Matrix remodeling in tumor growth and metastasis in a murine breast cancer model

小鼠乳腺癌模型中肿瘤生长和转移的基质重塑

• 批准号: 8203343
• 负责人: Lisa L Chang
• 金额: $ 4.84万
• 依托单位: WISTAR INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8203343
• 关键词: Address; Affect; Binding; Binding Sites; Biological Markers; Breast Cancer Model; Breeding; Cancer Diagnostics; Cancer Etiology; Cancer Patient; Carcinoma; Catalytic Domain; Cell Proliferation; Cessation of life; Characteristics; Cleaved cell; Clinic; Clinical; Collagen; Colon Carcinoma; Data; Development; Diagnosis; Dipeptidyl Peptidases; Disease; Drug resistance; Economics; Endopeptidases; Epithelial; Extracellular Matrix; Family; Fibroblasts; Genes; Human; Integrin Binding; Integrins; Interstitial Collagenase; Knock-in Mouse; Knockout Mice; Lead; Life; Link; Luciferases; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of pancreas; Mammary Neoplasms; Mediating; Membrane; Modeling; Molecular Target; Mouse Mammary Tumor Virus; Mouse Strains; Mus; Neoplasm Metastasis; Neoplastic Epithelial Cell; Peptide Hydrolases; Play; Primary Neoplasm; Process; Productivity; Protein Inhibition; Proteolytic Processing; Psyche structure; Reporting; Research; Resources; Role; Serine Protease; Signal Pathway; Signal Transduction; Signaling Molecule; Societies; Specificity; Stromal Cells; Structure; Testing; Therapeutic; Time; Transplantation; Vascularization; Wild Type Mouse; Woman; angiogenesis; base; cancer therapy; collagenase; cost; fibroblast-activating factor; inhibitor/antagonist; malignant breast neoplasm; mortality; mouse model; mutant; mutant mouse model; neoplastic cell; novel; outcome forecast; protein expression; spatial relationship; therapeutic target; tumor; tumor growth; tumor initiation; tumor progression; tumorigenesis; tumorigenic; unpublished works

DESCRIPTION (provided by applicant): My research aims to understand the tumorigenic role of fibroblast activation protein (FAP), a membrane-bound serine protease with dipeptidyl peptidase (DPP) and endopeptidase/collagenase activities. FAP is unique, in that it is expressed in cancer associated fibroblasts (CAFs) in 90% of all human epithelial derived cancers, but not in normal or transformed (malignant/neoplastic) epithelial cells. Importantly, unpublished work from our lab (J.Tchou and E. Puri) shows that FAP can be used as a robust pan-CAF marker in human breast cancer, it being superior to other CAF markers in its selectivity and specificity. CAFs play roles in ECM remodeling, angiogenesis and stromagenesis, and are important players in tumor growth and metastasis. A wide majority of reports on FAP activity describe correlations between FAP expression and poor prognosis, making FAP inhibition an appealing potential target for cancer therapeutics. Our lab recently demonstrated that FAP promotes tumorigenesis in an autochthonous mouse model of mutant K-ras- driven lung cancer and syngeneic transplant models of colon and pancreatic cancer and that the reduction in tumor growth in FAP-deficient mice was associated with enhanced accumulation of disorganized collagen, aberrant integrin signaling and reduced stromagenesis and angiogenesis. However, the mechanisms by which FAP promotes tumorigenesis are yet to be defined and its role in metastasis has not yet been investigated in any tumor type. Our preliminary data indicate that FAP mediates the proteolytic processing of the characteristic 3/4 and 1/4 fragments of collagen generated by collagenase mediated cleavage (eg. MMP-1). A central hypothesis of this proposal is that FAP promotes tumorigenesis through its protease activity by playing a critical role in ECM remodeling. Specifically, I hypothesize that by targeting collagen for degradation and turnover, FAP regulates matrix-dependent signaling of tumor cell proliferation, stromagenesis, angiogenesis and metastasis. To test these hypotheses I will compare tumorigenesis and metastasis of MMTV-Neu driven autochthonous mammary tumors in FAP wild-type mice, FAP-null mice (FAP-knock-ins expressing luciferase in place of the FAP gene) and knock-in mice expressing an enzymatic dead FAP mutant (FAPS624A) or a FAP mutant (FAPA657S) that retains DPP activity but lacks endopeptidase/collagenase activity. Therefore, by making use of these enzymatically defective FAP mice, this study will also examine the mechanism by which FAP acts on ECM remodeling. These novel FAP mouse strains have been produced in the lab and are currently breeding, while the MMTV-Neu mouse is commercially available. ! PUBLIC HEALTH RELEVANCE: Breast cancer is the second leading cause of cancer deaths in women today. The costs of cancer are a financial and mental toll on people diagnosed with cancer, their families, and society as a whole. In 2005 the burden of breast cancer in the U.S. was $12.096 billion in lost time and economic productivity (NCI, 2009/2010), therefore it is imperative to identify new molecular targets for early prognosis, treatment and eradication of this devastating disease. This research aims to better understand the causes and mechanisms underlying tumor initiation, progression and metastasis by studying the relationship between mammary tumor cells and their microenvironment. The research proposed will define the protumorigenic activity of a tumor stromal cell protease and extracellular matrix remodeling in an autochthonous breast cancer model. Results of the proposed studies will reveal novel mechanisms through which this protease regulates tumor development and therefore its value as a target for cancer therapeutics. Further, our studies may lead to an early breast cancer diagnostic biomarker that could be used in the clinic to save time, resources and most importantly, life. !

