Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 26
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Am J Surg Pathol ; 46(2): 159-168, 2022 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-34560682

RESUMO

Patients with multiple endocrine neoplasia 1 syndrome (MEN1) often develop multifocal duodenopancreatic neuroendocrine tumors (dpNETs). Nonfunctional pancreatic neuroendocrine tumors (PanNETs) and duodenal gastrinomas are the most frequent origins of metastasis. Current guidelines recommend surgery based on tumor functionality, size ≥2 cm, grade or presence of lymph node metastases. However, in case of multiple primary tumors it is often unknown which specific tumor metastasized. This study aims to unravel the relationship between primary dpNETs and metastases in patients with MEN1 by studying endocrine differentiation. First, it was shown that expression of the endocrine differentiation markers ARX and PDX1 was concordant in 18 unifocal sporadic neuroendocrine tumors (NETs) and matched metastases. Thereafter, ARX, PDX1, Ki67 and gastrin expression, and the presence of alternative lengthening of telomeres were determined in 137 microscopic and macroscopic dpNETs and 36 matched metastases in 10 patients with MEN1. ARX and PDX1 H-score clustering was performed to infer relatedness. For patients with multiple metastases, similar intrametastases transcription factor expression suggests that most metastases (29/32) originated from a single NET of origin, while few patients may have multiple metastatic primary NETs. In 6 patients with MEN1 and hypergastrinemia, periduodenopancreatic lymph node metastases expressed gastrin, and clustered with minute duodenal gastrinomas, not with larger PanNETs. PanNET metastases often clustered with high grade or alternative lengthening of telomeres-positive primary tumors. In conclusion, for patients with MEN1-related hypergastrinemia and PanNETs, a duodenal origin of periduodenopancreatic lymph node metastases should be considered, even when current conventional and functional imaging studies do not reveal duodenal tumors preoperatively.


Assuntos
Carcinoma Neuroendócrino/secundário , Neoplasias Duodenais/patologia , Neoplasia Endócrina Múltipla Tipo 1/patologia , Neoplasias Pancreáticas/patologia , Adulto , Idoso , Biomarcadores Tumorais/análise , Carcinoma Neuroendócrino/química , Carcinoma Neuroendócrino/genética , Bases de Dados Factuais , Neoplasias Duodenais/química , Neoplasias Duodenais/genética , Feminino , Gastrinas/análise , Proteínas de Homeodomínio/análise , Humanos , Antígeno Ki-67/análise , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Neoplasia Endócrina Múltipla Tipo 1/química , Neoplasia Endócrina Múltipla Tipo 1/genética , Gradação de Tumores , Neoplasias Pancreáticas/química , Neoplasias Pancreáticas/genética , Transativadores/análise , Fatores de Transcrição/análise
2.
Gut ; 71(5): 961-973, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-33849943

RESUMO

OBJECTIVE: Recent studies have found aristaless-related homeobox gene (ARX)/pancreatic and duodenal homeobox 1 (PDX1), alpha-thalassemia/mental retardation X-linked (ATRX)/death domain-associated protein (DAXX) and alternative lengthening of telomeres (ALT) to be promising prognostic biomarkers for non-functional pancreatic neuroendocrine tumours (NF-PanNETs). However, they have not been comprehensively evaluated, especially among small NF-PanNETs (≤2.0 cm). Moreover, their status in neuroendocrine tumours (NETs) from other sites remains unknown. DESIGN: An international cohort of 1322 NETs was evaluated by immunolabelling for ARX/PDX1 and ATRX/DAXX, and telomere-specific fluorescence in situ hybridisation for ALT. This cohort included 561 primary NF-PanNETs, 107 NF-PanNET metastases and 654 primary, non-pancreatic non-functional NETs and NET metastases. The results were correlated with numerous clinicopathological features including relapse-free survival (RFS). RESULTS: ATRX/DAXX loss and ALT were associated with several adverse prognostic findings and distant metastasis/recurrence (p<0.001). The 5-year RFS rates for patients with ATRX/DAXX-negative and ALT-positive NF-PanNETs were 40% and 42% as compared with 85% and 86% for wild-type NF-PanNETs (p<0.001 and p<0.001). Shorter 5-year RFS rates for ≤2.0 cm NF-PanNETs patients were also seen with ATRX/DAXX loss (65% vs 92%, p=0.003) and ALT (60% vs 93%, p<0.001). By multivariate analysis, ATRX/DAXX and ALT status were independent prognostic factors for RFS. Conversely, classifying NF-PanNETs by ARX/PDX1 expression did not independently correlate with RFS. Except for 4% of pulmonary carcinoids, ATRX/DAXX loss and ALT were only identified in primary (25% and 29%) and NF-PanNET metastases (62% and 71%). CONCLUSIONS: ATRX/DAXX and ALT should be considered in the prognostic evaluation of NF-PanNETs including ≤2.0 cm tumours, and are highly specific for pancreatic origin among NET metastases of unknown primary.


