RESUMO
Sebaceous carcinomas of the human ocular adnexa commonly exhibit pagetoid spread, mutations in tumor-suppressor genes, and protooncogene copy number gain. Sebaceous carcinomas are rarely reported in other species, and while the Meibomian gland (MG) represents the most common ocular adnexal structure of the canine eyelid to develop neoplasia, most are clinically and histologically benign. The objective of this study was to compare molecular features of canine MG carcinomas and adenomas. Two retrospectively identified MG carcinomas were subject to immunohistochemistry and qPCR. When compared with normal glands, MYC was upregulated in benign and malignant MG neoplasms. Aberrant p53 expression was restricted to the nuclei of intraepithelial neoplastic cells in MG carcinomas. Adipophilin expression was diminished in MG neoplasms compared with the normal MG. Our findings, if confirmed in a larger cohort of cases, could suggest that MG oncogenesis in a dog may exhibit similar molecular features as their human counterparts.
Assuntos
Adenoma , Carcinoma Basocelular , Doenças do Cão , Neoplasias das Glândulas Sebáceas , Neoplasias Cutâneas , Humanos , Cães , Animais , Glândulas Tarsais/metabolismo , Glândulas Tarsais/patologia , Proteína Supressora de Tumor p53 , Estudos Retrospectivos , Neoplasias das Glândulas Sebáceas/química , Neoplasias das Glândulas Sebáceas/metabolismo , Neoplasias das Glândulas Sebáceas/patologia , Neoplasias das Glândulas Sebáceas/veterinária , Neoplasias Cutâneas/veterinária , Carcinoma Basocelular/veterinária , Transformação Celular Neoplásica , Adenoma/patologia , Adenoma/veterinária , MutaçãoRESUMO
BACKGROUND AND PURPOSE: To report mature results for local control and survival in oligometastatic (OM) breast cancer patients treated with stereotactic body radiotherapy (SBRT) on lung and/or liver lesions in a phase II trial. METHODS: This is a prospective non-randomized phase II trial (NCT02581670) which enrolled patients from 2015 to 2021. Eligibility criteria included: age > 18 years, ECOG 0-2, diagnosis of breast cancer, maximum of 4 lung/liver lesions (with a maximum diameter < 5 cm), metastatic disease confined to the lungs and liver or extrapulmonary or extrahepatic disease stable or responding to systemic therapy. The primary end-points were local control (LC) and treatment-related toxicities. The secondary end-points included overall survival (OS), distant metastasis-free survival (DMFS), time to next systemic therapy (TTNS), poly-progression free survival (PPFS). RESULTS: The study included 64 patients with a total of 90 lesions treated with SBRT. LC at 1 and 2 years was 94.9 %, 91 % at 3 years. Median local control was not reached. Median OS was 16.5 months, OS at 1, 2 and 3 years was 87.5 %, 60.9 % and 51.9 %, respectively. Median DMFS was 8.3 months, DMFS at 1, 2 and 3 years was 38.1 %, 20.6 % and 16 % respectively. At univariate analysis, local response to SBRT was found to be statistically linked with better OS, DMFS and STFS. CONCLUSION: SBRT is a safe and valid option in oligometastatic breast cancer patients, with very high rates of local control. An optimal selection of patients is likely needed to improve survival outcomes and reduce the rate of distant progression.
Assuntos
Neoplasias da Mama , Neoplasias Hepáticas , Neoplasias Pulmonares , Radiocirurgia , Humanos , Feminino , Neoplasias da Mama/patologia , Neoplasias da Mama/radioterapia , Neoplasias da Mama/mortalidade , Radiocirurgia/métodos , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/radioterapia , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/cirurgia , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/radioterapia , Neoplasias Pulmonares/mortalidade , Pessoa de Meia-Idade , Estudos Prospectivos , Idoso , Adulto , Idoso de 80 Anos ou maisRESUMO
PURPOSE: Patients with oligo-metastatic disease (OMD) can be safely treated with Stereotactic Radiation Therapy (SRT). Further disease progression is common in these patients. In most cases, patients relapse again with oligo-metastases, however some can experience a poly-progression after a local ablative treatment (LAT). The purpose of this study was to retrospectively identify factors associated with poly-progression in patients receiving SRT for OMD. METHODS: Data from a monocentric database were retrospectively analyzed. Patients treated with SRT for OMD and who developed progression after LAT were selected. Patients were categorized as oligo- or poly-progressive according to the number of new/progressing metastases (≤ or > 5). Herein, we analyzed data about patients' characteristics, oligo-metastatic presentation and radiation treatment characteristics to evaluate their relationship with progression type. RESULTS: From 2013 to 2021, data on 700 patients progressing after LAT were analyzed. Among them, 227 patients (32.4%) experienced a poly-progression; the median time to poly-progression was 7.72 months (range 1-79.6). Five variables associated with poly-progression were found to be statistically significant in the univariate analysis: performance status (p < 0.001), site of the primary tumor (p = 0.016), ablative dose (p = 0.002), treated site (p = 0.002), single or double organ (p = 0.03). Of those, all but the number of involved organs retained their significant predictive value on the multivariate analysis. CONCLUSION: Our study identified four independent factors associated with poly-progression in patients with OMD receiving SRT. Our data may support comprehensive characterization of OMD, better understanding of factors associated with progression.
