Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 10 de 10
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Mol Oncol ; 15(9): 2330-2344, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33604999

RESUMO

Although therapeutic options for patients with advanced renal cell carcinoma (RCC) have increased in the past decade, no biomarkers are yet available for patient stratification or evaluation of therapy resistance. Given the dynamic and heterogeneous nature of clear cell RCC (ccRCC), tumor biopsies provide limited clinical utility, but liquid biopsies could overcome these limitations. Prior liquid biopsy approaches have lacked clinically relevant detection rates for patients with ccRCC. This study employed ccRCC-specific markers, CAIX and CAXII, to identify circulating tumor cells (CTC) from patients with metastatic ccRCC. Distinct subtypes of ccRCC CTCs were evaluated for PD-L1 and HLA-I expression and correlated with patient response to therapy. CTC enumeration and expression of PD-L1 and HLA-I correlated with disease progression and treatment response, respectively. Longitudinal evaluation of a subset of patients demonstrated potential for CTC enumeration to serve as a pharmacodynamic biomarker. Further evaluation of phenotypic heterogeneity among CTCs is needed to better understand the clinical utility of this new biomarker.


Assuntos
Carcinoma de Células Renais/diagnóstico , Neoplasias Renais/diagnóstico , Células Neoplásicas Circulantes , Adulto , Idoso , Antígeno B7-H1/sangue , Biomarcadores Tumorais/sangue , Carcinoma de Células Renais/sangue , Carcinoma de Células Renais/patologia , Linhagem Celular Tumoral , Feminino , Antígenos de Histocompatibilidade Classe I/sangue , Humanos , Neoplasias Renais/sangue , Neoplasias Renais/patologia , Biópsia Líquida , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica
2.
Prostate ; 73(4): 337-45, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22911222

RESUMO

BACKGROUND: The treatment of non-localized prostate cancer involves androgen deprivation (AD) therapy which results in tumor regression. Apoptosis has been implicated in the tumor response to AD, but constitutes a small fraction of the total tumor at any time. Cellular senescence is a response to sub-lethal stress in which cells are persistently growth arrested and develop distinct morphological and biochemical characteristics. The occurrence of senescence in prostate tumor tissue after AD therapy has not previously been investigated. METHODS: Phenotypic and molecular characteristics of senescence were examined in models of androgen-sensitive prostate cancer after AD and compared with androgen-intact controls. RESULTS: In vitro in LNCaP cells, AD induced elevated senescence-associated ß-galactosidase (SA-ß-gal) staining, decreased proliferation, and increased flow cytometric side scatter while minimally affecting cell viability. The increased expression of the senescence-related proteins Glb1, the cyclin-dependent kinase inhibitor p27(Kip1) and chromatin-regulating heterochromatin protein 1γ (HP1γ) were detected in LNCaP cells after AD in vitro by immunoblot and immunofluorescence microscopy. In mice bearing LuCaP xenograft tumors in vivo, surgical castration similarly increased SA-ß-gal staining, increased expression of p27(Kip1) and HP1γ, and decreased expression of the proliferation marker KI-67, with minimal induction of apoptosis identified by detection of cleaved caspase 3 and TUNEL. Immunohistochemical analysis of human prostate tumors removed after AD shows similar induction of Glb1, HP1γ and decreased KI-67. CONCLUSIONS: We conclude that AD induces characteristics consistent with cellular senescence in androgen-sensitive prostate cancer cells. This finding may explain incomplete tumor regression in response to AD.


Assuntos
Androgênios/deficiência , Senescência Celular/fisiologia , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Idoso , Androgênios/farmacologia , Animais , Linhagem Celular Tumoral , Senescência Celular/efeitos dos fármacos , Humanos , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
3.
Photochem Photobiol ; 88(5): 1037-47, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22277067

RESUMO

Biologically, light including ultraviolet (UV) radiation is vital for life. However, UV exposure does not come without risk, as it is a major factor in the development of skin cancer. Natural protections against UV damage may have been affected by lifestyle changes over the past century, including changes in our sun exposure due to working environments, and the use of sunscreens. In addition, extended "day time" through the use of artificial light may contribute to the disruption of our circadian rhythms; the daily cycles of changes in critical bio-factors including gene expression. Circadian disruption has been implicated in many health conditions, including cardiovascular, metabolic and psychiatric diseases, as well as many cancers. Interestingly, the pineal hormone melatonin plays a role in both circadian regulation as well as protection from UV skin damage, and is therefore an important factor to consider when studying the impact of UV light. This review discusses the beneficial and deleterious effects of solar exposure, including UV skin damage, Vitamin D production, circadian rhythm disruption and the impact of melatonin. Understanding these benefits and risks is critical for the development of protective strategies against solar radiation.


