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Effects of 17β-estradiol administration on apoptosis and polyamine content in AGS cell line
Abstract
Estrogens and polyamines seem to play an important role not only in cell growth and differentiation, but also in programmed cell death. The aim of the present study was to investigate the effects of 17beta-estradiol supplementation on apoptosis as well as on the polyamine content of an ER-positive human gastric cancer cell line (AGS).
Apoptosis was investigated by evaluating DNA fragmentation, using enzyme immunoassay and agarose gel electrophoresis and the phosphatidylserine exposure by flow cytometry analysis. Polyamine levels were evaluated by HPLC.
17Beta-estradiol gave rise to a marked pro-apoptotic effect at concentrations of 16 microM or higher compared to the control. Moreover, the hormone significantly reduced the contents of polyamines compared to control cells. The apoptotic effect of 17beta-estradiol was partially counteracted by exogenous spermine administration.
17Beta-estradiol administration induces apoptosis in AGS cells. Further, an increase in cell sensitivity to apoptosis due to a decline in the polyamine content may be suggested.
... Several anthropometric variables were positively associated with EA in both men and women (Table 1 and Table 2 45). In addition, weight and HC were positively associated with EA in men but not in women (Table 1 and Table 2). ...
... For gastric cancer, estrogens may protect against the development of this malignancy by acting on estrogen receptors (ERα and ERβ), which have been identified in gastric cancer cells 44 . Estrogen inhibits cell growth and increases apoptosis in gastric cancer cells 45,46 and stimulates the expression of trefoil factor proteins, which play a role in mucosal protection and repair and their trefoil factor genes may act as tumor suppressors 42 . ...
Obesity has been associated with upper gastrointestinal cancers; however, there are limited prospective data on associations by subtype/subsite. Obesity can impact hormonal factors, which have been hypothesized to play a role in these cancers. We investigated anthropometric and reproductive factors in relation to esophageal and gastric cancer by subtype and subsite for 476,160 participants from the European Prospective Investigation into Cancer and Nutrition cohort. Multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox models. During a mean follow‐up of 14 years, 220 esophageal adenocarcinomas (EA), 195 esophageal squamous cell carcinomas, 243 gastric cardia (GC) and 373 gastric noncardia (GNC) cancers were diagnosed. Body mass index (BMI) was associated with EA in men (BMI ≥30 vs. 18.5–25 kg/m²: HR = 1.94, 95% CI: 1.25–3.03) and women (HR = 2.66, 95% CI: 1.15–6.19); however, adjustment for waist‐to‐hip ratio (WHR) attenuated these associations. After mutual adjustment for BMI and HC, respectively, WHR and waist circumference (WC) were associated with EA in men (HR = 3.47, 95% CI: 1.99–6.06 for WHR >0.96 vs. <0.91; HR = 2.67, 95% CI: 1.52–4.72 for WC >98 vs. <90 cm) and women (HR = 4.40, 95% CI: 1.35–14.33 for WHR >0.82 vs. <0.76; HR = 5.67, 95% CI: 1.76–18.26 for WC >84 vs. <74 cm). WHR was also positively associated with GC in women, and WC was positively associated with GC in men. Inverse associations were observed between parity and EA (HR = 0.38, 95% CI: 0.14–0.99; >2 vs. 0) and age at first pregnancy and GNC (HR = 0.54, 95% CI: 0.32–0.91; >26 vs. <22 years); whereas bilateral ovariectomy was positively associated with GNC (HR = 1.87, 95% CI: 1.04–3.36). These findings support a role for hormonal pathways in upper gastrointestinal cancers.
... Within the minority of patients whose tumors expressed ERα and AR, the majority of expression was also detected in male EAC patients. Preclinical data have shown that estrogen and selective estrogen receptor modulator treatment decreases tumor growth, proliferation and increase apoptosis in EAC and Barrett's esophagus cell lines [13,14] and similar effects have been reported in vitro and in vivo for gastric [31,32] and colorectal cancer [33] and esophageal squamous cell carcinoma (OSSC) [20,34]. Interestingly, ERβ has been correlated with improved survival in non-small cell lung adenocarcinoma, particularly in men [35], although findings from other studies have been mixed [36,37] and a recent pooled analyses found no association between ERβ expression and survival in NSCLC patients [38]. ...
