Stages Of Prostate Carcinogenesis Research Articles

Морфологическое исследование лимфоидных органов на ранних этапах экспериментального канцерогенеза простаты

the aim of our study was to identify of structural transformations in the thymus and lymph nodes at the early stages of the development of an experimental prostate cancer. Experiments were performed on 60 adult male CBA mice weighing 28-30 g. An experimental model of a prostate cancer was created by inoculating a diluted cell strain of Ehrlich Ascites Carcinoma cells into the prostatic parenchyma through midline laparotomy under ether anesthesia. The animals were divided into three groups of 20 each: 1) control (intact animals) 2) animals on the 5th day of experimental prostate tumor growth and 3) animals on the 18th day of experimental prostate tumor growth. The pathological examination of the prostate, thymus, and pelvic lymph nodes was performed. The selection of structural components and cellular elements in the thymus and lymph nodes was carried out according to the International histological nomenclature. According to the results, there was an increase in the percentage of connective tissue elements and glandular tissue increased in the thymus and the number of immunoblasts increased on the 5th day of the experiment. However, disorganization of the thymus structure was detected on the 18th day as well as an increase in the cortical substance, the number of epithelial reticular cells and decrease in the number of immunoblasts. On the 5th day, paracortical hyperplasia, sinus histiocytosis and activation of the blast transformation were detected in lymphatic nodes. On the 18th day, metastases, follicular reaction and activation of the transport function were determined. Our data suggest that the accidental thymus involution and impairment of transport and immune functions of pelvic lymph nodes in experimental prostate cancer. The severity of disturbances depends on the stage of prostate carcinogenesis.

Inflammation and Prostate Cancer.

Chronic inflammation resulting from infections, altered metabolism, inflammatory diseases or other environmental factors can be a major contributor to the development of several types of cancer. In fact around 20% of all cancers are linked to some form of inflammation. Evidence gathered from genetic, epidemiological and molecular pathological studies suggest that inflammation plays a crucial role at various stages of prostatic carcinogenesis and tumor progression. These include initiation, promotion, malignant conversion, invasion, and metastasis. Detailed basic and clinical research in these areas, focused towards understanding the etiology of prostatic inflammation, as well as the exact roles that various signaling pathways play in promoting tumor growth, is critical for understanding this complex process. The information gained would be useful in developing novel therapeutic strategies such as molecular targeting of inflammatory mediators and immunotherapy-based approaches.

Abstract 2306: Sleep duration and risk of fatal prostate cancer in CPS-I and CPS-II

Abstract There is growing evidence that factors associated with circadian rhythm disruption may be associated with prostate cancer risk. In a previous analysis focusing on shift-work in the Cancer Prevention Study (CPS)-II that included only employed men, we observed an association between short sleep duration and higher risk of prostate cancer death that was limited to the first eight years of follow-up of the cohort. To corroborate and expand on these results, we examined the association between sleep duration and death from prostate cancer in a combined analysis of men in CPS-II and men enrolled in an earlier cohort study, CPS-I, regardless of employment status. After excluding men with uninterpretable sleep information, prevalent cancer and prevalent prostate disease at baseline, the analysis included 407,649 men from CPS-I followed from 1950 through 1972, and 416,040 men from CPS-II followed from 1982 through 2012. During follow-up, 1,546 men in CPS-I and 8,704 men in CPS-II died of prostate cancer. Cox proportional hazards regression was used to estimate multivariable-adjusted relative risks (RR) and 95% confidence intervals (CI) and estimates were meta-analyzed using a fixed-effects model because the design and population of CPS-I and CPS-II were similar. Among men aged 65 years and younger, short sleep duration was associated with higher risk of death from prostate cancer during the first eight years of follow-up; compared to 7 hours/night, the RRs (95% CIs) for 3-5, and 6 hours/night were 1.61 (1.10-2.37), and 1.25 (0.99-1.58), respectively. Among men older than age 65 years, the corresponding RRs (95% CIs) were 0.97 (0.68, 1.38), and 1.02 (0.82, 1.27), respectively. There was no association between sleep duration and fatal prostate cancer during later follow-up. These findings support evidence that factors related to circadian rhythms may increase fatal prostate cancer risk. The observed association between short sleep duration and higher risk of fatal prostate cancer only during the first 8-years of follow-up suggests that short sleep duration could affect later stages of prostate carcinogenesis. Reasons for lack of an association in older men are unclear but may include the marked decline in nocturnal melatonin levels with age, which could reduce the relative biologic impact of melatonin inhibition by sleep-deprivation. Citation Format: Susan M. Gapstur, Victoria L. Stevens, Brian D. Carter, Ying Wang, Eric J. Jacobs. Sleep duration and risk of fatal prostate cancer in CPS-I and CPS-II [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2306. doi:10.1158/1538-7445.AM2017-2306