Assuntos
Neoplasias , Radiocirurgia , Humanos , Estudos Retrospectivos , Neoplasias/radioterapiaRESUMO
BACKGROUND: We investigated prostate involvement during sexually transmitted infections by measuring serum prostate-specific antigen (PSA) as a marker of prostate infection, inflammation, and/or cell damage in young, male US military members. METHODS: We measured PSA before and during infection for 299 chlamydia, 112 gonorrhoea, and 59 non-chlamydial, non-gonococcal urethritis (NCNGU) cases, and 256 controls. RESULTS: Chlamydia and gonorrhoea, but not NCNGU, cases were more likely to have a large rise (î¶40%) in PSA than controls (33.6%, 19.1%, and 8.2% vs 8.8%, P<0.0001, 0.021, and 0.92, respectively). CONCLUSION: Chlamydia and gonorrhoea may infect the prostate of some infected men.
Assuntos
Antígeno Prostático Específico/sangue , Próstata/fisiologia , Infecções Sexualmente Transmissíveis/etiologia , Adulto , Estudos de Casos e Controles , Infecções por Chlamydia/sangue , Infecções por Chlamydia/epidemiologia , Gonorreia/sangue , Gonorreia/epidemiologia , Humanos , Masculino , Militares/estatística & dados numéricos , Concentração Osmolar , Próstata/microbiologia , Próstata/patologia , Antígeno Prostático Específico/análise , Infecções Sexualmente Transmissíveis/sangue , Infecções Sexualmente Transmissíveis/epidemiologia , Infecções Sexualmente Transmissíveis/transmissãoRESUMO
The terminology applied to canine prostatic epithelial lesions, especially carcinomas, is currently not standardized and this hampers the ability of pathologists to study the biological and clinical significance of these lesions. The aim of this review is to present the essential histomorphological diagnostic attributes of a wide spectrum of prostatic epithelial lesions in dogs. In addition to the traditionally recognized prostatic hyperplasia, hormonal atrophy, prostatitis, squamous metaplasia, adenocarcinoma and transitional cell (urothelial) carcinoma, new entities are described and discussed in order to provide veterinary pathologists with a basic atlas of common histological lesions of the canine prostate that is comprehensive and easy to use.
Assuntos
Doenças do Cão/patologia , Próstata/patologia , Hiperplasia Prostática/veterinária , Neoplasias da Próstata/veterinária , Terminologia como Assunto , Animais , Cães , Masculino , Hiperplasia Prostática/patologia , Neoplasias da Próstata/patologiaRESUMO
Proliferative inflammatory atrophy (PIA), which is comprised of highly proliferative but atrophic prostate epithelial cells in association with chronic inflammation, is considered a risk lesion for prostate cancer in men, while its role in canine prostate carcinogenesis is still unknown. We evaluated the value of immunohistochemical labelling for the basal cell marker cytokeratin-5 (CK5) in identifying PIA lesions in 87 samples of formalin-fixed and paraffin wax-embedded canine prostate. Canine PIA showed cytological features identical to the human counterpart and in most cases was associated with chronic lymphoplasmacytic inflammation. PIA lesions were identified in a higher number of CK5-labelled slides (43 out of 87) compared with slides stained by haematoxylin and eosin (HE) (24 out of 87). This lesion was frequently present in normal, hyperplastic and neoplastic canine prostates, although it was underestimated on evaluation of HE-stained slides. Therefore, CK5 can be considered a useful basal cell marker with high sensitivity and specificity for PIA.
Assuntos
Biomarcadores/análise , Doenças do Cão/diagnóstico , Queratina-5/análise , Lesões Pré-Cancerosas/veterinária , Próstata/patologia , Animais , Atrofia , Cães , MasculinoRESUMO
Transforming growth factor-beta type 1 (TGF-beta) has been implicated as both a tumor suppressor and a tumor promoter in many solid epithelial cancers. We have previously demonstrated that the cyclin dependent kinase (CDK) inhibitor p21 acts as a molecular switch in determining a growth inhibitory versus growth proliferative response to TGF-beta in the spontaneously immortalized human mammary epithelial cell line MCF-10A. We now demonstrate that this proliferative effect of TGF-beta is mediated through the proinflammatory cytokine, interleukin-1alpha (IL-1alpha). Using gene expression array analysis, we identified IL-1alpha as a cytokine specifically upregulated only in cells lacking p21 and only upon TGF-beta stimulation. Cell proliferation assays verified that recombinant IL-1alpha was capable of inducing a growth proliferative response in p21 null MCF-10A cells, while neutralizing antibodies against IL-1alpha prevented the growth proliferative effects of TGF-beta. Mechanistically, both the CDK and proliferating cell nuclear antigen (PCNA) inhibitory functions of p21 were responsible for preventing TGF-beta induced cell proliferation, but only PCNA inhibition by p21 regulated IL-1alpha gene expression. These studies demonstrate a novel role for IL-1alpha in mediating a proliferative response to TGF-beta signaling, and suggest that therapies directed against IL-1alpha could abate the growth proliferative effects of TGF-beta without compromising its tumor suppressive function.