Assuntos
Deficiência Intelectual , Tumores Neuroendócrinos , Neoplasias Pancreáticas , Talassemia alfa , Proteínas Correpressoras/genética , Genes Homeobox , Proteínas de Homeodomínio , Humanos , Deficiência Intelectual/genética , Chaperonas Moleculares/genética , Recidiva Local de Neoplasia/genética , Tumores Neuroendócrinos/genética , Proteínas Nucleares/genética , Neoplasias Pancreáticas/patologia , Telômero/genética , Telômero/patologia , Fatores de Transcrição/genética , Proteína Nuclear Ligada ao X/genética , Talassemia alfa/genética
3.
Clin Cancer Res ; 27(5): 1341-1350, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33355250

RESUMO

PURPOSE: The primary origin of neuroendocrine tumor metastases can be difficult to determine by histopathology alone, but is critical for therapeutic decision making. DNA methylation-based profiling is now routinely used in the diagnostic workup of brain tumors. This has been enabled by the availability of cost-efficient array-based platforms. We have extended these efforts to augment histopathologic diagnosis in neuroendocrine tumors. EXPERIMENTAL DESIGN: Methylation data was compiled for 69 small intestinal, pulmonary, and pancreatic neuroendocrine tumors. These data were used to build a ridge regression calibrated random forest classification algorithm (neuroendocrine neoplasm identifier, NEN-ID). The model was validated during 3 × 3 nested cross-validation and tested in a local and an external cohort (n = 198 cases). RESULTS: NEN-ID predicted the origin of tumor samples with high accuracy (>95%). In addition, the diagnostic approach was determined to be robust across a range of possible confounding experimental parameters, such as tumor purity and array quality. A software infrastructure and online user interface were built to make the model available to the scientific community. CONCLUSIONS: This DNA methylation-based prediction model can be used in the workup for patients with neuroendocrine tumors of unknown primary. To facilitate validation and clinical implementation, we provide a user-friendly, publicly available web-based version of NEN-ID.


Assuntos
Biomarcadores Tumorais/genética , Metilação de DNA , Regulação Neoplásica da Expressão Gênica , Neoplasias Intestinais/diagnóstico , Neoplasias Pulmonares/diagnóstico , Tumores Neuroendócrinos/diagnóstico , Neoplasias Pancreáticas/diagnóstico , Algoritmos , Genoma Humano , Humanos , Neoplasias Intestinais/genética , Intestino Delgado/patologia , Neoplasias Pulmonares/genética , Tumores Neuroendócrinos/genética , Sistemas On-Line , Neoplasias Pancreáticas/genética , Prognóstico , Software
4.
Cancers (Basel) ; 12(7)2020 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-32708070

