Normal fibroblasts (NFs) are reprogrammed into cancer-associated fibroblasts (CAFs) by miRNA-mediated regulation of FOXO3a/VEGF/CCL2 signalling in lung cancer. CAFs provide oncogenic signals to facilitate tumour initiation, progression and metastasis, and a study, conducted out of First Affiliated Hospital of Nanjing Medical University and Shanghai Jiao Tong University, China, has determined the factors and genes that mediate the conversion of NFs into CAFs, demonstrated this transformation in lung cancer cell studies and carried out some early testing of these factors as anti-cancer therapies.
Published last month in PLOS Genetics, the study initially characterised 3 miRNAs (miR-1, miR-206 and miR-31) that were specifically up- and down-regulated in lung CAFs compared to matched NFs. The team then demonstrated that manipulation of the miRNA levels modulated functional conversion of NFs to CAFs and vice versa. Using a combination of cytokine expression profiling and miRNA algorithms, VEGFA, CCL2 and FOXO3 were identified as direct targets of miR-1, miR-206 and miR-31, respectively. This knowledge, that miRNAs can be manipulated to control cancer cell transformation and identification of their gene targets, provides novel biomarkers and therapeutic targets for lung cancer. Finally, systemic delivery of anti-VEGFA/CCL2 or pre-miR-1, pre-miR-206 and anti-miR-31 was shown to significantly inhibit tumour angiogenesis, TAMs accumulation, tumour growth and lung metastasis. The results provide exciting evidence that such strategies are promising for treatment of lung cancer in the future.