Dissecting the Function of Cysteine Cathepsins in the Tumor Microenvironment

剖析半胱氨酸组织蛋白酶在肿瘤微环境中的功能

• 批准号: 7810699
• 负责人: Johanna Joyce
• 金额: $ 36.1万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7810699
• 关键词: Ablation; Affect; Angiogenic Factor; Angiogenic Switch; Apoptosis; Basement membrane; Binding; Biochemical; Biochemistry; Biological Assay; Biology; Blood Vessels; Cancerous; Cathepsins; Cathepsins B; Cell Proliferation; Cell surface; Cells; Cellular biology; Coculture Techniques; Collagen Type I; Collagen Type IV; Complex; Cysteine; Data; Development; Diagnostic Neoplasm Staging; E-Cadherin; Enzymes; Extracellular Protein; Family; Family member; Fibrinogen; Future; Genes; Genetic; Growth; Hand; Human; Immune; Individual; Laminin; Left; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Membrane Proteins; Molecular; Molecular Biology; Mus; Mutation; Normal Cell; Patients; Peptide Hydrolases; Play; Process; Provider; Publishing; Research Personnel; Resistance; Role; Source; Testing; Text; Therapeutic; Tissues; Tumor Angiogenesis; Tumor Cell Invasion; Tumor stage; Vascularization; angiogenesis; base; cathepsin-6; cell type; extracellular; host neoplasm interaction; in vivo; inhibitor/antagonist; insight; knockout gene; member; mouse model; neoplastic cell; novel; outcome forecast; pre-clinical; protein degradation; research study; tumor; tumor growth; tumor progression; tumorigenesis; tumorigenic; vascular factor

DESCRIPTION (provided by applicant): The tissue microenvironment in which a cancer arises plays a critical role in inhibiting tumor development, but conversely can also be misappropriated by cancerous cells into providing factors that support malignant growth. Our long-term objective is to understand the molecular crosstalk between tumor and host cells, and to determine the mechanisms by which host tissues are co-opted to facilitate cancer progression. This proposal focuses on the contribution of the Cysteine Cathepsin family of degradative enzymes to tumor-host molecular interactions. Cysteine cathepsins are up-regulated in many human and mouse cancers and their increased expression is associated with malignant progression and a poor patient prognosis. Some cathepsin family members are upregulated in tumor cells, however others are additionally or exclusively provided by host cells including endothelial and innate immune cells. Using a broad-spectrum cathepsin inhibitor, we have shown that the cathepsin family is important for all stages of tumor development in the RIP1-Tag2 pancreatic cancer mouse model. Treatment with this inhibitor decreased angiogenic switching, blocked tumor growth, and significantly impaired tumor vascularization, cell proliferation and tumor invasion. Despite the important role for cathepsins in cancer progression, the molecular mechanisms by which they facilitate tumorigenesis are still largely unknown. Our hypothesis is that individual members of the cathepsin family are crucial for distinct steps in acquiring each distinct 'hallmark capability' of cancer. We will identify which of the 6 cathepsin family members upregulated in cancers are important for tumor development. We will test the hypothesis that cathepsins promote tumor invasion by a molecular mechanism requiring the extracellular cleavage of E-cadherin, and facilitate angiogenesis through the degradation and release of vascular basement membrane proteins. We will also determine if the cellular source of cathepsin expression in the cancer microenvironment is necessary for its pro-tumorigenic functions. To achieve these aims, we will analyze 6 mouse gene knockouts of cathepsin family members with a combination of cell co-culture, biochemical and pharmacological experiments. These studies will provide vital insights into the biology of cathepsins in cancer, the role of the microenvironment in tumor progression, and enable the development and application of therapeutic cancer strategies based on studies in this pre-clinical mouse model.

描述（由申请人提供）：癌症发生的组织微环境在抑制肿瘤发展中起着关键作用，但相反地，也可能被癌细胞挪用，提供支持恶性生长的因子。 我们的长期目标是了解肿瘤和宿主细胞之间的分子串扰，并确定宿主组织被增选以促进癌症进展的机制。 该建议的重点是半胱氨酸组织蛋白酶家族的降解酶的肿瘤宿主分子相互作用的贡献。 半胱氨酸组织蛋白酶在许多人类和小鼠癌症中上调，并且它们的表达增加与恶性进展和不良患者预后相关。 一些组织蛋白酶家族成员在肿瘤细胞中被上调，然而其他组织蛋白酶家族成员另外或专门由宿主细胞（包括内皮和先天免疫细胞）提供。 使用广谱组织蛋白酶抑制剂，我们已经表明，组织蛋白酶家族是重要的RIP 1-Tag 2胰腺癌小鼠模型的肿瘤发展的所有阶段。 用这种抑制剂治疗降低了血管生成转换，阻断了肿瘤生长，并显著损害了肿瘤血管形成、细胞增殖和肿瘤侵袭。 尽管组织蛋白酶在癌症进展中起重要作用，但它们促进肿瘤发生的分子机制仍在很大程度上未知。 我们的假设是，组织蛋白酶家族的各个成员对于获得癌症的每个不同的“标志能力”的不同步骤至关重要。 我们将鉴定在癌症中上调的6个组织蛋白酶家族成员中的哪一个对肿瘤的发展是重要的。 我们将测试的假设，组织蛋白酶促进肿瘤侵袭的分子机制，需要细胞外切割的E-钙粘蛋白，并促进血管生成，通过降解和释放的血管基底膜蛋白。 我们还将确定在癌症微环境中组织蛋白酶表达的细胞来源是否是其促肿瘤发生功能所必需的。 为了实现这些目标，我们将结合细胞共培养、生化和药理学实验来分析6个组织蛋白酶家族成员的小鼠基因敲除。 这些研究将为癌症中组织蛋白酶的生物学、微环境在肿瘤进展中的作用提供重要的见解，并使基于这种临床前小鼠模型研究的治疗癌症策略的开发和应用成为可能。