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

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.

Reduced Protumorigenic Tumor-Associated Macrophages With Statin Use in Premalignant Human Lung Adenocarcinoma.

BACKGROUND: Statins have anticancer properties by acting as competitive inhibitors of the mevalonate pathway. They also have anti-inflammatory activity, but their role in suppressing inflammation in a cancer context has not been investigated to date. METHODS: We have analyzed the relationship between statin use and tumor-associated macrophages (TAMs) in a cohort of 262 surgically resected primary human lung adenocarcinomas. TAMs were evaluated by multiplex immunostaining for the CD68 pan-TAM marker and the CD163 protumorigenic TAM marker followed by digital slide scanning and partially automated quantitation. Links between statin use and tumor stage, virulence, and cancer-specific survival were also investigated in a wider cohort of 958 lung adenocarcinoma cases. All statistical tests were two-sided. RESULTS: We found a statin dose-dependent reduction in protumorigenic TAMs (CD68+CD163+) in both stromal (P = .021) and parenchymal (P = .003) compartments within regions of in situ tumor growth, but this association was lost in invasive regions. No statistically significant relationship between statin use and tumor stage was observed, but there was a statin dose-dependent shift towards lower histological grade as assessed by growth pattern (P = .028). However, statin use was a predictor of slightly worse cancer-specific survival (P = .032), even after accounting for prognostic variables in a multivariable Cox proportional hazards survival model (hazard ratio = 1.38, 95% confidence interval = 1.04 to 1.84). CONCLUSIONS: Statin use is associated with reduced numbers of protumorigenic TAMs within preinvasive lung adenocarcinoma and is related to reduced tumor invasiveness, suggesting a chemo-preventive effect in early tumor development. However, invasive disease is resistant to these effects, and no beneficial relationship between statin use and patient outcome is observed.

High prevalence of HER-2/neu overexpression in female breast cancer among an Iraqi population exposed to depleted uranium.

BACKGROUND: This study aimed to estimate the rate of HER-2/neu (c-erbB2) immunohistochemical overexpression in different histological types of breast cancer found in the middle Euphrates region of Iraq, a region that was exposed to high levels of depleted uranium. HER-2/neu (c-erbB2) overexpression was correlated with common clinicopathological parameters such as age, grade, stage, tumor size and lymph node involvement to determine if any particular biomarker for exposure to depleted uranium could be found in the tumor samples from this region. MATERIALS AND METHODS: The present investigation was performed over a period starting from September 2007 to June 2008. Formalin-fixed, paraffin-embedded blocks from 90 patients with breast cancer were included in this study. A group of 25 patients with benign breast lesions (fibroadenoma) was included as a comparative group, and 20 breast tissue sections were used as controls. Labeled streptavidin-biotin (LSAB) complex method was employed for immunohistochemical detection of HER-2/neu. RESULTS: HER-2/neu immuno-expression was positive in 67.8% of breast cancer, while it was negative in all benign breast lesions (fibroadenoma) ( P P P > 0.05). CONCLUSION: Based upon the findings of this study, it can be concluded that HER-2/neu overexpression plays an important role in the pathogenesis of breast cancer and is associated with a worse prognosis. The findings indicate that in regions exposed to high levels of depleted uranium, HER-2/neu overexpression is high, but its correlation with age, grade, stage, tumor size, and lymph node involvement is similar to studies that have been conducted on populations not exposed to depleted uranium.