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.

在上一次资助期间，我们获得了结缔组织生长表达的证据 因子 (CTGF) 在人类胰腺肿瘤中升高，但在正常胰腺或胰腺炎中则不升高。自从 胰腺肿瘤是高度缺氧的，已知 CTGF 是缺氧诱导的，我们重点关注这一点 资助了解缺氧和 CTGF 在胰腺肿瘤进展中的作用。这些的基础 调查 CTGF 在胰腺肿瘤进展中的重要性的研究源自我们 证明用单克隆特异性抗体靶向抑制 CTGF 会产生显着的效果 作为皮下肿瘤植入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将重点确定CTGF及其个体的机械作用 常氧和缺氧条件下胰腺肿瘤进展的领域。我们的初步数据 表明CTGF能够促进胰腺肿瘤细胞的生长。 CTGF的诱导没有 对塑料上的细胞生长有影响，但显着增强软琼脂中的球状生长。最引人注目的是 CTGF 表达诱导的细胞粘附增加。细胞粘附的这些变化是必要的 对于 3-D 生长的研究使我们检验了以下假设：CTGF 在恶性进展中的主要作用之一是 调节细胞间粘附，抑制这种活性将影响肿瘤生长和转移。因此， 该提案的目的是1）确定CTGF如何影响胰腺肿瘤细胞在以下条件下的细胞粘附： 在常氧和低氧条件下，在细胞中使用域特异性缺失突变体 表达不同水平的 HIF-1（项目 3），2) 确定 CTGF 对于 3-D 生长的重要性，以及 常氧和低氧条件下的侵袭，3) 确定 CTGF 的抑制如何介导粘附 影响转移生长，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头颈肿瘤项目 4 合作， 5) 确定基质和肿瘤细胞 CTGF 对肿瘤生长的作用，6) 确定其效果如何 CTGF Ab 与新型缺氧特异性细胞毒素 PR-104 的组合可控制胰腺肿瘤 与 CTGF Ab 和吉西他滨相比的生长（项目 2）。总之，拟议的研究是 旨在解决 CTGF 影响肿瘤进展的重要机制 胰腺癌并确定联合疗法的有效性 诊所。