant neoplasm of prostateMediatingMetastatic toMusMyeloid-derived suppressor cellsNormal CellNormal tissue morphologyPathway interactionsPhenotypePropertyProstate Cancer therapyProteomicsReceptor ActivationRegulationResearch PersonnelResistanceRoleSignal PathwaySignal TransductionSiteSmall Interfering RNASurfaceTechnologyTestingTherapeuticTimeUp-RegulationVariantantitumor effectbasecancer cellcancer typecastration resistant prostate cancerexosomeexperimental studyin vivoin vivo Modelinnovationinsightmonocytemouse modelmultidisciplinarynew therapeutic targetpreventprostate cancer cellprostate cancer modelprostate cancer preventionprostate cancer progressionreceptorresponsetranscriptome sequencingtumortumor growthtumor microenvironmenttumor progressionuptake
中文摘要
摘要
鉴于以下因素,旨在治愈前列腺癌 (PrCa) 的治疗方法仅取得部分成功
化学阉割经常导致高度转移抗性表型的出现
PrCa 患者。最近,我们首次描述了整合素家族的表面受体αvβ6
作为 PrCa 治疗的新治疗靶点;该分子是一个理想的靶标,因为与其他整合素不同,它
存在于不同类型的癌症中,但不存在于正常组织中。我们已经展示了这种独特的性能
PrCa 中的分子在其他整合素中未观察到:我们已经证明 αvβ6 促进去势-
通过激活 JNK 和雄激素受体 (AR) 来治疗耐药性前列腺癌 (CRPC)。此外,我们还有
研究表明,αvβ6 存在于癌细胞外泌体中,通过以下方式从癌细胞转移到受体细胞:
外泌体并在受体细胞中保持活性。我们还证明 αvβ6 对
微环境。具体来说,αvβ6 可以阻止供体中 Stat1/Mx1/2 信号通路的诱导
癌细胞及其外泌体,其在癌细胞外泌体中的下调抑制单核细胞 M2
极化。最后,我们证明体内 αvβ6 抑制会导致 Stat1/MxA/B 上调
癌细胞中的信号通路。
基于我们高度严格的机制研究,我们提出以下创新假设:αvβ6
表达通过下调供体细胞中 Stat1/Mx1 水平来影响微环境,随后
在癌细胞外泌体和受体细胞中,从而促进单核细胞分化、肿瘤生长和
癌症进展。因此,通过下调或抑制癌细胞中的 αvβ6,增加
细胞/外泌体/单核细胞中的 Stat1/MxA/B 水平将产生抗肿瘤作用。测试
根据这个假设,我们规划了以下三个具体目标。我们将在体外检查 αvβ6 整合素在
调节癌细胞-单核细胞串扰(目标1),并分析该通路的体内功能作用
外泌体 αvβ6 和/或 Stat1 在癌症进展中介导(目标 2)并表征 αvβ6
PrCa 细胞中的整合素/Stat1 通路(目标 3)。
创新方法、高度纯化的外泌体和体内模型将用于检验我们的假设:
整合素及其下游效应子从癌细胞转移到肿瘤中的其他细胞
微环境促进CRPC。该研究将得到多学科研究团队的支持
他们在所有所需技术方面拥有广泛且互补的专业知识。根据我们的初步
关于 αvβ6/Stat1 途径的数据和该项目计划的实验设计,我们预计我们的研究将
阐明促进 PrCa 的新机制并验证 PrCa 治疗方法的新靶点。
英文摘要
ABSTRACT
Therapeutic approaches aimed at curing prostate cancer (PrCa) are only partially successful given the
occurrence of highly metastatic resistant phenotypes that frequently develop in response to chemical castration
of PrCa patients. Recently, we have, for the first time, described αvβ6, a surface receptor of the integrin family
as a novel therapeutic target for PrCa treatment; this molecule is an ideal target since, unlike other integrins, it
is found in different types of cancer but not in normal tissues. We have demonstrated unique properties of this
molecule in PrCa that are not observed for other integrins: we have shown that αvβ6 promotes castrate-
resistant prostate cancer (CRPC) via activation of JNK and androgen receptor (AR). Furthermore, we have
shown that αvβ6 is found in cancer cell exosomes, is transferred from cancer cells to recipient cells by
exosomes and remains active in the recipient cells. We also demonstrate that αvβ6 has profound effects on
the microenvironment. Specifically, αvβ6 prevents induction of the Stat1/Mx1/2 signaling pathway in donor
cancer cells, and their exosomes, and its down-regulation in cancer cell exosomes inhibits monocyte M2
polarization. Finally, we demonstrate that αvβ6 inhibition in vivo causes upregulation of the Stat1/MxA/B
signaling pathway in cancer cells.
Based on our highly rigorous mechanistic studies, we propose the following innovative hypothesis: αvβ6
expression affects the microenvironment by down-regulating Stat1/Mx1 levels in donor cells, and subsequently
in cancer cell exosomes and recipient cells, thereby promoting monocyte differentiation, tumor growth, and
cancer progression. Consequently, by down-regulating or inhibiting αvβ6 in cancer cells, increased
Stat1/MxA/B levels in cells/ exosomes/ monocytes will be generated producing an anti-tumor effect. To test
this hypothesis, we plan the following three specific aims. We will examine in vitro the role of αvβ6 integrin in
regulating cancer cell - monocyte crosstalk (Aim 1), and analyze in vivo the functional role of the pathway
mediated by exosomal αvβ6 and/or Stat1 in cancer progression (Aim 2) and characterize the αvβ6
integrin/Stat1 pathway in PrCa cells (Aim 3).