... No study has specifically investigated ERβ expression in cancer tissues of the proximal stomach. Epidemiological studies of markers of endogenous and exogenous estrogen exposures have suggested protective associations for gastric cancer [45], which are possibly more marked for gastric cardia adenocarcinomas [46], and preclinical evidence shows an increase in apoptosis and an inhibition of cell migration with estrogen administration in gastric cancer cell lines [32,47]. A more marked prognostic benefit for ER receptor expression in GEJ tumors is therefore plausible but findings require replication in other large EAC cohorts. ...
Introduction:
A striking epidemiological feature of esophageal adenocarcinoma (EAC) is its strong, unexplained male predominance but few studies have evaluated the prevalence of sex hormone receptor expression in EAC.
Results:
A low proportion of EAC tumors stained positive for ERα (4%) and AR (3%) while approximately one third stained positive for ERβ (31%). After a mean follow-up of 3 years (max 9 years), no significant associations were seen for ERα, ERβ or AR expression and EAC recurrence or survival. A non-significant reduction in mortality was observed for positive ERβ tumor expression, when restricting to patients with gastro-esophageal junctional (GEJ) cancer (HR 0.58, 95% CI 0.33, 1.03, p = 0.06).
Materials and methods:
We identified all EAC patients who underwent neo-adjuvant chemotherapy prior to surgical resection between 2004-2012 in the Northern Ireland Cancer Centre. Immunohistochemical expression of ERα, ERβ and AR was scored on triplicate cores to generate H-scores. Cox proportional hazards regression was used to evaluate the association between sex hormone receptor expression and overall, cancer-specific and recurrence-free survival.
Conclusion:
We found little evidence of ERα or AR expression in EAC. A moderate proportion expressed ERβ and there was suggestive evidence that its expression was associated with improved survival in GEJ cancer patients.
... Many scientists have investigated the expression of estrogen receptors in malignant tissues and cells and the clinical significance of ERs expression in gastric cancer [3,13,[37][38][39][40][41][42][43][44][45]. There are numerous studies suggesting that estrogens play a protective role in gastric cancer progression also in both animal models [13,46,49,53] and in vitro studies [39,42,[50][51][52]. ...
... These studies indicate that estrogen may provide protection against the progression of GC and that the female sex hormones may decrease the incidence of gastric cancer and lower proliferation in SGC7901, BGC823, AGS gastric cancer cell lines [50][51][52]. It has been demonstrated that estrogen receptor-negative tumors cause higher proliferation in comparison to positive tumors in Table 4 The results presenting the occurrence of estrogen receptors ERa and ERb in analyzed gastric tissues using immunohistochemical methods. ...
In most populations, gastric cancer (GC) is approximately two times more prevalent in men than in women, which may suggest the protective role of sex steroid hormones in gastric carcinogenesis. Steroid hormones such as androgens and estrogens can be synthesized not only in the gonads but also in peripheral tissues. Many researchers have conducted studies examining the expression profile of enzymes involved in steroid synthesis, the occurrence of estrogen receptors (ERs) and the influence of ERs in the development, proliferation and progression of gastric cancer. Some studies have also evaluated the relationship between the presence of ERs and survival prognosis. However, the results of these studies are often controversial and divergent. In a recent study, it was indicated that sex steroid hormones and estrogen receptors are partly involved in gastric cancer but their clinicopathological significance still needs further investigation.
... Previous prospective cohort studies and human cell lines studies suggested that female hormones might play a protective role in GC risk [25][26][27][28][29][30][31]. However, the occurrence of GC was frequently observed that females were more susceptible than males in younger group, which prompted a reconsideration of the potential mechanisms of estrogen [4][5][6][7][8][9][10][11]. ...
Background
Male patients were twice as likely to develop gastric cancer (GC) compared to females, partly due to the protective effect of estrogen. However, the proportion of females increased in the young GC patients. The study was designed to explore comprehensive molecular profiles of younger female GC patients, as well as develop a prognostic gene model for female GC patients.
