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This review aims to present a comprehensive overview of the current landscape of artificial intelligence (AI) applications in the analysis of tubular gastrointestinal biopsies. These publications cover a spectrum of conditions, ranging from inflammatory ailments to malignancies. Moving beyond the conventional diagnosis based on hematoxylin and eosin-stained whole-slide images, the review explores additional implications of AI, including its involvement in interpreting immunohistochemical results, molecular subtyping, and the identification of cellular spatial biomarkers. Furthermore, the review examines how AI can contribute to enhancing the quality and control of diagnostic processes, introducing new workflow options, and addressing the limitations and caveats associated with current AI platforms in this context.
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Inteligencia Artificial , Tracto Gastrointestinal , Flujo de Trabajo , Humanos , Biopsia/métodos , Tracto Gastrointestinal/patología , Tracto Gastrointestinal/metabolismo , Enfermedades Gastrointestinales/patología , Enfermedades Gastrointestinales/diagnósticoRESUMEN
Ulcerative colitis is a chronic inflammatory bowel disease that is characterized by a relapsing and remitting course. Assessment of disease activity critically informs treatment decisions. In addition to endoscopic remission, histologic remission is emerging as a treatment target and a key factor in the evaluation of disease activity and therapeutic efficacy. However, manual pathologist evaluation is semiquantitative and limited in granularity. Machine learning approaches are increasingly being developed to aid pathologists in accurate and reproducible scoring of histology, enabling precise quantitation of clinically relevant features. Here, we report the development and validation of convolutional neural network models that quantify histologic features pertinent to ulcerative colitis disease activity, directly from hematoxylin and eosin-stained whole slide images. Tissue and cell model predictions were used to generate quantitative human-interpretable features to fully characterize the histology samples. Tissue and cell predictions showed comparable agreement to pathologist annotations, and the extracted slide-level human-interpretable features demonstrated strong correlations with disease severity and pathologist-assigned Nancy histological index scores. Moreover, using a random forest classifier based on 13 human-interpretable features derived from the tissue and cell models, we were able to accurately predict Nancy histological index scores, with a weighted kappa (κ = 0.91) and Spearman correlation (â´ = 0.89, P < .001) when compared with pathologist consensus Nancy histological index scores. We were also able to predict histologic remission, based on the absence of neutrophil extravasation, with a high accuracy of 0.97. This work demonstrates the potential of computer vision to enable a standardized and robust assessment of ulcerative colitis histopathology for translational research and improved evaluation of disease activity and prognosis.
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Colitis Ulcerosa , Enfermedades Inflamatorias del Intestino , Humanos , Colitis Ulcerosa/tratamiento farmacológico , Inteligencia Artificial , Índice de Severidad de la Enfermedad , Enfermedades Inflamatorias del Intestino/patología , Mucosa Intestinal/patología , ColonoscopíaRESUMEN
BACKGROUND: Gastric cancer is a heterogeneous disease with poorly understood genetic and microenvironmental factors. Mutations in collagen genes are associated with genetic diseases that compromise tissue integrity, but their role in tumor progression has not been extensively reported. Aberrant collagen expression has been long associated with malignant tumor growth, invasion, chemoresistance, and patient outcomes. We hypothesized that somatic mutations in collagens could functionally alter the tumor extracellular matrix. METHODS: We used publicly available datasets including The Tumor Cancer Genome Atlas (TCGA) to interrogate somatic mutations in collagens in stomach adenocarcinomas. To demonstrate that collagens were significantly mutated above background mutation rates, we used a moderated Kolmogorov-Smirnov test along with combination analysis with a bootstrap approach to define the background accounting for mutation rates. Association between mutations and clinicopathological features was evaluated by Fisher or chi-squared tests. Association with overall survival was assessed by Kaplan-Meier and the Cox-Proportional Hazards Model. Gene Set Enrichment Analysis was used to interrogate pathways. Immunohistochemistry and in situ hybridization tested expression of COL7A1 in stomach tumors. RESULTS: In stomach adenocarcinomas, we identified individual collagen genes and sets of collagen genes harboring somatic mutations at a high frequency compared to background in both microsatellite stable, and microsatellite instable tumors in TCGA. Many of the missense mutations resemble the same types of loss of function mutations in collagenopathies that disrupt tissue formation and destabilize cells providing guidance to interpret the somatic mutations. We identified combinations of somatic mutations in collagens associated with overall survival, with a distinctive tumor microenvironment marked by lower matrisome expression and immune cell signatures. Truncation mutations were strongly associated with improved outcomes suggesting that loss of expression of secreted collagens impact tumor progression and treatment response. Germline collagenopathy variants guided interpretation of impactful somatic mutations on tumors. CONCLUSIONS: These observations highlight that many collagens, expressed in non-physiologically relevant conditions in tumors, harbor impactful somatic mutations in tumors, suggesting new approaches for classification and therapy development in stomach cancer. In sum, these findings demonstrate how classification of tumors by collagen mutations identified strong links between specific genotypes and the tumor environment.