Innovative approaches, highly purified exosomes and in vivo models will be used to test our hypothesis that
transfer of integrins and their downstream effectors from cancer cells to other cells in the tumor
microenvironment promotes CRPC. The study will be supported by a multidisciplinary team of investigators
who have extensive and complementary expertise in all the required technologies. Based on our preliminary
data on the αvβ6/Stat1 pathway and planned experimental design for this project, we expect that our study will
elucidate new mechanisms that promote PrCa and validate new targets for PrCa therapeutic approaches.
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会议论文
Integrin-mediated mechanisms of prostate cancer progression
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批准号:10411395
-
项目类别:
-
资助金额:$6.43万
-
财政年份:2018
-
负责人:Lucia R. Languino
-
依托单位:
Integrin-mediated mechanisms of prostate cancer progression
-
批准号:10524161
-
项目类别:
-
资助金额:$0.49万
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财政年份:2018
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负责人:Lucia R. Languino
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依托单位:
Integrin-mediated mechanisms of prostate cancer progression
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批准号:10440435
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项目类别:
-
资助金额:$35.15万
-
财政年份:2018
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负责人:Lucia R. Languino
-
依托单位:
Integrin regulation of prostate cancer progression
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批准号:7991928
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项目类别:
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资助金额:$20.75万
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财政年份:2010
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负责人:Lucia R. Languino
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依托单位:
Beta1 Integrins and IGF-I Receptor in Prostate Cancer
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批准号:7364211
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项目类别:
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资助金额:$27.39万
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财政年份:2005
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负责人:Lucia R. Languino
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依托单位:
Beta1 Integrins and IGF-l Receptor in Prostate Cancer
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批准号:8616721
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项目类别:
-
资助金额:$25.34万
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财政年份:2005
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负责人:Lucia R. Languino
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依托单位:
Beta1 Integrins and IGF-I Receptor in Prostate Cancer
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批准号:6929602
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项目类别:
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资助金额:$28.8万
-
财政年份:2005
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负责人:Lucia R. Languino
-
依托单位:
Beta1 Integrins and IGF-l Receptor in Prostate Cancer
-
批准号:8244997
-
项目类别:
-
资助金额:$26.12万
-
财政年份:2005
-
负责人:Lucia R. Languino
-
依托单位:
Beta1 Integrins and IGF-I Receptor in Prostate Cancer
-
批准号:7047951
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项目类别:
-
资助金额:$28.18万
-
财政年份:2005
-
负责人:Lucia R. Languino
-
依托单位:
Beta1 Integrins and IGF-I Receptor in Prostate Cancer
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批准号:7220634
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项目类别:
-
资助金额:$28.21万
-
财政年份:2005
-
负责人:Lucia R. Languino
-
依托单位:
Beta1 Integrins and IGF-l Receptor in Prostate Cancer
-
批准号:8450018
-
项目类别:
-
资助金额:$24.56万
-
财政年份:2005
-
负责人:Lucia R. Languino
-
依托单位:
Beta1 Integrins and IGF-I Receptor in Prostate Cancer
-
批准号:7576863
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项目类别:
-
资助金额:$27.39万
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财政年份:2005
-
负责人:Lucia R. Languino
-
依托单位:
Beta1 Integrins and IGF-l Receptor in Prostate Cancer
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批准号:8051163
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项目类别:
-
资助金额:$26.07万
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财政年份:2005
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负责人:Lucia R. Languino
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依托单位:
INTEGRIN SIGNALING PATHWAYS IN PROSTATE CANCER
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批准号:6802680
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项目类别:
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资助金额:$26.87万
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财政年份:2001
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负责人:Lucia R. Languino
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依托单位:
Integrin Signaling Pathways in Prostate Cancer
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批准号:8462210
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项目类别:
-
资助金额:$25.6万
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财政年份:2001
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负责人:Lucia R. Languino
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依托单位:
Integrin Signaling Pathways in Prostate Cancer
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批准号:8657811
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项目类别:
-
资助金额:$32.08万
-
财政年份:2001
-
负责人:Lucia R. Languino
-
依托单位:
INTEGRIN SIGNALING PATHWAYS IN PROSTATE CANCER
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批准号:6633931
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项目类别:
-
资助金额:$26.87万
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财政年份:2001
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负责人:Lucia R. Languino
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依托单位:
Integrin Signaling Pathways in Prostate Cancer
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批准号:8150415
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项目类别:
-
资助金额:$26.16万
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财政年份:2001
-
负责人:Lucia R. Languino
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依托单位:
INTEGRIN SIGNALING PATHWAYS IN PROSTATE CANCER
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批准号:6514884
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项目类别:
-
资助金额:$27.63万
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财政年份:2001
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负责人:Lucia R. Languino
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依托单位:
INTEGRIN SIGNALING PATHWAYS IN PROSTATE CANCER
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批准号:6856528
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项目类别:
-
资助金额:$26.87万
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财政年份:2001
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负责人:Lucia R. Languino
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依托单位:
海外基金