Methods
Gene expression and clinical data of GC and non-tumor patients were downloaded from the Gene Expression Omnibus (GEO) database. Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene set enrichment analysis (GSEA) were used to find molecular characteristics and potential mechanisms of younger female GC patients. The prognostic gene model containing 6 differential expressed genes (DEGs), which were between younger and older female patients, was established using Lasso-Cox regression. Its performance was validated by external validation. Then, receiver operating characteristic (ROC) curve was applied to determine the prognostic value of the prognostic gene model.
Results
Six GEO cohorts with 305 female GC patients (69 younger patients and 236 older patients) and 38 female non-tumor patients were included. A total of 4557 DEGs between female GC patients and non-tumor patients were identified, including 2212 up-regulated genes and 2345 down-regulated genes. Estrogen response early (p < 0.001) and estrogen response late (p < 0.001) were enriched in female GC patients. In KEGG analysis, aldosterone (p = 0.023) and relaxin pathways (p = 0.043) were concentrated in younger group. Moreover, we further used GSE84437 cohort to construct a prognostic gene model containing 6 genes, namely NREP, GAD1, SLCO4A1, KRT17, DEFB1, and P3H2, to predict the overall survival (OS) of female GC patients (AUC = 0.810). Younger female patients, who were related with high-risk at the genetic level, showed worse OS compared with older female patients who showed low-risk (HR = 5.7688, 95%CI: 3.0108–11.0530, P < 0.001).
Conclusions
In conclusion, we provided the comprehensive molecular profiles of younger female GC patients and found that there was a significant difference in enriched hormone-related pathways between younger group and older group. In addition, we found younger female patients showed worse OS compared with older female patients using the prognostic gene model we created.
... Research has shown that the trefoil factor (TTF) protein offers protection and repair to damaged gastric mucosal epithelial cells, and estrogen can indirectly increase TTF protein expression by stimulating TTF gene expression [29]. Furthermore, in vitro experiments have observed that estrogen increases apoptosis in human GC cells [30]. For different age groups, the mortality and DALY rates related to GC caused by high sodium intake in the elderly are higher than in young people. ...
Background
This study aimed to conduct a comprehensive analysis and predict the global and regional disease burden of gastric cancer (GC) caused by high sodium intake.
Methods
We used the age-standardized mortality rate (ASMR) and disability-adjusted life years (DALYs) rate (ASDR) from the Global Burden of Disease (GBD) study 2019 to analyze the GC burden attributable to high sodium intake by sex, age, countries, regions, and Socio-demographic index (SDI). To quantify the secular trends of ASMR and ASDR from 1990 to 2019, we calculated the estimated annual percentage change (EAPC). And the Bayesian age-period-cohort (BAPC) model integrated nested Laplace approximations to predict the disease burden over the next 31 years.
Results
Globally, the ASMR and ASDR attributable to high sodium intake have both decreased, with EAPC of -1.83 (95% CI: -2.02, -1.65 ) and − 2.09 (95% CI: -2.29, -1.90 ), respectively. Across all sexes and age groups, this burden of disease is highest among males and the elderly population. Between 1990 and 2019, the highest global burden due to GC was observed in middle and high-middle SDI regions, especially in East Asia. According to predictions from the BAPC model, the age-standardized rate (ASR) of GC caused by high sodium intake has been decreasing from 2020 to 2040.
Conclusions
The burden of GC attributable to high sodium intake is decreasing, but the situation is not optimistic in some countries and regions. Specific health policies and interventions are necessary in the future.
... Several potential biological pathways that may regulate estrogen's protective effect against gastric cancer have been postulated including via interactions with cellular receptors in gastric mucosa [44,45], by increasing expression of trefoil factor family genes which encode products that protect gastric mucosa from endogenous and exogenous insults [46], through enhanced apoptosis in human gastric cancer cells seen in vitro [47] and due to strengthening of the immune response to bacterial pathogens by directly blocking expression of caspase-12 [48]. Related to how genetics would explain sex differences in gastric cancer, variants in genes involved in estrogen synthesis and metabolisms have been associated with gastric cancer risk [7]. ...