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Adenocarcinoma/genética , Colágeno Tipo VII/genética , Colágeno/genética , Neoplasias Gástricas/genética , Microambiente Tumoral/genética , Adenocarcinoma/mortalidad , Biología Computacional , Genotipo , Humanos , Estimación de Kaplan-Meier , Mutación , Tasa de Mutación , Modelos de Riesgos Proporcionales , Neoplasias Gástricas/mortalidadRESUMEN
Smooth muscle tumors represent the second most common mural mesenchymal neoplasm in the gastrointestinal tract, but established criteria for prognostic assessment of these tumors are lacking. A large cohort of surgically resected intramural gastrointestinal smooth muscle tumors from 31 institutions was analyzed to identify potential prognostic features. Pathologic features were assessed by expert gastrointestinal and/or soft tissue pathologists at each center. Immunohistochemical confirmation was required. A total of 407 cases from the esophagus (n = 97, 24%), stomach (n = 180, 44%), small bowel (n = 74, 18%), and colorectum (n = 56, 14%) were identified. Patients ranged in age from 19 to 92 years (mean 55 years), with a slight female predominance (57%). Mean tumor size was 5.4 cm, with the largest tumor measuring 29 cm. Disease progression following surgery, defined as local recurrence, metastasis, or disease-related death, occurred in 56 patients (14%). Colorectal tumors were most likely to progress, followed by small bowel and gastric tumors. None of the esophageal tumors in this series progressed. Receiver operator characteristic analysis identified optimal cutoffs of 9.8 cm and 3 mitoses/5 mm2 for discriminating between progressive and non-progressive tumors. Histologic features strongly associated with progression by univariate analysis included moderate-to-severe atypia, high cellularity, abnormal differentiation (defined as differentiation not closely resembling that of normal smooth muscle), tumor necrosis, mucosal ulceration, lamina propria involvement, and serosal involvement (P < 0.0001 for all features). Age, sex, and margin status were not significantly associated with progression (P = 0.23, 0.82, and 0.07, respectively). A risk assessment table was created based on tumor site, size, and mitotic count, and Kaplan-Meier plots of progression-free survival for each subgroup revealed progression-based tiers. Based on our findings, it appears that nonesophageal gastrointestinal smooth muscle tumors measuring >10 cm and/or showing ≥3 mitoses/5 mm2 may behave aggressively, and therefore close clinical follow-up is recommended in these cases.
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Neoplasias Gastrointestinales/patología , Tumor de Músculo Liso/patología , Adulto , Anciano , Anciano de 80 o más Años , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Supervivencia sin ProgresiónRESUMEN
Elastic fibers are found in the extracellular matrix (ECM) of tissues requiring resilience and depend on elasticity. Elastin and its degradation products have multiple roles in the oncologic process. In many malignancies, the remodeled ECM expresses high levels of the elastin protein which may have either positive or negative effects on tumor growth. Elastin cross-linking with other ECM components and the enzymes governing this process all have effects on tumorigenesis. Elastases, and specifically neutrophil elastase, are key drivers of invasion and metastasis and therefore are important targets for inhibition. Elastin degradation leads to the generation of bioactive fragments and elastin-derived peptides that further modulate tumor growth and spread. Interestingly, elastin-like peptides (ELP) and elastin-derived peptides (EDP) may also be utilized as nano-carriers to combat tumor growth. EDPs drive tumor development in a variety of ways, and specifically targeting EDPs and their binding proteins are major objectives for ongoing and future anti-cancer therapies. Research on both the direct anti-cancer activity and the drug delivery capabilities of ELPs is another area likely to result in novel therapeutic agents in the near future.
