Cancer In Adult Life Research Articles

Testicular cancer in mice: interplay between stem cells and endocrine insults.

BackgroundIncidence of type II germ cell tumors (T2GCT) has increased in young men possibly due to fetal/perinatal exposure to estrogenic compounds. Three-fold increased incidence of T2GCT was reported in men exposed in utero to diethylstilbestrol (DES). T2GCT is a development-related disease arising due to blocked differentiation of gonocytes into spermatogonia in fetal testes which survive as germ cell neoplasia in situ (GCNIS) and initiate T2GCT. In our earlier study, T2GCT-like features were observed in 9 out of 10 adult, 100-day-old mice testes upon neonatal exposure to DES (2 μg/pup/day on days 1–5). Neonatal DES exposure affected testicular very small embryonic-like stem cells (VSELs) and spermatogonial stem cells and resulted in infertility, reduced sperm counts and tumor-like changes leading to our postulate that testicular dysgenesis syndrome possibly has a stem cell basis. The present study was undertaken to further characterize testicular tumor in mice testes.MethodsDES-exposed mice pups (n = 70) were studied on D100 and after 12 months to understand how T2GCT progresses. Besides histological studies, a carefully selected panel of markers were studied by immuno-fluorescence and qRT-PCR.ResultsDES resulted in either atrophied or highly vascularized, big-sized testes and extra-testicular growth was also observed. GCNIS-like cells with big, vacuolated cytoplasm and increased expression of OCT-4, SSEA-1, SCA-1 and CD166 (cancer stem cells marker) along with reduced c-KIT, MVH and PTEN were evident. Global hypomethylation was found associated with altered expression of Dnmts, Igf2-H19 and Dlk-Meg3 imprinted genes along with reduced expression of Ezh2, cell cycle regulator p57KIP2 and Meg3; however, Pten remained unaltered. Increased expression of PCNA and Ki67 was observed in concert with complete lack of SOX-9 suggesting Sertoli cells independent proliferation.ConclusionsMouse model for T2GCT is described which will have immense potential to understand cancer initiation, cancer stem cells and also to develop effective therapies in future. T2GCT initiates from tissue-resident, pluripotent VSELs due to their altered epigenome. Neonatal exposure to DES blocks differentiation (spermatogenesis) and VSELs get transformed into CD166 positive cancer stem cells that undergo excessive self-renewal and initiate cancer in adult life challenging existing concept of fetal origin of T2GCT.Supplementary InformationThe online version contains supplementary material available at 10.1186/s13287-022-02784-5.

Dietary Fiber, Insulin and Breast Tissue Composition at Age 15–18: A Cross-Sectional Study

Background Risk of breast cancer in adult life is influenced by body size and height in childhood, but the mechanisms responsible for these associations are currently unknown. We carried out research to determine if, at age 15–18, measures of dietary intake were associated with body size, hormones, and with variations in breast tissue composition that in adult life are associated with risk of breast cancer. Methods In a cross-sectional study of 766 healthy Caucasian women aged 15–18, we measured percent breast water (PBW), total breast water and fat by magnetic resonance (MR), and assessed dietary intake using a validated food frequency questionnaire. We also measured height, weight, skin-fold thicknesses and waist-to-hip ratio, and in fasting blood assayed glucose and insulin. Results After adjustment for age, measures of body size, and energy intake, dietary fiber (insoluble and total fiber) and insulin were associated positively and significantly with PBW. Conclusions Dietary fiber and fasting insulin were associated with breast tissue measures. These data suggest a potential approach to breast cancer prevention.

Early-Life Risk Factors for Breast Cancer – Prospective Follow-up in the Northern Finland Birth Cohort 1966

