RESUMO
CONTEXT.: The original guideline, "Validating Whole Slide Imaging for Diagnostic Purposes in Pathology," was published in 2013 and included 12 guideline statements. The College of American Pathologists convened an expert panel to update the guideline following standards established by the National Academies of Medicine for developing trustworthy clinical practice guidelines. OBJECTIVE.: To assess evidence published since the release of the original guideline and provide updated recommendations for validating whole slide imaging (WSI) systems used for diagnostic purposes. DESIGN.: An expert panel performed a systematic review of the literature. Frozen sections, anatomic pathology specimens (biopsies, curettings, and resections), and hematopathology cases were included. Cytology cases were excluded. Using the Grading of Recommendations Assessment, Development, and Evaluation approach, the panel reassessed and updated the original guideline recommendations. RESULTS.: Three strong recommendations and 9 good practice statements are offered to assist laboratories with validating WSI digital pathology systems. CONCLUSIONS.: Systematic review of literature following release of the 2013 guideline reaffirms the use of a validation set of at least 60 cases, establishing intraobserver diagnostic concordance between WSI and glass slides and the use of a 2-week washout period between modalities. Although all discordances between WSI and glass slide diagnoses discovered during validation need to be reconciled, laboratories should be particularly concerned if their overall WSI-glass slide concordance is less than 95%.
Assuntos
Interpretação de Imagem Assistida por Computador , Microscopia , Humanos , Biópsia , Interpretação de Imagem Assistida por Computador/métodos , Laboratórios , Microscopia/métodos , Variações Dependentes do Observador , Revisões Sistemáticas como AssuntoRESUMO
Triple negative breast cancer (TNBC) is an aggressive breast cancer subtype. Recent studies have shown that MHC class II (MHCII) expression and tumor infiltrating lymphocytes are important prognostic factors in patients with TNBC, although the relative importance of lymphocyte subsets and associated protein expression is incompletely understood. NanoString Digital Spatial Profiling (DSP) allows for spatially resolved, highly multiplexed quantification of proteins in clinical samples. In this study, we sought to determine if DSP could be used to characterize expression of MHCII and other immune related proteins in tumor epithelial versus stromal compartments of patient-derived TNBCs (N = 10) using a panel of 39 markers. We confirmed that a subset of TNBCs have elevated expression of HLA-DR in tumor epithelial cells; HLA-DR expression was also significantly higher in the tumors of patients with long-term disease-free survival when compared to patients that relapsed. HLA-DR expression in the epithelial compartment was correlated with high expression of CD4 and ICOS in the stromal compartment of the same tumors. We also identified candidate protein biomarkers with significant differential expression between patients that relapsed versus those that did not. In conclusion, DSP is a powerful method that allows for quantification of proteins in the immune microenvironment of TNBCs.
Assuntos
Proteínas de Neoplasias/metabolismo , Neoplasias de Mama Triplo Negativas/imunologia , Microambiente Tumoral/imunologia , Antígenos CD4/metabolismo , Linhagem Celular Tumoral , Antígenos HLA-DR/imunologia , Humanos , Proteína Coestimuladora de Linfócitos T Induzíveis/metabolismo , Linfócitos/patologia , Prognóstico , Recidiva , Células Estromais/patologia , Neoplasias de Mama Triplo Negativas/patologiaAssuntos
Angiolipoma , Neoplasias da Mama , Carcinoma Ductal , Mastectomia Radical Modificada/métodos , Segunda Neoplasia Primária , Paclitaxel/administração & dosagem , Ultrassonografia Mamária/métodos , Idoso , Angiolipoma/diagnóstico , Angiolipoma/patologia , Antineoplásicos Fitogênicos/administração & dosagem , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Carcinoma Ductal/patologia , Carcinoma Ductal/terapia , Quimiorradioterapia Adjuvante/métodos , Diagnóstico Diferencial , Feminino , Humanos , Imuno-Histoquímica , Estadiamento de Neoplasias , Segunda Neoplasia Primária/diagnóstico , Segunda Neoplasia Primária/patologiaAssuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimioterapia Adjuvante/mortalidade , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Adulto , Idoso , Carboplatina/administração & dosagem , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Invasividade Neoplásica , Metástase Neoplásica , Recidiva Local de Neoplasia/patologia , Paclitaxel/administração & dosagem , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Neoplasias de Mama Triplo Negativas/patologiaRESUMO