Background
Gastric cancer incidence is higher in men, and a protective hormone-related effect in women is postulated. We aimed to investigate and quantify the relationship in the Stomach cancer Pooling (StoP) Project consortium.
Methods
A total of 2,084 cases and 7,102 controls from 11 studies in seven countries were included. Summary odds ratios (ORs) and 95% confidence intervals (CIs) assessing associations of key reproductive factors and menopausal hormone therapy (MHT) with gastric cancer were estimated by pooling study-specific ORs using random-effects meta-analysis.
Results
A duration of fertility of ≥ 40 years (vs. < 20), was associated with a 25% lower risk of gastric cancer (OR = 0.75; 95% CI: 0.58–0.96). Compared with never use, ever, 5–9 years and ≥ 10 years use of MHT in postmenopausal women, showed ORs of 0.73 (95% CI: 0.58–0.92), 0.53 (95% CI: 0.34–0.84) and 0.71 (95% CI: 0.50–1.00), respectively. The associations were generally similar for anatomical and histologic subtypes.
Conclusion
Our results support the hypothesis that reproductive factors and MHT use may lower the risk of gastric cancer in women, regardless of anatomical or histologic subtypes. Given the variation in hormones over the lifespan, studies should address their effects in premenopausal and postmenopausal women. Furthermore, mechanistic studies may inform potential biological processes.
... ODC catalyzes the formation of putrescine from ornithine, whereas AMD1 produces the aminopropyl donor, decarboxylated S-adenosylmethionine (dcAdoMet), required for spermidine and spermine synthesis (1). Polyamine metabolism is closely related to many fundamental cellular processes such as differentiation, apoptosis, nucleic acid synthesis, transcription, translation, autophagy and protection from oxidative stress (1)(2)(3)(4)(5). The contribution of polyamines to protein translation is exemplified by the need of spermidine for formation of an uncommon amino acid hypusine that is present in eukaryotic initiation factor 5A isoform 1 (eIF5A) to prevent ribosomal stalling during the translation of messenger RNAs (mRNAs) encoding polyproline tracts (6). ...
Adenosylmethionine decarboxylase 1 (AMD1) is a key enzyme involved in biosynthesis of polyamines includingspermidine and spermine. The potential function of AMD1 in human gastric cancers is unknown. We analyzed AMD1 expression level in 319 human gastric cancers samples together with the adjacent normal tissues. The protein expression level of AMD1 was significantly increased in human gastric cancer samples compared with their corresponding para-cancerous histological normal tissues (P<0.0001). The expression level of AMD1 was positively associated with Helicobactor pylori 16sRNA (P<0.0001), tumor size (P<0.0001), tumor differentiation (P<0.05), tumor venous invasion (P<0.0001), tumor lymphatic invasion (P<0.0001), blood vessel invasion (P<0.0001), and TNM stage (P<0.0001). Patients with high expression of AMD1 had a much shorter overall survival than those with normal/low expression of AMD1. Knockdown of AMD1 in human gastric cancer cells suppressed cell proliferation, colony formation and cell migration. In a tumor xenograft model, knockdown of AMD1 suppressed the tumor growth in vivo. Inhibition of AMD1 by an inhibitor SAM486A in human gastric cancer cells arrested cell cycle progression during G1-to-S transition. Collectively, our studies at the cellular, animal and human levels indicate that AMD1 has a tumorigenic effect on human gastric cancers and affect the prognosis of the patients.
