Neoplasia In Men Research Articles

Urinary Markers in the Everyday Diagnosis of Bladder Cancer

Bladder cancer (BC) represents the fourth most common neoplasia in men and the ninth most common cancer in women, with a significant morbidity and mortality. Cystoscopy and voided urine cytology (involving the examination of cells in voided urine to detect the presence of cancerous cells) are currently the routine initial investigations in patients with hematuria or other symptoms suggestive of BC. Around 75-85% of the patients are diagnosed as having non-muscle-invasive bladder cancer (NMIBC). Despite the treatment, these patients have a probability of recurrence at 5 years ranging from 50 to 70% and of progression to muscle invasive disease of 10-15%. Patients with NMIBC must undergo life-long surveillance, consisting of serial cystoscopies, possibly urine cytology and ultrasonography. Cystoscopy is unsuitable for screening because of its invasiveness and costs; serial cystoscopies may cause discomfort and distress to patients. Furthermore, cystoscopy may be inconclusive, falsely positive or negative. Although urine cytology has a reasonable sensitivity for the detection of high-grade BC, it lacks sensitivity to detect low-grade tumors (sensitivity ranging from 4 to 31%). The overall sensitivity and specificity of urine cytology range from 7 to 100 and from 30 to 70%, respectively. There is a need for new urine biomarkers that may help in BC diagnosis and surveillance. A lot of urinary biomarkers with high sensitivity and/or specificity have been investigated. Although none of these markers have proven to be powerful enough to replace standard cystoscopy, some of them may represent accurate predictors of BC. A review of recent studies is presented.

Helicobacter spp. Infection Induces Changes in Epithelial Proliferation and E-cadherin Expression in the Gastric Mucosa of Pigs

Gastric disease is common in finishing pigs. Helicobacter spp. infection has been associated with gastritis, gastric ulcers and gastric neoplasia in man and animals. The aim of this study was to determine the effects of Helicobacter spp. infection on gastric morphology in pigs, with emphasis on glandular cell proliferation and E-cadherin expression. Samples of fundus and antrum from 67 finishing pigs were examined microscopically and by immunohistochemistry. The presence of Helicobacter spp. was confirmed by polymerase chain reaction (PCR). Mucosal changes were evaluated and epithelial proliferation was determined by evaluation of the morphometry of nucleolar organizer regions and counting proliferating cell nuclear antigen-positive cells and mitotic figures. Intercellular adhesion was evaluated by E-cadherin expression. In 47 (70%) pigs, Helicobacter spp. infection was confirmed by PCR. Histological findings associated with the infection included mononuclear cell infiltration of the lamina propria and glandular degeneration. There was a significant association between infection and epithelial proliferation in both regions as well as a decrease in the expression of E-cadherin in the antrum.

Elemental concentration analysis in prostate tissues using total reflection X-ray fluorescence

Prostate cancer (PCa) currently represents the second most prevalent malignant neoplasia in men, representing 21% of all cancer cases. Benign Prostate Hyperplasia (BPH) is an illness prevailing in men above the age of 50, close to 90% after the age of 80. The prostate presents a high zinc concentration, about 10-fold higher than any other body tissue. In this work, samples of human prostate tissues with cancer, BPH and normal tissue were analyzed utilizing total reflection X-ray fluorescence spectroscopy using synchrotron radiation technique (SR-TXRF) to investigate the differences in the elemental concentrations in these tissues. SR-TXRF analyses were performed at the X-ray fluorescence beamline at Brazilian National Synchrotron Light Laboratory (LNLS), in Campinas, São Paulo. It was possible to determine the concentrations of the following elements: P, S, K, Ca, Fe, Cu, Zn and Rb. By using Mann–Whitney U test it was observed that almost all elements presented concentrations with significant differences (α=0.05) between the groups studied.