RESUMO

BACKGROUND: Gastric cancer is the fourth most common cause of cancer-related death. Currently, it is broadly accepted that the molecular complexity and heterogeneity of gastric cancer, both inter- and intra-tumor, display important barriers for finding specific biomarkers for the early detection and diagnosis of this malignancy. Early-onset gastric cancer is not as prevalent as conventional gastric carcinoma, but it is a preferable model for studying the genetic background, as young patients are less exposed to environmental factors, which influence cancer development. AIM: The main objective of this study was to reveal age-dependent genotypic characteristics of gastric cancer subtypes, as well as conduct mutation profiling for the most frequent alterations in gastric cancer development, using targeted next-generation sequencing technology. PATIENTS AND METHODS: The study group included 53 patients, consisting of 18 patients with conventional gastric cancer and 35 with an early-onset subtype. The DNA of all index cases was used for next-generation sequencing, employing a panel of 94 genes and 284 single nucleotide polymorphisms (SNPs) (TruSight Cancer Panel, Illumina), which is characteristic for common and rare types of cancer. RESULTS: From among the 53 samples processed for sequencing, we were able to identify seven candidate genes (STK11, RET, FANCM, SLX4, WRN, MEN1, and KIT) and nine variants among them: one splice_acceptor, four synonymous, and four missense variants. These were selected for the age-dependent differentiation of gastric cancer subtypes. We found four variants with C-Score ≥ 10, as 10% of the most deleterious substitutions: rs1800862 (RET), rs10138997 (FANCM), rs2230009 (WRN), and rs2959656 (MEN1). We identified 36 different variants, among 24 different genes, which were the most frequent genetic alterations among study subjects. We found 16 different variants among the genes that were present in 100% of the total cohort: SDHB (rs2746462), ALK (rs1670283), XPC (rs2958057), RECQL4 (rs4925828; rs11342077, rs398010167; rs2721190), DDB2 (rs326212), MEN1 (rs540012), AIP (rs4930199), ATM (rs659243), HNF1A (rs1169305), BRCA2 (rs206075; rs169547), ERCC5 (rs9514066; rs9514067), and FANCI (rs7183618). CONCLUSIONS: The technology of next-generation sequencing is a useful tool for studying the development and progression of gastric carcinoma in a high-throughput way. Our study revealed that early-onset gastric cancer has a different mutation frequency profile in certain genes compared to conventional subtype.

5.
Diagn Pathol ; 15(1): 99, 2020 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-32711552

RESUMO

BACKGROUND: Molecular diagnostics can be decisive in the differential diagnosis between a somatic metastasis of type II testicular germ cell tumor (TGCT) or a second primary carcinoma. This is in line with recent recommendations from the International Society of Urological Pathology, based on an international survey which showed that molecular testing is currently only performed by a minority of urological pathologists. CASE PRESENTATIONS: This case report illustrates the necessity of molecular testing in two patients with a history of type II TGCT and a metastatic (retro) peritoneal carcinoma years later. The genetic hallmark of type II TGCT, chromosome 12p gain, was studied by fluorescence in situ hybridization and whole genome methylation profiling in case 1, and by single nucleotide polymorphism (SNP)-array in case 2. Next generation sequencing (NGS) was used to further explore clonality between the primary TGCT and peritoneal metastasis in case 2. In case 1, chromosome 12p gain was found in the primary type II TGCT and in the acinar cell carcinoma of the metastatic malignancy. In case 2, SNP array showed 12p gain in the epithelial component of the primary teratomatous TGCT but not in the peritoneal adenocarcinoma. Furthermore, NGS showed no mutations in the primary teratomatous TGCT but a KRAS and GNAS mutation in the peritoneal adenocarcinoma, suggestive of an appendicular origin. CONCLUSIONS: Without the molecular data, both cases would have been regarded as a metastatic TGCT with development of somatic-type malignancy, which appeared a wrong diagnosis for case 2. These cases demonstrate the importance of molecular methods as an adjunct in today's pathology practice.


Assuntos
Metástase Neoplásica/patologia , Neoplasias Embrionárias de Células Germinativas/patologia , Patologia Molecular , Teratoma/patologia , Neoplasias Testiculares/patologia , Aberrações Cromossômicas/efeitos dos fármacos , Humanos , Hibridização in Situ Fluorescente/métodos , Masculino , Teratoma/diagnóstico , Teratoma/metabolismo
6.
Nat Commun ; 11(1): 1501, 2020 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-32198375

RESUMO

Most human cancers are aneuploid, due to a chromosomal instability (CIN) phenotype. Despite being hallmarks of cancer, however, the roles of CIN and aneuploidy in tumor formation have not unequivocally emerged from animal studies and are thus still unclear. Using a conditional mouse model for diverse degrees of CIN, we find that a particular range is sufficient to drive very early onset spontaneous adenoma formation in the intestine. In mice predisposed to intestinal cancer (ApcMin/+), moderate CIN causes a remarkable increase in adenoma burden in the entire intestinal tract and especially in the distal colon, which resembles human disease. Strikingly, a higher level of CIN promotes adenoma formation in the distal colon even more than moderate CIN does, but has no effect in the small intestine. Our results thus show that CIN can be potently oncogenic, but that certain levels of CIN can have contrasting effects in distinct tissues.


