Regulation of Tumor and Metastatic Growth by Hypoxia and CTGF

缺氧和 CTGF 对肿瘤和转移性生长的调节

• 批准号: 8492949
• 负责人: Amato J. Giaccia
• 金额: $ 11.84万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-01 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8492949
• 关键词: 3-Dimensional; Address; Adhesions; Adhesives; Affect; Agar; Antibodies; Cancer cell line; Cell Adhesion; Cell Adhesion Inhibition; Cell-Cell Adhesion; Cells; Characteristics; Clinic; Clinical; Collaborations; Combined Modality Therapy; Cytostatics; Cytotoxic agent; Cytotoxin; Data; Effectiveness; Employee Strikes; Grant; Growth; Head and Neck Neoplasms; Human; Hypoxia; Implant; Individual; Lead; Malignant - descriptor; Malignant neoplasm of pancreas; Mediating; Molecular; Mus; Neoplasm Metastasis; Pancreas; Pancreatitis; Plastics; Principal Investigator; Protocols documentation; Regulation; Role; Stromal Cells; Testing; Tumor-Derived; base; cell growth; connective tissue growth factor; effective therapy; expectation; gemcitabine; matrigel; mutant; neoplastic cell; pancreatic cancer cells; pancreatic neoplasm; programs; subcutaneous; tumor; tumor growth; tumor progression

During the last grant period, we have obtained evidence that the expression of connective tissue growth factor (CTGF) is elevated in human pancreatic tumors, but not in normal pancreas or pancreatitis. Since pancreatic tumors are highly hypoxia and CTGF is known to be hypoxia inducible, we have focused this grant to understand the role of hypoxia and CTGF in pancreatic tumor progression. The basis for these studies to investigate the importance of CTGF in pancreatic tumor progression derive from our demonstration that targeted inhibition of CTGF with a monoclonal specific antibody results in significant growth inhibition of two different pancreatic cancer cell lines implanted as subcutaneous tumors. In this competitive renewal, Project 1 will focus on determining the mechanistic role of CTGF and its individual domains on pancreatic tumor progression under normoxic and hypoxic conditions. Our preliminary data suggests that CTGF is able to enhance the growth of pancreatic tumor cells. Induction of CTGF had no effect on cell growth on plastic, but significantly enhanced spheroid growth in soft agar. Most striking was the increase in cell adhesion induced by CTGF expression. These changes in cell adhesion that are necessary for 3-D growth lead us to test the hypothesis that one of the major roles of CTGF in malignant progression is to regulate cell-cell adhesion, and that inhibiting this activity will impact tumor growth and metastases. Thus, the aims of this proposal are to 1) determine how CTGF affects cell adhesion of pancreatic tumor cells under normoxic and hypoxic conditions using domain specific deletion mutants in cells that are manipulated to express different levels of HIF-1 (Project 3), 2) determine how important CTGF is for 3-D growth and invasion under normoxic and hypoxic conditions, 3) determine how inhibition of CTGF mediated adhesion affects metastatic growth, 4) determine how inhibition of cell adhesion by CTGF affects subcutaneous and orthotopic tumor growth of pancreatic tumor cells and in collaboration with Project 4 head and neck tumors, 5) determine the role of stromal and tumor cell CTGF on tumor growth, 6) determine how effective the combination of CTGF Ab and the new hypoxic specific cytotoxin PR-104 are in controlling pancreatic tumor growth compared to CTGF Ab and gemcitabine (Project 2). In summary, the proposed studies are intended to address an important mechanism by which CTGF affects tumor progression in pancreatic cancers and to determine how effective it is in combination therapy to bring it to the clinic.

在最后一个赠款期间，我们获得了结缔组织生长表达的证据 人胰腺肿瘤中因子（CTGF）升高，但在正常胰腺或胰腺炎中却没有升高。自从 胰腺肿瘤是高度缺氧，CTGF是可诱导的缺氧，我们已经重点了 授予了解缺氧和CTGF在胰腺肿瘤进展中的作用。这些基础 研究CTGF在胰腺肿瘤进展中的重要性是从我们的 证明用单克隆特异性抗体靶向抑制CTGF导致显着的 植入皮下肿瘤的两种不同胰腺癌细胞系的生长抑制。在这个 竞争性更新，项目1将重点放在确定CTGF及其个体的机理作用上 胰腺肿瘤进展的结构域在常氧和低氧条件下。我们的初步数据 表明CTGF能够增强胰腺肿瘤细胞的生长。 CTGF的诱导没有 对细胞生长对塑料的影响，但显着增强了软琼脂的球体生长。最引人注目的是 CTGF表达诱导的细胞粘附增加。这些细胞粘附的变化是必要的 对于3-D增长，我们测试了CTGF在恶性进展中的主要作用之一的假设是 为了调节细胞 - 细胞粘附并抑制这种活性会影响肿瘤的生长和转移。因此， 该提案的目的是1）确定CTGF如何影响胰腺细胞的细胞粘附 使用域特异性缺失突变体在被操纵为 表达不同水平的HIF-1（项目3），2）确定CTGF对于3-D增长和 在常氧和低氧条件下的侵袭，3）确定CTGF介导的粘附的抑制 影响转移性生长，4）确定CTGF对细胞粘附的抑制如何影响皮下和 胰腺肿瘤细胞的原位肿瘤生长，并与项目4头和颈部肿瘤合作， 5）确定基质和肿瘤细胞CTGF对肿瘤生长的作用，6）确定 CTGF AB和新的缺氧特异性细胞毒素PR-104的组合在控制胰腺肿瘤中 与CTGF AB和吉西他滨相比，增长（项目2）。总而言之，拟议的研究是 旨在解决CTGF影响肿瘤进展的重要机制 胰腺癌并确定将其带入联合疗法的有效性 诊所。