Approximately 40% of patients with stage I-III triple-negative breast cancer (TNBC) recur after standard treatment, whereas the remaining 60% experience long-term disease-free survival (DFS). There are currently no clinical tests to assess the risk of recurrence in TNBC patients. We previously determined that TNBC patients with MHC class II (MHCII) pathway expression in their tumors experienced significantly longer DFS. To translate this discovery into a clinical test, we developed an MHCII Immune Activation assay, which measures expression of 36 genes using NanoString technology. Preanalytical testing confirmed that the assay is accurate and reproducible in formalin-fixed paraffin-embedded (FFPE) tumor specimens. The assay measurements were concordant with RNA-seq, MHCII protein expression, and tumor-infiltrating lymphocyte counts. In a training set of 44 primary TNBC tumors, the MHCII Immune Activation Score was significantly associated with longer DFS (HR = 0.17; P = 0.015). In an independent validation cohort of 56 primary FFPE TNBC tumors, the Immune Activation Score was significantly associated with longer DFS (HR = 0.19; P = 0.011) independent of clinical stage. An Immune Activation Score threshold for identifying patients with very low risk of relapse in the training set provided 100% specificity in the validation cohort. The assay format enables adoption as a standardized clinical prognostic test for identifying TNBC patients with a low risk of recurrence. Correlative data support future studies to determine if the assay can identify patients in whom chemotherapy can be safely deescalated and patients likely to respond to immunotherapy. SIGNIFICANCE: The MHCII Immune Activation assay identifies TNBC patients with a low risk of recurrence, addressing a critical need for prognostic biomarker tests that enable precision medicine for TNBC patients.
Assuntos
Biomarcadores Tumorais/genética , Antígenos de Histocompatibilidade Classe II/metabolismo , Recidiva Local de Neoplasia/diagnóstico , Neoplasias de Mama Triplo Negativas/patologia , Adulto , Idoso , Biomarcadores Tumorais/metabolismo , Estudos de Coortes , Feminino , Seguimentos , Humanos , Linfócitos do Interstício Tumoral , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/metabolismo , Prognóstico , Fatores de Risco , Taxa de Sobrevida , Neoplasias de Mama Triplo Negativas/cirurgiaRESUMO
CONTEXT.: Advancements in genomic, computing, and imaging technology have spurred new opportunities to use quantitative image analysis (QIA) for diagnostic testing. OBJECTIVE.: To develop evidence-based recommendations to improve accuracy, precision, and reproducibility in the interpretation of human epidermal growth factor receptor 2 (HER2) immunohistochemistry (IHC) for breast cancer where QIA is used. DESIGN.: The College of American Pathologists (CAP) convened a panel of pathologists, histotechnologists, and computer scientists with expertise in image analysis, immunohistochemistry, quality management, and breast pathology to develop recommendations for QIA of HER2 IHC in breast cancer. A systematic review of the literature was conducted to address 5 key questions. Final recommendations were derived from strength of evidence, open comment feedback, expert panel consensus, and advisory panel review. RESULTS.: Eleven recommendations were drafted: 7 based on CAP laboratory accreditation requirements and 4 based on expert consensus opinions. A 3-week open comment period received 180 comments from more than 150 participants. CONCLUSIONS.: To improve accurate, precise, and reproducible interpretation of HER2 IHC results for breast cancer, QIA and procedures must be validated before implementation, followed by regular maintenance and ongoing evaluation of quality control and quality assurance. HER2 QIA performance, interpretation, and reporting should be supervised by pathologists with expertise in QIA.
