RESUMO
Fibroblast Growth Factor Receptor-1 (FGFR1) is commonly overexpressed in advanced prostate cancer (PCa). To investigate causality, we utilized an inducible FGFR1 (iFGFR1) prostate mouse model. Activation of iFGFR1 with chemical inducers of dimerization (CID) led to highly synchronous, step-wise progression to adenocarcinoma that is linked to an epithelial-to-mesenchymal transition (EMT). iFGFR1 inactivation by CID withdrawal led to full reversion of prostatic intraepithelial neoplasia, whereas PCa lesions became iFGFR1-independent. Gene expression profiling at distinct stages of tumor progression revealed an increase in EMT-associated Sox9 and changes in the Wnt signaling pathway, including Fzd4, which was validated in human PCa. The iFGFR1 model clearly implicates FGFR1 in PCa progression and demonstrates how CID-inducible models can help evaluate candidate molecules in tumor progression and maintenance.
Assuntos
Células Epiteliais/enzimologia , Células Epiteliais/patologia , Mesoderma/enzimologia , Mesoderma/patologia , Neoplasias da Próstata/enzimologia , Neoplasias da Próstata/patologia , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/biossíntese , Animais , Dimerização , Progressão da Doença , Ativação Enzimática , Indução Enzimática , Regulação Neoplásica da Expressão Gênica , Proteínas de Grupo de Alta Mobilidade/metabolismo , Humanos , Imuno-Histoquímica , Masculino , Camundongos , Metástase Neoplásica , Neoplasia Prostática Intraepitelial/genética , Neoplasias da Próstata/genética , Indução de Remissão , Fatores de Transcrição SOX9 , Transdução de Sinais , Fatores de Transcrição/metabolismoRESUMO
Fibroblast growth factor receptors (FGFRs) comprise a subfamily of receptor tyrosine kinases (RTKs) that are master regulators of a broad spectrum of cellular and developmental processes, including apoptosis, proliferation, migration and angiogenesis. Due to their broad impact, FGFRs and other RTKs are highly regulated and normally only basally active. Deregulation of FGFR signaling by activating mutations or ligand/receptor overexpression could allow these receptors to become constitutively active, leading to cancer development, including both hematopoietic and solid tumors, such as breast, bladder and prostate carcinomas. In this review, we focus on potential modes of FGFR-mediated tumorigenesis, in particular, the role of FGFR1 during prostate cancer progression.