Gastric carcinoids after long‐term use of a proton pump inhibitor

Proton pump inhibitors (PPIs) are potent inhibitors of gastric acid secretion and give hypergastrinemia secondary to gastric hypoacidity. PPI treatment therefore induces enterochromaffin-like (ECL) cell hyperplasia. Long-term hypergastrinemia in rodents and man also leads to ECL cell neoplasia. Whether long-term PPI treatment will induce ECL cell neoplasia in man has been disputed. To describe gastric carcinoids in two patients with a history of long-term PPI use. Two patients had been taking PPI for 12-13 years due to gastro-oesophageal reflux disease. At routine upper gastrointestinal endoscopy a solitary tumour was found in the oxyntic mucosa of both patients. Histology from the tumours showed in both cases a well-differentiated neuroendocrine tumour. Biopsies from flat oxyntic mucosa showed no signs of atrophic gastritis and a normal presence of parietal cells in both cases, but hyperplasia of ECL cells. The tumour in patient 1 was resected endoscopically. After cessation of PPI treatment the tumour regressed in patient 2 and the ECL cell hyperplasia regressed in both patients. In patient 2 serum gastrin and chromogranin A were elevated during PPI treatment, and normalised after cessation of treatment. In patient 1, unfortunately, we had serum only after treatment, and at that time both parameters were normal. These cases show that hypergastrinemia secondary to proton pump inhibitors treatment, like other causes of hypergastrinemia, may induce enterochromaffin-like cell carcinoids in man.

Anal Intraepithelial Neoplasia in Men Living with HIV in the Era of Highly Active Antiretroviral Therapy

The introduction of highly active antiretroviral therapy (HAART) has achieved a sustained improvement in the immune status of patients with AIDS. HAART has reduced infectious complications to such a degree that infections have become a relatively uncommon cause of death among people living with the human immunodeficiency virus (HIV) and, thankfully, the life expectancy of such individuals has dramati

Identification of Apo-A1 as a biomarker for early diagnosis of bladder transitional cell carcinoma

BackgroundBladder transitional cell carcinoma (BTCC) is the fourth most frequent neoplasia in men, clinically characterized by high recurrent rates and poor prognosis. Availability of urinary tumor biomarkers represents a convenient alternative for early detection and disease surveillance because of its direct contact with the tumor and sample accessibility.ResultsWe tested urine samples from healthy volunteers and patients with low malignant or aggressive BTCC to identify potential biomarkers for early detection of BTCC by two-dimensional electrophoresis (2-DE) coupled with mass spectrometry (MS) and bioinformatics analysis. We observed increased expression of five proteins, including fibrinogen (Fb), lactate dehydrogenase B (LDHB), apolipoprotein-A1 (Apo-A1), clusterin (CLU) and haptoglobin (Hp), which were increased in urine samples of patients with low malignant or aggressive bladder cancer. Further analysis of urine samples of aggressive BTCC showed significant increase in Apo-A1 expression compared to low malignant BTCC. Apo-A1 level was measured quantitatively using enzyme-linked immunosorbent assay (ELISA) and was suggested to provide diagnostic utility to distinguish patients with bladder cancer from controls at 18.22 ng/ml, and distinguish patients with low malignant BTCC from patients with aggressive BTCC in two-tie grading system at 29.86 ng/ml respectively. Further validation assay showed that Apo-A1 could be used as a biomarker to diagnosis BTCC with a sensitivity and specificity of 91.6% and 85.7% respectively, and classify BTCC in two-tie grading system with a sensitivity and specificity of 83.7% and 89.7% respectively.ConclusionTaken together, our findings suggest Apo-A1 could be a potential biomarker related with early diagnosis and classification in two-tie grading system for bladder cancer.

Weighing the Benefits and Costs of HPV Vaccination of Young Men

New data suggest that a human papillomavirus (HPV) vaccine prevents anal intraepithelial neoplasia in men, particularly in men who have sex with men. As the FDA reviews this new evidence, the debate over routine HPV vaccination of boys and men is likely to be reignited.