Abstract 1821: Sympathetic nerves regulate a metabolic switch promoting angiogenesis through adrenergic signaling in prostate cancer

Abstract Nerves pattern the vasculature during development and regeneration. Recent studies have shown that the sympathetic nervous system (SNS) is coopted to promote carcinogenesis, and that depletion of SNS β-adrenergic receptors (βARs) in the prostate stromal compartment inhibits tumor growth. As the vasculature is in direct contact with the SNS, and regulates tumor glucose and oxygen delivery, we aimed to identify the stromal populations that mediate SNS signaling and the mechanisms by which loss of βAR signaling inhibits prostate cancer progression. In vivo xenograft tumor growth was measured in Adrb2-/-; Adrb3-/- mice using an orthotopic PC3-luciferase model. Prostate cancer progression in the transgenic autochthonous HI-myc model was assessed after conditional Adrb2 deletion in stromal populations by intercrossing Adrb2fl/fl line to stromal Cre lines. Metabolism was measured ex vivo by flow quantification of the lipophilic cationic dye TMRE whose accumulation reflects mitochondrial membrane potential, and by NADH autofluorescence under UV excitation. In vitro oxidative phosphorylation and glycolytic flux were measured in primary prostate endothelial cells (VeraVec) using the Seahorse bioanalyzer and targeted gas chromatography-mass spectrometry (GC/MS). Deletion of the SNS βAR neural receptors in the microenvironment synergized to arrest exponential tumor growth. Imaging the tumor vasculature revealed a defect in vessel branching, a phenotype also observed after chemical sympathectomy, suggesting altered angiogenesis in the absence of βAR stimulation. Histology revealed an increase in vascular innervation and density during the transition from low to high grade pre-neoplastic PIN. Conditional Adrb2 deletion (Adrb2cKO) in endothelial cells (ECs), but not myeloid cells or pericytes, not only inhibited angiogenesis, but also reduced disease progression throughout all histopathological cancer stages. Transcriptome analysis of flow isolated Adrb2cKO ECs suggested an increase in oxidative metabolism and upregulation of mitochondrial Coa6. Ex vivo analysis of ECs revealed a metabolic switch during the low to high grade PIN transition, and this switch was inhibited by Adrb2cKO. Further in vitro characterization by Adrb2 knockdown revealed a metabolic shift in ECs to oxidative phosphorylation, which was mediated by Coa6 upregulation. As Coa6 cooperates with Cox10 in respiratory complex IV assembly, conditional co-deletion of Adrb2 and Cox10 in the HI-myc mouse rescued aerobic glycolysis, angiogenesis, and cancer progression. Our data thus demonstrates that the SNS mediates a pro-angiogenic switch during the early stages of prostate carcinogenesis. Moreover, we identified ECs as SNS stromal targets, and that abrogation of βAR signaling inhibits the angio-metabolic switch and delays prostate cancer progression, suggesting a novel therapeutic target for prostate cancer treatment. Citation Format: Ali Zahalka, Anna Arnal-Estape, Maria Maryanovich, Fumio Nakahara, Cristian Cruz, Paul S. Frenette. Sympathetic nerves regulate a metabolic switch promoting angiogenesis through adrenergic signaling in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1821. doi:10.1158/1538-7445.AM2017-1821

