RESUMO
Squamous cell lung cancer (SCLC) occurs as a result of dysregenerative changes in the bronchial epithelium: basal cell hyperplasia (BCH), squamous cell metaplasia (SM), and dysplasia. We previously suggested that combinations of precancerous changes detected in the small bronchi of patients with SCLC may reflect various "scenarios" of the precancerous process: isolated BCHâstopping at the stage of hyperplasia, BCH+SMâprogression of hyperplasia into metaplasia, SM+dysplasiaâprogression of metaplasia into dysplasia. In this study, DNA methylome of various forms of precancerous changes in the bronchial epithelium of SCLC patients was analyzed using the genome-wide bisulfite sequencing. In BCH combined with SM, in contrast to isolated BCH, differentially methylated regions were identified in genes of the pathogenetically significant MET signaling pathway (RNMT, HPN). Differentially methylated regions affecting genes involved in inflammation regulation (IL-23, IL-23R, IL12B, IL12RB1, and FIS1) were detected in SM combined with dysplasia in comparison with SM combined with BCH. The revealed changes in DNA methylation may underlie various "scenarios" of the precancerous process in the bronchial epithelium.
Assuntos
Brônquios , Metilação de DNA , Hiperplasia , Neoplasias Pulmonares , Metaplasia , Lesões Pré-Cancerosas , Humanos , Hiperplasia/patologia , Hiperplasia/genética , Metaplasia/genética , Metaplasia/patologia , Metaplasia/metabolismo , Brônquios/patologia , Brônquios/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/metabolismo , Lesões Pré-Cancerosas/genética , Lesões Pré-Cancerosas/patologia , Lesões Pré-Cancerosas/metabolismo , Masculino , Feminino , Pessoa de Meia-Idade , Epigenoma/genética , Mucosa Respiratória/patologia , Mucosa Respiratória/metabolismo , Idoso , Carcinoma de Pequenas Células do Pulmão/genética , Carcinoma de Pequenas Células do Pulmão/patologia , Carcinoma de Pequenas Células do Pulmão/metabolismo , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/metabolismoRESUMO
BACKGROUND: Squamous cell lung cancer (SCLC) arises from bronchial changes: basal cell hyperplasia (BCH), squamous metaplasia (SM), and dysplasia. However, the premalignant process preceding SCLC is not inevitable; it can stop at any of the bronchial lesions. Previously, we hypothesized that combinations of premalignant lesions observed in the small bronchi of SCLC patients can reflect the different "scenarios" of the premalignant process: BCHi-the stoppage at the stage of hyperplasia and BCHSM-the progression of hyperplasia to metaplasia. METHODS AND RESULTS: In this study, using whole-genome bisulfite sequencing we analyzed the DNA methylome of two forms of BCH: isolated BCH (BCHi) and BCH co-occurred with SM (BCHSM) in the small bronchi of SCLC patients. It was shown that BCHi harbored differentially methylated regions (DMRs) affecting genes associated with regulating phosphatase activity. In BCHSM, DMRs were found in genes involved in PI3K-Akt and AMPK signaling pathways. DMRs were also found to affect specific miRNA genes: miR-34a and miR-3648 in BCHi and miR-924 and miR-100 in BCHSM. CONCLUSIONS: Thus, this study demonstrated the significant changes in DNA methylome between the isolated BCH and BCH combined with SM. The identified epigenetic alterations may underlie different "scenarios" of the premalignant process in the bronchial epithelium.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Carcinoma de Células Escamosas , Neoplasias Pulmonares , MicroRNAs , Lesões Pré-Cancerosas , Humanos , Hiperplasia/genética , Epigenoma , Fosfatidilinositol 3-Quinases , Lesões Pré-Cancerosas/genética , Metaplasia , MicroRNAs/genéticaRESUMO
The spread of tumor cells from the primary focus, metastasis, is the main cause of cancer mortality. Therefore, anticancer therapy should be focused on the prevention of metastatic disease. Key targets can be conditions in the primary tumor that are favorable for the appearance of metastatic cells and the first steps of the metastatic cascade. Here, we discuss different approaches for targeting metastasis causes (hypoxia, metabolism changes, and tumor microenvironment) and roots (angiogenesis, epithelial-mesenchymal transition, migration, and invasion). Also, we emphasize the challenges of the existing approaches for metastasis prevention and suggest opportunities to overcome them. In conclusion, we highlight the importance of clinical evaluation of the agents showing antimetastatic effects in vivo, especially in patients with early-stage cancers, the identification of metastatic seeds, and the development of therapeutics for their eradication.