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Elastina , Matriz Extracelular , Neoplasias/metabolismo , Microambiente Tumoral , Elastina/metabolismo , Humanos , Neoplasias/terapia , Fragmentos de Péptidos/metabolismoRESUMEN
BACKGROUND: Cytokeratin 7 (CK7) and GATA binding protein 3 (GATA3) are considered as immunohistochemical hallmarks of breast cancers; however, there are breast tumors lacking these markers. Clinicopathological characterization of CK7 negative breast cancer has not been addressed previously and similar studies on GATA3 negative tumors are limited. METHODS: This study included 196 consecutive cases of Nottingham Grade 3 breast cancers with 159 cases of Grade 1 and Grade 2 tumors for comparison. CK7 and GATA3 expression was correlated with patient's age, histological type, pathological grade and stage, hormone receptor status, molecular subtype and overall survival. RESULTS: CK7 negativity was seen in 13% of Grade 3, 9% of Grade 2, and 2% of Grade 1 cases (P = 0.0457). Similarly, 28% of Grade 3, 5% of Grade 2 and 2% of Grade 1 cases were GATA3 negative (P < 0.0001). CK7 negative tumors did not show association with other clinicopathological parameters. GATA3 negative tumors were enriched in the basal-like molecular subgroup and were associated with negative estrogen receptor (ER) and negative progesterone receptor (PR) statuses. Both CK7 and GATA3 expression showed no association with overall survival in patients with Grade 3 tumor. CONCLUSIONS: This is the first study to characterize CK7 negative breast tumors in the context of clinicopathology. Profiling the CK7 negative and GATA3 negative breast cancers helps to understand the biology of these specific tumor subgroups and may aid in their diagnosis.
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Biomarcadores de Tumor , Neoplasias de la Mama/genética , Factor de Transcripción GATA3/genética , Queratina-7/genética , Anciano , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Femenino , Factor de Transcripción GATA3/metabolismo , Humanos , Inmunohistoquímica , Queratina-7/metabolismo , Persona de Mediana Edad , Clasificación del Tumor , Estadificación de Neoplasias , Pronóstico , Modelos de Riesgos ProporcionalesRESUMEN
BACKGROUND: The breast cancer microenvironment contributes to tumor progression and response to chemotherapy. Previously, we reported that increased stromal Type X collagen α1 (ColXα1) and low TILs correlated with poor pathologic response to neoadjuvant therapy in estrogen receptor and HER2-positive (ER+/HER2+) breast cancer. Here, we investigate the relationship of ColXα1 and long-term outcome of ER+/HER2+ breast cancer patients in an adjuvant setting. METHODS: A total of 164 cases with at least 5-year follow-up were included. Immunohistochemistry for ColXα1 was performed on whole tumor sections. Associations between ColXα1expression, clinical pathological features, and outcomes were analyzed. RESULTS: ColXα1 expression was directly proportional to the amount of tumor associated stroma (p = 0.024) and inversely proportional to TILs. Increased ColXα1 was significantly associated with shorter disease free survival and overall survival by univariate analysis. In multivariate analysis, OS was lower in ColXα1 expressing (HR = 2.1; 95% CI = 1.2-3.9) tumors of older patients (> = 58 years) (HR = 5.3; 95% CI = 1.7-17) with higher stage (HR = 2.6; 95% CI = 1.3-5.2). Similarly, DFS was lower in ColXα1 expressing (HR = 1.8; 95% CI = 1.6-5.7) tumors of older patients (HR = 3.2; 95% CI = 1.3-7.8) with higher stage (HR = 2.7; 95% CI = 1.6-5.7) and low TILs. In low PR+ tumors, higher ColXα1 expression was associated with poorer prognosis. CONCLUSION: ColXα1 expression is associated with poor disease free survival and overall survival in ER+/HER2+ breast cancer. This study provides further support for the prognostic utility of ColXα1 as a breast cancer associated stromal factor that predicts response to chemotherapy.
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Neoplasias de la Mama/metabolismo , Colágeno Tipo X/metabolismo , Linfocitos Infiltrantes de Tumor/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/mortalidad , Quimioterapia Adyuvante , Femenino , Estudios de Seguimiento , Regulación Neoplásica de la Expresión Génica , Humanos , Inmunohistoquímica , Persona de Mediana Edad , Mutación/genética , Pronóstico , Receptor ErbB-2/genética , Receptores de Estrógenos/genética , Estudios Retrospectivos , Microambiente TumoralRESUMEN
BACKGROUND: Declining Helicobacter pylori (H. pylori) eradication rates have prompted a switch in first-line therapy from standard triple (PPI, clarithromycin, and amoxicillin) to bismuth-based quadruple therapy. A caveat of the ACG 2017 H. pylori treatment guidelines was a paucity of recent US eradication data. AIM: To determine Rhode Island H. pylori eradication data, in the largest US study from the last two decades. METHODS: Electronic records were queried for patients with H. pylori infection diagnosed by pathology, urea breath test, or stool antigen from 2015 to 2017. Demographics, diagnostic test, treatment regimen, and test of cure were extracted. Eradication rates were calculated, and treatment regimens were compared. RESULTS: A total of 1710 patients were identified (64% female): 825 (46%) diagnosed by breath test, 755 (42%) by biopsy, and 191 (12%) by stool antigen. Full data were obtained on 1101 patients. Seven regimens were used: quadruple (64%), triple (25%), doxycycline quadruple (5%), and miscellaneous (6%). Quadruple was superior to triple: (85% vs. 75%, P = 0.002), quadruple 14 days versus triple 14 days (87% vs. 79%, P = 0.0052), quadruple 10 days versus triple 10 days (77% vs. 67%, P = 0.33). Increased therapy length improved eradication (quadruple 14 days vs. 10 days, 87% vs. 77%, P = 0.002; triple 14 days versus 10 days 79% vs. 67%, P = 0.13). Finally, substituting doxycycline for tetracycline yielded lower eradication (85% vs. 67%, P = 0.006). CONCLUSION: Quadruple therapy is superior to triple therapy within the Rhode Island population. Fourteen-day therapy achieves superior eradication compared to 10-day therapy, and doxycycline is inferior to tetracycline for quadruple therapy. Our findings support adherence to ACG and international guidelines advising 14-day quadruple therapy.