Background
Recent studies showed inverse relationship between hypercholesterolemia and the risk of gastric cancer, especially among male. However evidence among female is inconsistent. We aimed to investigate the relationship between cholesterol level and the risk of gastric cancer among female according to menopausal status.Methods
We analyzed the data from a population-based prospective cohort of female ≥ 30 years old who underwent cancer screening and general health screening provided by the Korean National Health Insurance Corporation in 2009. Under quartile stratification of the level of cholesterol components, we calculated the hazard ratio (HR) for gastric cancer incidence until 2018 for each level group according to the menopausal status at 2009.ResultsAmong total 2,722,614 individuals, 17,649 gastric cancer cases developed after mean 8.26 years of follow-up (premenopausal 3746/1180666; postmenopausal 13,903/1541948). Total cholesterol, high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) showed inverse relationship with the risk of gastric cancer among postmenopausal women (adjusted HR (95% confidence interval) for the highest quartile vs. lowest quartile and p-for-trend: 0.88 (0.84–0.92) and < 0.001 for total cholesterol; 0.89 (0.85–0.92) and < 0.001 for HDL-C; 0.92 (0.89–0.97) and 0.001 for LDL-C), whereas none showed statistically significant risk relationship among premenopausal women. Triglyceride was not independently related with gastric cancer risk among both pre- and postmenopausal women.Conclusions
Cholesterol levels, including total cholesterol, HDL-C, and LDL-C, are inversely related with the risk of gastric cancer among postmenopausal women, but not among premenopausal women.
Patients with gastric ulcer (GU) have a significantly higher risk of developing gastric cancer (GC), especially within 2 years after diagnosis. The main way to improve the prognosis of GC is to predict the tumorigenesis and metastasis in the early stage. The objective of this study was to demonstrate the ability of human plasma amino acid metabolic profile for discriminating GC and GU. In this study, we first used liquid chromatography-tandem mass spectrometry technique to characterize the plasma amino acid metabolism in GC and GU patients. Plasma samples were collected from 84 GC patients and 82 GU patients, and 22 amino acids were detected in each patient. Partial least squares-discriminant analysis model was performed to analyze the data of these amino acids. We observed seven differential amino acids between GC and GU. A regression analysis model was established using these seven amino acids. Finally, a panel of five differential amino acids, including glutamine, ornithine, histidine, arginine and tryptophan, was identified for discriminating GC and GU with good specificity and sensitivity. The receiver operating characteristic curve was used to evaluate diagnostic ability of the regression model and area under the curve was 0.922. In conclusion, this study demonstrated the potential values of plasma amino acid metabolic profile and metabolomic analysis technique in assisting diagnosis of GC. More studies are needed to highlight the theoretical strengths of metabolomics to understand the potential metabolic mechanisms in GC. © 2018 IUBMB Life, 2018.
Background: In recent years, it is found that a large number of genes are differentially expressed in two sexes; this can be referred to sexual dimorphism in gene expression. One of the main reasons for the differences in gene expression between male and female is assigned to sex hormones. Regarding to the presence of estrogen and androgen response elements in the regulatory region of Foxa1 and Foxa2 genes and sexual dimorphism in the incidence of gastric cancer, in this study, we compared the expression of these genes in the stomach of healthy men and women.
Methods: Sampling was done from 20 healthy men and 21 healthy women using endoscopy from the gastric antrum. Following RNA extraction and complementary DNA (cDNA) synthesis, expression of Foxa1 and Foxa2 genes was compared between the men and women using semi-quantitative technique of reverse transcription polymerase chain reaction (RT-PCR). Then, the data were analyzed using statistical t and ANOVA tests.
Findings: The expression of Foxa1 was significantly higher in women than men (P = 0.041, df = 36,
t = 2.12). In addition, the expression of this gene was significantly higher in people under the age of 45 years than people above it (P = 0.010, df = 36, t = 2.71). But about Foxa2 gene, no significantly results were seen.
Conclusion: Foxa1 gene expression in women’s stomach is higher than men’s; besides, the expression of this gene in the stomach is decreased by age.