MP79-09 CHROMOSOME 8 ALTERATIONS AND PTEN LOSS IN GLEASON GRADE 3 CORES PREDICT THE PRESENCE OF UNSAMPLED GRADE 4 TUMOR: IMPLICATIONS FOR ACTIVE SURVEILLANCE

status was determined by FISH. TMPRSS2:ERG status was also determined by FISH. Differences in demographics, clinical and pathologic factors were compared with Chi-squared tests between controls and cases with and without PTEN loss. The hazard ratio for PCa recurrence/progression was determined with age-adjusted and multivariate Cox proportional hazard analyses adjusting for age, family history of PCa, TMPRSS2:ERG status, smoking status, BMI, PSA, Gleason sum and stage. RESULTS: Of the 496 cases with evaluable PTEN status, PTEN loss was present in 68 (14%). A family history of prostate cancer was seen in 11%, 16% and 24% of controls, cases with PTEN loss and cases with PTEN normal tumors, respectively (p < 0.01 ). As PSA at diagnosis increased, patients were more likely to have PTEN loss (p < 0.01). In prostate cancer cases, PTEN loss was more common in those with the TMPRSS2:ERG gene fusion (22%) than those without TMPRSS2:ERG re-arrangement (7%, p < 0.01). Recurrence/progression data were available for 379 cases and such events were observed in 21% and 35% of PTEN normal and PTEN loss patients (p 1⁄4 0.036). In the age-adjusted model, PTEN loss was associated with a 72% increased risk of disease recurrence/progression compared to cases with normal PTEN (HR 1.72, 95% CI 1.02 e 2.89), although this estimate was attenuated in the multivariate model, (adjusted HR 1.63, 95% CI 0.91-2.95). CONCLUSIONS: PTEN loss was observed in 14% of cases with localized prostate cancer undergoing RP, yet PTEN loss was associated with a higher risk of recurrence/progression. Men with a family history of prostate cancer less commonly had PTEN loss whereas loss of PTEN was more commonly observed in patients with the TMPRSS2:ERG gene fusion. Further studies into the role of PTEN loss in the earlier stages of prostate carcinogenesis may be warranted.

Work Schedule, Sleep Duration, Insomnia, and Risk of Fatal Prostate Cancer

Studies of breast cancer in women and laboratory studies provide evidence that shift work involving circadian rhythm disruption is a probable human carcinogen. However, evidence linking shift work and other circadian disruption factors to prostate cancer risk is limited. To examine associations of work schedule (i.e., rotating shift work, fixed night and fixed afternoon/evening shift work); sleep duration; and insomnia frequency with prostate cancer mortality. The Cancer Prevention Study-II is a large prospective cohort study of U.S. adults. Work schedule, sleep duration, insomnia frequency, and other information was self-reported in 1982. Among 305,057 employed men, aged ≥29 years who were cancer free at baseline, there were 4974 prostate cancer deaths during follow-up through 2010. In 2013, multivariable-adjusted relative risks (RRs) and 95% CIs were computed using Cox proportional hazards regression. Work schedule and insomnia frequency were not associated with risk of fatal prostate cancer. Short sleep duration was associated with higher risk of prostate cancer during the first 8 years of follow-up, compared to 7 hours/night, the RRs (95% CIs) for 3-5 and 6 hours/night were 1.64 (1.06, 2.54), and 1.28 (0.98, 1.67), respectively. There was no association between sleep duration and fatal prostate cancer during later follow-up. These results do not support associations of work schedule or insomnia frequency with prostate cancer mortality. The association between short sleep duration and higher risk of fatal prostate cancer only during the first 8 years of follow-up suggests that short sleep duration could affect later stages of prostate carcinogenesis.