Assuntos
Ritmo Circadiano/efeitos da radiação , Melanoma/metabolismo , Melatonina/biossíntese , Neoplasias Cutâneas/metabolismo , Pele/metabolismo , Vitamina D/biossíntese , Fatores de Transcrição ARNTL/genética , Fatores de Transcrição ARNTL/metabolismo , Proteínas CLOCK/genética , Proteínas CLOCK/metabolismo , Ritmo Circadiano/fisiologia , Desidrocolesteróis/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos da radiação , Humanos , Melanoma/etiologia , Melanoma/genética , Melanoma/prevenção & controle , Melatonina/genética , Fatores de Risco , Pele/efeitos dos fármacos , Pele/efeitos da radiação , Neoplasias Cutâneas/etiologia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/prevenção & controle , Protetores Solares/farmacologia , Raios Ultravioleta/efeitos adversos
4.
J Natl Cancer Inst ; 102(20): 1536-46, 2010 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-20858887

RESUMO

Cellular senescence is a response to nonlethal stress that results in persistent cytostasis with a distinct morphological and biochemical phenotype. The senescence phenotype, detected in tumors through the expression of mRNA and protein markers, can be generated in cancer cells lacking functional p53 and retinoblastoma protein. Current research suggests that therapy-induced senescence (TIS) represents a novel functional target that may improve cancer therapy. TIS can be induced in immortal and transformed cancer cells by selected anticancer compounds or radiation, and accumulating data indicate that TIS may produce reduced toxicity-related side effects and increased tumor-specific immune activity. This review examines the current status of TIS-regulated mechanisms, agents, and senescence biomarkers with the goal of encouraging further development of this approach to cancer therapy. Remaining hurdles include the lack of efficient senescence-inducing agents and incomplete biological data on tumor response. The identification of additional compounds and other targeted approaches to senescence induction will further the development of TIS in the clinical treatment of cancer.


Assuntos
Senescência Celular , Neoplasias/patologia , Neoplasias/terapia , Animais , Apoptose , Proliferação de Células , Senescência Celular/efeitos dos fármacos , Senescência Celular/genética , Humanos , Estresse Oxidativo , Qualidade de Vida , Fatores de Tempo
5.
J Biomol Screen ; 14(7): 853-8, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19641224

RESUMO

Cellular senescence is a persistently growth-arrested phenotype in normal and transformed cells induced by noncytotoxic stress. Cytostasis as a method of cancer treatment has recently generated significant interest. Research into the induction of cellular senescence as cancer therapy has been hindered by a lack of compounds that efficiently induce this response. The authors describe a semiautomated high-throughput method to identify library compounds that induce senescence using prostate cancer cells cultured in 96-well plates. Primary hits are identified by low cell numbers after 3 days in culture, measured by Hoechst 33342 fluorescence. A secondary visual assessment of senescence-associated beta-galactosidase staining and cellular morphology in the same wells distinguishes senescence from quiescence, apoptosis, and other false positives. This method was used to screen a 4160-compound library of known bioactive compounds and natural products at a 10-microM dose. Candidate compounds were further selected based on persistent growth arrest after drug removal and increased expression of previously described senescence marker genes. Four lead compounds not previously associated with senescence were identified for further investigation. This is the first successful assay to identify novel agents from compound libraries based on senescence induction in cancer cells.


Assuntos
Senescência Celular/efeitos dos fármacos , Ensaios de Triagem em Larga Escala/métodos , Bibliotecas de Moléculas Pequenas/análise , Bibliotecas de Moléculas Pequenas/farmacologia , Benzimidazóis/metabolismo , Linhagem Celular Tumoral , Fluorescência , Humanos , Projetos Piloto , Reprodutibilidade dos Testes
6.
Cancer Res ; 68(16): 6797-802, 2008 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-18701505

RESUMO

Loss of imprinting (LOI) is an epigenetic alteration involving loss of parental origin-specific expression at normally imprinted genes. A LOI for Igf2, a paracrine growth factor, is important in cancer progression. Epigenetic modifications may be altered by environmental factors. However, is not known whether changes in imprinting occur with aging in prostate and other tissues susceptible to cancer development. We found a LOI for Igf2 occurs specifically in the mouse prostate associated with increased Igf2 expression during aging. In older animals, expression of the chromatin insulator protein CTCF and its binding to the Igf2-H19 imprint control region was reduced. Forced down-regulation of CTCF leads to Igf2 LOI. We further show that Igf2 LOI occurs with aging in histologically normal human prostate tissues and that this epigenetic alteration was more extensive in men with associated cancer. This finding may contribute to a postulated field of cancer susceptibility that occurs with aging. Moreover, Igf2 LOI may serve as a marker for the presence of prostate cancer.


