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1.
Nat Commun ; 14(1): 8484, 2023 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-38123565

RESUMO

The naked mole rat (NMR), Heterocephalus glaber, the longest-living rodent, provides a unique opportunity to explore how evolution has shaped adult stem cell (ASC) activity and tissue function with increasing lifespan. Using cumulative BrdU labelling and a quantitative imaging approach to track intestinal ASCs (Lgr5+) in their native in vivo state, we find an expanded pool of Lgr5+ cells in NMRs, and these cells specifically at the crypt base (Lgr5+CBC) exhibit slower division rates compared to those in short-lived mice but have a similar turnover as human LGR5+CBC cells. Instead of entering quiescence (G0), NMR Lgr5+CBC cells reduce their division rates by prolonging arrest in the G1 and/or G2 phases of the cell cycle. Moreover, we also observe a higher proportion of differentiated cells in NMRs that confer enhanced protection and function to the intestinal mucosa which is able to detect any chemical imbalance in the luminal environment efficiently, triggering a robust pro-apoptotic, anti-proliferative response within the stem/progenitor cell zone.


Assuntos
Células-Tronco Adultas , Longevidade , Camundongos , Humanos , Animais , Mucosa Intestinal/metabolismo , Intestinos , Células-Tronco Adultas/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Ratos-Toupeira
2.
Clin Cancer Res ; 25(2): 629-640, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30322876

RESUMO

PURPOSE: The molecular events that determine intestinal cell differentiation are poorly understood and it is unclear whether it is primarily a passive event or an active process. It is clinically important to gain a greater understanding of the process, because in colorectal cancer, the degree of differentiation of a tumor is associated with patient survival. SGK1 has previously been identified as a gene that is principally expressed in differentiated intestinal cells. In colorectal cancer, there is marked downregulation of SGK1 compared with normal tissue.Experimental Design: An inducible SGK1 viral overexpression system was utilized to induce reexpression of SGK1 in colorectal cancer cell lines. Transcriptomic and phenotypic analyses of these colorectal cancer lines was performed and validation in mouse and human cohorts was performed. RESULTS: We demonstrate that SGK1 is upregulated in response to, and an important controller of, intestinal cell differentiation. Reexpression of SGK1 in colorectal cancer cell lines results in features of differentiation, decreased migration rates, and inhibition of metastasis in an orthotopic xenograft model. These effects may be mediated, in part, by SGK1-induced PKP3 expression and increased degradation of MYC. CONCLUSIONS: Our results suggest that SGK1 is an important mediator of differentiation of colorectal cells and may inhibit colorectal cancer metastasis.


Assuntos
Neoplasias Colorretais/sangue , Neoplasias Colorretais/patologia , Proteínas Imediatamente Precoces/sangue , Proteínas Serina-Treonina Quinases/sangue , Animais , Biomarcadores Tumorais , Diferenciação Celular , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias Colorretais/genética , Neoplasias Colorretais/mortalidade , Modelos Animais de Doenças , Feminino , Expressão Gênica , Genes Reporter , Humanos , Proteínas Imediatamente Precoces/genética , Camundongos , Gradação de Tumores , Metástase Neoplásica , Prognóstico , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , RNA Mensageiro , Ratos , Transdução de Sinais , Ensaios Antitumorais Modelo de Xenoenxerto
3.
J Pathol ; 242(2): 178-192, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28299802

RESUMO

The functional role of bone morphogenetic protein (BMP) signalling in colorectal cancer (CRC) is poorly defined, with contradictory results in cancer cell line models reflecting the inherent difficulties of assessing a signalling pathway that is context-dependent and subject to genetic constraints. By assessing the transcriptional response of a diploid human colonic epithelial cell line to BMP ligand stimulation, we generated a prognostic BMP signalling signature, which was applied to multiple CRC datasets to investigate BMP heterogeneity across CRC molecular subtypes. We linked BMP and Notch signalling pathway activity and function in human colonic epithelial cells, and normal and neoplastic tissue. BMP induced Notch through a γ-secretase-independent interaction, regulated by the SMAD proteins. In homeostasis, BMP/Notch co-localization was restricted to cells at the top of the intestinal crypt, with more widespread interaction in some human CRC samples. BMP signalling was downregulated in the majority of CRCs, but was conserved specifically in mesenchymal-subtype tumours, where it interacts with Notch to induce an epithelial-mesenchymal transition (EMT) phenotype. In intestinal homeostasis, BMP-Notch pathway crosstalk is restricted to differentiating cells through stringent pathway segregation. Conserved BMP activity and loss of signalling stringency in mesenchymal-subtype tumours promotes a synergistic BMP-Notch interaction, and this correlates with poor patient prognosis. BMP signalling heterogeneity across CRC subtypes and cell lines can account for previous experimental contradictions. Crosstalk between the BMP and Notch pathways will render mesenchymal-subtype CRC insensitive to γ-secretase inhibition unless BMP activation is concomitantly addressed. © 2017 The Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.