While some risk factors for breast cancer have been confirmed, less is known about the role of early biological and social risk factors for breast cancer in adult life. In a prospective follow-up in the Northern Finland Birth Cohort 1966 consisting of 5308 women, 120 breast cancers were reported via national registers by the end of 2018. Early risk factors were examined with univariate and multivariate analyses using Cox regression analysis. The main results are reported with hazard ratios (HR) and their 95 % confidence intervals (CI). In the multivariate-adjusted models, women whose mothers lived in urban areas (HR 1.68; 95 % CI, 1.13-2.51) during pregnancy, were low-educated (HR 2.40; 95 % CI, 1.30-4.45) and had been diagnosed with breast cancer (HR 1.97; 95 % CI, 1.09-3.58), had a higher risk for breast cancer in adult life. Lower BMI at the age of 14 associated nonsignificantly with the risk of breast cancer (Mann-Whitney U test, P = 0.087). No association between birth size and breast cancer risk in adult life was found. Early-life residence and socioeconomical conditions may have an impact on developing breast cancer in women in adult life. All breast cancer cases of this study were relatively young and most of them are assumed to be premenopausal. This study is one of a few prospective birth cohort studies to examine early-life socioeconomic factors and breast cancer risk in adult life. This study is limited due to small number of cases.

Abstract 1605: Time-dependent maternal soybean genistein exposure leads to later-life breast cancer chemoprevention in mice

Abstract Breast cancer is the most common type of cancer and the second leading cause of death among women in the United States. Studies have shown that both environmental and genetic factors contribute to breast cancer risk over women's lifespans. Early-life nutritional status has a significant impact on the uterine environment and subsequent fetal development, predisposing the developing fetus to certain diseases such as breast cancer in adult life. During these windows of susceptibility including maternal pre-pregnancy, pregnancy and lactation periods, certain dietary exposure during these critical time periods may change breast cancer risk in an individual’s later life. Alterations of the maternal diet have been shown to induce modifications in the fetal epigenome. Nevertheless, the vulnerability to maternal nutrition status during the critical developmental stage provides an excellent opportunity to re-program epigenetic profiles that may lead to a beneficial outcome such as cancer prevention in the offspring. The bioactive dietary component, genistein (GE) enriched in soybean products, is an important epigenetic modulator that can prevent various cancers including breast cancer. Our study focuses on how maternal dietary soybean GE exposure during the specific time periods may prevent breast cancer in later-life and the potential mechanisms. In this study, we included multiple exposure time points of maternal GE diet (250 mg/kg) including prior-pregnancy (PP-GE), long-term (LT-GE) and short-term (ST-GE) exposures to further determine the efficacy of these strategies on transplacental chemoprevention of breast cancer in the progenies of two spontaneous breast cancer transgenic mouse models. Our pilot study indicates a time-dependent effect of maternal GE exposure on early-life breast cancer development in spontaneous breast cancer mouse models. We also integrated transcriptome and methylome data from mouse breast tumors and identified several candidate genes such as Trp63 and Tprg in response to maternal GE treatment, and considered to play important roles in regulation of development and tumorigenesis. These results suggest that an appropriate exposure window to soybean dietary GE could be a key factor for prevention of human breast cancer and comprehensive mechanisms may be involved in dietary GE-induced in utero breast cancer intervention. Citation Format: Yuanyuan Li, Min Chen, Shizhao Li, Trygve Tollefsbol. Time-dependent maternal soybean genistein exposure leads to later-life breast cancer chemoprevention in mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1605.

The association between weight at birth and breast cancer risk revisited using Mendelian randomisation

Observational studies suggest that higher birth weight (BW) is associated with increased risk of breast cancer in adult life. We conducted a two-sample Mendelian randomisation (MR) study to assess whether this association is causal. Sixty independent single nucleotide polymorphisms (SNPs) known to be associated at P < 5 × 10−8 with BW were used to construct (1) a 41-SNP instrumental variable (IV) for univariable MR after removing SNPs with pleiotropic associations with other breast cancer risk factors and (2) a 49-SNP IV for multivariable MR after filtering SNPs for data availability. BW predicted by the 41-SNP IV was not associated with overall breast cancer risk in inverse-variance weighted (IVW) univariable MR analysis of genetic association data from 122,977 breast cancer cases and 105,974 controls (odds ratio = 0.86 per 500 g higher BW; 95% confidence interval 0.73–1.01). Sensitivity analyses using four alternative methods and three alternative IVs, including an IV with 59 of the 60 BW-associated SNPs, yielded similar results. Multivariable MR adjusting for the effects of the 49-SNP IV on birth length, adult height, adult body mass index, age at menarche, and age at menopause using IVW and MR-Egger methods provided estimates consistent with univariable analyses. Results were also similar when all analyses were repeated after restricting to estrogen receptor-positive or -negative breast cancer cases. Point estimates of the odds ratios from most analyses performed indicated an inverse relationship between genetically-predicted BW and breast cancer, but we are unable to rule out an association between the non-genetically-determined component of BW and breast cancer. Thus, genetically-predicted higher BW was not associated with an increased risk of breast cancer in adult life in our MR study.