Assuntos
Carcinogênese/genética , Instabilidade Cromossômica , Oncogenes/genética , Adenoma/genética , Aneuploidia , Animais , Proliferação de Células , Segregação de Cromossomos , Colo/patologia , Modelos Animais de Doenças , Feminino , Neoplasias Gastrointestinais/genética , Neoplasias Intestinais/genética , Intestinos/patologia , Cariótipo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Organoides
7.
Endocr Pathol ; 31(2): 108-118, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32103422

RESUMO

Insulin-producing pancreatic neuroendocrine tumors (PanNETs)/insulinomas are generally considered to be indolent tumors with an excellent prognosis after complete resection. However, some insulinomas have a poor prognosis due to relapses and metastatic disease. Recently, studies in non-functional PanNETs indicated that behavior can be stratified according to alpha- and beta-cell differentiation, as defined by expression of the transcription factors ARX and PDX1, respectively. It is unknown whether similar mechanisms play a role in insulinomas. Therefore, we determined ARX and PDX1 expression in a cohort of 35 sporadic primary insulinomas and two liver metastases of inoperable primary insulinomas. In addition, WHO grade and loss of ATRX or DAXX were determined by immunohistochemistry, and alternative lengthening of telomeres (ALT) and CDKN2A status by fluorescence in situ hybridization. These findings were correlated with tumor characteristics and clinical follow-up data. In total, five out of 37 insulinoma patients developed metastatic disease. Metastatic insulinomas were all larger than 3 cm, whereas the indolent insulinomas were smaller (p value < 0.05). All three primary insulinomas that metastasized showed ARX expression, 2/3 showed ALT, and 1/3 had a homozygous deletion of CDKN2A as opposed to absence of ARX expression, ALT, or CDKN2A deletions in the 32 non-metastatic cases. The two liver metastases also showed ARX expression and ALT (2/2). The presence of ARX expression, which is usually absent in beta-cells, and genetic alterations not seen in indolent insulinomas strongly suggest a distinct tumorigenic mechanism in malignant insulinomas, with similarities to non-functional PanNETs. These observations may inform future follow-up strategies after insulinoma surgery.


Assuntos
Proteínas de Homeodomínio/metabolismo , Insulinoma/patologia , Neoplasias Pancreáticas/patologia , Transativadores/metabolismo , Fatores de Transcrição/metabolismo , Adulto , Idoso , Biomarcadores Tumorais/análise , Feminino , Humanos , Insulinoma/diagnóstico , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/diagnóstico , Homeostase do Telômero/fisiologia
8.
Diagn Cytopathol ; 48(4): 308-315, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31846235

RESUMO

BACKGROUND: The transcription factors ARX and PDX1, and alternative lengthening of telomeres (ALT) were recently described as prognostic markers for resected non-functional pancreatic neuroendocrine tumors (PanNETs). ALT positive tumors with ARX expression relapse most often. Currently, tumor size is the only preoperative marker used to decide whether or not to operate, thus additional preoperative prognostic markers are needed. Therefore, it is critical to assess the performance of these biomarkers on preoperative cytologic specimens. METHODS: Endoscopic fine-needle aspiration cellblock material and corresponding surgical specimens of 13 patients with PanNETs were assessed for histology, immunohistochemical staining of ARX, PDX1, Synaptophysin, Ki67, and telomere-specific fluorescence in situ hybridization to detect ALT, and then associated with clinicopathological features. Scoring for ARX and PDX1 was performed blinded by two independent observers. RESULTS: Of the 13 surgical specimens, 8 were ARX+/PDX1-, 2 ARX-/PDX1+, and 3 ARX+/PDX1+. Concordance between cytologic and surgical specimens for ARX protein expression was 100%, whereas concordance for PDX1, ALT, and WHO tumor grade was 85%, 91%, and 73%, respectively. There was a perfect inter-observer agreement in ARX and PDX1 scoring. CONCLUSION: ARX can reliably be determined in cytologic specimens and has low inter-observer variability. For cytology, false-positive PDX1 expression was observed, possibly due to contamination or sampling, while ALT had a false-negative case due to incomplete sampling. As previously observed, tumor grade is underestimated in cytologic specimens. Thus, ARX and ALT are the most promising markers to predict metastatic behavior in PanNETs, thereby warranting further validation in larger studies.