Assuntos
Envelhecimento/genética , Impressão Genômica , Fator de Crescimento Insulin-Like II/genética , Próstata/patologia , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Sítios de Ligação , Fator de Ligação a CCCTC , Imunoprecipitação da Cromatina , Metilação de DNA , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Epigênese Genética , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Feminino , Imunofluorescência , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Próstata/metabolismo , RNA Longo não Codificante , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA não Traduzido/genética , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo
7.
Prostate ; 68(11): 1187-95, 2008 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-18459101

RESUMO

BACKGROUND: Folate and methyl-group deficiency has been linked to prostate cancer susceptibility, yet the mechanisms underlying these observations are incompletely understood. The region of the genome containing the imprinted genes insulin-like growth factor 2 (Igf2) and H19, both of which display oncogenic functions, may be particularly sensitive to environmental influences. METHODS: To determine whether a methyl-deficient diet impacts epigenetic controls at the Igf2-H19 locus, we placed C57BL/6 mice containing a polymorphism at the imprinted Igf2-H19 locus on a choline and methionine deficient (CMD) diet. We interrogated this locus for expression and epigenetic changes in prostate tissues. RESULTS: A significant increase in both Igf2 and H19 expression was found in CMD prostate tissues compared to controls. These expression changes were reversible with shorter exposure to the CMD diet. Chromatin immunoprecipitation (ChIP) revealed significant decreases in repressive histone modifications (dimethyl-H3K9) within the H19 promoter, as well as Igf2 P2 and P3 promoters. DNA methylation within these promoters was not altered. No significant change in Igf2 or H19 imprinting was observed. CONCLUSIONS: These findings highlight the plasticity of the epigenome in an epithelial organ vulnerable to neoplastic change. They further suggest that chromatin modifications are more susceptible to methyl-deficient diets than DNA methylation at this locus.


Assuntos
Metilação de DNA , Histonas/metabolismo , Fator de Crescimento Insulin-Like II/genética , Metionina/deficiência , Próstata/fisiologia , RNA não Traduzido/genética , Ração Animal , Animais , Peso Corporal , Deficiência de Colina/genética , Deficiência de Colina/metabolismo , Imunoprecipitação da Cromatina , Epigênese Genética/fisiologia , Impressão Genômica/fisiologia , Fator de Crescimento Insulin-Like II/metabolismo , Masculino , Camundongos , Camundongos Congênicos , Camundongos Endogâmicos C57BL , Tamanho do Órgão , Polimorfismo Genético , Regiões Promotoras Genéticas/fisiologia , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , RNA Longo não Codificante , RNA não Traduzido/metabolismo , Glândulas Seminais/citologia
8.
Neoplasia ; 7(9): 816-23, 2005 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16229804

RESUMO

Classic mechanisms of tumor response to chemotherapy include apoptosis and mitotic catastrophe. Recent studies have suggested that cellular senescence, a terminal proliferation arrest seen in vitro, may be invoked during the exposure of cancer cells to chemotherapeutic agents. To identify markers associated specifically with the cellular senescence phenotype, we utilized expression data from cDNA microarray experiments identifying transcripts whose expression levels increased as human prostate epithelial cells progressed to senescence. When screened against other growth-inhibitory conditions, including quiescence and apoptosis, many of these transcripts were also upregulated, indicating that similar pathways occur between apoptosis and senescence. A senescent-like phenotype was then induced in several prostate cancer cell lines using 5-aza-2'-deoxycytidine, doxorubicin, or Docetaxel. Treatment with these agents resulted in a significant increase in the induction of senescence-specific genes when compared to nonsenescent conditions. The performance of the panel was improved with fluorescence-activated cell sorting using PKH26 to isolate nonproliferating, viable, drug-treated populations, indicating that a heterogeneous response occurs with chemotherapy. We have defined an RNA-based gene panel that characterizes the senescent phenotype induced in cancer cells by drug treatment. These data also indicate that a panel of genes, rather than one marker, needs to be utilized to identify senescence.