DNA Repair Gene X-Ray Repair Cross-Complementing Group 1 and Xeroderma Pigmentosum Group D Polymorphisms and Risk of Prostate Cancer: A Study from North India

Interindividual variation in prostate cancer (PCa) susceptibility may be modulated in part through genetic polymorphisms in the DNA repair genes, especially the genes involved in the base excision repair and nucleotide excision repair pathway. Two of the common single-nucleotide polymorphisms X-ray repair cross-complementing group 1 (XRCC1) and Xeroderma pigmentosum group D (XPD) genes in PCa, which is one of the most common neoplasias in men all over the world, have been studied. In a case-control study of 171 PCa patients and 200 age-matched healthy controls, of similar ethnicity, genotyping was done to determine XPD exon 10 (G23592A), exon 23 (A35931C), and XRCC1 exon 6 (C26304T), exon 9 (G27466A), exon 10 (G23591A) gene polymorphisms by amplification refractory mutation-specific and polymerase chain reaction-restriction fragment length polymorphism methods, respectively. We observed that XPD exon 10 variant AA genotype was associated with increased risk for PCa (adjusted odds ratio [OR] 2.63, 95% confidence interval [95% CI] 1.40-4.92, p = 0.003), and XRCC1 exon 9 GA genotype was also statistically associated with PCa (adjusted OR 2.61, 95% CI 1.53-4.43, p < 0.001). However, XPD exon 23 (A>C) and XRCC1 exon 6 (C>T) and exon 10 (G>A) did not have significantly increased risk for PCa. The haplotype analysis of XPD exon 10 and exon 23 G-C (OR 3.44, 95% CI 2.15-5.51, p < 0.0001) and A-A (OR 4.96, 95% CI 3.08-7.98, p < 0.0001) was associated with a significant increase in PCa risk. Similarly, the combined analysis of XRCC1 exon 6, exon 9, and exon 10 C-G-A (OR 2.93, 95% CI 1.91-4.50, p < 0.001) and C-A-G (OR 2.48, 95% CI 1.62-3.80, p < 0.001) demonstrated statistically significant risk in PCa. XRCC1 exon 9 GA genotype showed protective association with high grade of PCa. Our results suggest a positive association of XRCC1 exon 9 and XPD exon 10 genotypes that may play an important role in the pathophysiology and may modulate the risk of PCa.

Differences in Colon Adenomas and Carcinomas Among Women and Men

COLORECTAL CANCER REMAINS THE THIRD LEADING cause of cancer deaths among women and men in the United States, underscoring the need for more effective preventive strategies for both sexes. Many promising approaches are based on the adenoma-carcinoma paradigm of colon carcinogenesis. The clinical corollary to this model is that the presence of adenomas represents a robust marker of colon carcinogenesis. This leads to 2 distinct applications for colorectal cancer prevention: target for intervention and risk marker. Indeed, removing adenomas through colonoscopy has been shown to decrease future colorectal cancer occurrence by 75% to 90%. From a screening perspective, the colonoscopic adenoma identification is used clinically to gauge long-term risk and dictate the frequency of future colorectal cancer screening. Most data suggest that the effect of colorectal cancer is approximately equivalent in both sexes. In 2009, an estimated 71 380 women and 75 590 men will develop colorectal cancer. This is consistent with data from 1993-2003 in which women composed 50% of patients in an unselected cohort of 161 172 patients with colorectal cancer from US community cancer centers. Moreover, while estimates of incidence of colorectal cancer has suggested up to a 2-fold male predominance, the more robust lifetime risk estimates for US women and men are comparable (5.1% vs 5.5%, respectively). Taken together, this and other evidence would suggest that colorectal cancer is, by and large, a sex-neutral malignancy. Therefore, it would logically follow that colonic adenomas should also be equivalent in women and men. However, several large-scale studies have indicated that women have a substantially lower adenoma detection rate than men. For instance, in a cross-sectional analysis of 50 148 patients undergoing colonoscopybased screening program, Regula et al demonstrated that, compared with women, men had an adjusted odds ratio for advanced adenomas of 1.73 (95% confidence interval [CI], 1.52-1.98). Additionally, Schoenfeld et al noted that the relative risk (RR) of clinically significant neoplasia (advanced adenomas) in men was 1.91 (95% CI, 1.42-2.56) compared with women. In a recent metaanalysis including 924 932 adults, Nguyen et al reported that the RR of advanced neoplasia in men vs women was 1.83 (95% CI, 1.69-1.97). These findings would imply that adenomas (even those designated as advanced, ie, size 1 cm or high-grade dysplasia or 25% villous features) represent a less reliable marker of colorectal cancer risk in women than in men, and would lead to speculation that colonoscopic identification of adenomas may be less protective of colorectal cancer in women than in men. Although rigorous evidence for this hypothesis is lacking, an administrative database review by Bressler et al noted that women were 41% more likely than men to develop colorectal cancer despite undergoing colonoscopy (4.1% vs 2.9%, P .001). Other supportive evidence centers on the predilection for proximal lesions among women. Baxter et al demonstrated that even though having a colonoscopy was associated with decreased risk of subsequent colorectal cancer by two-thirds in the distal colon, no protective effect was found for lesions in the proximal colon. These studies suggest that the lower prevalence of adenomas in women may translate into possibly less efficacy of colonoscopy. There is biological precedence for the sex-related differential clinical behavior of colonic neoplasia. Randomized controlled studies have demonstrated the chemopreventive abilities of estrogens/progesterones, potentially mediated by the tumor suppressor role of estrogen receptor . Moreover, numerous studies have documented the higher proportion of microsatellite-unstable (MSI-high) lesion in women consonant with their slightly better prognosis. From a risk factor perspective, women appear to have differential sensitivity to the carcinogenic effect of cigarette smoking. From an epidemiological perspective, women develop more proximal colorectal cancer, but lesions generally occur somewhat later in life com-

