Pathogenesis-lung cancer

Pathogenesis[edit]

See also: Carcinogenesis

False-color scanning electron micrograph of a lung cancer cell dividing

Similar to many other cancers, lung cancer is initiated by activation of oncogenes or inactivation of tumor suppressor genes.^[47]Carcinogens cause mutations in these genes which induce the development of cancer.^[48]

Mutations in the K-ras proto-oncogene are responsible for 10–30% of lung adenocarcinomas.^[49][50] About 4% of non-small-cell lung carcinomas involve an EML4-ALK tyrosine kinase fusion gene.^[51]

Epigenetic changes—such as alteration of DNA methylation, histone tail modification, or microRNA regulation—may lead to inactivation of tumor suppressor genes.^[52]

The epidermal growth factor receptor (EGFR) regulates cell proliferation, apoptosis, angiogenesis, and tumor invasion.^[49] Mutations and amplification of EGFR are common in non-small-cell lung carcinoma and provide the basis for treatment with EGFR-inhibitors. Her2/neu is affected less frequently.^[49] Other genes that are often mutated or amplified are c-MET, NKX2-1, LKB1, PIK3CA, and BRAF.^[49]

The cell lines of origin are not fully understood.^[1] The mechanism may involve abnormal activation of stem cells. In the proximal airways, stem cells that express keratin 5 are more likely to be affected, typically leading to squamous-cell lung carcinoma. In the middle airways, implicated stem cells include club cells and neuroepithelial cells that express club cell secretory protein. Small-cell lung carcinoma may be derived from these cell lines^[53] orneuroendocrine cells,^[1] and may express CD44.^[53]

Metastasis of lung cancer requires transition from epithelial to mesenchymal cell type. This may occur through activation of signaling pathways such as Akt/GSK3Beta, MEK-ERK,Fas, and Par6.^[54]