Assuntos
Neoplasias da Mama , Processamento de Imagem Assistida por Computador , Laboratórios , Receptor ErbB-2 , Feminino , Humanos , Acreditação , Neoplasias da Mama/patologia , Medicina Baseada em Evidências , Processamento de Imagem Assistida por Computador/normas , Imuno-Histoquímica , Laboratórios/normas , Patologistas , Controle de Qualidade , Receptor ErbB-2/metabolismo , Reprodutibilidade dos Testes , Sociedades Médicas , Estados Unidos , Revisões Sistemáticas como AssuntoRESUMO
BACKGROUND: We evaluated five key proteins involved in various cancer-related pathways and assessed their relation to breast cancer recurrence. METHODS: We used the Kentucky Cancer Registry to retrospectively identify primary invasive breast cancer cases (n = 475) that were diagnosed and treated at University of Kentucky Medical Center between 2000 and 2007. Breast cancer recurrence was observed in 62 cases during the 5-year follow-up after diagnosis. Protein expression or activity level was analyzed from surgery tissue using immuno-histochemical assays. RESULTS: Compared to ER+/PR+/HER2- patients without recurrence, those with recurrence had higher TWIST expression (p = 0.049) but lower ABL1/ABL2 activity (p = 0.003) in primary tumors. We also found that triple-negative breast cancer patients with recurrence had higher SNAI1 expression compared to those without recurrence (p = 0.03). After adjusting for potential confounders, the higher ABL1/ABL2 activity in primary tumors was associated with a decreased risk of recurrence (OR 0.72, 95% CI 0.85-0.90) among ER+/PR+/HER2- patients. In addition, among patients with recurrence we observed that the activity level of ABL1/ABL2 was significantly increased in recurrent tumors compared to the matched primary tumors regardless of the subtype (p = 0.013). CONCLUSIONS: These findings provide evidence that the expression/activity level of various proteins may be differentially associated with risk of recurrence of breast tumor subtypes.
Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/patologia , Neoplasias de Mama Triplo Negativas/patologia , Adulto , Idoso , Neoplasias da Mama/diagnóstico , Estudos de Coortes , Feminino , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Estudos RetrospectivosRESUMO
BRD4 assembles transcriptional machinery at gene super-enhancer regions and governs the expression of genes that are critical for cancer progression. However, it remains unclear whether BRD4-mediated gene transcription is required for tumor cells to develop drug resistance. Our data show that prolonged treatment of luminal breast cancer cells with AKT inhibitors induces FOXO3a dephosphorylation, nuclear translocation, and disrupts its association with SirT6, eventually leading to FOXO3a acetylation as well as BRD4 recognition. Acetylated FOXO3a recognizes the BD2 domain of BRD4, recruits the BRD4/RNAPII complex to the CDK6 gene promoter, and induces its transcription. Pharmacological inhibition of either BRD4/FOXO3a association or CDK6 significantly overcomes the resistance of luminal breast cancer cells to AKT inhibitors in vitro and in vivo. Our study reports the involvement of BRD4/FOXO3a/CDK6 axis in AKTi resistance and provides potential therapeutic strategies for treating resistant breast cancer.