Assuntos
Inibidor de Quinase Dependente de Ciclina p21/genética , Interleucina-1/metabolismo , Sistemas do Segundo Mensageiro , Fator de Crescimento Transformador beta/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Dactinomicina/farmacologia , Humanos , Interleucina-1/genética , Inibidores da Síntese de Ácido Nucleico/farmacologia , Análise de Sequência com Séries de Oligonucleotídeos , Antígeno Nuclear de Célula em Proliferação/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais , Regulação para CimaRESUMO
Somatic changes in CpG dinucleotide methylation occur quite commonly in human cancer cell DNA. Relative to DNA from normal human colonic cells, DNA from human colorectal cancer cells typically displays regional CpG dinucleotide hypermethylation amid global CpG dinucleotide hypomethylation. The role of the maintenance DNA methyltransferase (DNMT1) in the acquisition of such abnormal CpG dinucleotide methylation changes in colorectal cancer cells remains controversial; in one study, 60-200-fold increases in DNMT1 mRNA expression were detected in colorectal polyps and cancers relative to normal colonic tissue [W. S. El-Deiry et al., Proc. Natl. Acad. Sci. USA, 88: 3470-3474, 1991], whereas in another study, only small increases in DNMT1 mRNA expression, commensurate with differences in cell proliferation accompanying colonic tumorigenesis, were observed [P. J. Lee et al., Proc. Natl. Acad. Sci. USA, 93: 10366-10370, 1996]. To definitively ascertain whether abnormal DNMT1 expression might accompany human colorectal carcinogenesis, we subjected a series of normal and neoplastic colonic tissues to immunohistochemical staining using a polyclonal antiserum raised against a DNMT1 polypeptide. A concordance of DNMT1 expression with the expression of PCNA and other cell proliferation markers, such as Ki-67 and DNA topoisomerase IIalpha, was observed in normal colonic epithelial cells and in cells comprising other normal epithelia and lymphoid tissues. The polypeptide p21, which has been reported to undermine DNMT1 binding to proliferating cell nuclear antigen at DNA replication sites, was not expressed by normal colonic cells containing DNMT1 and other cell proliferation markers. In adenomatous polyps, although DNMT1 expression coincided with the expression of other cell proliferation markers, many DNMT1-expressing cells also expressed p21. The fidelity of DNMT1 expression was further undermined in colorectal carcinomas, in which a striking heterogeneity in DNMT1 expression, with some carcinoma cells containing very high DNMT1 levels and others containing very low DNMT1 levels, was observed. These results indicate that human colorectal carcinogenesis is accompanied by a progressive dysregulation of DNMT1 expression and suggest that abnormalities in DNMT1 expression may contribute to the abnormal CpG dinucleotide methylation changes characteristic of human colorectal carcinoma cell DNA.
Assuntos
Neoplasias Colorretais/enzimologia , Metilases de Modificação do DNA/biossíntese , Colo/enzimologia , Neoplasias Colorretais/genética , Metilação de DNA , Metilases de Modificação do DNA/genética , Replicação do DNA , DNA de Neoplasias/genética , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-HistoquímicaRESUMO
The prostate has been identified as a target for 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-induced carcinogenesis. Humans are exposed to PhIP through ingestion of well-done cooked meats, and there is evidence from epidemiological studies that implicates red meat consumption in prostate carcinogenesis. The alpha and pi class isoforms of glutathione S-transferases (GSTs) have been shown to inhibit adduction of activated PhIP metabolites to DNA in cell-free systems. In humans, silencing of GST pi(GSTP1) through CpG island hypermethylation is found in nearly all prostate carcinomas and is believed to be an early event in prostate carcinogenesis. We hypothesized that suppressed GSTP1 expression in prostate cells would increase their vulnerability to cytotoxicity and DNA adduct formation mediated by activated PhIP metabolites. To test this hypothesis, the human prostate adenocarcinoma cell line, LNCaP, which contains a silenced GSTP1 gene, was genetically modified to constitutively express high levels of GSTP1. Both LNCaP and LNCaP-GSTP1 cells exposed to N-OH-PhIP, but not parent PhIP, for 24 h showed a dose-dependent decrease in cell viability. GSTP1-overexpressing cells had LC50s 30-40% higher than cells transfected with the vector alone. PhIP-DNA adducts isolated from LNCaP-derived cells and primary human prostate tissue cultures exposed to N-OH-PhIP were analyzed by liquid chromatography/electrospray ionization mass spectrometry. Primary cultures of human prostate tissue and LNCaP-GSTP1 cells had approximately 50% lower adduct levels than parental LNCaP and vector control cells. Bioactivation assays using LNCaP cytosols showed that enzymatic activation of N-OH-PhIP to a DNA binding species was dependent on ATP and could be inhibited by recombinant human GSTP1 in the presence of glutathione. This evidence confirms that N-OH-PhIP can be bioactivated to a DNA binding species in human prostate and human prostate-derived cells. These observations provide the basis for using LNCaP and LNCaP-GSTP1 cells as a model system for studying the role of this enzyme in protection against N-OH-PhIP induced DNA damage in prostate carcinogenesis. Loss of GSTP1 expression in human prostate may, therefore, enhance its susceptibility to carcinogenic insult by compounds such as N-OH-PhIP. Conversely, induction of GSTs in early-stage prostate carcinogenesis may be a useful protective strategy.