S30 Initial 24-core biopsy improves the detection of clinically significant prostate cancer and high grade prostatic intraepithelial neoplasia in men with PSA less than 10 ng/ml

S30 Initial 24-core biopsy improves the detection of clinically significant prostate cancer and high grade prostatic intraepithelial neoplasia in men with PSA less than 10 ng/ml

Simultaneous inactivation of Par-4 and PTEN in vivo leads to synergistic NF-κB activation and invasive prostate carcinoma

Prostate cancer is one of the most common neoplasias in men. The tumor suppressor Par-4 is an important negative regulator of the canonical NF-kappaB pathway and is highly expressed in prostate. Here we show that Par-4 expression is lost in a high percentage of human prostate carcinomas, and this occurs in association with phosphatase and tensin homolog deleted from chromosome 10 (PTEN) loss. Par-4 null mice, similar to PTEN-heterozygous mice, only develop benign prostate lesions, but, importantly, concomitant Par-4 ablation and PTEN-heterozygosity lead to invasive prostate carcinoma in mice. This strong tumorigenic cooperation is anticipated in the preneoplastic prostate epithelium by an additive increase in Akt activation and a synergistic stimulation of NF-kappaB. These results establish the cooperation between Par-4 and PTEN as relevant for the development of prostate cancer and implicate the NF-kappaB pathway as a critical event in prostate tumorigenesis.

Claudin-11 is over-expressed and dislocated from the blood–testis barrier in Sertoli cells associated with testicular intraepithelial neoplasia in men

In mouse testis, claudin-11 is responsible for the formation of specific parallel TJ strands of the blood-testis barrier (BTB). Concerning the human BTB, there is no information about the transmembrane TJ proteins. We recently demonstrated the loss of functional integrity of the BTB in testicular intraepithelial neoplasia (TIN), associated with a dislocation of the peripheral TJ proteins ZO-1 and ZO-2. Here, we determined the expression and distribution of claudin-11 at the human BTB in seminiferous tubules with normal spermatogenesis (NSP) and TIN. Immunostaining of claudin-11 revealed intense signals at the basal BTB region in seminiferous epithelium with NSP. Within TIN tubules, claudin-11 immunostaining became diffuse and cytoplasmic. Double immunogold labeling demonstrated a co-localization of claudin-11 and ZO-1 at the inter-Sertoli cell junctions. Real-time RT-PCR of laser microdissected tubules showed an up-regulation of claudin-11 mRNA in TIN. Additionally, increased claudin-11 protein was observed by Western blot. We conclude that claudin-11 constitutes a TJ protein at the human BTB. In TIN tubules, claudin-11 is up-regulated and dislocated from the BTB. Therefore, the disruption of the BTB is related to a dysfunction of claudin-11 and not to a failure of its expression.