Assuntos
Neoplasias da Mama/metabolismo , Quinase 6 Dependente de Ciclina/metabolismo , Proteína Forkhead Box O3/metabolismo , Proteínas Nucleares/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fatores de Transcrição/metabolismo , Acetilação/efeitos dos fármacos , Animais , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Proteínas de Ciclo Celular , Linhagem Celular Tumoral , Núcleo Celular/genética , Núcleo Celular/metabolismo , Quinase 6 Dependente de Ciclina/genética , Feminino , Proteína Forkhead Box O3/genética , Regulação da Expressão Gênica , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Humanos , Camundongos , Camundongos Nus , Proteínas Nucleares/química , Proteínas Nucleares/genética , Oxidiazóis/administração & dosagem , Regiões Promotoras Genéticas , Ligação Proteica/efeitos dos fármacos , Domínios Proteicos , Inibidores de Proteínas Quinases/administração & dosagem , Transporte Proteico/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/genética , Pirimidinas/administração & dosagem , Pirróis/administração & dosagem , Sirtuínas/genética , Sirtuínas/metabolismo , Fatores de Transcrição/química , Fatores de Transcrição/genéticaRESUMO
Collagen prolyl 4-hydroxylase (P4H) expression and collagen hydroxylation in cancer cells are necessary for breast cancer progression. Here, we show that P4H alpha 1 subunit (P4HA1) protein expression is induced in triple-negative breast cancer (TNBC) and HER2 positive breast cancer. By modulating alpha ketoglutarate (α-KG) and succinate levels P4HA1 expression reduces proline hydroxylation on hypoxia-inducible factor (HIF) 1α, enhancing its stability in cancer cells. Activation of the P4HA/HIF-1 axis enhances cancer cell stemness, accompanied by decreased oxidative phosphorylation and reactive oxygen species (ROS) levels. Inhibition of P4HA1 sensitizes TNBC to the chemotherapeutic agent docetaxel and doxorubicin in xenografts and patient-derived models. We also show that increased P4HA1 expression correlates with short relapse-free survival in TNBC patients who received chemotherapy. These results suggest that P4HA1 promotes chemoresistance by modulating HIF-1-dependent cancer cell stemness. Targeting collagen P4H is a promising strategy to inhibit tumor progression and sensitize TNBC to chemotherapeutic agents.
Assuntos
Resistencia a Medicamentos Antineoplásicos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Pró-Colágeno-Prolina Dioxigenase/genética , Pró-Colágeno-Prolina Dioxigenase/metabolismo , Neoplasias de Mama Triplo Negativas/enzimologia , Neoplasias de Mama Triplo Negativas/fisiopatologia , Animais , Linhagem Celular , Colágeno/metabolismo , Feminino , Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Ácidos Cetoglutáricos/metabolismo , Camundongos , Camundongos SCID , Metástase Neoplásica/prevenção & controle , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/prevenção & controle , Células-Tronco Neoplásicas/enzimologia , Células-Tronco Neoplásicas/metabolismo , Pró-Colágeno-Prolina Dioxigenase/antagonistas & inibidores , RNA Mensageiro/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Análise de Sobrevida , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologiaRESUMO
The 2013 American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) recommendations for HER2 testing contain a recommendation for pathologists with respect to invasive micropapillary carcinoma. The guidelines suggest that HER2 immunohistochemical staining that is intense but incomplete and would be considered 1+ may actually be HER2-amplified by fluorescence in situ hybridization. Thus, pathologists should consider reporting the immunohistochemistry as equivocal (2+) and employ an alternative testing methodology. This recommendation is based largely on one paper wherein the authors tested a series of 22 micropapillary carcinomas that were considered 1+ by immunohistochemistry and identified HER2 amplification in one case (5%). In order to assess for a possible discordance between HER2 immunohistochemistry and fluorescence in situ hybridization, we evaluated a series of invasive carcinomas with micropapillary features using both methodologies. As described by the WHO, invasive carcinomas with micropapillary features have small, hollow, or morula-like clusters of cells surrounded by clear stromal spaces. All cases had HER2 immunohistochemistry and fluorescence in situ hybridization performed, and for cases with equivocal fluorescence in situ hybridization results, an alternative Chromosome 17 probe (RAI1) was employed. All assays were scored according to the 2013 ASCO/CAP guidelines. Specifically for this study, immunohistochemistry was scored irrespective of the presence of micropapillary features. Overall, we identified HER2 amplification in 21 (47%) of the cases assayed, with the corresponding immunohistochemistry being 1+ (n=9), 2+ (n=11), and 3+ (n=1). The ASCO/CAP recommendation that this morphology may deviate from the typical staining pattern is highlighted, as we found that 43% of cases with micropapillary features and HER2 staining that would otherwise be scored as 1+ were HER2-amplified by fluorescence in situ hybridization. This study supports the ASCO/CAP recommendation that pathologists should consider reporting immunohistochemistry in this morphology as equivocal and perform reflex testing using in situ hybridization.
