FGF-2 Autocrine Signaling in Lung Cancer

肺癌中的 FGF-2 自分泌信号传导

• 批准号: 7370013
• 负责人: LYNN E HEASLEY
• 金额: $ 31.51万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-12-01 至 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7370013
• 关键词: Apoptosis; Archives; Autocrine Communication; Biopsy; Cancer cell line; Cell Line; Cells; Cellular Morphology; Clinical; Cultured Cells; Data; Diagnostic Neoplasm Staging; Dominant-Negative Mutation; Dysplasia; EGF gene; Epidermal Growth Factor Receptor; Epithelial; Epithelial Cells; Erlotinib; Exhibits; Extracellular Signal Regulated Kinases; FGFR1 gene; Family; Fibroblast Growth Factor; Fibroblast Growth Factor 2; Fibroblast Growth Factor Receptors; Gefitinib; Gene Expression; Growth; Growth Factor; Growth Factor Receptors; Heterogeneity; Human; Immune; In Vitro; Lesion; Ligands; Lung; Lung Neoplasms; Malignant neoplasm of lung; Measures; Mediating; Mesenchymal; Morphology; Mus; Neoplasm Metastasis; Non-Small-Cell Lung Carcinoma; Outcome; Pathway interactions; Patients; Pattern; Phosphorylation; Primary Neoplasm; Protein Tyrosine Kinase; Receptor Protein-Tyrosine Kinases; Receptor Signaling; Regulation; Relative (related person); Resistance; Role; Signal Pathway; Signal Transduction; Snails; Staining method; Stains; Testing; Thinking; Transfection; Tumor Tissue; Tumor stage; Tyrosine Kinase Inhibitor; Xenograft procedure; angiogenesis; autocrine; cancer cell; cancer therapy; in vivo; inhibitor/antagonist; mutant; programs; receptor; receptor expression; response; slug; small hairpin RNA; success; therapeutic target; tumor; tumor growth; tumor progression

DESCRIPTION (provided by applicant): Autocrine growth factor signaling, often through receptor tyrosine kinases (RTKs), is a hallmark of cancer cells. While EGF receptors (EGFRs) and the EGF family of ligands were thought to constitute a dominant autocrine pathway in human non-small cell lung cancer (NSCLC), only 10-20% of patients exhibit a clinical response to the EGFR tyrosine kinase inhibitors (TKI), gefitinib and erlotinib. Thus, consistent with the known heterogeneity of NSCLC, EGFR is likely not the only RTK mediating autocrine growth in lung cancer. Importantly, we show that fibroblast growth factor 2 (FGF2) and FGF receptors (FGFRs) are frequently co-expressed in NSCLC. Moreover, FGF2 shRNAs, dominant-negative FGFR1 and a FGFR TKI (RO4383596) selectively reduce growth of NSCLC cell lines that co-express FGF2 and FGFRs. By contrast, cell lines lacking FGF2 expression are resistant to RO4383596 and sensitive to gefitinib. Other NSCLC cells exhibit an additive response to combinations of FGFR and EGFR TKIs, implying dual EGFR and FGFR autocrine inputs. Finally, our preliminary data support a dominant role for FGFR and EGFR loops in the induction of epithelial-mesenchymal transition (EMT), a program critical to tumor progression and metastasis. Together, our findings support a hypothesis that FGF2 and FGFRs comprise an autocrine pathway that functions in NSCLC as an auxiliary to EGFR autocrine loops to drive an EMT program. To test this hypothesis, we will complete these specific aims. Aim 1: Define whether FGF2 and FGFR co-expression contributes to NSCLC cell transformed growth. Aim 2: Test the role of FGFR and EGFR autocrine signaling through the ERK MAP kinases in the regulation of EMT in NSCLC. Aim 3: Define when FGFR autocrine loops arise during human lung cancer progression and explore the association of FGF2 and FGFR co-expression with resistance to EGFR TKIs in patients. Growth factor receptors mediating transformed growth of specific tumors represent attractive therapeutic targets. In NSCLC, EGFR inhibitors have already been deployed, but with only limited success. Our preliminary studies indicate that many NSCLC cells employ FGFR autocrine signaling, either alone or in combination with EGFR signaling, as evidenced by additive inhibition of transformed growth by FGFR and EGFR inhibitors. Therefore, establishing FGF2 and specific FGFRs as components of a co-dominant autocrine signal pathway in NSCLC represents a significant problem with a high potential for impact on lung cancer treatment.

描述（由申请人提供）：自分泌生长因子信号传导通常通过受体酪氨酸激酶（RTK）进行，是癌细胞的标志。虽然 EGF 受体 (EGFR) 和 EGF 配体家族被认为构成人类非小细胞肺癌 (NSCLC) 的主要自分泌途径，但只有 10-20% 的患者对 EGFR 酪氨酸激酶抑制剂 (TKI)、吉非替尼和厄洛替尼表现出临床反应。因此，与已知的 NSCLC 异质性一致，EGFR 可能不是唯一介导肺癌自分泌生长的 RTK。重要的是，我们发现成纤维细胞生长因子 2 (FGF2) 和 FGF 受体 (FGFR) 在 NSCLC 中经常共表达。此外，FGF2 shRNA、显性失活 FGFR1 和 FGFR TKI (RO4383596) 选择性降低共表达 FGF2 和 FGFR 的 NSCLC 细胞系的生长。相比之下，缺乏 FGF2 表达的细胞系对 RO4383596 具有抗性，对吉非替尼敏感。其他 NSCLC 细胞对 FGFR 和 EGFR TKI 组合表现出加性反应，这意味着 EGFR 和 FGFR 自分泌双重输入。最后，我们的初步数据支持 FGFR 和 EGFR 环在诱导上皮间质转化 (EMT) 中发挥主导作用，EMT 是肿瘤进展和转移的关键程序。总之，我们的研究结果支持这样的假设：FGF2 和 FGFR 构成自分泌途径，在 NSCLC 中作为 EGFR 自分泌环路的辅助来驱动 EMT 程序。为了检验这个假设，我们将完成这些具体目标。目标 1：确定 FGF2 和 FGFR 共表达是否有助于 NSCLC 细胞转化生长。目标 2：测试 FGFR 和 EGFR 自分泌信号通过 ERK MAP 激酶在 NSCLC 中 EMT 调节中的作用。目标 3：定义人类肺癌进展过程中 FGFR 自分泌环何时出现，并探讨 FGF2 和 FGFR 共表达与患者对 EGFR TKI 耐药的关系。介导特定肿瘤转化生长的生长因子受体代表了有吸引力的治疗靶点。在 NSCLC 中，EGFR 抑制剂已经得到应用，但取得的成功有限。我们的初步研究表明，许多 NSCLC 细胞单独或与 EGFR 信号联合使用 FGFR 自分泌信号，FGFR 和 EGFR 抑制剂对转化生长的加性抑制就证明了这一点。因此，将 FGF2 和特定 FGFR 作为 NSCLC 中共显性自分泌信号通路的组成部分是一个对肺癌治疗具有很大影响潜力的重大问题。