N-Acetylcysteine Suppresses LPS-Induced Pathological Angiogenesis

Background/Aims: Angiogenesis is a key feature during embryo development but is also part of the pathogenesis of cancer in adult life. Angiogenesis might be modulated by inflammation. Methods: We established an angiogenesis model in chick chorioallantoic membrane (CAM) induced by the exposure of lipopolysaccharide (LPS), and analyzed the effects of the antioxidant N-acetylcysteine (NAC) on angiogenesis in this model as well as on the expression of key genes known to involved in the regulation of angiogenesis. Results: Treatment with NAC was able to normalize LPS induced angiogenesis and restore the LPS-induced damage of vascular epithelium in chick CAM. Using quantitative PCR, we showed that NAC administration normalized the LPS induced expression of Keap1-Nrf2 signaling and oxidative stress key enzyme gene expressions (SOD, GPx and YAP1). Conclusion: We established a LPS-induced angiogenesis model in chick CAM. NAC administration could effectively inhibit LPS-induced angiogenesis and restore the integrity of endothelium on chick CAM. LPS exposure caused an increased expression of genes involved in oxidative stress in chick CAM. NAC administration could abolish this effect.

The diagnostic impact of testicular biopsies for intratubular germ cell neoplasia in cryptorchid boys and the subsequent risk of testicular cancer in men with prepubertal surgery for syndromic or non-syndromic cryptorchidism

IntroductionCryptorchidism is a risk factor for testicular cancer in adult life. It remains unclear how prepubertal surgery for cryptorchidism impacts later development of adult testicular cancer. The aim of study was to investigate tools to identify the cryptorchid boys who later develop testicular cancer. MethodsThe study cohort consisted of 1403 men operated prepubertally/pubertally for undescended testis between 1971 and 2003. At surgery testicular biopsies were taken from the cryptorchid testes. The boys were followed for occurrence of testicular cancer. The testicular cancer risk was compared to the risk in the Danish Population. Testicular biopsies from the boys who developed testicular cancer during follow-up underwent histological examination with specific diagnostic immunohistochemical markers for germ cell neoplasia. ResultsThe cohort was followed for 33,627 person years at risk. We identified 16 cases with testicular cancer in adulthood. The standardized incidence ratio was 2.66 (95% CI: 1.52–4.32). At time of primary surgery in prepubertal/pubertal age Intratubular Germ Cell Neoplasia (ITGCN) was diagnosed in 5 cases and the boys were unilaterally orchiectomized. At follow-up new immunohistochemical staining indicated ITGCN in two of the 16 cancer cases at reevaluation of the original biopsies from time of prepubertal/pubertal surgery. One had syndromic cryptorchid and developed seminoma, and another showed nonsyndromic cryptorchidism and developed embryonic teratocarcinoma. Totally, ITGCN was diagnosed in 0.5% (7/1403) of prepubertal cryptorchid boys, whereof 57% (4/7) in syndromic-cryptorchidism. DiscussionITGCN is predominantly observed prepubertally in boys with syndromic-cryptorchidism. In nonsyndromic cryptorchidism testicular cancer develops postpubertally, generally not based on dormant germ cells of ITGCN caused by an early fetal maldevelopment. Levels of EvidenceLEVEL I.

Abstract LB-375: Childhood body size at age 13 years and associations with ovarian cancer in adult life