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Bismuto/administración & dosificación , Infecciones por Helicobacter , Helicobacter pylori/aislamiento & purificación , Metronidazol/administración & dosificación , Inhibidores de la Bomba de Protones/administración & dosificación , Tetraciclina/administración & dosificación , Antiácidos/administración & dosificación , Antibacterianos/administración & dosificación , Quimioterapia Combinada/métodos , Quimioterapia Combinada/normas , Registros Electrónicos de Salud/estadística & datos numéricos , Femenino , Infecciones por Helicobacter/diagnóstico , Infecciones por Helicobacter/tratamiento farmacológico , Infecciones por Helicobacter/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Evaluación de Procesos y Resultados en Atención de Salud , Estudios Retrospectivos , Estados Unidos/epidemiologíaRESUMEN
AIMS: The immune microenvironment is a prognostic factor for various malignancies. The significance of key players of this immune microenvironment, including tumour-infiltrating lymphocytes (TILs) and expression of programmed death-ligand 1 (PD-L1), indoleamine 2,3-dioxygenase (IDO) and tryptophanyl-tRNA synthetase (WARS) in gastrointestinal stromal tumours (GISTs) is largely unknown. METHODS AND RESULTS: Tissue microarrays were constructed from pathology files, 1996-2016. Immunohistochemistry for PD-L1, IDO and WARS was correlated with tumour size, mitoses and outcomes. TILs expressing CD3, CD4, CD8, FoxP3 and GBP5 were counted. A total of 129 GISTs were analysed. Mean patient age was 62.5 years; 52.0% were male. Tumour location included 89 stomach (69.0%), 33 small bowel (25.6%) and seven other (5.4%). Mean tumour size was 5.6 cm; mean mitoses were 7.2 per 50 high-power field. Nineteen patients (15.0%) developed disease progression, to abdominal wall (n = 8), liver (n = 6) and elsewhere (n = 5). Median progression-free survival was 56.6 months; five patients died of disease. PD-L1 was positive in 88 of 127 tumour samples (69.0%), 114 of 127 tumours were IDO-positive (89.8%) and 60 of 127 were positive for WARS (47.2%). PD-L1 was associated with increased size (P = 0.01), necrosis (P = 0.018) and mitoses (P = 0.006). Disease progression was not associated with PD-L1 (P = 0.44), IDO (P = 0.14) or WARS (P = 0.36) expression. PD-L1-positive GISTs with CD8+ or CD3+ TILs were significantly smaller than tumours with CD8+ or CD3+ TILs. CONCLUSIONS: PD-L1 expression was associated with increased size and mitoses. High CD8+ or CD3+ TIL counts were associated with decreased PD-L1/IDO+ GIST size. PD-L1 and IDO could be significant in GIST tumour biology, which invites consideration of immunotherapy as a potential treatment option.