Assuntos
Biomarcadores Tumorais/biossíntese , Regulação da Expressão Gênica , Proteínas de Homeodomínio/biossíntese , Proteínas de Neoplasias/biossíntese , Tumores Neuroendócrinos/metabolismo , Neoplasias Pancreáticas/metabolismo , Fatores de Transcrição/biossíntese , Adulto , Idoso , Aspiração por Agulha Fina Guiada por Ultrassom Endoscópico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Tumores Neuroendócrinos/patologia , Tumores Neuroendócrinos/cirurgia , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/cirurgia , Cuidados Pré-Operatórios , Transativadores/biossíntese
10.
Nat Med ; 25(8): 1260-1265, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31263286

RESUMO

Most pancreatic neuroendocrine tumors (PNETs) do not produce excess hormones and are therefore considered 'non-functional'1-3. As clinical behaviors vary widely and distant metastases are eventually lethal2,4, biological classifications might guide treatment. Using enhancer maps to infer gene regulatory programs, we find that non-functional PNETs fall into two major subtypes, with epigenomes and transcriptomes that partially resemble islet α- and ß-cells. Transcription factors ARX and PDX1 specify these normal cells, respectively5,6, and 84% of 142 non-functional PNETs expressed one or the other factor, occasionally both. Among 103 cases, distant relapses occurred almost exclusively in patients with ARX+PDX1- tumors and, within this subtype, in cases with alternative lengthening of telomeres. These markedly different outcomes belied similar clinical presentations and histology and, in one cohort, occurred irrespective of MEN1 mutation. This robust molecular stratification provides insight into cell lineage correlates of non-functional PNETs, accurately predicts disease course and can inform postoperative clinical decisions.


Assuntos
Elementos Facilitadores Genéticos , Neoplasias Pancreáticas/genética , Linhagem da Célula , Proteínas de Homeodomínio/análise , Humanos , Mutação , Neoplasias Pancreáticas/química , Proteínas Proto-Oncogênicas/genética , Telômero , Transativadores/análise , Fatores de Transcrição/análise
11.
Am J Surg Pathol ; 43(9): 1297-1302, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31261289

RESUMO

Germline mutations in CDKN2A result in Familial Atypical Multiple Mole Melanoma Syndrome (FAMMM), which is associated with an increased risk for pancreatic ductal adenocarcinoma and melanoma. CDKN2A is somatically inactivated in multiple neoplasms, raising the possibility that, although the data are not conclusive, germline CDKN2A mutation may also impose an increased risk for other neoplasms. We present a patient with a CDKN2A germline mutation (p16-Leiden mutation) and mosaicism for neurofibromatosis type 2, who presented with a small asymptomatic pancreatic lesion, detected during endoscopic ultrasound screening of the pancreas. After resection, the lesion was found to be a well-differentiated pancreatic neuroendocrine tumor (PanNET). Molecular analysis of the tumor showed somatic loss of the second allele, supporting a causal relation of the PanNET to the underlying FAMMM syndrome. Recent data, showing the association between certain single-nucleotide polymorphisms in the CDKN2A gene and an increased incidence for PanNET, further support a role for germline CDKN2A alterations in PanNET risk. We conclude that PanNETs can be a phenotypic expression of FAMMM syndrome. This can have implications for screening and for the diagnosis of pancreatic neoplasms in carriers of germline CDKN2A mutations.


Assuntos
Inibidor p16 de Quinase Dependente de Ciclina/genética , Melanoma/genética , Síndromes Neoplásicas Hereditárias/genética , Tumores Neuroendócrinos/genética , Neoplasias Pancreáticas/genética , Genes p16 , Humanos , Masculino , Pessoa de Meia-Idade , Mutação
12.
Cancer Biol Ther ; 20(7): 949-955, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31002019