Abstract Background: Among women, body mass index (BMI; kg/m2) and attained height are positively associated with ovarian cancer. Few studies have, however, investigated associations with childhood body size. As such, it remains largely unknown if it is body size development in early life or adult life that contributes to these associations. Therefore, we examined if childhood BMI and height at age 13 years were associated with ovarian cancer in adult life. Methods: Individuals were girls in the Copenhagen School Health Records Register who were born between 1930 and1989 and had available measures of height and weight at age 13 years. BMI and height z-scores were calculated from an internal age-specific reference. Via a personal identification number, individuals were followed up for ovarian cancer diagnosis by linkage to the Danish Cancer Registry. Cox proportional hazard regressions were performed and stratified by birth cohort. Results: Among the included 137,416 girls, 1048 cases of ovarian cancer occurred during 5.2 million person-years of follow-up with a median age of diagnosis of 57 years (range: 19-83 years). BMI tended to be non-linearly associated with ovarian cancer such that only the heaviest girls had positive associations with ovarian cancer. Compared with a 13-year-old girl of average-size (BMI z-score = 0, corresponding to a weight of 45 kg and a height of 157 cm), an equally tall girl who was at least 9 kg heavier (corresponding to a BMI z-score &amp;gt;1.28) had a hazard ratio (HR) for ovarian cancer of 1.33 (95% confidence interval [CI]: 1.08-1.63). In analyses adjusted for childhood height, the association was only marginally attenuated (HR = 1.30, 95% CI: 1.06-1.60). Childhood height was positively and statistically significantly associated with ovarian cancer. At age 13 years, per height z-score (corresponding to approximately 7 cm), the HR for ovarian cancer was 1.07 (95% CI: 1.01-1.14). Conclusion: Body size in early life was associated with ovarian malignancies later in life suggesting that childhood height and BMI might impact if women are later diagnosed with ovarian cancer. As ovarian cancers vary widely in their etiologies, associations with childhood body size may differ depending on the tumor type, which will be investigated. Citation Format: Julie Aarestrup, Michael Gamborg, Nicolas Wentzensen, Lian G. Ulrich, Thorkild IA Sørensen, Jennifer L. Baker. Childhood body size at age 13 years and associations with ovarian cancer in adult life. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-375.

Adolescent immunization - Protecting youth and preparing them for a healthy future.

Adolescence is a period of profound biological, physical, intellectual and neuro-cognitive growth and development, during which new social roles and responsibilities are acquired. Vaccination has the potential to avert acute and chronic illness during this period and to decrease the risk of illness, disability, and cancer in adult life. Here, the vaccines recommended for adolescents are reviewed, and the essential role of health care providers in providing education to adolescents about immunization is highlighted. Each health care encounter is an opportunity to ensure that the adolescent has the benefit of all available vaccines.

Body composition by dilution of deuterium oxide in Mexican children with lymphoma and solid tumors

Objective Scant information exists about the changes in body composition of children during the first months of chemotherapy. These changes can be determined by using a better method than the body mass index. This study compared the changes of body composition by dilution of deuterium oxide in Mexican children with lymphoma and with solid tumors. Methods Seventeen patients were enrolled and classified as having lymphoma or solid tumor. Body composition was measured by a deuterium dilution technique after the first course of chemotherapy and again after 2 and 6 mo of therapy. Data were compared by means of paired t and Student’s t tests. Simple linear regression was applied to examine the relation between age and changes in fat mass (FM) and fat-free mass (FFM). Results The groups were similar at baseline. Six months after initiation of chemotherapy, weight and height had increased ( P < 0.05) in the lymphoma group, whereas only height had increased in the solid-tumor group; total body water, FM, and FFM increased in the lymphoma group ( P < 0.01) but not in the solid-tumor group. Age did not influence FM or FFM in either group. Conclusion In children with lymphoma whose treatment included corticosteroid use, increase in FM content was demonstrated during the first 6 mo of treatment. In patients with solid tumors, FM content did not change during treatment. With an increase in FM content, one should bear in mind that overweight and obesity may result in cardiovascular disease and development of breast cancer in adult life.

Data collected on maternal dietary exposures in the Danish National Birth Cohort

Recent research suggests that the diet consumed in, or shortly before, pregnancy can potentially lead to maldevelopment and diseases in the offspring, which may become apparent at any time from the embryonic stage until old age. For example, maternal diet may affect the chance of twinning (and associated complications), malformation risk, brain development, and the offspring's fecundity and risk of contracting cardiovascular diseases and cancer in adult life. Prospectively designed longitudinal studies with sufficient size and data quality are much needed to substantiate or refute these hypotheses. At present, the Danish National Birth Cohort is likely to be the largest epidemiological database containing extensive information on maternal dietary exposures. By October 2002, 100 000 women had been recruited in early pregnancy, for long-term follow-up of themselves and their offspring. The present paper details the information available in the database on early nutritional exposures with emphasis on maternal dietary intake. We also present distributions of selected nutritional exposures.