Assuntos
Biomarcadores Tumorais/análise , Neoplasias da Mama/genética , Carcinoma Papilar/genética , Receptor ErbB-2/análise , Feminino , Amplificação de Genes , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Receptor ErbB-2/genéticaRESUMO
S100A4 (metastasin-1), a metastasis-associated protein and marker of the epithelial to mesenchymal transition, contributes to several hallmarks of cancer and has been implicated in the progression of several types of cancer. However, the impacts of S100A4 signaling in lung cancer progression and its potential use as a target for therapy in lung cancer have not been properly explored. Using established lung cancer cell lines, we demonstrate that S100A4 knockdown reduces cell proliferation, invasion and three-dimensional invasive growth, while overexpression of S100A4 increases invasive potential. In patient-derived tissues, S100A4 is preferentially elevated in lung adenocarcinoma. This elevation is associated with lymphovascular invasion and decreased overall survival. In addition, depletion of S100A4 by shRNA inhibits NF-κB activity and decreases TNFα-induced MMP9 expression. Furthermore, inhibition of the NF-κB/MMP9 axis decreases lung carcinoma invasive potential. Niclosamide, a reported inhibitor of S100A4, blocks expression and function of S100A4 with a reduction in proliferation, invasion and NF-κB-mediated MMP9 expression. Collectively, this study highlights the importance of the S100A4/NF-κB/MMP9 axis in lung cancer invasion and provides a rationale for targeting S100A4 to combat lung cancer.
Assuntos
Adenocarcinoma/tratamento farmacológico , Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Niclosamida/farmacologia , Proteína A4 de Ligação a Cálcio da Família S100/antagonistas & inibidores , Proteína A4 de Ligação a Cálcio da Família S100/metabolismo , Células A549 , Adenocarcinoma/patologia , Adenocarcinoma de Pulmão , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Humanos , Neoplasias Pulmonares/patologia , Metaloproteinase 9 da Matriz/biossíntese , NF-kappa B/metabolismo , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Prognóstico , Interferência de RNA , RNA Interferente Pequeno/genética , Proteína A4 de Ligação a Cálcio da Família S100/genética , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Lung cancer carries a poor prognosis and is the most common cause of cancer-related death worldwide. The integrin α6ß4, a laminin receptor, promotes carcinoma progression in part by cooperating with various growth factor receptors to facilitate invasion and metastasis. In carcinoma cells with mutant TP53, the integrin α6ß4 promotes cell survival. TP53 mutations and integrin α6ß4 overexpression co-occur in many aggressive malignancies. Because of the high frequency of TP53 mutations in lung squamous cell carcinoma (SCC), we sought to investigate the association of integrin ß4 expression with clinicopathologic features and survival in non-small cell lung cancer (NSCLC). We constructed a lung cancer tissue microarray and stained sections for integrin ß4 subunit expression using immunohistochemistry. We found that integrin ß4 expression is elevated in SCC compared with adenocarcinoma (P<.0001), which was confirmed in external gene expression data sets (P<.0001). We also determined that integrin ß4 overexpression associates with the presence of venous invasion (P=.0048) and with reduced overall patient survival (hazard ratio, 1.46; 95% confidence interval, 1.01-2.09; P=.0422). Elevated integrin ß4 expression was also shown to associate with reduced overall survival in lung cancer gene expression data sets (hazard ratio, 1.49; 95% confidence interval, 1.31-1.69; P<.0001). Using cBioPortal, we generated a network map demonstrating the 50 most highly altered genes neighboring ITGB4 in SCC, which included laminins, collagens, CD151, genes in the EGFR and PI3K pathways, and other known signaling partners. In conclusion, we demonstrate that integrin ß4 is overexpressed in NSCLC where it is an adverse prognostic marker.
