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Background: Cellular metabolism is a tightly controlled process during which cell growth and survival are maintained. Lung cancer is a disease with clear sex differences, where female patients have better survival rates than males. Evidence of sex differences is demonstrated in cancer risk, prognosis and response to different therapies, yet a sex-specific approach to cancer studies is not widely considered. These different tumour characteristics attributed to sex that impact disease outcome, including constitutional genetic and somatic molecular differences, make it essential to assess viral and hormonal influences. Methods: In silico analysis of lung adenocarcinoma (LUAD) TCGA data, including K-means clustering algorithm, dimensional reduction with principal component analysis and differential expression analysis using EdgeR (p < 0.05), were used to explore some robust sex differences in LUAD that exist in core signalling pathways and metabolic processes between males and females. The correlation of differentially expressed genes (DEGs) expression with immune abundance in the LUAD cohort was analysed on TIMER2.0 and adjusted by tumour purity utilising Cox proportional hazard. Multiple factorial analysis heatmap visualisation was used to examine endogenous steroid hormonal effects on LUAD patients with different smoking status and age groups. Results: We found 161 DEGs showing key differences in regulation of immune system and cellular homeostasis, key elements of divergent cancer progression, between the two sexes. We also found male and female LUAD patients to favour different metabolic intermediates for energy production to support tumourigenesis. Additionally, high levels of Tregs accompanied by DEGs correlated with better LUAD prognosis, and circulating hormonal transcriptional targets affect proliferation and progression in males and females differently. Finally, we examined the role of oestrogen protection in men and pre-/postmenopausal women. Conclusions: Further studies should focus on sex-specific changes and investigate sex-specific gene regulatory networks of these DEGs. Several lifestyle factors, including tobacco smoking and diet, differ between males and females. These factors might affect metabolic pathways and can influence the activity of epigenetic regulators, resulting in significant global epigenetic changes. [ABSTRACT FROM AUTHOR]

Sex-associated differences in bone metastasis formation from breast, lung, and prostate cancer exist in clinical studies, but have not been systematically reviewed. Differences in the bone marrow niche can be attributed to sexual dimorphism, to genetic variations that affect sex hormone levels, or to the direct effects of sex hormones, natural or exogenously delivered. This review describes the present understanding of sex-associated and sex hormone level differences in the marrow niche and in formation of bone metastasis during the transition of these three cancers from treatable disease to an often untreatable, lethal metastatic one. Our purpose is to provide insight into some underlying molecular mechanisms for hormonal influence in bone metastasis formation, and to the potential influence of sexual dimorphism, genetic differences affecting sex assignment, and sex hormone level differences on the bone niche and its favorability for metastasis formation. We reviewed publications in PubMed and EMBASE, including full length manuscripts, case reports, and clinical studies of relevance to our topic. We focused on bone metastasis formation in breast, lung, and prostate cancer because all three commonly present with bone metastases. Several clear observations emerged. For breast cancer bone metastasis formation, estrogen receptor (ER) signaling pathways indicate a role for ER beta (ERβ). Estrogen influences the bone microenvironment, creating and conditioning a favorable niche for colonization and breast cancer progression. For lung cancer, studies support the hypothesis that females have a more favorable bone microenvironment for metastasis formation. For prostate cancer, a decrease in the relative androgen to estrogen balance or a "feminization" of bone marrow favors bone metastasis formation, with a potentially important role for ERβ that may be similar to that in breast cancer. Long-term estrogen administration or androgen blockade in males may feminize the bone marrow niche to one more favorable for bone metastases in prostate cancer. Administration of androgens in females, especially combined with mastectomy, may reduce risk of developing bone metastatic breast cancer. We conclude that it should be considered that females, those with female-leaning genetic variations, or hormonal states that feminize the bone marrow, may offer favorable sites for bone metastases. [ABSTRACT FROM AUTHOR]

Aims Seven cases of primary giant cell carcinomas of the lung are presented. Methods and results The patients were five women and two men between the ages of 48 and 72 years (average: 63 years). Clinically, the patients presented with symptoms of cough, chest pain, dyspnoea and general malaise. Diagnostic imaging revealed the presence of intrapulmonary masses; five tumours were located in the right lung and two in the left, with a general predilection for the upper lobes. All patients underwent surgical resection and staging of their tumours. Five patients were staged as T2 and T3 with nodal metastasis, while two patients in stages T1 and T3, respectively, had no nodal disease. Histologically, the giant cells were typed as syncytiotrophoblast-like or 'null type', according to the expression of β-human chorionic gonadotrophin or expression of cytokeratin alone. Follow-up information revealed that five patients died within a period of 1-3 years, while two patients remain alive between 1 and 3 years. Conclusions The cases presented herein highlight the importance of separating these tumours from the group of sarcomatoid carcinomas and analysing them carefully by immumohistochemical means, as we believe that these neoplasms represent a specific tumour entity. [ABSTRACT FROM AUTHOR]