Early during the process of apoptosis, cells lose their phospholipid membrane asymmetry and expose phosphatidylserine (PS) at the cell surface while maintaining their plasma membrane integrity intact. This process can be monitored for suspended cell types by using annexin V-FITC, which is a Ca(2+)-dependent, phospholipid-binding protein with high affinity for PS, and flow cytometry. If adherent cell types are to be studied for this apoptosis-associated phenomenon, then a problem is encountered, in that specific membrane damage occurs during harvesting. In this paper, a flow cytometric-based method is described that allows the measurement of loss of phospholipid asymmetry during apoptosis of adherent cells in culture. The method relies on the phospholipid binding property of biotinylated annexin V. Furthermore, the use of this conjugate allows tricolor flow cytometric analysis of apoptosis. Employing the method to MR65 cells, which were initiated by olomoucine to enter apoptosis, it is shown that PS exposure occurs early after the onset of apoptosis and, at the prevalent time-resolution, that PS exposure is accompanied by loss of both cytokeratin and DNA. The annexin V+ cells appear as a characteristic sub-G1 peak in the DNA histogram.
Glucocorticoid hormones, Ca2+ ionophores, and some toxic chemicals activate a suicide process in thymocytes, known as apoptosis or programmed cell death. A crucial event in apoptosis is the activation of a Ca(2+)- and Mg(2+)-dependent endonuclease that promotes extensive DNA fragmentation. In this study, we investigated the effect of various polyamines on endonuclease activation leading to thymocyte apoptosis. We found that both glucocorticoid- and Ca2+ ionophore-induced DNA fragmentation and apoptosis were prevented by spermine. Other polyamines such as putrescine or spermidine had moderate or no effect. Moreover, spermine, and to a lesser extent spermidine, but not putrescine, prevented endonuclease activation in permeabilized liver nuclei incubated in the presence of Ca2+ and Mg2+, indicating that spermine efficiency in blocking DNA fragmentation was related to the interaction of this polyamine with the endonuclease or its substrate, DNA. Experiments with the fluorescent dye, ethidium bromide, and a purified preparation of liver endonuclease revealed that the protective effect of spermine on DNA fragmentation was related to its ability to modify the chromatin arrangement. Thymocytes incubated with methyl glyoxal bis(guanylhydrazone) to deplete intracellular spermine exhibited spontaneous DNA fragmentation, which suggests that modulation of the intracellular polyamine content and regulation of chromatin structure may play a critical role in the early phases of apoptosis. Finally, these results demonstrate that inhibition of DNA fragmentation also prevents the onset of apoptosis, directly linking endonuclease activation and cell death.
We assayed the estrogen receptors and polyamine levels (putrescine, spermidine and spermine) in the neoplastic and "normal" surrounding tissue of patients with colorectal cancer. Polyamine levels and the spermidine/spermine ratio were significantly higher in the neoplastic tissue than in the "normal" surrounding colonic mucosa of the same patients. Estrogen receptors were fewer in neoplastic mucosa than in the surrounding tissue, and polyamine levels were higher in estrogen-receptor negative tumours than in estrogen-receptor positive ones, although this was statistically significant only in the case of spermidine. Polyamine levels and estrogen receptor concentrations did not correlate with the tumour site, histological differentiation, or the age and sex of patients.
We assayed the estrogen and progesterone cytosolic receptors by using the enzyme immunoassay method, the epidermal growth factor (EGF) cell surface receptors by using 125I-labeled hormone, and the levels of polyamines (putrescine, spermine, and spermidine) by using a high-pressure liquid chromatography (HPLC) procedure in neoplastic and surrounding normal tissues of patients with colorectal cancer. Our findings show that mean polyamine levels in neoplastic tissue were approximately two-fold greater than the levels in normal colonic mucosa. Estrogen and progesterone receptorial content in normal mucosa were twofold greater than those in neoplastic tissue. No significant differences in EGF receptors were found between colonic cancer tissue and the surrounding normal tissues. The correlations we found between 1) estrogen and polyamine levels and 2) estrogen and EGF binding suggest the existence of a modulation of the estrogens on colonic mucosa cell proliferation. Furthermore, there was no significant dependency of polyamine and receptor concentrations from the tumor site, the histologic differentiation, or the age and sex of patients.
The polyamines putrescine, spermidine and spermine are important cellular constituents involved in the regulation of cell growth and differentiation. Their intracellular levels are regulated by a multitude of mechanisms affecting their synthesis, degradation, uptake and excretion. As a result of the application of molecular biology techniques, some of these mechanisms are presently being unravelled, and are providing a basis for the rational development of novel agents effective against proliferative disorders and various parasitic diseases.