Early Life Diet and the Risk for Adult Breast Cancer

: A hypothesis postulating intrauterine and early life influences on the occurrence of breast cancer in adult life has received considerable support in the literature. We present alternative or complementary ways through which diet could affect breast cancer risk in this context. Emphasis is placed on evidence that reduced energy intake in early life is associated with smaller body size, which, in turn, constrains birth weight and subsequent development of offspring and is associated with reduced breast cancer risk.

Normal breast stem cells, malignant breast stem cells, and the perinatal origin of breast cancer

Both experimental and epidemiological evidence support the concept that the in utero environment can influence an individual's risk of breast cancer in adult life. Recently identified breast stem cells may be the key to understanding the mechanism underlying this phenomenon. It has been theorized that breast cancers arise from breast stem cells. Our emerging view of the characteristics of normal breast stem cells and their link to malignant breast stem cells is reviewed here. It has also been postulated that factors that expand the normal breast stem cell pool in utero would increase the probability that one such cell might undergo an oncogenic mutation or epigenetic change. We discuss how a number of proposed perinatal determinants of adult breast cancer risk, including (1) in utero estrogen and IGF-1 levels, (2) birthweight, (3) breast density, and (4) early-life mutagen exposure, can be tied together by this "breast stem cell burden" hypothesis.

Being breastfed in infancy and breast cancer incidence in adult life: results from the two nurses' health studies.

Events during perinatal and early life may influence the incidence of breast cancer in adult life, and some case-control studies suggest that having been breastfed may reduce breast cancer risk. The authors studied this association among premenopausal and postmenopausal women by using data from the two Nurses' Health Studies, the Nurses' Health Study (using data from 1992 to 1996) and the Nurses' Health Study II (using data from 1991 to 1997). A history of being breastfed was self-reported by the study participants. During a total of 695,655 person-years, 1,073 cases of invasive breast cancer were diagnosed. The authors did not observe any important overall association between having been breastfed and the development of breast cancer later in life among premenopausal women (covariate-adjusted relative risk = 0.97, 95% confidence interval (CI): 0.78, 1.20) or postmenopausal women (covariate-adjusted relative risk = 1.12, 95% CI: 0.92, 1.37). No significant trend was observed with increasing duration of breastfeeding. The authors also used data on breastfeeding retrospectively collected from 2,103 mothers of participants of the two Nurses' Health Studies. With the mothers' reports, the covariate-adjusted odds ratio of breast cancer was 1.11 (95% CI: 0.88, 1.39) for women who were breastfed compared with those who were not. Data from these two large cohorts do not support the hypothesis that being breastfed confers protection against subsequent breast cancer.

Dietary fat and adult diseases and the implications for childhood nutrition: an epidemiologic approach

Reducing dietary saturated fat by 7% of energy, a realistic target, would reduce serum cholesterol by 10% and mortality from ischemic heart disease by 25-30%. Randomized trials show that this mortality reduction is attained rapidly, usually by the third year after initial reduction of dietary saturated fat intake. Dietary change in adulthood may therefore reverse the adverse health effects of a high-fat diet in childhood. In the absence of such change, however, dietary fat in childhood may increase the risk of cardiovascular disease in adult life because of a longer duration of exposure to a high-fat diet. Assessing the effects of diet on cancer risk is more difficult. The intermediary markers of risk that are analogous to serum cholesterol are less satisfactory and there are negligible trial data. Cohort studies of diet and cancer, although subject to bias, do not favor a direct causal relation between dietary fat and cancer. But a reduction in risk is likely when dietary fat is reduced as part of a general change toward a healthier diet. The trend toward increased energy intake and body size in childhood and relatively low dietary fiber contribute to the decreasing age at menarche, which is associated with an increased risk of breast cancer. Low dietary fiber, low fruit and vegetable consumption, and high red meat consumption are associated with colon cancer and other cancers, and important causal effects of diet on cancer are likely. As with cardiovascular disease, this dietary trend that is commenced in childhood is likely to increase age-specific rates of colon cancer in adult life, but the risk may be reversed with later dietary change.