Gender as a Risk Factor for Advanced Neoplasia and Colorectal Cancer: A Systematic Review and Meta-analysis

Studies have reported higher rates of advanced colorectal neoplasia in men than in women. We performed a meta-analysis to provide a quantitative pooled risk estimate of the association between gender and advanced colorectal neoplasia. We conducted a systematic review to identify studies of average risk and asymptomatic individuals undergoing screening colonoscopy. We also included studies of subjects with a family history of colorectal neoplasia. We used random effects models to evaluate pooled relative risk estimates and performed heterogeneity and publication bias analyses. The primary outcome measure was relative risk of advanced neoplasia in men compared with women. A secondary outcome measure was relative risk for colorectal cancer. Seventeen studies consisting of 18 different populations were included, comprising 924,932 men and women. The pooled relative risk estimate for advanced neoplasia for men compared with women was 1.83 (95% confidence interval [CI], 1.69 -1.97). This positive association between gender and advanced neoplasia was significant across all age groups from 40 to older than 70 years. In 5 studies, the relative risk estimate for cancer for men compared with women was 2.02 (95% CI, 1.53-2.66). Significant heterogeneity was found for the overall analysis and for studies reporting on cancer but not for studies thate xcluded subjects with a family history or for those analyses grouped by age. This meta-analysis provides strong evidence that men are at greater risk for advanced colorectal neoplasia across all age groups. This might inform decisions to create sex-specific colorectal cancer screening recommendations.

Elevation of C-Reactive Protein Level Is Associated With Synchronous and Advanced Colorectal Neoplasm in Men

Chronic inflammation has been implicated in the development of colorectal cancer (CRC). The presence of low-grade systemic inflammation, as determined by an elevation of high-sensitivity C-reactive protein (CRP), has been associated with an increased risk of cardiovascular diseases and cancers. However, previous studies of CRP and CRC in cohorts that comprised different genders have yielded conflicting results and little is known about CRP levels in individuals with colorectal adenomas, the precursor lesion of CRC. This study aims to elucidate the association of CRP and colorectal neoplasia. Plasma CRP levels were examined using a cross-sectional design in 6,695 consecutive ethnic Chinese adults who had undergone a complete colonoscopy following a thorough routine health evaluation. Logistic regression analysis was used to correlate the risk of colorectal neoplasia with CRP levels. Plasma CRP levels were significantly higher in subjects with colorectal neoplasia than in those without neoplasia (1.85 mg/L vs 1.55 mg/L, P= 0.04). The presence of synchronous neoplasia, advanced neoplasia, and concurrent synchronous and advanced neoplasia were associated with elevated levels of plasma CRP, after adjustment for other risk factors. Gender stratification revealed a positive association between elevated CRP levels and the risk of colorectal neoplasia in men, but no such corresponding association existed in women. Elevated plasma CRP levels are independently associated with an increased risk of colorectal neoplasia in men, but not in women. These data support the association between chronic inflammation and colorectal neoplasia in men and provide new insights into the underlying mechanisms that warrant further investigation.

Diet, Gender, and Colorectal Neoplasia

The association between diet and colorectal cancer has been studied in depth for many decades, with equivocal results. It has been hypothesized that cancers arising in the distal and proximal colon have different pathologies, and therefore different risk factors. As such, it is possible that diet-related factors might influence colorectal neoplasia differently depending on the subsite. Recent evidence indicates that women may be more likely to develop proximal cancers than men. Additionally, the link between certain dietary factors and colorectal neoplasia in women seems to vary by menopausal status. Given these observations, women may be affected differently than men by diet-related factors. The objective of this article was therefore to review the data for diet and colorectal adenomas and cancer, and then attempt to address the potential differences in the association of diet-related factors and colorectal neoplasia in men and women. For total energy intake, selenium, and fiber, it seems that there may be slightly stronger effects in men as compared with women, whereas calcium and folate seem to affect both sexes similarly. With regard to vitamin D and colorectal cancer, women may exhibit stronger associations than men. Perhaps the most evidence for a sex-specific effect is observed for obesity, where more substantial direct relationships between body size and colorectal neoplasia have been reported for men than for women. However, this observation may be influenced by the differential effects in women by menopausal status. Further research on sex-specific dietary effects is warranted.