RESUMO

Acinar cell carcinoma (ACC) is a rare pancreatic neoplasm with dismal prognosis. Insights into the molecular basis of ACC can pave the way for the application of more effective, personalized therapies and detection of patients with hereditary predisposition. Molecular analysis revealed a germline BRCA2 (and CHEK2) mutation in a patient with a rare pancreatic ACC with extensive intraductal growth. Somatic loss of the wild-type BRCA2 allele in the tumor indicated the causal relationship of ACC with the germline defect. A thorough literature review identified another nine ACCs associated with germline BRCA2 mutation and two ACCs associated with germline BRCA1 mutation, resulting in a prevalence of BRCA1/2 germline mutations in almost 7% of ACCs. Moreover, somatic BRCA1/2 alterations are reported in 16% of sporadic ACCs. Overall, about one fifth (22%) of all pancreatic ACCs exhibit BRCA1/2 deficiency. This study underscores the important role of BRCA1/2 mutations in pancreatic ACC. All ACC patients should undergo genetic testing for BRCA1/2 mutations to identify carriers of pathogenic variants. This will allow to select patients that can benefit from targeted therapies directed against BRCA1/2-deficient tumors and is also crucial as a referral to genetic screening for the relatives of affected individuals carrying germline BRCA1/2 alterations. Abbreviations: ACC: acinar cell carcinoma; HBOC: Hereditary Breast and Ovarian Cancer; LOH: loss of heterozygosity; PARP: poly (ADP-ribose) polymerase; PDAC: pancreatic ductal adenocarcinoma; PP: pancreatic panniculitis; SD: standard deviation; WES: whole-exome sequencing.


Assuntos
Proteína BRCA2/genética , Carcinoma de Células Acinares/diagnóstico , Carcinoma de Células Acinares/genética , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/genética , Proteína BRCA1/genética , Biomarcadores Tumorais , Biópsia , Gerenciamento Clínico , Estudos de Associação Genética , Testes Genéticos , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Técnicas de Amplificação de Ácido Nucleico , Medicina de Precisão
13.
Sci Rep ; 7(1): 11972, 2017 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-28931879

RESUMO

The non-steroidal anti-inflammatory drug sulindac decreases size and number of adenomas after 4-6 months of treatment for familial adenomatous polyposis (FAP) patients. However, the underlying mechanism remains unknown. As stem cells are thought to be the tumor precursor cells, visualizing their behavior is crucial for monitoring tumor progression. Increased tag diversity in inactive genes is indicative of a protracted clonal evolution and consequently, increased risk for tumor formation. Therefore, the effect of sulindac on stem cell dynamics was studied. Normal appearing single crypts were laser microdissected in placebo- and sulindac- treated FAP patient tissue after which the methylation patterns were visualized by Next Generation Sequencing. A significant difference in tag diversity over time was found in the sulindac group compared to the placebo group (*p = 0.018), indicative of a shortened clonal evolution treated sulindac. The rate of change in tag diversity over time was correlated with polyp number change over time. No significant difference over time was observed in the percent methylation when comparing placebo vs sulindac. In conclusion, daily sulindac administration in FAP patients significantly altered colorectal stem cell dynamics, which might explain the chemopreventive action of this drug indicating that tag diversity may be used as a predictive biomarker.


Assuntos
Polipose Adenomatosa do Colo/tratamento farmacológico , Anti-Inflamatórios não Esteroides/administração & dosagem , Colo/efeitos dos fármacos , Células-Tronco/efeitos dos fármacos , Sulindaco/administração & dosagem , Adolescente , Biópsia , Criança , Feminino , Perfilação da Expressão Gênica , Humanos , Estudos Longitudinais , Masculino , Placebos/administração & dosagem , Resultado do Tratamento
15.
J Gastroenterol ; 51(9): 841-52, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27108415

RESUMO

Colorectal carcinogenesis is a process that follows a stepwise cascade that goes from the normal to an invisible pretumor stage ultimately leading to grossly visible tumor progression. During pretumor progression, an increasing accumulation of genetic alterations occurs, by definition without visible manifestations. It is generally thought that stem cells in the crypt base are responsible for this initiation of colorectal cancer progression because they are the origin of the differentiated epithelial cells that occupy the crypt. Furthermore, they are characterized by a long life span that enables them to acquire these cumulative mutations. Recent studies visualized the dynamics of stem cells both in vitro and in vivo. Translating this work into clinical applications will contribute to the evaluation of patients' predisposition for colorectal carcinogenesis and may help in the design of preventive measures for high-risk groups. In this review, we outline the progress made in the research into tracing stem cell dynamics. Further, we highlight the importance and potential clinical value of tracing stem cell dynamics in pretumor progression.