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Biomarcadores de Tumor/inmunología , Neoplasias Gastrointestinales/inmunología , Tumores del Estroma Gastrointestinal/inmunología , Linfocitos Infiltrantes de Tumor/inmunología , Microambiente Tumoral/inmunología , Adulto , Anciano , Antígeno B7-H1/análisis , Antígeno B7-H1/biosíntesis , Femenino , Neoplasias Gastrointestinales/patología , Tumores del Estroma Gastrointestinal/patología , Humanos , Interpretación de Imagen Asistida por Computador , Indolamina-Pirrol 2,3,-Dioxigenasa/análisis , Indolamina-Pirrol 2,3,-Dioxigenasa/biosíntesis , Linfocitos Infiltrantes de Tumor/patología , Masculino , Persona de Mediana Edad , Triptófano-ARNt Ligasa/análisis , Triptófano-ARNt Ligasa/biosíntesisRESUMEN
Fatty acid-binding protein 1 (FABP1) is an intracellular protein responsible for the transportation of long chain fatty acids. Aside from its functions in lipid metabolism and cellular differentiation, FABP1 also plays a role in inflammation through its interaction with peroxisome proliferator-activated receptors (PPARs). Previously, we compared expression of colonic epithelium genes in a subset of microsatellite instable (MSI) colorectal carcinomas (medullary carcinomas) to normal colonic mucosa and found that FABP1 expression was markedly decreased in the tumors. Further analysis of RNA expression in the colorectal subtypes and The Cancer Genome Atlas data set found that FABP1 expression is decreased in the CMS1 subset of colorectal carcinomas, which is characterized by microsatellite instability. As MSI colorectal carcinomas are known for their robust immune response, we then aimed to link FABP1 to the immune microenvironment of MSI carcinomas. To confirm the gene expression results, we performed immunohistochemical analysis of a cohort of colorectal carcinomas. FABP1 was preferentially lost in MSI carcinomas (123/133, 93%) compared with microsatellite stable carcinomas (240/562, 43%, P<0.0001). In addition, higher numbers of tumor-infiltrating lymphocytes were present in tumors with loss of FABP1 (P<0.0001). Decreased expression of the fatty acid storage and glucose regulator, PPARγ, was associated with the loss of FABP1 (P<0.0001). Colorectal cancer cell lines treated with interferon γ exhibited decreased expression of FABP1. FABP1 expression was partially recovered with the treatment of the cell lines with rosiglitazone, a PPARγ agonist. This study demonstrated that the loss of FABP1 expression is associated with MSI carcinomas and that interferon γ stimulation plays a role in this process via its interaction with PPARγ.
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Neoplasias Colorrectales/genética , Proteínas de Unión a Ácidos Grasos/genética , Regulación Neoplásica de la Expresión Génica , Interferón gamma/metabolismo , Línea Celular Tumoral , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Proteínas de Unión a Ácidos Grasos/metabolismo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/fisiología , Humanos , Interferón gamma/farmacología , Inestabilidad de Microsatélites , PPAR gamma/agonistas , Rosiglitazona , Tiazolidinedionas/farmacología , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/fisiologíaRESUMEN
Medullary carcinoma of the colon is a unique histologic subtype of microsatellite unstable colorectal carcinoma but little is known regarding its tumor-immunoregulatory microenvironment. The aims of this study were to characterize the immune environment of medullary carcinoma and compare it with other microsatellite unstable and microsatellite stable colorectal carcinomas. An initial gene expression microarray analysis of six cases of medullary carcinoma was used to detect potentially differentially expressed genes. We extended this analysis utilizing genomic data from the Cancer Genome Atlas to compare eight cases of medullary carcinoma with other microsatellite unstable and stable carcinomas. Finally, we evaluated expression of key immune pathway proteins and lymphocyte subsets via immunohistochemistry of a large group of medullary carcinomas (n=105) and compared these findings with three other groups: poorly differentiated, microsatellite unstable well-differentiated and microsatellite stable well-differentiated carcinomas. Microarray and the Cancer Genome Atlas data analysis identified significant upregulation of several immunoregulatory genes induced by IFNγ including IDO-1, WARS (tRNA(trp)), GBP1, GBP4, GBP5, PDCD1 (PD-1), and CD274 (PD-L1) in medullary carcinoma compared with other microsatellite unstable and microsatellite stable tumors. By immunohistochemistry, IDO-1 was expressed in 64% of medullary carcinomas compared with 19% (9/47) of poorly differentiated carcinomas, 14% (3/22) of microsatellite unstable, and 7% (2/30) of the microsatellite stable well-differentiated carcinomas (P<0.0001). tRNA(trp) was overexpressed in 81% (84/104) of medullary carcinomas, 19% (9/47) of poorly differentiated, 32% (7/22) of microsatellite unstable, and 3% (1/30) of microsatellite stable well-differentiated carcinomas (P<0.0001). Medullary carcinoma had higher mean CD8+ and PD-L1+ tumor-infiltrating lymphocytes compared with all other groups (P<0.0001). This study demonstrates overexpression of several immunoregulatory genes in microsatellite unstable colorectal carcinomas and that expression of these genes and proteins is more prevalent in the medullary carcinoma subtype, which may be of use both diagnostically and therapeutically.