Tratamento cirúrgico dos aneurismas da aorta abdominal: existe diferença dos resultados entre homens e mulheres?

OBJETIVO: Avaliar os resultados cirúrgicos após o tratamento convencional e eletivo do aneurisma da aorta abdominal, verificando se existe diferença entre homens e mulheres na mortalidade e morbidade cirúrgicas, bem como nos resultados a longo prazo. PACIENTES E MÉTODOS: Entre dezembro de 1983 e dezembro de 2003, 675 pacientes foram submetidos ao tratamento cirúrgico do aneurisma da aorta abdominal infra-renal, sendo divididos em dois grupos: homens (n = 575) e mulheres (n = 100). Os dados demográficos e aqueles relacionados ao procedimento cirúrgico, bem como os resultados perioperatórios, foram coletados pela revisão dos prontuários. Os pacientes com alta hospitalar formaram uma coorte retrospectiva, onde foram avaliadas as causas tardias de óbito e a sobrevida. RESULTADOS: A média das idades foi similar, sem diferença estatística entre mulheres e homens (68,9 ± 9,1 versus 67,4 ± 7,1 anos; P = 0,089). A presença de hipertensão arterial foi significativamente superior nas mulheres (73 versus 62,4%; P = 0,042), e a cardiopatia isquêmica e história de tabagismo foram mais freqüentes nos homens (P &lt;0,05). A mortalidade operatória total foi de 2,8%, não havendo diferença significativa entre mulheres e homens (4 versus 2,6%, respectivamente; P = 0,43). A morbidade cirúrgica envolveu 14% dos pacientes femininos e 18,4% dos masculinos (P 0,05). A taxa de sobrevida global em 1, 3, 5 e 10 anos não diferiu entre os grupos, sendo a sobrevida em 5 anos de 71% para as mulheres e 72% para os homens (P 0,05). A principal causa de morte tardia foi de origem cardiovascular, seguida de complicações renais nas mulheres e neoplasia nos homens. CONCLUSÂO: A taxa de mortalidade e morbidade cirúrgicas não aumentou significativamente nas mulheres após a correção eletiva do aneurisma da aorta abdominal infra-renal. Além disso, os resultados a longo prazo são semelhantes entre os dois gêneros.

Penile Intraepithelial Neoplasia: Results of Photodynamic Therapy

Failure of response to treatment or recurrent disease is often noted in patients with penile intraepithelial neoplasia. Photodynamic therapy has recently been added to the list of treatment modalities used for this diagnosis. Our primary objective was to study the results of photodynamic therapy in the treatment of penile intraepithelial neoplasia in men over the age of 40 years. Ten patients aged 42-82 years with histopathologically confirmed lesions were studied. Lesions initially responded to photo-dynamic therapy in 7 out of 10 patients. Four of these patients presented no recurrences during a mean follow-up of 35 months, and were completely cleared after 2-8 treatments (mean 4.5 treatments). Three patients presented recurrences after treatment. No patient developed invasive penile cancer (mean follow-up 46.5 months). Photodynamic therapy is an alternative in the treatment of penile intraepithelial neoplasia, although prospective randomized trials are required to provide therapeutic guidelines.

Is diverticulosis associated with colorectal neoplasia? A cross-sectional colonoscopic study.

