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））是癌细胞的标志。虽然EGF受体（EGFR）和EGF家族配体被认为是人类非小细胞肺癌（NSCLC）中的主要自分泌途径，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应答。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（FGF 2）和FGF受体（FGFRs）在NSCLC中经常共表达。此外，FGF 2 shRNA、显性阴性FGFR 1和FGFR TKI（RO 4383596）选择性降低共表达FGF 2和FGFR的NSCLC细胞系的生长。相比之下，缺乏FGF 2表达的细胞系对RO 4383596耐药，对吉非替尼敏感。其他NSCLC细胞对FGFR和EGFR TKI组合表现出相加反应，这意味着EGFR和FGFR双重自分泌输入。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）中的主导作用，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了一个假设，即FGF 2和FGFRs组成了一个自分泌途径，在NSCLC中作为EGFR自分泌环的辅助作用来驱动EMT程序。为了验证这一假设，我们将完成这些具体目标。目的1：确定FGF 2和FGFR共表达是否有助于NSCLC细胞转化生长。目的2：检测FGFR和EGFR自分泌信号通过ERK MAP激酶在NSCLC EMT调控中的作用。目标3：确定在人肺癌进展期间何时出现FGFR自分泌环，并探索FGF 2和FGFR共表达与患者EGFR TKI耐药的相关性。生长因子受体介导特定肿瘤的转化生长，代表了有吸引力的治疗靶点。在NSCLC中，EGFR抑制剂已经部署，但仅取得有限的成功。我们的初步研究表明，许多NSCLC细胞采用FGFR自分泌信号传导，单独或与EGFR信号传导组合，如FGFR和EGFR抑制剂对转化生长的加性抑制所证明的。因此，将FGF 2和特异性FGFR确定为NSCLC中共显性自分泌信号通路的组分代表了对肺癌治疗具有高潜在影响的重大问题。