Statins mediate anti- and pro-tumourigenic functions by remodelling the tumour microenvironment

• Published in: Disease models & mechanisms Vol. 15; no. 2
• Main Authors: Kamata, Tamihiro, Al Dujaily, Esraa, Alhamad, Salwa, So, Tsz Y, Margaritaki, Olga, Giblett, Susan, Pringle, J Howard, Le Quesne, John, Pritchard, Catrin
• Format: Journal Article
• Language: English
• Published: England The Company of Biologists Ltd 01-02-2022; The Company of Biologists
• Subjects: Adenocarcinoma of Lung - drug therapy; Animals; Apoptosis; Atorvastatin - pharmacology; Atorvastatin - therapeutic use; Cancer; Cell cycle; Cholesterol; DMM ras; drug resistance; Flow cytometry; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology; Hydroxymethylglutaryl-CoA Reductase Inhibitors - therapeutic use; lung adenocarcinoma; Lung cancer; Lung Neoplasms - pathology; Mice; Mortality; mouse models; Statins; Tumor Microenvironment; Tumors; tumour microenvironment; Lung adenocarcinoma; Drug resistance; Mouse models; Statins; Tumour microenvironment
• ISSN: 1754-8403; 1754-8411
• DOI: 10.1242/dmm.049148

Anti-cancer properties of statins are controversial and possibly context dependent. Recent pathology/epidemiology studies of human lung adenocarcinoma showed reduced pro-tumourigenic macrophages associated with a shift to lower-grade tumours amongst statin users but, paradoxically, worse survival compared with that of non-users. To investigate the mechanisms involved, we have characterised mouse lung adenoma/adenocarcinoma models treated with atorvastatin. Here, we show that atorvastatin suppresses premalignant disease by inhibiting the recruitment of pro-tumourigenic macrophages to the tumour microenvironment, manifested in part by suppression of Rac-mediated CCR1 ligand secretion. However, prolonged atorvastatin treatment leads to drug resistance and progression of lung adenomas into invasive disease. Pathological progression is not driven by acquisition of additional driver mutations or immunoediting/evasion but is associated with stromal changes including the development of desmoplastic stroma containing Gr1+ myeloid cells and tertiary lymphoid structures. These findings show that any chemopreventive functions of atorvastatin in lung adenocarcinoma are overridden by stromal remodelling in the long term, thus providing mechanistic insight into the poor survival of lung adenocarcinoma patients with statin use.