描述（由申请人提供）：我的研究旨在了解成纤维细胞激活蛋白（FAP）的致膜性作用，这是一种膜结合的丝网丝氨酸蛋白酶，具有二肽基肽酶（DPP）和内肽酶/胶原酶活性。 FAP是独一无二的，因为它在90％的人类上皮衍生的癌症中在癌症相关的成纤维细胞（CAF）中表达，但在正常或转化（恶性/肿瘤）上皮细胞中不表达。重要的是，我们实验室（J.Tchou和E. puri）的未发表的作品表明，FAP可以用作人类乳腺癌中强大的PAN-CAF标记物，其选择性和特异性优于其他CAF标记。 CAFS在ECM重塑，血管生成和曲折的作用中起着作用，并且是肿瘤生长和转移的重要参与者。关于FAP活性的大多数报告都描述了FAP表达与预后不良之间的相关性，这使得FAP抑制成为癌症治疗剂的潜在潜在靶标。我们的实验室最近表明，FAP在突变体K-RAS驱动的肺癌和结肠癌和胰腺癌的合成性移植模型的自chhonous小鼠模型中促进了肿瘤发生，并且FAP缺陷小鼠的肿瘤生长的减少与异常的collagen和Angeis commentic and Synecog和Redomagens and Solomagen and Solomagen and Solomagen and Syneragen和Rysogagen的肿瘤生长有关。但是，FAP促进肿瘤发生的机制尚未定义，并且在任何肿瘤类型中尚未研究其在转移中的作用。我们的初步数据表明，FAP介导了胶原酶介导的裂解（例如MMP-1）产生的胶原蛋白特征3/4和1/4片段的蛋白水解处理。该提案的一个核心假设是，FAP通过其蛋白酶活性在ECM重塑中起关键作用来促进肿瘤发生。具体而言，我假设通过将胶原蛋白靶向降解和离职，FAP调节了肿瘤细胞增殖，曲折性，血管生成和转移的基质依赖性信号传导。要测试这些假设，我将比较FAP野生型小鼠中MMTV-NEU驱动的自卫乳乳腺肿瘤的肿瘤发生和转移，FAP-NULL小鼠（FAP-NULL小鼠（FAP-NULL小鼠（表达荧光素酶）表达荧光素酶，以fap基因为代替fap gene），表达敲击的小鼠，表达enzys fap fap fap sutant or a fap 62 fap62224 （FAPA657）保留DPP活性但缺乏内肽酶/胶原酶活性。因此，通过利用这些酶促缺陷的FAP小鼠，本研究还将检查FAP对ECM重塑作用的机制。这些新型的FAP小鼠菌株是在实验室中产生的，目前正在繁殖，而MMTV-Neu小鼠则可在市售。呢 公共卫生相关性：乳腺癌是当今女性癌症死亡的第二大原因。癌症的成本是对被诊断为癌症，家庭和整个社会的人的财务和心理损失。 2005年，美国的乳腺癌负担损失了120.96亿美元（NCI，2009/2010），因此必须确定对这种毁灭性疾病的早期预后，治疗和消除的新分子靶标。 这项研究旨在通过研究乳腺肿瘤细胞及其微环境之间的关系来更好地了解肿瘤起步，进展和转移的原因和机制。提出的研究将定义肿瘤基质细胞蛋白酶和在自我卫生乳腺癌模型中的细胞外基质重塑的原始活性。拟议研究的结果将揭示这种蛋白酶调节肿瘤发育的新型机制，因此其价值是癌症治疗剂的靶标。此外，我们的研究可能会导致早期的乳腺癌诊断生物标志物，该标志物可以在诊所中用于节省时间，资源，最重要的是生命。呢