Assuntos
Proteínas Morfogenéticas Ósseas/genética , Neoplasias Colorretais/genética , Transição Epitelial-Mesenquimal , Receptores Notch/genética , Transdução de Sinais , Secretases da Proteína Precursora do Amiloide/genética , Secretases da Proteína Precursora do Amiloide/metabolismo , Proteínas Morfogenéticas Ósseas/metabolismo , Diferenciação Celular , Estudos de Coortes , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/patologia , Células Epiteliais/patologia , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Modelos Biológicos , Fenótipo , Prognóstico , Receptores Notch/metabolismo , Proteínas Smad/genética , Proteínas Smad/metabolismo
4.
J Pathol ; 237(2): 135-45, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25974319

RESUMO

The conventional model of intestinal epithelial architecture describes a unidirectional tissue organizational hierarchy with stem cells situated at the crypt base and daughter cells proliferating and terminally differentiating as they progress along the vertical (crypt-luminal) axis. In this model, the fate of a cell that has left the niche is determined and its lifespan limited. Evidence is accumulating to suggest that stem cell control and daughter cell fate determination is not solely an intrinsic, cell autonomous property but is heavily influenced by the microenvironment including paracrine, mesenchymal, and endogenous epithelial morphogen gradients. Recent research suggests that in intestinal homeostasis, stem cells transit reversibly between states of variable competence in the niche. Furthermore, selective pressures that disrupt the homeostatic balance, such as intestinal inflammation or morphogen dysregulation, can cause committed progenitor cells and even some differentiated cells to regain stem cell properties. Importantly, it has been recently shown that this disruption of cell fate determination can lead to somatic mutation and neoplastic transformation of cells situated outside the crypt base stem cell niche. This paper reviews the exciting developments in the study of stem cell dynamics in homeostasis, intestinal regeneration, and carcinogenesis, and explores the implications for human disease and cancer therapies.


Assuntos
Diferenciação Celular , Linhagem da Célula , Enteropatias/patologia , Intestinos/patologia , Nicho de Células-Tronco , Células-Tronco/patologia , Animais , Biomarcadores/metabolismo , Proliferação de Células , Homeostase , Humanos , Doenças Inflamatórias Intestinais/metabolismo , Doenças Inflamatórias Intestinais/patologia , Enteropatias/genética , Enteropatias/metabolismo , Mucosa Intestinal/metabolismo , Neoplasias Intestinais/metabolismo , Neoplasias Intestinais/patologia , Fenótipo , Transdução de Sinais , Células-Tronco/metabolismo
5.
Nat Med ; 21(1): 62-70, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25419707

RESUMO

Hereditary mixed polyposis syndrome (HMPS) is characterized by the development of mixed-morphology colorectal tumors and is caused by a 40-kb genetic duplication that results in aberrant epithelial expression of the gene encoding mesenchymal bone morphogenetic protein antagonist, GREM1. Here we use HMPS tissue and a mouse model of the disease to show that epithelial GREM1 disrupts homeostatic intestinal morphogen gradients, altering cell fate that is normally determined by position along the vertical epithelial axis. This promotes the persistence and/or reacquisition of stem cell properties in Lgr5-negative progenitor cells that have exited the stem cell niche. These cells form ectopic crypts, proliferate, accumulate somatic mutations and can initiate intestinal neoplasia, indicating that the crypt base stem cell is not the sole cell of origin of colorectal cancer. Furthermore, we show that epithelial expression of GREM1 also occurs in traditional serrated adenomas, sporadic premalignant lesions with a hitherto unknown pathogenesis, and these lesions can be considered the sporadic equivalents of HMPS polyps.


