RESUMO
Inflammation in the established tumor microenvironment (TME) is often associated with a poor prognosis of breast cancer. Bisphenol A (BPA) is an endocrine-disrupting chemical that acts as inflammatory promoter and tumoral facilitator in mammary tissue. Previous studies demonstrated the onset of mammary carcinogenesis at aging when BPA exposure occurred in windows of development/susceptibility. We aim to investigate the inflammatory repercussions of BPA in TME in mammary gland (MG) during neoplastic development in aging. Female Mongolian gerbils were exposed to low (50 µg/kg) or high BPA (5000 µg/kg) doses during pregnancy and lactation. They were euthanized at 18 months of age (aging) and the MG were collected for inflammatory markers and histopathological analysis. Contrarily to control MG, BPA induced carcinogenic development mediated by COX-2 and p-STAT3 expression. BPA was also able to promote macrophage and mast cell (MC) polarization in tumoral phenotype, evidenced by pathways for recruitment and activation of these inflammatory cells and tissue invasiveness triggered by tumor necrosis factor-alpha and transforming growth factor-beta 1 (TGF-ß1). Increase of tumor-associated macrophages, M1 (CD68 + iNOS+) and M2 (CD163+) expressing pro-tumoral mediators and metalloproteases was observed; this aspect greatly contributed to stromal remodeling and invasion of neoplastic cells. In addition, the MC population drastically increased in BPA-exposed MG. Tryptase-positive MCs increased in disrupted MG and expressed TGF-ß1, contributing to EMT process during carcinogenesis mediated by BPA. BPA exposure interfered in inflammatory response by releasing and enhancing the expression of mediators that contribute to tumor growth and recruitment of inflammatory cells that promote a malignant profile.
Assuntos
Fator de Crescimento Transformador beta1 , Microambiente Tumoral , Gravidez , Feminino , Humanos , Compostos Benzidrílicos , Carcinogênese , FenótipoRESUMO
The development and maintenance of prostate function depend on a fine balance between oestrogen and androgen levels. Finasteride inhibits 5α-reductase, which is responsible for the conversion of testosterone into its most active form, dihydrotestosterone. Enzymes that metabolize these hormones have a highly relevant role in both the normal prostate metabolism and in the occurrence of pathological conditions. There are few studies on the impact of finasteride on male prostate development and fewer studies on the female prostate and possible intersexual differences. Therefore, we treated male and female gerbils from 7 to 14 days in postnatal life with a high dose of finasteride (500 µg/kg/day); the prostate complexes were then removed and submitted to immunohistochemistry, immunofluorescence and three-dimensional reconstruction. In addition, hormonal serum dosages were administered. Treatment with finasteride resulted in an increased thickness of the periductal smooth musculature in the prostate of both male and female gerbils, such as well as a reduction in the thickness of developing prostate alveoli in both sexes. In addition, intersexual differences were observed as increased epithelial proliferation and decreases in the number of developing alveoli in females. Together, the data indicate that postnatal exposure to finasteride causes greater changes in the female gerbil prostate than in the male.
Assuntos
Finasterida/toxicidade , Gerbillinae/crescimento & desenvolvimento , Próstata , Animais , Feminino , Masculino , Próstata/efeitos dos fármacos , Próstata/crescimento & desenvolvimento , Receptores Androgênicos/metabolismo , Testosterona/sangueRESUMO
The prostate is an accessory reproductive gland that is sensitive to the action of exogenous compounds known as endocrine disrupters that alter normal hormonal function. Finasteride is a widely used chemical that acts to inhibit the conversion of testosterone in its most active form, dihydrotestosterone. It is known that intrauterine exposure to finasteride causes changes in the male prostate even at low dosages; however, it is not known whether these dosages are capable of causing changes in the female prostate, which is present in a large number of mammalian species, including humans. In the present study, histochemistry, immunohistochemistry, immunofluorescence, serological dosages, and three-dimensional reconstruction techniques were employed to evaluate the effects of intrauterine exposure to a low dose of finasteride (100 µg.BW/d) on postnatal prostate development in male and female Mongolian gerbils. The results indicate that the gerbil female prostate also undergoes alterations following intrauterine exposure to finasteride, exhibiting a thickening of periductal smooth muscle and increased stromal proliferation. There are also intersex differences in the impact of exposure on the expression of the androgen receptor, which was increased in males, and of the estrogen-α receptor, which was decreased in the male prostate but unchanged in females. Altogether, this study indicates there are sex differences in the effects of finasteride exposure even at low dosages.