Assuntos
Carcinógenos/toxicidade , Adutos de DNA/biossíntese , Glutationa Transferase/metabolismo , Imidazóis/toxicidade , Isoenzimas/metabolismo , Próstata/efeitos dos fármacos , Piridinas/toxicidade , Adenocarcinoma/enzimologia , Adenocarcinoma/genética , Adenocarcinoma/prevenção & controle , Idoso , Biotransformação , Carcinógenos/antagonistas & inibidores , Carcinógenos/farmacocinética , Citosol/metabolismo , DNA/efeitos dos fármacos , DNA/metabolismo , Glutationa S-Transferase pi , Glutationa Transferase/biossíntese , Glutationa Transferase/genética , Humanos , Imidazóis/antagonistas & inibidores , Imidazóis/metabolismo , Imidazóis/farmacocinética , Isoenzimas/biossíntese , Isoenzimas/genética , Masculino , Pessoa de Meia-Idade , Próstata/enzimologia , Próstata/metabolismo , Neoplasias da Próstata/enzimologia , Neoplasias da Próstata/genética , Neoplasias da Próstata/prevenção & controle , Piridinas/antagonistas & inibidores , Piridinas/farmacocinética , Transfecção , Células Tumorais CultivadasRESUMO
Neovascularization and increased glycolysis, two universal characteristics of solid tumors, represent adaptations to a hypoxic microenvironment that are correlated with tumor invasion, metastasis, and lethality. Hypoxia-inducible factor 1 (HIF-1) activates transcription of genes encoding glucose transporters, glycolytic enzymes, and vascular endothelial growth factor. HIF-1 transcriptional activity is determined by regulated expression of the HIF-1alpha subunit. In this study, HIF-1alpha expression was analyzed by immunohistochemistry in 179 tumor specimens. HIF-1alpha was overexpressed in 13 of 19 tumor types compared with the respective normal tissues, including colon, breast, gastric, lung, skin, ovarian, pancreatic, prostate, and renal carcinomas. HIF-1alpha expression was correlated with aberrant p53 accumulation and cell proliferation. Preneoplastic lesions in breast, colon, and prostate overexpressed HIF-1alpha, whereas benign tumors in breast and uterus did not. HIF-1alpha overexpression was detected in only 29% of primary breast cancers but in 69% of breast cancer metastases. In brain tumors, HIF-1alpha immunohistochemistry demarcated areas of angiogenesis. These results provide the first clinical data indicating that HIF-1alpha may play an important role in human cancer progression.
Assuntos
Proteínas de Ligação a DNA/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias/metabolismo , Proteínas Nucleares/metabolismo , Fatores de Transcrição/metabolismo , Animais , Anticorpos Monoclonais/metabolismo , Proteínas de Ligação a DNA/imunologia , Progressão da Doença , Humanos , Fator 1 Induzível por Hipóxia , Subunidade alfa do Fator 1 Induzível por Hipóxia , Antígeno Ki-67/metabolismo , Camundongos , Proteínas Nucleares/imunologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , RNA Mensageiro/metabolismo , Reprodutibilidade dos Testes , Fatores de Transcrição/imunologia , Proteína Supressora de Tumor p53/metabolismoRESUMO
Among the many somatic genome alterations present in cancer cells, changes in DNA methylation may represent reversible "epigenetic" lesions, rather than irreversible "genetic" alterations. Cancer cell DNA is typically characterized by increases in the methylation of CpG dinucleotides clustered into CpG islands, near the transcriptional regulatory regions of critical genes, and by an overall reduction in CpG dinucleotide methylation. The transcriptional "silencing" of gene expression associated with such CpG island DNA hypermethylation presents an attractive therapeutic target: restoration of "silenced" gene expression may be possible via therapeutic reversal of CpG island hypermethylation. 5-Aza-cytidine (5-aza-C) and 5-aza-deoxycytidine (5-aza-dC), nucleoside analogue inhibitors of DNA methyltransferases, have been widely used in attempts to reverse abnormal DNA hypermethylation in cancer cells and restore "silenced" gene expression. However, clinical utility of the nucleoside analogue DNA methyltransferase inhibitors has been limited somewhat by myelosuppression and other side effects. Many of these side effects are characteristic of nucleoside analogues that are not DNA methyltransferase inhibitors, offering the possibility that nonnucleoside analogue DNA methyltransferase inhibitors might not possess such side effects. Human prostate cancer (PCA) cells characteristically contain hypermethylated CpG island sequences encompassing the transcriptional regulatory region of GSTP1, the gene encoding the pi-class glutathione S-transferase (GSTP1), and fail to express GSTP1 as a consequence of transcriptional "silencing." Inactivation of GSTP1 by CpG island hypermethylation, the most common somatic genome alteration yet reported for human PCAs, occurs early during human prostatic carcinogenesis and results in a loss of GSTP1 "caretaker" function, leaving prostate cells with inadequate defenses against oxidant and electrophile carcinogens. We report here that the drug procainamide, a nonnucleoside inhibitor of DNA methyltransferases, reversed GSTP1 CpG island hypermethylation and restored GSTP1 expression in LNCaP human PCA cells propagated in vitro or in vivo as xenograft tumors in athymic nude mice.