Assuntos
Adenoma/patologia , Carcinoma/patologia , Transformação Celular Neoplásica/patologia , Neoplasias Colorretais/patologia , Mucosa Intestinal/patologia , Lesões Pré-Cancerosas/patologia , Células-Tronco/patologia , Adenoma/genética , Carcinoma/genética , Transformação Celular Neoplásica/genética , Neoplasias Colorretais/genética , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Humanos , Lesões Pré-Cancerosas/genética
16.
Med Mol Morphol ; 49(2): 110-8, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26700225

RESUMO

Homeostasis of the continuously self-renewing intestinal tract involves cell proliferation, migration, differentiation along the crypt-villus-axis and shedding of cells into the gut lumen. CD95-ligand (FAS-ligand, CD95L) is a cytokine that is known for its capacity to induce apoptosis by binding its cognate receptor, CD95 (Fas). More recently, it was discovered that CD95L can also induce other cellular responses, such as proliferation, differentiation and cell migration. CD95L is highly expressed in Paneth cells of the small intestine which are in close contact with intestinal stem cells. This suggests a potential role for CD95L in controlling stem cell function and, possibly, intestinal homeostasis. We analyzed the intestines of mice deficient for functional CD95L (gld) for potential alterations in the diversity of stem-cell-lineages and parameters of intestinal homeostasis. Stem cell diversity was assessed by analyzing methylation patterns of the non-transcribed mMYOD gene. Proliferation was analyzed by BrdU labeling and differentiation was assessed by immunohistochemistry. Of all parameters analyzed, only epithelial cell proliferation was significantly reduced in the small intestines of gld-mice, but not in their colons which lack CD95L expression. We conclude that CD95L has a proliferation-stimulating role during normal turnover of the small intestine, but has a marginal effect on overall intestinal homeostasis.


Assuntos
Proteína Ligante Fas/metabolismo , Homeostase , Mucosa Intestinal/citologia , Animais , Diferenciação Celular , Proliferação de Células , Mucosa Intestinal/metabolismo , Intestino Delgado/citologia , Intestino Delgado/metabolismo , Camundongos , Transdução de Sinais , Células-Tronco/citologia , Células-Tronco/metabolismo , Receptor fas/metabolismo
17.
Cell ; 160(1-2): 324-38, 2015 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-25557080

RESUMO

Pancreatic cancer is one of the most lethal malignancies due to its late diagnosis and limited response to treatment. Tractable methods to identify and interrogate pathways involved in pancreatic tumorigenesis are urgently needed. We established organoid models from normal and neoplastic murine and human pancreas tissues. Pancreatic organoids can be rapidly generated from resected tumors and biopsies, survive cryopreservation, and exhibit ductal- and disease-stage-specific characteristics. Orthotopically transplanted neoplastic organoids recapitulate the full spectrum of tumor development by forming early-grade neoplasms that progress to locally invasive and metastatic carcinomas. Due to their ability to be genetically manipulated, organoids are a platform to probe genetic cooperation. Comprehensive transcriptional and proteomic analyses of murine pancreatic organoids revealed genes and pathways altered during disease progression. The confirmation of many of these protein changes in human tissues demonstrates that organoids are a facile model system to discover characteristics of this deadly malignancy.


Assuntos
Carcinoma Ductal Pancreático/patologia , Modelos Biológicos , Técnicas de Cultura de Órgãos , Organoides/patologia , Neoplasias Pancreáticas/patologia , Animais , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Nus , Pâncreas/metabolismo , Pâncreas/patologia
18.
Hum Pathol ; 44(5): 923-6, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23332926

RESUMO

Primary multiple pleomorphic adenomas in a unilateral parotid gland in previously untreated patients is a rare finding, and little is known about the etiology and pathogenesis. Here, a highly unusual case of a primary multifocal pleomorphic adenoma consisting of 15 individual nodules is presented. It is shown that all nodes are clonally related and thus share a common cell of origin excluding an independent multifocal pathogenesis. Most likely, multifocal pleomorphic adenoma represents parasitic nodules that have been detached from a main nodule, which may have been the result of undisclosed trauma.