To determine the relationship between distal diverticulosis and risk for colorectal neoplasia. Patients undergoing first-time colonoscopy for any indication were eligible if they had no prior polypectomy, colonic resection, or inflammatory bowel disease. Patients completed a survey about risk factors for colorectal cancer (CRC) prior to colonoscopy. Endoscopists, blinded to study objective and survey results, recorded the size, extent (none, few, or many), and location of diverticuli and polyps. The 502 participants were 67% male with a mean age of 58.6 yr. Twenty-three percent had extensive distal diverticulosis (EDD), 36% had > or =1 adenoma, and 14% had advanced neoplasia. Overall comparison of those with EDD versus few or no diverticuli revealed no differences in the risks of any neoplasia or advanced neoplasia, either distally (26.7%vs 25.4%; 12.9%vs 8.8%, respectively) or proximally (25%vs 18.4%; 6.0%vs 4.9%). Compared to women with few or no distal diverticuli, however, women with EDD were more likely to have any neoplasia and advanced neoplasia, both distally (34.6%vs 16.3%; p= 0.03, and 23.1%vs 5.7%; p= 0.003) and proximally (30.8%vs 14.9%; p= 0.049, and 11.5%vs 4.3%, p= 0.13). Adjustment for age did not affect results for advanced distal neoplasia (OR = 3.92; CI: 1.18-13); however, adjustment for the presence of a distal neoplasm eliminated the increased risk of proximal neoplasia associated with EDD (OR = 1.31; CI: 0.43-4.02). In this study, women with EDD were more likely to have advanced distal neoplasia. The presence of distal neoplasia in women with EDD accounted for their increased risk of proximal neoplasia. Distal diverticulosis was not independently associated with proximal neoplasia in men or women.

Estrogen receptor pathways in lung cancer.

Lung cancer is the leading cause of death from neoplasia in men and women in the United States. Some studies suggest that women are more susceptible than men to tobacco-induced carcinogenesis and may show higher risk than men for lung cancer development from smoking. More recently, increasing biochemical and genetic data have supported this male-female difference in response to tobacco. Estrogens may be involved in lung carcinogenesis, and estrogen receptors (ERs), mainly ERb, are present and functional in normal lung and tumor cell lines and tissues. Estrogen can directly stimulate the transcription of estrogen-responsive genes in the nucleus of lung cells, and it can also transactivate growth factor signaling pathways, in particular the epidermal growth factor pathway. Lung cancer patients currently have few effective therapeutic options. An understanding of these new developments in estrogen signaling and cross-talk pathways may pave the way for innovative combinatorial approaches for treatment of lung cancer and possibly chemoprevention.

Gene mutations and altered gene expression in azoxymethane-induced colon carcinogenesis in rodents.

Studies of colon carcinogenesis in animal models are very useful to elucidate mechanisms and provide pointers to potential prevention approaches in the human situation. In the rat colon carcinogenesis model induced by azoxymethane (AOM), we have documented frequent mutations of specific genes. K-ras mutations at codon 12 were found to be frequent in hyperplastic aberrant crypt foci (ACF) and large adenocarcinomas. In addition, mutations of the beta-catenin gene in its GSK-3beta phosphorylation consensus motif could also be identified in many adenomas and adenocarcinomas, and altered cellular localization of beta-catenin protein was observed in all of the dysplastic ACF, adenomas and adenocarcinomas examined, indicating that activation of Wnt signaling by accumulation of beta-catenin is a major mechanism in the AOM-induced colon carcinogenesis model. Frequent gene mutations of beta-catenin and altered cellular localization of the protein are also features of AOM-induced colon tumors in mice. Expression of enzymes associated with inflammation, such as inducible nitric oxide synthase (iNOS) and the inducible type of cyclooxygenase (COX), COX-2, is increased in AOM-induced rat colon carcinogenesis, and overproduction of nitric oxide (NO) and prostaglandins is considered to be involved in colon tumor development. We have demonstrated that increased expression of iNOS is an early and important event occurring in step with beta-catenin alteration in rat colon carcinogenesis. Activation of K-ras was also found to be involved in up-regulation of iNOS in the presence of inflammatory stimuli. In addition, expression levels of prostaglandin E(2) (PGE(2)) receptors may be altered in colon cancers. For example, the EP(1) and EP(2) subtypes have been shown to be up-regulated and EP(3) down-regulated in AOM-induced colon cancers in rats and mice. EP(1) and EP(4) appear to be involved in ACF formation, while alteration in EP(2) and EP(3) is considered to contribute to later steps in colon carcinogenesis. Increased expression of some other gene products, such as the targets of Wnt/beta-catenin signaling, have also been reported. The further accumulation of data with this chemically-induced animal colon carcinogenesis model should provide useful information for understanding colorectal neoplasia in man.