Assuntos
Metilação de DNA/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Glutationa Transferase/genética , Isoenzimas/genética , Procainamida/farmacologia , Neoplasias da Próstata/genética , Animais , Ilhas de CpG/fisiologia , Metilases de Modificação do DNA/antagonistas & inibidores , Ativação Enzimática/efeitos dos fármacos , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Inativação Gênica/efeitos dos fármacos , Glutationa S-Transferase pi , Glutationa Transferase/biossíntese , Humanos , Isoenzimas/biossíntese , Masculino , Camundongos , Camundongos Nus , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/enzimologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Cyclooxygenase-2 (COX-2) is the inducible isoform of the rate-limiting enzymes that convert arachidonic acid to proinflammatory prostaglandins as well as a primary target for nonsteroidal anti-inflammatory drugs. Accumulating evidence suggests that up-regulation of COX-2 is associated with carcinogenesis in multiple organ systems including the large bowel, lung, breast, and prostate. In this report, we examine the expression of COX-2 protein and mRNA in prostate tissue containing various lesions and in prostate cancer cell lines. In the cell lines, LNCaP, DU145, PC-3, and TSU, COX-2 protein expression was undetectable under basal conditions but could be induced transiently by phorbol ester treatment in PC-3 and TSU cells, but not in DU145 and LNCaP cells. Immunohistochemical analysis of 144 human prostate cancer cases suggested that, in contrast to several previous reports, there was no consistent overexpression of COX-2 in established prostate cancer or high-grade prostatic intraepithelial neoplasia, as compared with adjacent normal prostate tissue. Positive staining was seen only in scattered cells (<1%) in both tumor and normal tissue regions but was much more consistently observed in areas of proliferative inflammatory atrophy, lesions that have been implicated in prostatic carcinogenesis. Staining was also seen at times in macrophages. Western blotting and quantitative RT-PCR analyses confirmed these patterns of expression. These results suggest that if nonsteroidal anti-inflammatory drugs are indeed chemopreventive and/or chemotherapeutic for prostate cancer, their effects are likely to be mediated by modulating COX-2 activity in non-PCa cells (either inflammatory cells or atrophic epithelial cells) or by affecting a COX-2-independent pathway.
Assuntos
Isoenzimas/biossíntese , Prostaglandina-Endoperóxido Sintases/biossíntese , Próstata/patologia , Neoplasias da Próstata/enzimologia , Atrofia/enzimologia , Western Blotting , Ciclo-Oxigenase 2 , Progressão da Doença , Epitélio/enzimologia , Epitélio/patologia , Humanos , Imuno-Histoquímica , Isoenzimas/genética , Masculino , Proteínas de Membrana , Prostaglandina-Endoperóxido Sintases/genética , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Estromais/enzimologia , Células Estromais/patologia , Células Tumorais Cultivadas , Regulação para CimaRESUMO
The prognostic value of phosphatase and tensin homolog (PTEN) loss in prostate cancer has primarily been evaluated by either fluorescence in situ hybridization (FISH) or immunohistochemistry (IHC). Previously, we found that PTEN loss by IHC was associated with increased risk of upgrading from biopsy (Gleason 3 + 3) to prostatectomy (Gleason 7+). Now, using an evaluable subset of 111 patients with adjacent biopsy sections, we analyzed the association between PTEN deletion in cancer and the odds of upgrading by a highly sensitive and specific four-color FISH assay. We also compared the concordance of PTEN loss by IHC and PTEN deletion by FISH. PTEN deletion was found in 27 % (12/45) of upgraded cases compared with 11 % (7/66) of controls (P = 0.03). Cancers with PTEN deletions were more likely to be upgraded than those without deletions (adjusting for age odds ratio = 3.40, 95 % confidence interval 1.14-10.11). With respect to concordance, of 93 biopsies with PTEN protein detected by IHC, 89 (96 %) had no PTEN deletion by FISH, and of 18 biopsies without PTEN protein by IHC, 15 had homozygous or hemizygous PTEN deletion by FISH. Only 4 biopsies of the 93 (4 %) with PTEN protein intact had PTEN deletion by FISH. When the regions of uncertainty in these biopsies were systematically studied by FISH, intra-tumoral variation of PTEN deletion was found, which could account for variation in immunoreactivity. Thus, FISH provides a different approach to determining PTEN loss when IHC is uncertain. Both FISH and IHC are concordant, showing consistent positive associations between PTEN loss and upgrading.