The measurement of estrogen as well as progesterone receptors has been applied clinically to predict the effectiveness of endocrine therapy in patients with breast or endometrial carcinoma. The presence of cytosolic estrogen receptors in human colorectal carcinomas has been reported by several different groups during the past 10 yr. The aim of our current study was to evaluate the estrogen binding activity in the nuclear and cytosolic fractions of these carcinomas, as well as in surrounding noncancerous colonic tissue. Twenty-six patients, operated on for colorectal carcinoma, were studied: 16 were men and 10 were postmenopausal women, mean age 61 yr (range 43-78 yr). In neoplastic tissue, cytosolic estradiol receptors were detected in 42.3% of the patients (women 40%, men 43.7%). The values for cytosolic estrogen receptor ranged from 118 to 1214 fmol/g wet colon. Nuclear estrogen receptors were detectable in 46.1% of the patients (women 40%, men 50%) and their values displayed a range from 3.4 to 2554 fmol/g wet colon. In 30.7% of the patients, both nuclear and cytosolic receptors were demonstrated. In 38.4% of the patients, receptors were found in neither cytosol nor nuclei. Receptor positivity in men was most frequently associated with tumors removed from the rectum, and those with Dukes' classification of C1. In the surrounding noncancerous tissue cytosolic estrogen receptors were also detected (range 133-1105 fmol/g wet colon) and were present in 34.6% of the patients (women 30%, men 37.5%). Nuclear estrogen receptors (range 225-1105 fmol/g wet colon) were detected in 57.6% of the patients (women 40%, men 68.7%). In 23% of the patients, both nuclear and cytosolic receptors were demonstrated. In 30.7% of the patients, no receptors were found in either cytosol or nucleus. Therefore, the presence of cytosolic or nuclear estrogen receptors, or both, in 61.6% of human colorectal cancer specimens emphasizes the need to evaluate both forms of these receptors for studies of potential hormone dependence in these tumors.
Steroid hormone receptors in three human gastric adenocarcinoma cell lines and their transplanted tumors (except nontumorigenic KATO-III) in nude mice were determined by dextran-coated charcoal assay. Progesterone receptors (PgR) were found in all cell lines, transplanted NUGC-3, and AZ 521 tumors. Estrogen receptors (ER) were found in KATO-III cells, transplanted NUGC-3, and AZ 521 tumors, whereas glucocorticoid receptors (GR) were found only in NUGC-3 tumor and no androgen receptor was found in any cell lines or transplanted tumors. Since NUGC-3 cells had ER, PgR, and GR, it was used for the study of the effects of steroid hormones on growth. The results showed the cell cycle phase distributions and growth rate of transplanted tumors were similar in hormone-treated and nontreated groups. The persistent expression of PgR in gastric cancer cell lines and tumors, and the slight increase of tumor volumes in the progesterone-treated group suggests that progesterone and its receptors may be important in the pathogenesis of gastric cancer, but their biological function remains to be elucidated.
We evaluated polyamine (putrescine, spermidine, and spermine) levels, estrogen receptor concentrations, and their relationship in neoplastic tissue and surrounding mucosa from 30 patients with gastric adenocarcinoma. Cytosolic estrogen receptors were measured with an immunoenzymatic assay. Polyamine levels were evaluated with high-performance liquid chromatography. Estrogen receptor concentrations were statistically higher in surrounding mucosa than in neoplastic tissue (p = 0.023). Putrescine and spermidine levels and the spermidine to spermine ratio were statistically higher in neoplastic tissue than in surrounding mucosa (p < 0.004). Significant correlations were found between the levels of spermidine and total polyamines in neoplastic tissue and surrounding mucosa (r = 0.48, p = 0.014, and r = 0.45, p = 0.021, respectively). Polyamine levels were lower in estrogen-receptor-positive tumors than in estrogen-receptor-negative ones, although this decrease was statistically significant only in the case of spermine (p = 0.02). The significance of these findings is that the cellular activity of normal and neoplastic gastric mucosa may be partly controlled by estrogens.