Assuntos
Carcinogênese/genética , Neoplasias Colorretais/genética , Peptídeos e Proteínas de Sinalização Intercelular/biossíntese , Nicho de Células-Tronco/genética , Animais , Proliferação de Células/genética , Neoplasias Colorretais/patologia , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Regulação Neoplásica da Expressão Gênica , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Camundongos , Mutação , Receptores Acoplados a Proteínas G/genética
6.
Sci Transl Med ; 5(202): 202ra122, 2013 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-24027026

RESUMO

Many newly diagnosed prostate cancers present as low Gleason score tumors that require no treatment intervention. Distinguishing the many indolent tumors from the minority of lethal ones remains a major clinical challenge. We now show that low Gleason score prostate tumors can be distinguished as indolent and aggressive subgroups on the basis of their expression of genes associated with aging and senescence. Using gene set enrichment analysis, we identified a 19-gene signature enriched in indolent prostate tumors. We then further classified this signature with a decision tree learning model to identify three genes--FGFR1, PMP22, and CDKN1A--that together accurately predicted outcome of low Gleason score tumors. Validation of this three-gene panel on independent cohorts confirmed its independent prognostic value as well as its ability to improve prognosis with currently used clinical nomograms. Furthermore, protein expression of this three-gene panel in biopsy samples distinguished Gleason 6 patients who failed surveillance over a 10-year period. We propose that this signature may be incorporated into prognostic assays for monitoring patients on active surveillance to facilitate appropriate courses of treatment.


Assuntos
Perfilação da Expressão Gênica , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Idoso , Envelhecimento/genética , Envelhecimento/patologia , Animais , Biomarcadores Tumorais/metabolismo , Árvores de Decisões , Regulação Neoplásica da Expressão Gênica , Genes Neoplásicos/genética , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Modelos Biológicos , Prognóstico , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reprodutibilidade dos Testes , Especificidade da Espécie
7.
Mol Cancer Res ; 11(7): 736-47, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23538858

RESUMO

MED1 is a key coactivator of the androgen receptor (AR) and other signal-activated transcription factors. Whereas MED1 is overexpressed in prostate cancer cell lines and is thought to coactivate distinct target genes involved in cell-cycle progression and castration-resistant growth, the underlying mechanisms by which MED1 becomes overexpressed and its oncogenic role in clinical prostate cancer have remained unclear. Here, we report that MED1 is overexpressed in the epithelium of clinically localized human prostate cancer patients, which correlated with elevated cellular proliferation. In a Nkx3.1:Pten mutant mouse model of prostate cancer that recapitulates the human disease, MED1 protein levels were markedly elevated in the epithelium of both invasive and castration-resistant adenocarcinoma prostate tissues. Mechanistic evidence showed that hyperactivated ERK and/or AKT signaling pathways promoted MED1 overexpression in prostate cancer cells. Notably, ectopic MED1 overexpression in prostate cancer xenografts significantly promoted tumor growth in nude mice. Furthermore, MED1 expression in prostate cancer cells promoted the expression of a number of novel genes involved in inflammation, cell proliferation, and survival. Together, these findings suggest that elevated MED1 is a critical molecular event associated with prostate oncogenesis.


Assuntos
Carcinogênese/patologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Subunidade 1 do Complexo Mediador/metabolismo , Neoplasias da Próstata/patologia , Proteínas Proto-Oncogênicas c-myc/metabolismo , Transdução de Sinais , Animais , Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular/genética , Modelos Animais de Doenças , Regulação Neoplásica da Expressão Gênica , Proteínas de Homeodomínio/metabolismo , Humanos , Inflamação/genética , Masculino , Camundongos , Camundongos Nus , PTEN Fosfo-Hidrolase/metabolismo , Neoplasias da Próstata/enzimologia , Neoplasias da Próstata/genética , Análise Serial de Tecidos , Fatores de Transcrição/metabolismo , Regulação para Cima/genética
8.
Cancer Metastasis Rev ; 32(1-2): 109-22, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23114843

RESUMO

More than 15 years ago, the first generation of genetically engineered mouse (GEM) models of prostate cancer was introduced. These transgenic models utilized prostate-specific promoters to express SV40 oncogenes specifically in prostate epithelium. Since the description of these initial models, there have been a plethora of GEM models of prostate cancer representing various perturbations of oncogenes or tumor suppressors, either alone or in combination. This review describes these GEM models, focusing on their relevance for human prostate cancer and highlighting their strengths and limitations, as well as opportunities for the future.