Assuntos
Biomarcadores Tumorais/análise , Hibridização in Situ Fluorescente , PTEN Fosfo-Hidrolase/metabolismo , Neoplasias da Próstata/química , Neoplasias da Próstata/patologia , Idoso , Biópsia por Agulha , Humanos , Imuno-Histoquímica/métodos , Hibridização in Situ Fluorescente/métodos , Masculino , Pessoa de Meia-Idade , Prostatectomia/métodosRESUMO
BACKGROUND: Biopsies performed for elevated serum PSA often show inflammatory infiltrates. However, the influence of intraprostatic inflammation on serum PSA in men without biopsy indication and negative for prostate cancer has not been described in detail. METHODS: We studied 224 men in the placebo arm of the Prostate Cancer Prevention Trial (PCPT) who underwent end-of-study biopsy per trial protocol, had PSA <4 ng ml(-1), normal digital rectal examination and a biopsy negative for cancer. We analyzed data from hematoxylin and eosin-stained slides containing a mean of three biopsy cores. Inflammation measures included the extent (percentage of tissue area with inflammation) and intensity (product of scores for extent and grade) of total, acute and chronic inflammation in the entire tissue area examined, and by tissue compartment. We calculated median measures of inflammation by prebiopsy serum PSA tertile (>0 to ≤0.8, >0.8 to ≤1.5 and >1.5 to <4.0 ng ml(-1)). We estimated the association between percentage of tissue area with inflammation and natural logarithm of PSA using linear regression adjusting for age at biopsy. RESULTS: Median percentage of tissue area with inflammation increased from 2 to 5 to 9.5% across PSA tertiles (P-trend <0.0001). For every 5% increase in tissue area with inflammation, log PSA increased by 0.061 ng ml(-1) (P=0.0002). Median extent and intensity scores increased across PSA tertiles in luminal and intraepithelial compartments for acute inflammation and in stromal and intraepithelial compartments for chronic inflammation (all P-trend ≤0.05). CONCLUSIONS: In men without clinical suspicion of prostate cancer, greater overall inflammation, luminal and intraepithelial acute inflammation and stromal and intraepithelial chronic inflammation were associated with higher serum PSA.
Assuntos
Inflamação/patologia , Antígeno Prostático Específico/sangue , Próstata/patologia , Neoplasias da Próstata/sangue , Neoplasias da Próstata/patologia , Idoso , Idoso de 80 Anos ou mais , Biópsia , Estudos de Casos e Controles , Estudos Transversais , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
Intrinsic and acquired antineoplastic drug resistance remain a major problem for advanced prostate cancer treatment. In order to characterize mechanisms of anti-neoplastic drug resistance in human prostate cancer cell lines, resistant sublines of four of the commonly studied prostate cancer cell lines (DU 145, PC-3, PPC-1, and TSU-PR1) were selected following exposure to increasing concentrations of doxorubicin (from 10-1000 nM). Sensitivity patterns of the parent and doxorubicin-resistant sublines to various anti-neoplastic drugs, including adriamycin, amsacrine, etoposide, camptothecin, vinblastine, vincristine, fluorodeoxyuridine, and melphalan, were determined using a sulforhodamine B growth inhibition assay. The expression of three well-described antineoplastic drug resistance proteins, P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP), and lung resistance protein (LRP), was assessed using reverse transcriptase-polymerase chain reaction (RT-PCR) assays specific for each of the mRNA species, and using immunocytochemical staining procedures specific for each of the polypeptides. All four of the doxorubicin-selected prostate cancer cell lines exhibited a multidrug resistance phenotype; administration of verapamil restored doxorubicin sensitivity for each of the drug resistant sublines. Although significant MDR1 expression was not detected in any of the parent cell lines before drug exposure by RT-PCR analysis or by immunocytochemistry, both MDR1 mRNA and P-gp protein were expressed by the TSU-PR1 Adr 1000 subline. In contrast, MRP mRNA and protein were present in each of the prostate cancer cell lines before doxorubicin-selection, and an increase in MRP expression appeared to accompany the acquisition of drug resistance in DU 145, PC-3, and PPC-1 doxorubicin-resistant sublines. LRP was variably expressed by each of the parent and resistant cell lines. These data suggest that drug resistance in human prostate cancer may be multifactorial, with MRP and LRP frequently expressed in prostate cancer cells before antineoplastic drug treatment and P-gp expression occasionally acquired after drug exposure.