Assuntos
Biomarcadores Tumorais/análise , Carcinoma Pulmonar de Células não Pequenas/química , Integrina alfa6/análise , Integrina beta4/análise , Neoplasias Pulmonares/química , Veias Pulmonares/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Biologia Computacional , Mineração de Dados , Bases de Dados Genéticas , Feminino , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Imuno-Histoquímica , Integrina alfa6/genética , Integrina beta4/genética , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Prognóstico , RNA Mensageiro/genética , Fatores de Tempo , Análise Serial de Tecidos , Regulação para CimaRESUMO
Integrin α6ß4 is up-regulated in pancreatic adenocarcinomas where it contributes to carcinoma cell invasion by altering the transcriptome. In this study, we found that integrin α6ß4 up-regulates several genes in the epidermal growth factor receptor (EGFR) pathway, including amphiregulin (AREG), epiregulin (EREG), and ectodomain cleavage protease MMP1, which is mediated by promoter demethylation and NFAT5. The correlation of these genes with integrin α6ß4 was confirmed in The Cancer Genome Atlas Pancreatic Cancer Database. Based on previous observations that integrin α6ß4 cooperates with c-Met in pancreatic cancers, we examined the impact of EGFR signaling on hepatocyte growth factor (HGF)-stimulated migration and invasion. We found that AREG and EREG were required for autocrine EGFR signaling, as knocking down either ligand inhibited HGF-mediated migration and invasion. We further determined that HGF induced secretion of AREG, which is dependent on integrin-growth factor signaling pathways, including MAPK, PI3K, and PKC. Moreover, matrix metalloproteinase activity and integrin α6ß4 signaling were required for AREG secretion. Blocking EGFR signaling with EGFR-specific antibodies or an EGFR tyrosine kinase inhibitor hindered HGF-stimulated pancreatic carcinoma cell chemotaxis and invasive growth in three-dimensional culture. Finally, we found that EGFR was phosphorylated in response to HGF stimulation that is dependent on EGFR kinase activity; however, c-Met phosphorylation in response to HGF was unaffected by EGFR signaling. Taken together, these data illustrate that integrin α6ß4 stimulates invasion by promoting autocrine EGFR signaling through transcriptional up-regulation of key EGFR family members and by facilitating HGF-stimulated EGFR ligand secretion. These signaling events, in turn, promote pancreatic carcinoma migration and invasion.
Assuntos
Receptores ErbB/metabolismo , Fator de Crescimento de Hepatócito/metabolismo , Integrina alfa6beta4/metabolismo , Anfirregulina , Linhagem Celular Tumoral , Movimento Celular , Família de Proteínas EGF/genética , Família de Proteínas EGF/metabolismo , Epirregulina/genética , Epirregulina/metabolismo , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Técnicas de Silenciamento de Genes , Humanos , Integrina alfa6beta4/genética , Metaloproteinase 1 da Matriz/genética , Metaloproteinase 1 da Matriz/metabolismo , Modelos Biológicos , Invasividade Neoplásica , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Neoplásico/genética , RNA Neoplásico/metabolismo , Transdução de Sinais , Microambiente Tumoral , Regulação para CimaRESUMO
Integrin α6ß4 is a cellular adhesion molecule that binds to laminins in the extracellular matrix and nucleates the formation of hemidesmosomes. During carcinoma progression, integrin α6ß4 is released from hemidesmosomes, where it can then signal to facilitate multiple aspects of tumor progression including sustaining proliferative signaling, tumor invasion and metastasis, evasion of apoptosis, and stimulation of angiogenesis. The integrin achieves these ends by cooperating with growth factor receptors including EGFR, ErbB-2, and c-Met to amplify downstream pathways such as PI3K, AKT, MAPK, and the Rho family small GTPases. Furthermore, it dramatically alters the transcriptome toward a more invasive phenotype by controlling promoter DNA demethylation of invasion and metastasis-associated proteins, such as S100A4 and autotaxin, and upregulates and activates key tumor-promoting transcription factors such as the NFATs and NF-κB. Expression of integrin α6ß4 has been studied in many human malignancies where its overexpression is associated with aggressive behavior and a poor prognosis. This review provides an assessment of integrin α6ß4 expression patterns and their prognostic significance in human malignancies, and describes key signaling functions of integrin α6ß4 that contribute to tumor progression.