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Carcinoma Medular/genética , Carcinoma Medular/patología , Neoplasias del Colon/genética , Neoplasias del Colon/patología , Microambiente Tumoral/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma Medular/inmunología , Neoplasias del Colon/inmunología , Femenino , Perfilación de la Expresión Génica , Humanos , Linfocitos Infiltrantes de Tumor/patología , Masculino , Persona de Mediana Edad , TranscriptomaRESUMEN
BACKGROUND: The influence of the tumor microenvironment and tumor-stromal interactions on the heterogeneity of response within breast cancer subtypes have just begun to be explored. This study focuses on patients with estrogen receptor-positive/human epidermal growth factor receptor 2-positive (ER+/HER2+) breast cancer receiving neoadjuvant chemotherapy and HER2-targeted therapy (NAC+H), and was designed to identify novel predictive biomarkers by combining gene expression analysis and immunohistochemistry with pathologic response. METHODS: We performed gene expression profiling on pre-NAC+H tumor samples from responding (no or minimal residual disease at surgery) and non-responding patients. Gene set enrichment analysis identified potentially relevant pathways, and immunohistochemical staining of pre-treatment biopsies was used to measure protein levels of those pathways, which were correlated with pathologic response in both univariate and multivariate analysis. RESULTS: Increased expression of genes encoding for stromal collagens, including Col10A1, and reduced expression of immune-associated genes, reflecting lower levels of total tumor-infiltrating lymphocytes (TILs), were strongly associated with poor pathologic response. Lower TILs in tumor biopsies correlated with reduced likelihood of achieving an optimal pathologic response, but increased expression of the Col10A1 gene product, colXα1, had greater predictive value than stromal abundance for poor response (OR = 18.9, p = 0.003), and the combination of increased colXα1 expression and low TILs was significantly associated with poor response in multivariate analysis. ROC analysis suggests strong specificity and sensitivity for this combination in predicting treatment response. CONCLUSIONS: Increased expression of stromal colXα1 and low TILs correlate with poor pathologic response in ER+/HER2+ breast tumors. Further studies are needed to confirm their predictive value and impact on long-term outcomes, and to determine whether this collagen exerts a protective effect on the cancer cells or simply reflects other factors within the tumor microenvironment.
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Neoplasias de la Mama/patología , Colágeno Tipo X/aislamiento & purificación , Linfocitos Infiltrantes de Tumor/patología , Receptor ErbB-2/genética , Receptores de Estrógenos/genética , Adulto , Anciano , Biomarcadores de Tumor/sangre , Biomarcadores de Tumor/genética , Neoplasias de la Mama/sangre , Neoplasias de la Mama/genética , Colágeno Tipo X/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Persona de Mediana Edad , Pronóstico , Resultado del Tratamiento , Microambiente Tumoral/genéticaRESUMEN
Glycogen synthase kinase 3 beta (GSK3ß) is a critical protein kinase that phosphorylates numerous proteins in cells and thereby impacts multiple pathways including the ß-Catenin/TCF/LEF-1 pathway. MicroRNAs (miRs) are a class of noncoding small RNAs of â¼22 nucleotides in length. Both GSK3ß and miR play myriad roles in cell functions including stem cell development, apoptosis, embryogenesis and tumorigenesis. Here we show that GSK3ß inhibits the expression of miR-96, miR-182 and miR-183 through the ß-Catenin/TCF/LEF-1 pathway. Knockout of GSK3ß in mouse embryonic fibroblast cells increases expression of miR-96, miR-182 and miR-183, coinciding with increases in the protein level and nuclear translocation of ß-Catenin. In addition, overexpression of ß-Catenin enhances the expression of miR-96, miR-182 and miR-183 in human gastric cancer AGS cells. GSK3ß protein levels are decreased in human gastric cancer tissue compared with surrounding normal gastric tissue, coinciding with increases of ß-Catenin protein, miR-96, miR-182, miR-183 and primary miR-183-96-182 cluster (pri-miR-183). Furthermore, suppression of miR-183-96-182 cluster with miRCURY LNA miR inhibitors decreases the proliferation and migration of AGS cells. Knockdown of GSK3ß with siRNA increases the proliferation of AGS cells. Mechanistically, we show that ß-Catenin/TCF/LEF-1 binds to the promoter of miR-183-96-182 cluster gene and thereby activates the transcription of the cluster. In summary, our findings identify a novel role for GSK3ß in the regulation of miR-183-96-182 biogenesis through ß-Catenin/TCF/LEF-1 pathway in gastric cancer cells.
