The reasons why the lungs are preferential metastatic targets for some human cancers are unknown.
Anastasios D. Giannou, Theodora Agalioti, Nikolaos Kanellakis, Dimitra E. Zazara, Ioannis Lilis and Georgios T. Stathopoulos
Laboratory for Molecular Respiratory Carcinogenesis, Department of Physiology, Faculty of Medicine, University of Patras, Rio, Greece
Background: The reasons why the lungs are preferential metastatic targets for some human cancers are unknown.
Aims: To unravel the mechanism of tumor pneumotropism.
Methods: Several mouse and human tumor cell lines were genotyped for key oncogenes and tumor suppressors. Their potential for spontaneous lung metastasis was assessed by subcutaneous inoculation into receptive host mice. Mutant oncogenes were silenced via shRNA or introduced using relevant expression vectors. Chemokine signaling was studied using microarray, qPCR, ELISA and immunobloting and was abrogated using chemokine receptor-deficient mice.
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Results: Spontaneous lung metastasis co-segregated with the presence of NRAS mutations detected in 3 of 11 cell lines studied. The expected frequency of NRAS mutations based on COSMIC (http://cancer.sanger.ac.uk/cosmic/) was tightly correlated (P=0.0000054, R2=0.652) with lung metastasis at necropsy in 3827 patients with various cancers (Disibio, G. et al. Arch Pathol Lab Med 2008;132:931–9). Mutant NRAS was required and sufficient for lung colonization since mutant NRAS silencing and overexpression inhibited and installed tumor pneumotropism, respectively. NRAS mutations functioned to up-regulate Cxcl5/Ppbp and CXCL6/7/8 expression by mouse and human tumor cells, respectively, directly targeting circulating tumor cells to the CXCR1+ lung vasculature. Lung-homed tumor cells secondarily recruited CXCR2+ myeloid cells to the lungs. Chemokine signaling was essential for NRAS-dictated lung metastasis, since Cxcr1 and Cxcr2 deficient mice were immune to lung colonization.
Conclusions: Mutant NRAS drives lung metastasis via CXCR1/2-mediated signaling events.