Abstract: Recent epidemiological studies have disputed whether females are at increased risk of lung cancer compared to males. However, several molecular studies are in support of an increased susceptibility to tobacco smoke carcinogens among females. Our earlier findings suggest that women display higher levels of smoking-induced bulky/hydrophobic DNA adducts which may be related to an increased expression of CYP1A1 in their lungs, compared to men. In this in vitro study, 11 lung adenocarcinoma cell lines, 6 of male and 5 of female origin, were exposed to benzo[a]pyrene, cigarette smoke condensate (CSC), or vehicle control. Subsequent expression analysis of genes in the polycyclic aromatic hydrocarbon bioactivation pathway was conducted with Real-Time RT-PCR. DNA adducts were measured in benzo[a]pyrene-exposed cells by 32P-postlabelling analysis, and CYP1 activity was measured by EROD assay. Analysis of benzo[a]pyrene-DNA adducts showed higher levels of adducts in cell lines from women compared to cell lines from men (p =0.03). The results also revealed significant sex differences in CYP1A1 gene expression, both in untreated cells (p =0.03), and in cells exposed to benzo[a]pyrene (p =0.017) and cigarette smoke condensate (p =0.0043). In CSC-exposed cells, significantly higher levels of CYP1 activity was found in cell lines of female origin (p =0.049). These results are in support of the previously published in vivo data, providing evidence for a higher susceptibility to PAH of women''s lungs. [Copyright &y& Elsevier]

Abstract: Epidemiological studies clearly outline some disparities in cancer onset, progression as well as prognosis and therapeutic response between sexes. In particular, in lung cancer, the leading cause of cancer death, at least in Western countries, a gender disparity appears now to emerge, especially for non-small cell lung cancer (NSCLC). Such a disparity is apparently due to a variety of mechanisms, ranging from genetic and epigenetic differences to gender-specific lifestyle as well as to behavioral causes and, clearly, to sex hormones activity. Here we briefly recapitulate gender differences in terms of risk factors, histopathological features and pathogenetic mechanisms in NSCLC, and hypothesize that a gender-oriented pharmacology could beneficially impact on innovative therapeutic strategies. [ABSTRACT FROM AUTHOR]

Objective: It remains controversial whether there is a gender difference in survival of patients with resected non–small cell lung cancer. Methods: We retrospectively analyzed 2770 patients (1689 men and 1081 women) with non–small cell lung cancer who underwent pulmonary resection between 1995 and 2005 at the National Cancer Center Hospital, Tokyo. A gender difference in survival was studied in all patients, in those divided according to histology or pathologic stage, and in propensity-matched gender pairs. Results: There were no differences in background, such as preoperative pulmonary function, operation procedures, or operative mortality. The proportions of adenocarcinoma and pathologic stage I in women were greater than those in men (93.6% vs 61.7% and 71.4% vs 58.6%, respectively) (P < .001). Overall 5-year survival of women was better than that of men (81% vs 70%, P < .001). In adenocarcinoma, the overall 5-year survival for women was better than that for men in pathologic stage I (95% vs 87%, P < .001) and in pathologic stage II or higher (58% vs 51%, P = .017). In non-adenocarcinoma, there was no significant gender difference in survival in pathologic stage I (P = .313) or pathologic stage II or higher (P = .770). The variables such as age, smoking status, histology, and pathologic stage were used for propensity score matching, and survival analysis of propensity score-matched gender pairs did not show a significant difference (P = .69). Conclusion: Women had better survival than men; however, there was no survival advantage in propensity-matched gender pairs. A gender difference in survival was observed only in the adenocarcinoma subset, suggesting pathobiology in adenocarcinoma in women might be different from that of men. [Copyright &y& Elsevier]

Objective: To determine whether patient gender affects the outlook following lung resection for non-small cell lung cancer (NSCLC). Patients and methods: Prospectively collected data on 833 patients undergoing lung resection for NSCLC between 1990 and 2000 in a single unit were analysed. Results: 581 patients were male (mean age 64.7±7 years) and 252 were female (mean age 62.6±7.8 years) (P=0.006). Male patients were more likely to have a history of ischaemic heart disease (P=0.03), to have poorer preoperative spirometry as demonstrated by their % predicted FEV1 (P=0.02) and to need pneumonectomy (P=0.0001) than their female counterparts. Squamous cell carcinoma was the predominant histological cell type in men and adenocarcinoma in women (P<0.0001). There was a trend towards a lower pathological stage among women, but this was not significant. Operative mortality for men was 4.6 and 1.2% for women (P=0.01). Overall 5-year survival for men was 34.2±2.65% and 47.5±4.2% for women (P=0.001) and, for the hospital survivors, was 36.5±2.7% and 48.1±4.2%, respectively (P=0.01). On univariate analysis, older age, the need for pneumonectomy and higher pathological stage were significant adverse factors whereas squamous cell type and female gender were significant favourable factors for survival (P<0.05). On Cox proportional hazards model (with and without hospital deaths), pathological stage (P<0.0001), female gender (P=0.0006) and squamous cell type (P=0.001) were independent predictors of survival. The survival was significantly better for women having squamous cell (P=0.01) or non-squamous cell cancers (adenocarcinoma and other) (P=0.002). Regarding the stage, women had a significant survival advantage at pathological stage I (P=0.01) and a relatively better survival at stage II and stage III disease (P=0.3). Conclusions: This study suggests that female gender exerts a significant positive effect on survival following lung resection for NSCLC. This effect is pronounced at early disease stage and persists after adjusting for important differences in the clinical, histo-pathological features and extent of pulmonary resection between male and female patients. [Copyright &y& Elsevier]

Discusses how women are more likely to develop lung cancer than men after much less smoking exposure. Possible link between greater expression of gastrin-releasing-peptide receptor (GRPR) and the lung cancer in women; Need for more research.