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Regulación Neoplásica de la Expresión Génica , Glucógeno Sintasa Quinasa 3/metabolismo , Factor de Unión 1 al Potenciador Linfoide/metabolismo , MicroARNs/genética , Neoplasias Gástricas/genética , Factores de Transcripción TCF/metabolismo , beta Catenina/metabolismo , Transporte Activo de Núcleo Celular , Animales , Núcleo Celular/metabolismo , Células Cultivadas , Glucógeno Sintasa Quinasa 3/antagonistas & inhibidores , Glucógeno Sintasa Quinasa 3 beta , Humanos , Ratones , MicroARNs/metabolismo , Fenotipo , Regiones Promotoras Genéticas , Transducción de Señal , Neoplasias Gástricas/enzimología , Neoplasias Gástricas/metabolismo , Activación TranscripcionalRESUMEN
AIMS: Cadherin 17 (CDH17) is expressed primarily in normal intestinal epithelium and digestive tract tumours, and has limited expression in other neoplasms. The aims of this study were to examine CDH17 expression in well-differentiated neuroendocrine tumours (WDNETs) from various primary sites, representing the foregut, midgut, and hindgut, and tumours metastasizing to the liver, and to correlate the differences between the expression of CDH17, CDX2, and thyroid transcription factor 1 (TTF1). METHODS AND RESULTS: We investigated CDH17 immunohistochemical expression in 150 primary WDNETs from eight anatomical sites, including 68 from the foregut, 70 from the midgut, and 12 from the hindgut, and 15 metastases. CDH17 immunoreactivity increased significantly from foregut to hindgut WDNETs (P < 0.0001). Pancreatic WDNETs expressed CDH17 at a significantly higher frequency than other foregut tumours. Within the midgut, appendiceal and small-intestinal WDNETs were more frequently positive for CDH17 than for CDX2. All hindgut WDNETs expressed CDH17, in contrast to CDX2 (positive in one rectal case). CDH17 expression in liver metastases was similar to that of the primary tumours. CONCLUSIONS: This study is the first to comprehensively examine CDH17 expression in WDNETs from different sites. CDH17 is a sensitive marker for midgut WDNETs, and the CDH17+/CDX2-/TTF1- phenotype was found to be sensitive (92%) and specific (91%) for hindgut WDNETs.
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Biomarcadores de Tumor/metabolismo , Cadherinas/metabolismo , Proteínas de Unión al ADN/metabolismo , Neoplasias Intestinales/metabolismo , Tumores Neuroendocrinos/metabolismo , Humanos , Inmunohistoquímica , Neoplasias Intestinales/patología , Masculino , Tumores Neuroendocrinos/patología , Factores de TranscripciónAsunto(s)
Neoplasias de la Mama/diagnóstico , Carcinoma Ductal de Mama/diagnóstico , Carcinoma Intraductal no Infiltrante/diagnóstico , Receptor ErbB-2/metabolismo , Anciano , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/patología , Carcinoma Intraductal no Infiltrante/genética , Carcinoma Intraductal no Infiltrante/patología , Femenino , Humanos , Persona de Mediana Edad , Receptor ErbB-2/genéticaRESUMEN
Increased numbers of S100A4(+) cells are associated with poor prognosis in patients who have cancer. Although the metastatic capabilities of S100A4(+) cancer cells have been examined, the functional role of S100A4(+) stromal cells in metastasis is largely unknown. To study the contribution of S100A4(+) stromal cells in metastasis, we used transgenic mice that express viral thymidine kinase under control of the S100A4 promoter to specifically ablate S100A4(+) stromal cells. Depletion of S100A4(+) stromal cells significantly reduced metastatic colonization without affecting primary tumor growth. Multiple bone marrow transplantation studies demonstrated that these effects of S100A4(+) stromal cells are attributable to local non-bone marrow-derived S100A4(+) cells, which are likely fibroblasts in this setting. Reduction in metastasis due to the loss of S100A4(+) fibroblasts correlated with a concomitant decrease in the expression of several ECM molecules and growth factors, particularly Tenascin-C and VEGF-A. The functional importance of stromal Tenascin-C and S100A4(+) fibroblast-derived VEGF-A in metastasis was established by examining Tenascin-C null mice and transgenic mice expressing Cre recombinase under control of the S100A4 promoter crossed with mice carrying VEGF-A alleles flanked by loxP sites, which exhibited a significant decrease in metastatic colonization without effects on primary tumor growth. In particular, S100A4(+) fibroblast-derived VEGF-A plays an important role in the establishment of an angiogenic microenvironment at the metastatic site to facilitate colonization, whereas stromal Tenascin-C may provide protection from apoptosis. Our study demonstrates a crucial role for local S100A4(+) fibroblasts in providing the permissive "soil" for metastatic colonization, a challenging step in the metastatic cascade.