Assuntos
Adenoma Pleomorfo/patologia , Neoplasias Primárias Múltiplas/patologia , Neoplasias Parotídeas/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Glândula Parótida/patologia , Inativação do Cromossomo X
19.
BMC Cancer ; 12: 240, 2012 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-22695343

RESUMO

BACKGROUND: Mammographic population screening in The Netherlands has increased the number of breast cancer patients with small and non-palpable breast tumors. Nevertheless, mammography is not ultimately sensitive and specific for distinct subtypes. Molecular imaging with targeted tracers might increase specificity and sensitivity of detection. Because development of new tracers is labor-intensive and costly, we searched for the smallest panel of tumor membrane markers that would allow detection of the wide spectrum of invasive breast cancers. METHODS: Tissue microarrays containing 483 invasive breast cancers were stained by immunohistochemistry for a selected set of membrane proteins known to be expressed in breast cancer. RESULTS: The combination of highly tumor-specific markers glucose transporter 1 (GLUT1), epidermal growth factor receptor (EGFR), insulin-like growth factor-1 receptor (IGF1-R), human epidermal growth factor receptor 2 (HER2), hepatocyte growth factor receptor (MET), and carbonic anhydrase 9 (CAIX) 'detected' 45.5% of tumors, especially basal/triple negative and HER2-driven ductal cancers. Addition of markers with a 2-fold tumor-to-normal ratio increased the detection rate to 98%. Including only markers with >3 fold tumor-to-normal ratio (CD44v6) resulted in an 80% detection rate. The detection rate of the panel containing both tumor-specific and less tumor-specific markers was not dependent on age, tumor grade, tumor size, or lymph node status. CONCLUSIONS: In search of the minimal panel of targeted probes needed for the highest possible detection rate, we showed that 80% of all breast cancers express at least one of a panel of membrane markers (CD44v6, GLUT1, EGFR, HER2, and IGF1-R) that may therefore be suitable for molecular imaging strategies. This study thereby serves as a starting point for further development of a set of antibody-based optical tracers with a high breast cancer detection rate.


Assuntos
Neoplasias da Mama/diagnóstico , Neoplasias da Mama/metabolismo , Imunofenotipagem , Imagem Molecular , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Feminino , Humanos , Glândulas Mamárias Humanas/metabolismo , Proteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Gradação de Tumores , Invasividade Neoplásica , Estadiamento de Neoplasias
20.
Cell Oncol (Dordr) ; 35(2): 119-26, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22351431

RESUMO

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis with a 5-year survival rate of <5% and an average survival of only 6 months. Although advances have been made in understanding the pathogenesis of PDAC in the last decades, overall survival has not changed. Various clinicopathological and immunohistological variables have been associated with survival time but the exact role that these variables play in relation to survival is not clear. METHODS AND RESULTS: To examine how the variables affected survival independently, multivariate analysis was conducted in a study group of 78 pancreatic ductal adenocarcinomas. The analysis included clinicopathological parameters and protein expression examined by immunohistochemistry of p53, Smad4, Axl, ALDH, MSH2, MSH6, MLH1 and PMS2. Lymph node ratio <0.2 (p = 0.004), tumor free resection margins (p = 0.044) and Smad4 expression (p = 0.004) were the only independent prognostic variables in the multivariate analysis. Expression of the other proteins examined was not significantly related to survival. CONCLUSIONS: Discrepancies with other studies in this regard are likely due to differences in quantification of immunohistochemical staining and the lack of multivariate analysis. It underscores the importance to standardize the methods used for the application of immunohistochemistry in prognostic studies.


Assuntos
Carcinoma Ductal Pancreático/diagnóstico , Carcinoma Ductal Pancreático/patologia , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/patologia , Proteína Smad4/metabolismo , Adulto , Idoso , Família Aldeído Desidrogenase 1 , Carcinoma Ductal Pancreático/enzimologia , Feminino , Humanos , Imuno-Histoquímica , Isoenzimas/metabolismo , Estimativa de Kaplan-Meier , Linfonodos/patologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estadiamento de Neoplasias , Neoplasias Pancreáticas/enzimologia , Prognóstico , Retinal Desidrogenase/metabolismo , Proteína Supressora de Tumor p53/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...