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Heparanase regulation of tumor host interactions in myeloma and breast cancer

乙酰肝素酶对骨髓瘤和乳腺癌肿瘤宿主相互作用的调节

基本信息

批准号：
8300186
负责人：
Ralph D Sanderson
金额：
$ 29.12万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-05 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8300186
关键词：
Automobile Driving Behavior Biological Models Biology Cancer Patient Cell surface Cells Cleaved cell Clinical Data Clinical Trials Data Employee Strikes Enzymes Event Extracellular Matrix Funding Gelatinase B Goals Growth Growth Factor Heparan Sulfate Proteoglycan Heparin Heparitin Sulfate Home environment Homing Human In Vitro Knowledge Light Link Location Malignant Neoplasms Mediating Metastatic Neoplasm to the Bone Modeling Multiple Myeloma Neoplasm Metastasis Osteolysis Osteolytic Pharmaceutical Preparations Phenotype Play Probability Proteins Publishing Regulation Resources Role SCID-hu Mice Signal Pathway Staging Structure Testing Therapeutic Tumor Biology Tumor Cell Invasion Up-Regulation Work angiogenesis base bone cancer cell cancer therapy cell behavior chemokine design experience heparanase host neoplasm interaction in vivo in vivo Model inhibitor/antagonist insight malignant breast neoplasm mouse model neoplastic cell novel pre-clinical promoter research study success syndecan therapy development tumor tumor growth tumor progression

项目摘要

Project Summary The long-term objective of our work is to determine how the heparan sulfate / heparanase axis regulates tumor behavior and to use this knowledge to develop new therapies for cancer. We have demonstrated that the heparan sulfate proteoglycan syndecan-1 and heparanase work synergistically to condition the tumor microenvironment thereby promoting an aggressive tumor phenotype in myeloma and breast cancer two devastating cancers that home to and degrade bone. Our goal now is to determine the mechanism of heparanase activity in tumors and to target heparanase therapeutically using novel drugs. Although work in the field suggests that heparanase functions to degrade extracellular matrix and thereby promote tumor metastasis, based on our new discoveries we hypothesize that heparanase expression and activity initiates broad downstream effects that dramatically alter the tumor microenvironment to stimulate growth, angiogenesis, metastasis and osteolysis of bone-homing tumors. Data from in vivo models indicates that these events occur largely via heparanase-mediated upregulation of syndecan-1 shedding, enhanced MMP-9 expression and activated destruction of bone. The following specific aims will define the function and mechanism of action of heparanase in myeloma and breast cancer and test novel anti-heparanase drugs with the aim of eradicating these cancers. Aim 1 will determine the functional link between heparanase, syndecan-1 and MMP-9; Aim 2 will determine how heparanase enhances osteolysis; Aim 3 will test the anti-tumor efficacy and mechanism of action of a new class of heparin-based inhibitors of heparanase against breast cancer. These studies will utilize well-developed in vitro and in vivo models including the SCID-hu model in which human tumor cells are grown within human bone. This work will generate novel insight into heparanase function and mechanism of action and provide pre-clinical data necessary to drive new heparanase inhibitors toward clinical trials. Project Narrative Heparanase is a protein made by cancer cells that plays a major role in helping them grow and spread throughout the body. This project is designed to provide a new understanding about how heparanase works in multiple myeloma and breast cancer and to test new anti-heparanase drugs to block cancer growth.

项目摘要我们工作的长期目标是确定硫酸乙酰肝素/乙酰肝素酶轴如何调节肿瘤的行为，并利用这些知识来开发新的癌症疗法。我们已经证明硫酸乙酰肝素蛋白聚糖多配体蛋白聚糖-1和乙酰肝素酶协同作用以调节肿瘤微环境，从而促进骨髓瘤和乳腺癌中的侵袭性肿瘤表型两破坏性的癌症，并使骨骼退化。我们现在的目标是确定本发明涉及在肿瘤中的乙酰肝素酶活性以及使用新型药物治疗性靶向乙酰肝素酶。虽然工作在 Field提出乙酰肝素酶的功能是降解细胞外基质并由此促进肿瘤转移，基于我们的新发现，我们假设乙酰肝素酶的表达和活性启动广泛的显著改变肿瘤微环境以刺激生长，血管生成，转移和骨溶解的骨归巢肿瘤。来自体内模型的数据表明这些事件发生在主要通过乙酰肝素酶介导的多配体蛋白聚糖-1脱落的上调，MMP-9表达的增强，骨的活化破坏。以下具体目标将确定在骨髓瘤和乳腺癌中的乙酰肝素酶，并测试新的抗乙酰肝素酶药物，这些癌症。目的1将确定乙酰肝素酶、syndecan-1和MMP-9之间的功能联系;目的2 将确定乙酰肝素酶如何增强骨质溶解; Aim 3将测试乙酰肝素酶的抗肿瘤功效和机制。一类新的肝素基类肝素酶抑制剂对乳腺癌的作用。这些研究将利用良好开发的体外和体内模型，包括SCID-hu模型，其中人肿瘤细胞生长在人骨中这项工作将对乙酰肝素酶的功能和作用机制产生新的认识。行动，并提供必要的临床前数据，以推动新的乙酰肝素酶抑制剂的临床试验。项目叙述乙酰肝素酶是一种由癌细胞产生的蛋白质，在帮助癌细胞生长和扩散方面起着重要作用在整个身体。本项目旨在提供一个新的理解肝素酶如何在多发性骨髓瘤和乳腺癌，并测试新的抗乙酰肝素酶药物，以阻止癌症的生长。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The heparanase/syndecan-1 axis in cancer: mechanisms and therapies.

DOI：
10.1111/febs.12168
发表时间：
2013-05
期刊：
The FEBS journal
影响因子：
0
作者：
Ramani VC;Purushothaman A;Stewart MD;Thompson CA;Vlodavsky I;Au JL;Sanderson RD
通讯作者：
Sanderson RD

Heparanase-induced shedding of syndecan-1/CD138 in myeloma and endothelial cells activates VEGFR2 and an invasive phenotype: prevention by novel synstatins.

肝素酶诱导的骨髓瘤和内皮细胞中Syndecan-1/CD138的脱落会激活VEGFR2和侵入性表型：新型合成蛋白预防。

DOI：
10.1038/oncsis.2016.5
发表时间：
2016-02-29
期刊：
ONCOGENESIS
影响因子：
6.2
作者：
Jung, O.;Trapp-Stamborski, V.;Purushothaman, A.;Jin, H.;Wang, H.;Sanderson, R. D.;Rapraeger, A. C.
通讯作者：
Rapraeger, A. C.

Heparan sulfate in the nucleus and its control of cellular functions.