Assuntos
Transportadores de Cassetes de Ligação de ATP/fisiologia , Adenocarcinoma/patologia , Antibióticos Antineoplásicos/farmacologia , Antineoplásicos/farmacologia , Doxorrubicina/farmacologia , Resistência a Múltiplos Medicamentos/genética , Resistencia a Medicamentos Antineoplásicos/genética , Proteínas de Neoplasias/fisiologia , Neoplasias da Próstata/patologia , Partículas de Ribonucleoproteínas em Forma de Abóbada/fisiologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/fisiologia , Transportadores de Cassetes de Ligação de ATP/genética , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/metabolismo , Antineoplásicos/administração & dosagem , Antineoplásicos/metabolismo , Relação Dose-Resposta a Droga , Doxorrubicina/administração & dosagem , Doxorrubicina/metabolismo , Regulação Neoplásica da Expressão Gênica , Genes MDR , Humanos , Masculino , Proteínas Associadas à Resistência a Múltiplos Medicamentos , Proteínas de Neoplasias/genética , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Tumorais Cultivadas/efeitos dos fármacos , Partículas de Ribonucleoproteínas em Forma de Abóbada/genéticaRESUMO
Glutathione S-transferases, enzymes that defend cells against damage mediated by oxidant and electrophilic carcinogens, may be critical determinants of cancer pathogenesis. We report here that the pathogenesis of hepatocellular carcinoma (HCC), one of the most common cancers in the world, frequently involves an accumulation of somatic
Assuntos
Carcinoma Hepatocelular/enzimologia , Ilhas de CpG , Metilação de DNA , Glutationa Transferase/genética , Isoenzimas/genética , Neoplasias Hepáticas/enzimologia , Adulto , Idoso , Carcinoma Hepatocelular/etiologia , Carcinoma Hepatocelular/genética , DNA Viral/análise , Desoxicitidina/genética , Feminino , Glutationa S-Transferase pi , Vírus da Hepatite B/genética , Humanos , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/genética , Masculino , Pessoa de Meia-Idade , Regiões Promotoras GenéticasRESUMO
Environmental factors, especially the diet, play a prominent role in the epidemic of prostate cancer (PCA), in the United States. Many candidate dietary components have been proposed to influence human prostatic carcinogenesis, including fat, calories, fruits and vegetables, anti-oxidants, and various micronutrients, but the specific roles dietary agents play in promoting or preventing PCA remain controversial. We have collected evidence to suggest that GSTP1, the gene encoding the pi-class glutathione S-transferase (GST), may serve a "caretaker" function for prostatic cells. Although GSTP1 can be detected in normal prostatic epithelium, in almost all PCA cases, PCA cells fail to express GSTP1 polypeptides, and lack of GSTP1 expression most often appears to be the result of somatic "CpG island" DNA methylation changes. Loss of GSTP1 function also appears to be characteristic of prostatic epithelial neoplasia (PIN) lesions, thought to represent PCA precursors. We have recently learned that a new candidate early PCA precursor lesion, proliferative inflammatory atrophy (PIA), characterized by proliferating prostatic cells juxtaposed to inflammatory cells, contains epithelial cells that express high levels of GSTP1. These findings have formed the basis for a new model of prostatic carcinogenesis, in which prostatic cells in PIA lesions, subjected to a barrage of inflammatory oxidants, induce GSTP1 expression as a defense against oxidative genome damage. When cells with defective GSTP1 genes appear amongst the PIA cells, such cells become vulnerable to oxidants and electrophiles that inflict genome damage that tends to promote neoplastic transformation to PIN and PCA cells. Subsequently, PIN and PCA cells with defective GSTPI genes remain vulnerable to similar stresses tending to promote malignant progression. This new model for prostatic carcinogenesis has implications for the design of new prostate cancer prevention strategies. Rational prevention approaches might include: (i) restoration of GSTPI expression via treatment with inhibitors of CpG methylation, (ii) compensation for inadequate GSTPI activity via treatment with inducers of general GST activity, and (iii) abrogation of genome-damaging stresses via avoidance of exogenous carcinogens and/or reduction of endogenous carcinogenic (particularly oxidant) stresses.
Assuntos
Adenocarcinoma/prevenção & controle , Glutationa Transferase/deficiência , Isoenzimas/deficiência , Lesões Pré-Cancerosas/enzimologia , Próstata/enzimologia , Doenças Prostáticas/enzimologia , Neoplasias da Próstata/prevenção & controle , Adenocarcinoma/enzimologia , Adenocarcinoma/epidemiologia , Adenocarcinoma/genética , Adulto , Idoso , Anticarcinógenos/uso terapêutico , Antioxidantes/uso terapêutico , Atrofia , Transformação Celular Neoplásica/genética , Ilhas de CpG , Dano ao DNA , Metilação de DNA , Progressão da Doença , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Glutationa Transferase/biossíntese , Glutationa Transferase/genética , Humanos , Isoenzimas/biossíntese , Isoenzimas/genética , Masculino , Pessoa de Meia-Idade , Estresse Oxidativo , Lesões Pré-Cancerosas/tratamento farmacológico , Lesões Pré-Cancerosas/genética , Próstata/patologia , Doenças Prostáticas/tratamento farmacológico , Doenças Prostáticas/genética , Neoplasia Prostática Intraepitelial/enzimologia , Neoplasia Prostática Intraepitelial/epidemiologia , Neoplasia Prostática Intraepitelial/genética , Neoplasia Prostática Intraepitelial/patologia , Neoplasias da Próstata/enzimologia , Neoplasias da Próstata/epidemiologia , Neoplasias da Próstata/genética , Prostatite/complicações , Prostatite/enzimologiaRESUMO
Of the hundreds of species of mammals, all of which have prostate glands, only humans and dogs are known to suffer from benign prostatic hyperplasia (BPH) and prostate carcinoma. In humans, prostate carcinoma is common, yet carcinomas of other sex accessory tissues are rare. In addition, different anatomic regions within the prostate gland have very different rates of BPH and carcinoma. In this article, we explore ideas and potential mechanisms relating to these paradoxical findings that may help explain the species, organ, and zone specificity of BPH and prostate cancer. We present an evolutionary argument that attempts to relate a high-fat diet, with its potential for generating oxidative DNA damage, to the species selectivity of prostate cancer. In addition, we outline an argument based on our preliminary studies indicating that chronic inflammation and the associated increase in cell turnover in the setting of increased oxidative stress may help to account for the organ selectivity of genitourinary carcinomas.
