Perturbation of hyaluronan function in cancer

癌症中透明质酸功能的扰动

基本信息

批准号：
7846084
负责人：
BRYAN P TOOLE
金额：
$ 25.11万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-09-01 至 2011-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7846084
关键词：
1-Phosphatidylinositol 4-Kinase ABCB1 gene ABCG2 gene ATP-Binding Cassette Transporters Abbreviations Address Adult Anchorage-Independent Growth Animal Model Animals Apoptosis Apoptotic Atherosclerosis CD44 Antigens Cancer Patient Cell Communication Cell Survival Cells Characteristics Chronic Coculture Techniques Data Development Dinoprostone Disease Drug Efflux Drug resistance ERBB2 gene Extracellular Matrix Family Growth Factor Hepatocyte Growth Factor Hyaluronan Inflammation Inflammatory Intervention Laboratories Lead Leukocytes Link Malignant - descriptor Malignant Neoplasms Matrix Metalloproteinases Mediator of activation protein Membrane Glycoproteins Modeling Multi-Drug Resistance Outcome P-Glycoprotein Pathway interactions Pharmaceutical Preparations Phosphatidylinositols Phosphotransferases Population Premalignant Process Production Property Protein Tyrosine Kinase Proto-Oncogene Protein c-met Reactive Oxygen Species Receptor Protein-Tyrosine Kinases Resistance Role Side Signal Pathway Signal Transduction Stem cells System Testing Therapeutic Therapeutic Intervention Time Tissues Work base cancer cell cell behavior design in vivo macrophage macrophage product mouse model neoplastic cell novel progenitor prognostic receptor research study tumor tumor growth tumor progression

项目摘要

DESCRIPTION (provided by applicant): Malignant cell behavior can arise by several mechanisms but is frequently associated with amplified activities of receptor tyrosine kinases and downstream signaling cascades. These pathways have been linked to anchorage-independent growth, to invasiveness and to multidrug resistance, common properties of malignant cancer cells. Drug resistance is also associated with enhanced drug efflux via ATP-dependent, ABC family transporters, and recent work emphasizes a potential role for cancer progenitor/ "side population" cells enriched in the ABCG2 transporter in resistance. Close regulatory connections have now been revealed between all of these cellular properties and hyaluronan, a major component of the pericellular matrix surrounding tumor cells in vivo. Emmprin (CD 147), a cell surface glycoprotein enriched in malignant tumor cells, induces hyaluronan synthesis and its effects. Thus the long-term objective of this work is to determine the mechanisms whereby hyaluronan and emmprin regulate these hallmark properties of malignant cells as a basis for designing therapeutic interventions in cancer patients. A central question addressed in this proposal is how hyaluronan signaling becomes activated in malignant cells. Chronic inflammation and associated alterations in the stromal microenvironment of tumors induce or enhance malignant cell properties and tumor progression. In particular, tumor-associated macrophages promote signaling pathways linked to tumor cell survival, invasiveness and multidrug resistance. Both hyaluronan and emmprin are now known to be crucial components of inflammatory processes. The novel hypothesis guiding the proposed work is that mediators produced by cells in the stromal microenvironment, especially macrophages, induce hyaluronan-dependent signaling and consequent malignant outcomes, such as resistance to apoptosis/ drug resistance in tumor cells. The proposed studies address this question in macrophage-tumor co-culture systems, in drug-resistant side population cells and in animal models. These experiments will help illuminate the mechanisms whereby hyaluronan-induced receptor tyrosine kinase signaling is initiated in cancer cells and results in malignant cell properties, especially drug resistance and its relationship to cancer progenitor cells. Consequently, these approaches will help to guide further development of therapeutic interventions in cancer patients, employing antagonists of deregulated HA interactions.

描述（由申请人提供）：恶性细胞行为可由多种机制引起，但通常与受体酪氨酸激酶和下游信号级联的放大活性相关。这些途径与不依赖贴壁的生长、侵袭性和多药耐药性以及恶性癌细胞的共同特性有关。耐药性还与通过 ATP 依赖性 ABC 家族转运蛋白增强的药物流出有关，最近的工作强调了富含 ABCG2 转运蛋白的癌症祖细胞/“侧群”细胞在耐药性中的潜在作用。现在已经揭示了所有这些细胞特性与透明质酸（体内肿瘤细胞周围细胞周基质的主要成分）之间存在密切的调节联系。 Emmprin (CD 147) 是一种富含于恶性肿瘤细胞中的细胞表面糖蛋白，可诱导透明质酸合成及其作用。因此，这项工作的长期目标是确定透明质酸和 emmprin 调节恶性细胞的这些标志特性的机制，作为设计癌症患者治疗干预措施的基础。该提案解决的一个核心问题是透明质酸信号如何在恶性细胞中被激活。慢性炎症和肿瘤基质微环境的相关改变诱导或增强恶性细胞特性和肿瘤进展。特别是，肿瘤相关巨噬细胞促进与肿瘤细胞存活、侵袭性和多药耐药性相关的信号通路。现在已知透明质酸和 emmprin 都是炎症过程的关键成分。指导拟议工作的新假设是，基质微环境中的细胞（尤其是巨噬细胞）产生的介质会诱导透明质酸依赖性信号传导和随之而来的恶性结果，例如肿瘤细胞对细胞凋亡/耐药性的抵抗。拟议的研究在巨噬细胞-肿瘤共培养系统、耐药侧群细胞和动物模型中解决了这个问题。这些实验将有助于阐明透明质酸诱导的受体酪氨酸激酶信号在癌细胞中启动并导致恶性细胞特性的机制，特别是耐药性及其与癌症祖细胞的关系。因此，这些方法将有助于指导癌症患者治疗干预的进一步发展，采用解除管制的 HA 相互作用的拮抗剂。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Synthetic emmprin peptides with chitobiose substitution stimulate MMP-2 production by fibroblasts.

DOI：
10.1186/1471-2407-11-300
发表时间：
2011-07-17
期刊：
BMC cancer
影响因子：
3.8
作者：
Kawakami T;Sameshima T;Hojo H;Koga K;Nakahara Y;Toole BP;Suzumiya J;Okada Y;Iwasaki A;Nabeshima K
通讯作者：
Nabeshima K

Emmprin and KSHV: new partners in viral cancer pathogenesis.

Emmprin 和 KSHV：病毒性癌症发病机制的新伙伴。

DOI：
10.1016/j.canlet.2013.05.037
发表时间：
2013-09-01
期刊：
CANCER LETTERS
影响因子：
9.7
作者：
Dai, Lu;Bai, Lihua;Lu, Ying;Xu, Zengguang;Reiss, Krys;Del Valle, Luis;Kaleeba, Johnan;Toole, Bryan P.;Parsons, Chris;Qin, Zhiqiang
通讯作者：
Qin, Zhiqiang

Kaposi sarcoma-associated herpesvirus (KSHV) induces a functional tumor-associated phenotype for oral fibroblasts.