Glutamate, a metabolic biomarker of aggressiveness and a potential therapeutic target for prostate cancer

Glutamate, a metabolic biomarker of aggressiveness and a potential therapeutic target for prostate cancer

Androgen Receptor Signalling in Prostate Cancer: The Functional Consequences of Acetylation

The androgen receptor (AR) is a ligand activated transcription factor and member of the steroid hormone receptor (SHR) subfamily of nuclear receptors. In the early stages of prostate carcinogenesis, tumour growth is dependent on androgens, and AR directly mediates these effects by modulating gene expression. During transcriptional regulation, the AR recruits numerous cofactors with acetylation-modifying enzymatic activity, the best studied include p300/CBP and the p160/SRC family of coactivators. It is known that recruitment of histone acetyltransferases (HATs) and histone deacetylases (HDACs) is key in fine-tuning responses to androgens and is thus likely to play a role in prostate cancer progression. Further, these proteins can also modify the AR itself. The functional consequences of AR acetylation, the role of modifying enzymes in relation to AR transcriptional response, and prostate cancer will be discussed.

Age-dependent histopathological findings in the prostate of probasin/SV40 T antigen transgenic rats: lack of influence of carcinogen or testosterone treatment.

Sequential changes in the phenotype of prostatic lesions and the impact of additional carcinogen treatment or castration on development and progression of prostate cancers were examined in probasin/simian virus 40 (SV40) T antigen transgenic (TG) rats. Non-invasive prostate adenocarcinomas were evident in all lobes at 15 weeks of age. Invasive tumors were limited to the anterior lobe at this time point and were found in all lobes in an age-dependent manner thereafter. No metastasis was apparent at any age. Additional carcinogen treatment or castration did not enhance progression or generate selective growth of hormone-independent prostate cancer cells. These results suggest that our TG rats are suitable for clarification of mechanisms in early stages of prostate carcinogenesis, that is, from prostatic intraepithelial neoplasia (PIN) to non-invasive and then invasive lesions.

Effects of herbal preparation Equiguard™ on hormone-responsive and hormone-refractory prostate carcinoma cells: Mechanistic studies

The Equiguard is a dietary supplement comprised of standardized extracts from nine herbs, respectively, Herba epimedium brevicornum Maxim (stem and leaves), Radix morindae officinalis (root), Fructus rosa laevigatae michx (fruit), Rubus chingii Hu (fruit), Schisandra chinensis (Turz.) Baill (fruit), Ligustrum lucidum Ait (fruit), Cuscuta chinensis Lam (seed), Psoralea corylifolia L. (fruit), and Astragalus membranaceus (Fisch.) Bge (root). This proprietary product, formulated according to Chinese traditional medicinal concepts, is aimed at restoring harmony in the <primordial (original) ying-yang> of the kidney, an organ which Chinese medicinal principles consider to be vital for invigorating as well as maintaining balance of the entire urological system. As the prostate is an integral component of the urological system, we performed in vitro studies to test the effects of ethanol extracts of Equiguard to modulate prostate growth and gene expression. These studies used prostate cancer cells mimicking the androgen-dependent (AD) and androgen-independent (AI) states of prostate carcinogenesis. Results show that Equiguard significantly reduced cancer cell growth, induced apoptosis, suppressed expression of the androgen receptor (AR) and lowered intracellular and secreted prostate specific antigen (PSA), and almost completely abolished colony forming abilities of prostate cancer cells. These data support the interpretation that this herbal formulation contains ingredients that collectively may be efficacious in preventing or treating AD and AI prostate carcinoma. The anti-prostatic activities of Equiguard may stem from its complex composition capable of targeting multiple signal transduction/metabolic pathways, to effectively correct, counteract or circumvent the impaired or dysfunctional mechanisms accompanying different stages of prostate carcinogenesis.