Assuntos
Desenvolvimento Embrionário/efeitos dos fármacos , Disruptores Endócrinos/toxicidade , Finasterida/toxicidade , Genitália Feminina/efeitos dos fármacos , Gerbillinae/embriologia , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Próstata/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Feminino , Genitália Feminina/embriologia , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Próstata/embriologia , Receptores Androgênicos/metabolismo , Reprodução/efeitos dos fármacos , Testosterona/metabolismoRESUMO
Finasteride is a drug that is widely used in the treatment of benign prostatic hyperplasia, hair loss and even as a chemotherapeutic agent in the treatment of prostatic adenocarcinoma. However, its use is known to cause several side effects in adults and it can also cause changes in the embryonic development of the male prostate, which is a cause for concern given the possibility of the accumulation of finasteride in the environment. Nevertheless, no studies have investigated the effects of finasteride on the development of the prostate in females, which occurs in several species of mammals. To evaluate the effects of intrauterine exposure to finasteride (500µgkg-1 day-1) on postnatal prostate development in the Mongolian gerbil in the present study, we used immunohistochemistry, immunofluorescence, serological analysis and three-dimensional reconstruction techniques. Differences were observed in the effects of finasteride on periductal smooth muscle and cell proliferation between the sexes, as well as intersex differences in the presence of the androgen receptor, which was elevated in males, and the oestrogen receptor ERα, which was increased in females. Together, the data indicate that the female prostate has its own hormone dynamics and that there are sex-specific differences in the way in which the female prostate reacts to prenatal exposure to finasteride.
Assuntos
Finasterida/farmacologia , Gerbillinae/crescimento & desenvolvimento , Efeitos Tardios da Exposição Pré-Natal , Próstata/efeitos dos fármacos , Próstata/crescimento & desenvolvimento , Animais , Feminino , Imuno-Histoquímica , Masculino , Organogênese/efeitos dos fármacos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Efeitos Tardios da Exposição Pré-Natal/veterinária , Próstata/metabolismo , Receptores Androgênicos/efeitos dos fármacos , Receptores Androgênicos/metabolismo , Receptores de Estrogênio/efeitos dos fármacos , Receptores de Estrogênio/metabolismo , Caracteres SexuaisRESUMO
Penile carcinoma is a rare, male cancer. Although the incidence of penile carcinoma is very low in Western countries, in some countries, the incidence is significantly greater, with penile carcinoma accounting for ≤10% of all male malignancies. Greater insight has been gained in recent years as to its pathogenesis, the risk factors associated with its development, and the clinical and histological precursor lesions related to this disease. In this review, risk and conditions factors for penile carcinoma, molecular alterations in this type of cancer, histological types, and prognostic factors will be discussed in order to further our understanding of the biology and behavior of this cancer.
Assuntos
Carcinoma/diagnóstico , Carcinoma/epidemiologia , Neoplasias Penianas/diagnóstico , Neoplasias Penianas/epidemiologia , Carcinoma/etiologia , Carcinoma/metabolismo , Humanos , Masculino , Neoplasias Penianas/etiologia , Neoplasias Penianas/metabolismo , Fatores de RiscoRESUMO
Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous disease affecting the epithelium of the oral cavity, pharynx and larynx. Conditions of most patients are diagnosed at late stages of the disease, and no sensitive and specific predictors of aggressive behavior have been identified yet. Therefore, early detection and prognostic biomarkers are highly desirable for a more rational management of the disease. Hypermethylation of CpG islands is one of the most important epigenetic mechanisms that leads to gene silencing in tumors and has been extensively used for the identification of biomarkers. In this study, we combined rapid subtractive hybridization and microarray analysis in a hierarchical manner to select genes that are putatively reactivated by the demethylating agent 5-aza-2'-deoxycytidine (5Aza-dC) in HNSCC cell lines (FaDu, UM-SCC-14A, UM-SCC-17A, UM-SCC-38A). This combined analysis identified 78 genes, 35 of which were reactivated in at least 2 cell lines and harbored a CpG island at their 5' region. Reactivation of 3 of these 35 genes (CRABP2, MX1, and SLC15A3) was confirmed by quantitative real-time polymerase chain reaction (PCR; fold change, >or=3). Bisulfite sequencing of their CpG islands revealed that they are indeed differentially methylated in the HNSCC cell lines. Using methylation-specific PCR, we detected a higher frequency of CRABP2 (58.1% for region 1) and MX1 (46.3%) hypermethylation in primary HNSCC when compared with lymphocytes from healthy individuals. Finally, absence of the CRABP2 protein was associated with decreased disease-free survival rates, supporting a potential use of CRABP2 expression as a prognostic biomarker for HNSCC patients.
Assuntos
Carcinoma de Células Escamosas/genética , Metilação de DNA , Proteínas de Ligação ao GTP/genética , Neoplasias de Cabeça e Pescoço/genética , Receptores do Ácido Retinoico/genética , Azacitidina/análogos & derivados , Azacitidina/farmacologia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Ilhas de CpG/genética , Decitabina , Epigênese Genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Proteínas de Resistência a Myxovirus , Análise de Sequência com Séries de Oligonucleotídeos , Prognóstico , Receptores do Ácido Retinoico/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Análise Serial de TecidosRESUMO
Hypermethylation in the promoter region has been associated with a loss of gene function that may give a selective advantage to neoplastic cells. In this study, the methylation pattern of genes CDKN2A (alias p14, p14(ARF), p16, p16(INK4a)), DAPK1, CDH1, and ADAM23 was analyzed in 43 samples of head and neck tumors using methylation-specific polymerase chain reaction. In the oropharynx, there was a statistically significant association between hypermethylation of the DAPK1 gene and the occurrence of lymph node metastases, and in the larynx there was statistically significant evidence of an association between hypermethylation of the ADAM23 gene and advanced stages of the tumors. Thus, a correlation was observed between hypermethylation of the promoter region of genes DAPK1 and ADAM23 and the progression of head and neck cancer.