No abstract

Liver X receptors (LXRαβ) play essential roles in the maintenance of the normal functions of macrophages, in modulation of immune system responses and cholesterol homeostasis. We have reported that LXRαβ -/- mice develop squamous cell lung cancer. We now report that those LXRαβ -/- mice, which live to 18-months of age, spontaneously develop a second type of lung cancer resembling a rare subtype of NSCLC (TTF-1 and P63-positive). The lesions are characterized as follows: a high proliferation rate; a marked accumulation of abnormal macrophages; an increase in the number of regulatory T cells; a remarkably low level of CD8 + cytotoxic T lymphocytes; enhanced TGFβ signaling; an increased expression of matrix metalloproteinases accompanied by degradation of lung collagen; and a loss of estrogen receptor β (ERβ). Because NSCLC is associated with cigarette smoking, we investigated the possible links between loss of LXRαβ and CS. A Kaplan-Meier Plotter database revealed reduced expression of LXRαβ and ERβ was correlated with low overall survival (OS). Thus, reduction of LXRαβ expression by cigarette smoking may be one mechanism through which CS causes lung cancer. The possibility that maintenance of LXRαβ and ERβ signaling could be used in the treatment of NSCLC needs further investigation.

Cigarette smoking (CS) is one of the principal risk factors leading to development of lung cancer. Macrophage dysfunction and immune escape have been suggested as mechanisms of CS-induced lung cancer. Liver X receptors (LXRαβ) play essential roles in the maintenance of the normal functions of macrophages and in modulation of immune system responses. Here we report the spontaneous development, in 18-month-old LXRαβ−/− mouse lungs, of a lesion resembling a rare subtype of non-small-cell lung cancer, i.e., one that is both TTF-1and p63-positive. The lesion is characterized by a high proliferation rate, a marked accumulation of abnormal macrophages, an increase in the number of regulatory T cells and a remarkably low level of cytotoxic T lymphocytes, and increased expression of matrix metalloproteinases accompanied by degradation of collagen. In addition, enhanced TGFβ signaling was evidenced by the upregulation of TGFβ1, TGFβR1, TGFβR2, pSMAD2 and SMAD4 and a downregulation of TGFβR3. Examination of a tissue microarray of lung cancer patients with a history of smoking revealed that expression of LXRαβ was repressed in both tumor-associated macrophages (TAM) and in cancer cells. There were three correlations: 1) Upregulation of MMP12 in the TAM correlated with downregulation of LXRαβ; 2) shorter overall survival (OS) correlated with high expression of MMP12; 3) longer OS correlated with high expression of either LXRα or LXRβ. The study reveals an unexpected role for loss of LXRαβ in the etiology of TTF-1/p63-positive lung cancer and suggests that maintenance of LXRαβ may have a beneficial role in treatment/prevention of this disease.