Assuntos
Proteínas de Ciclo Celular , Hiperplasia Prostática/patologia , Neoplasias da Próstata/patologia , Proteínas Supressoras de Tumor , Animais , Evolução Biológica , Inibidor de Quinase Dependente de Ciclina p27 , Dano ao DNA , Dieta , Epitélio , Genes Supressores de Tumor/genética , Glutationa Transferase/genética , Humanos , Masculino , Proteínas Associadas aos Microtúbulos/genética , Próstata/citologia , Hiperplasia Prostática/etiologia , Neoplasias da Próstata/etiologia , Prostatite/complicações , Glândulas Seminais , Especificidade da Espécie , Células-TroncoRESUMO
OBJECTIVES: Approximately 30% of clinically localized prostate adenocarcinomas treated by radical prostatectomy (RP) will recur within 10 years. To prevent recurrence, new adjuvant therapies are in development that seek to treat high-risk patients after surgery. To identify patients as candidates for these treatments, improved biomarkers for predicting prognosis are needed. Reduced expression of E-cadherin has been proposed as a new marker for predicting prognosis in prostate adenocarcinoma. Since few studies have examined the relation between risk factors for disease progression and E-cadherin expression using routinely processed RP specimens, we used RP specimens to correlate downregulation of E-cadherin and pathologic stage at RP. METHODS: Primary adenocarcinomas (n = 76) from formalin-fixed and paraffin-embedded RP specimens were evaluated by immunohistochemistry against E-cadherin (HECD-1) using heat-induced epitope retrieval and automated staining (BioTek Solutions). Normal appearing prostate epithelium was used as an internal control for each specimen. Staining was scored as an estimate of the percentage of tumor cells in each specimen that showed strong plasma membrane staining. RESULTS: Specimens were divided into three categories with respect to Gleason score: intermediate (score 5 to 6, n = 31), intermediate to high (score 7, n = 25), and high (score 8 to 9, n = 20). For pathologic stage, specimens were divided into three categories: low stage/organ confined (pT2, n = 30), intermediate stage/limited extraprostatic extension (pT3a, n = 25), and high stage/seminal vesicle-pelvic lymph node metastases (pT3b-any pTN1, n = 21). In univariate analysis, reduced levels of E-cadherin correlated with advanced Gleason score (P = 0.003) and advanced pathologic stage (P = 0.008). In multivariate analysis, E-cadherin, preoperative prostate-specific antigen, and Gleason score all contributed independently to the prediction of high-stage disease (P<0.0001). Ten pelvic lymph node metastases from this same patient cohort were stained for E-cadherin. All were positive and 9 of 10 were moderately to strongly positive. CONCLUSIONS: Since essentially all patients in the high-stage category have a very high likelihood of disease recurrence, we conclude that the study of E-cadherin in a prospective manner as a potential biomarker of disease progression in patients with clinically organ-confined prostate cancer who undergo RP is warranted. Additionally, our finding that most metastatic tumor cells in pelvic lymph nodes express E-cadherin supports the notion that the establishment of the distant colonization and growth of metastatic tumor cells may be facilitated by expression or re-expression of previously downregulated E-cadherin. This would strongly suggest that irreversible genetic inactivation through mutation or allelic loss at 16q2.3 is probably not the mechanism of E-cadherin downregulation in most abnormally expressing primary prostate carcinomas.
Assuntos
Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Biomarcadores Tumorais/biossíntese , Caderinas/biossíntese , Prostatectomia , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Adenocarcinoma/cirurgia , Idoso , Regulação para Baixo , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estadiamento de Neoplasias , Neoplasias da Próstata/cirurgiaRESUMO
The field of prostate cancer research is poised for dramatic improvements in our ability to better diagnose men at risk of prostate cancer and to better predict prognosis and response to treatment. Histopathologic and molecular analyses lie at the heart of these issues. Improvements in our understanding of the mechanisms of prostate carcinogenesis and in determining why the prostate seems to be so highly targeted for cancer development will lead to rational strategies of disease prevention.