FGF-2 Autocrine Signaling in Lung Cancer

肺癌中的 FGF-2 自分泌信号传导

• 批准号: 7534819
• 负责人: LYNN E HEASLEY
• 金额: $ 31.47万
• 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/7534819
• 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 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; 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）：通常通过受体酪氨酸激酶（RTK）的自分泌生长因子信号传导是癌细胞的标志。尽管EGF受体（EGFR）和EGF配体家族被认为是人类非小细胞肺癌（NSCLC）的主要自分泌途径，但只有10-20％的患者表现出对EGFR酪氨酸酪氨酸激酶抑制剂（TKI），gefititinib和Erlotinib和Erlotinib和Erlotinib和Erlotinib的临床反应。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，我们表明成纤维细胞生长因子2（FGF2）和FGF受体（FGFR）经常在NSCLC中共表达。此外，FGF2 SHRNA，主导阴性FGFR1和FGFR TKI（RO4383596）有选择地降低了共表达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，并且对吉非替尼敏感。其他NSCLC细胞对FGFR和EGFR TKI的组合表现出添加响应，这意味着双EGFR和FGFR自分泌输入。最后，我们的初步数据支持FGFR和EGFR回路在诱导上皮 - 间质转变（EMT）中的主要作用，这是对肿瘤进展和转移至关重要的程序。总之，我们的发现支持了一个假设，即FGF2和FGFR构成了一种自分泌途径，该途径在NSCLC中起作用，作为EGFR Autocrine循环驱动EMT程序的辅助。为了检验这一假设，我们将完成这些特定目标。目标1：定义FGF2和FGFR共表达是否有助于NSCLC细胞转化生长。 AIM 2：通过ERK MAP激酶在NSCLC中的EMT调节中测试FGFR和EGFR自分泌信号的作用。 AIM 3：定义在人肺癌进展过程中FGFR自分泌环何时出现，并探索FGF2和FGFR共表达与患者对EGFR TKIS的抗性的关联。介导的特定肿瘤生长转化的生长因子受体代表有吸引力的治疗靶标。在NSCLC中，已经部署了EGFR抑制剂，但成功仅限。我们的初步研究表明，许多NSCLC细胞单独或与EGFR信号传导使用FGFR自分泌信号传导，这可以通过FGFR和EGFR抑制剂对转化生长的转化抑制作用证明。因此，建立FGF2和特定的FGFR作为NSCLC中共同主导自分泌信号途径的组成部分，这是一个重大问题，具有对肺癌治疗影响的高潜力。