Assuntos
Carcinoma/metabolismo , Carcinoma/fisiopatologia , Metilação de DNA/fisiologia , Regulação Neoplásica da Expressão Gênica/fisiologia , Integrina alfa6beta4/metabolismo , Receptores de Fatores de Crescimento/metabolismo , Transdução de Sinais/fisiologia , Hemidesmossomos/metabolismo , HumanosAssuntos
Neoplasias da Mama/diagnóstico , Carcinoma Ductal de Mama/diagnóstico , Carcinoma Lobular/diagnóstico , Erros de Diagnóstico , Sarcoma Mieloide/diagnóstico , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/metabolismo , Carcinoma Ductal de Mama/metabolismo , Carcinoma Lobular/metabolismo , Diagnóstico Diferencial , Feminino , Humanos , Pessoa de Meia-Idade , Sarcoma Mieloide/metabolismoRESUMO
A case of lymphoma of T-cell derivation with aberrant expression of three B-cell lineage markers (CD19, CD20, and CD79a), which was diagnosed on a left axillary excision, is described. Immunohistochemical studies and flow cytometry analysis demonstrated neoplastic cells expressing CD3, CD19, CD20, and CD79a with absence of CD4, CD8, CD10, CD30, CD34, CD56, CD68, TDT, MPO, PAX-5, and surface immunoglobulin. Gene rearrangement studies performed on paraffin blocks demonstrated monoclonal T-cell receptor gamma chain rearrangement with no evidence of clonal heavy chain rearrangement. The neoplastic cells were negative for Epstein-Barr virus (EBV) or Human Herpes Virus 8 (HHV-8). At the time of diagnosis, the PET scan demonstrated hypermetabolic neoplastic cells involving the left axilla, bilateral internal jugular areas, mediastinum, right hilum, bilateral lungs, and spleen. However, bone marrow biopsy performed for hemolytic anemia revealed normocellular bone marrow with trilineage maturation. The patient had no evidence of immunodeficiency or infection with EBV or HHV-8. This is the first reported case of a mature T-cell lymphoma with aberrant expression of three B-cell lineage markers. The current report also highlights the need for molecular gene rearrangement studies to determine the precise lineage of ambiguous neoplastic clones.
RESUMO
Magnetic resonance imaging (MRI) can be used to relate structure to function mapped with high-temporal resolution electrophysiological recordings using metal electrodes. Additionally, MRI may be used to guide the placement of electrodes or conductive cannula in the brain. However, the magnetic susceptibility mismatch between implanted metals and surrounding brain tissue can severely distort MR images and spectra, particularly in high magnetic fields. In this study, we present a modified MR method of characterizing the magnetic susceptibility of materials that can be used to develop biocompatible, metal alloys that match the susceptibility of host tissue in order to eliminate MR distortions proximal to the implant. This method was applied at 4.7T and 11.1T to measure the susceptibility of a model solid-solution alloy of Cu and Sn, which is inexpensive but not biocompatible. MR-derived relative susceptibility values of four different compositions of Cu-Sn alloy deviated by less than 3.1% from SQUID magnetometry absolute susceptibility measurements performed up to 7T. These results demonstrate that the magnetic susceptibility varies linearly with atomic percentage in these solid-solution alloys, but are not simply the weighted average of Cu and Sn magnetic susceptibilities. Therefore susceptibility measurements are necessary when developing susceptibility-matched, solid-solution alloys for the elimination of susceptibility artifacts in MR. This MR method does not require any specialized equipment and is free of geometrical constraints, such as sample shape requirements associated with SQUID magnetometry, so the method can be used at all stages of fabrication to guide the development of a susceptibility matched, biocompatible device.