Assuntos
Modelos Animais de Doenças , Camundongos/genética , Neoplasias da Próstata/etiologia , Neoplasias da Próstata/patologia , Animais , Genes Supressores de Tumor , Humanos , Masculino , Camundongos Transgênicos , Metástase Neoplásica , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Lesões Pré-Cancerosas , Proto-Oncogenes , Transdução de Sinais
9.
J Biol Chem ; 279(20): 21617-27, 2004 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-14970234

RESUMO

Neuroblastomas are the second most common solid tumor in children but the molecular mechanisms underlying the initiation and progression of this disease are poorly understood. We previously showed that the Brn-3b transcription factor is highly expressed in actively proliferating neuroblastoma cells but is significantly decreased when these cells are induced to differentiate. In this study, we analyzed the effects of manipulating Brn-3b levels in the human neuroblastoma cell line, IMR-32 and showed that constitutive overexpression of Brn-3b consistently increased cellular growth and proliferation in monolayer as well as in an anchorage-independent manner compared with controls whereas stably decreasing Brn-3b can reduce the rate of growth of these cells. Cells with high Brn-3b also fail to respond to growth inhibitory retinoic acid, as they continue to proliferate. Moreover, Brn-3b levels significantly modified tumor growth in vivo with elevated Brn-3b resulting in faster tumor growth in xenograft models whereas decreasing Brn-3b resulted in slower growth compared with controls. Interestingly, elevated Brn-3b levels also enhances the invasive capacity of these neuroblastoma cells with significantly larger numbers of migrating cells observed in overexpressing clones compared with controls. Because invasion and metastasis influence morbidity and mortality in neuroblastoma and so significantly affect the course and outcome of neuroblastomas, this finding is very important. Our results therefore suggest that Brn-3b transcription factor contributes to proliferation of neuroblastoma cells in vivo and in vitro but may also influence progression and/or invasion during tumorigenesis. It is possible that decreasing Brn-3b levels may reverse some effects on growth and proliferation of these cells.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Neuroblastoma/patologia , Fatores de Transcrição/metabolismo , Adesão Celular , Divisão Celular , Linhagem Celular Tumoral , Progressão da Doença , Humanos , Cinética , Invasividade Neoplásica , Fator de Transcrição Brn-3 , Fator de Transcrição Brn-3B
10.
Neurosci Lett ; 334(1): 1-4, 2002 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-12431761

RESUMO

The Brn-3a POU family transcription factor is able to induce the expression of genes encoding anti-apoptotic proteins such as Bcl-2 and Bcl-x and protects neuronal cells from apoptosis. This effect is opposed by the pro-apoptotic p53 protein which completely inhibits the ability of Brn-3a to activate the Bcl-2 and Bcl-x promoters. Here we demonstrate that Brn-3a is able to stimulate p53 expression. Thus, in co-transfection experiments, Brn-3a activates the p53 promoter acting via a region from +22 to +67, located between the most proximal (+1) and the most distal (+105) transcriptional start sites. Similarly, reduction of Brn-3a expression using anti-sense constructs reduces endogenous p53 expression in human neuroblastoma or cervical carcinoma cell lines growing in vitro and as tumours in nude mice whilst increasing Brn-3a levels enhances p53 expression. These results suggest the existence of a negative feedback loop in which elevated Brn-3a expression induces the expression of p53 which, in turn, antagonises the anti-apoptotic activity of Brn-3a.


Assuntos
Proteínas de Ligação a DNA/genética , Fatores de Transcrição/genética , Ativação Transcricional/genética , Proteína Supressora de Tumor p53/genética , Animais , Apoptose/genética , Apoptose/fisiologia , Carcinoma de Células Escamosas , Proteínas de Ligação a DNA/antagonistas & inibidores , Proteínas de Ligação a DNA/biossíntese , Humanos , Camundongos , Camundongos Nus , Neuroblastoma , Regiões Promotoras Genéticas , Fator de Transcrição Brn-3 , Fator de Transcrição Brn-3A , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/biossíntese , Fatores de Transcrição/fisiologia , Ativação Transcricional/fisiologia , Transfecção , Células Tumorais Cultivadas , Proteína Supressora de Tumor p53/biossíntese
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