Assuntos
Antineoplásicos/farmacologia , Senescência Celular/genética , Neoplasias da Próstata/genética , Antineoplásicos/uso terapêutico , Apoptose/genética , Linhagem Celular Tumoral , Docetaxel , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Análise em Microsséries , Fenótipo , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/metabolismo , Taxoides/farmacologia , Taxoides/uso terapêutico
9.
Endocrinology ; 144(2): 484-90, 2003 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-12538608

RESUMO

The hypothalamic peptide GnRH is the primary neuroendocrine signal regulating pituitary LH in females. The neuropeptide galanin is cosecreted with GnRH from hypothalamic neurons, and in vitro studies have demonstrated that galanin can act at the level of the pituitary to directly stimulate LH secretion and also augment GnRH-stimulated LH secretion. Several lines of evidence have suggested that the hypophysiotropic effects of galanin are important for the generation of preovulatory LH surges. To determine whether the pituitary actions of galanin are enhanced by the preovulatory steroidal milieu, LH responses to galanin administration (with or without GnRH) were examined in: 1) ovariectomized (OVX); 2) OVX, estrogen (E)-primed; and 3) OVX, E- and progesterone-treated female rats. Results from the study indicate that galanin enhances GnRH-stimulated LH secretion only in the presence of E (in OVX, E-primed, or E- and progesterone-treated rats). Galanin alone does not directly stimulate LH secretion under any of the steroid conditions examined. In the absence of gonadal steroids (OVX rats), galanin inhibits GnRH-stimulated LH secretion. These findings suggest that the primary pituitary effect of galanin is to modulate GnRH-stimulated LH secretion, and that the potentiating effects of galanin occur only in the presence of E.


Assuntos
Estrogênios/farmacologia , Galanina/farmacologia , Hormônio Liberador de Gonadotropina/farmacologia , Hormônio Luteinizante/metabolismo , Animais , Feminino , Fase Folicular/efeitos dos fármacos , Fase Folicular/fisiologia , Moduladores GABAérgicos/farmacologia , Hormônio Luteinizante/sangue , Ovariectomia , Pentobarbital/farmacologia , Progesterona/farmacologia , Ratos , Ratos Sprague-Dawley
10.
Biol Reprod ; 68(2): 363-9, 2003 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-12533397

RESUMO

Galanin is a 29-amino-acid peptide that colocalizes with GnRH in hypothalamic neurons. High concentrations of galanin are present in portal vessel blood of both male and female rats, and galanin receptors are present on gonadotropes in both sexes. Results from studies of female rats indicate that galanin acts at the level of the pituitary to directly stimulate LH secretion and also to enhance GnRH-stimulated LH secretion. The effects of galanin on pituitary LH secretion in male rats are relatively uncharacterized; thus, the present in vivo study was conducted 1). to examine the ability of galanin to affect basal or GnRH-stimulated LH secretion in male rats and 2). to determine whether the effects of galanin on LH secretion in male rats are testosterone-dependent. All three doses of galanin used (1, 5, and 10 micro g/pulse) significantly enhanced GnRH-stimulated LH secretion in intact male rats. Only the highest dose of galanin directly stimulated LH secretion (without GnRH coadministration) in intact males. Galanin did not directly stimulate LH secretion or enhance GnRH-stimulated LH secretion in castrated male rats. In fact, the highest dose of galanin inhibited GnRH-stimulated LH secretion in castrated males. Upon testosterone replacement, the ability of galanin to directly stimulate LH secretion and to enhance GnRH-stimulated LH secretion was restored in castrated males. These results suggest a role for galanin in the regulation of LH release in male rats and demonstrate that testosterone upregulates the ability of the pituitary to respond to the stimulatory effects of galanin.


Assuntos
Galanina/fisiologia , Hormônio Luteinizante/metabolismo , Hipófise/metabolismo , Testosterona/fisiologia , Animais , Galanina/farmacologia , Hormônio Liberador de Gonadotropina/farmacologia , Hormônio Luteinizante/antagonistas & inibidores , Masculino , Orquiectomia , Pentobarbital/farmacologia , Ratos , Testosterona/sangue , Testosterona/farmacologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...