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Proteínas S100/metabolismo , Células del Estroma/metabolismo , Tenascina/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Animales , Línea Celular Tumoral , Proteínas de la Matriz Extracelular/genética , Proteínas de la Matriz Extracelular/metabolismo , Femenino , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Ganciclovir/farmacología , Perfilación de la Expresión Génica , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Humanos , Inmunohistoquímica , Masculino , Ratones , Ratones Noqueados , Ratones Transgénicos , Metástasis de la Neoplasia , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patología , Análisis de Secuencia por Matrices de Oligonucleótidos , Proteína de Unión al Calcio S100A4 , Proteínas S100/genética , Células del Estroma/efectos de los fármacos , Tenascina/genética , Timidina Quinasa/genética , Timidina Quinasa/metabolismo , Microambiente Tumoral/efectos de los fármacos , Factor A de Crecimiento Endotelial Vascular/genéticaRESUMEN
BACKGROUND: Liver histopathologic assessment is the accepted surrogate endpoint in NASH trials; however, the scoring of NASH Clinical Research Network (CRN) histologic parameters is limited by intraobserver and interobserver variability. We designed a consensus panel approach to minimize variability when using this scoring system. We assessed agreement between readers, estimated linear weighted kappas between 2 panels, compared them with published pairwise kappa estimates, and addressed how agreement or disagreement might impact the precision and validity of the surrogate efficacy endpoint in NASH trials. METHODS: Two panels, each comprising 3 liver fellowship-trained pathologists who underwent NASH histology training, independently evaluated scanned whole slide images, scoring fibrosis, inflammation, hepatocyte ballooning, and steatosis from baseline and month 18 biopsies for 100 patients from the precirrhotic NASH study REGENERATE. The consensus score for each parameter was defined as agreement by ≥2 pathologists. If consensus was not reached, all 3 pathologists read the slide jointly to achieve a consensus score. RESULTS: Between the 2 panels, the consensus was 97%-99% for steatosis, 91%-93% for fibrosis, 88%-92% for hepatocyte ballooning, and 84%-91% for inflammation. Linear weighted kappa scores between panels were similar to published NASH CRN values. CONCLUSIONS: A panel of 3 trained pathologists independently scoring 4 NASH CRN histology parameters produced high consensus rates. Interpanel kappa values were comparable to NASH CRN metrics, supporting the accuracy and reproducibility of this method. The high concordance for fibrosis scoring was reassuring, as fibrosis is predictive of liver-specific outcomes and all-cause mortality.
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Enfermedad del Hígado Graso no Alcohólico , Patólogos , Humanos , Consenso , Enfermedad del Hígado Graso no Alcohólico/diagnóstico , Reproducibilidad de los Resultados , Inflamación , FibrosisRESUMEN
The mechanisms of progression from Barrett's esophagus (BE) to esophageal adenocarcinoma (EA) are not known. Cycloxygenase-2 (COX-2)-derived prostaglandin E2 (PGE2) has been shown to be important in esophageal tumorigenesis. We have shown that COX-2 mediates acid-induced PGE2 production. The prostaglandin E synthase (PGES) responsible for acid-induced PGE2 production in BE, however, is not known. We found that microsomal PGES1 (mPGES1), mPGES2, and cytosolic PGES (cPGES) were present in FLO EA cells. Pulsed acid treatment significantly increased mPGES1 mRNA and protein levels but had little or no effect on mPGES2 or cPGES mRNA. Knockdown of mPGES1 by mPGES1 small interfering RNA (siRNA) blocked acid-induced increase in PGE2 production and thymidine incorporation. Knockdown of NADPH oxidase, NOX5-S, a variant lacking calcium-binding domains, by NOX5 siRNA significantly inhibited acid-induced increase in mPGES1 expression, thymidine incorporation, and PGE2 production. Overexpression of NOX5-S significantly increased the luciferase activity in FLO cells transfected with a nuclear factor κB (NF-κB) in vivo activation reporter plasmid pNF-κB-Luc. Knockdown of NF-κB1 p50 by p50 siRNA significantly decreased acid-induced increase in mPGES1 expression, thymidine incorporation, and PGE2 production. Two novel NF-κB binding elements, GGAGTCTCCC and CGGGACACCC, were identified in the mPGES1 gene promoter. We conclude that mPGES1 mediates acid-induced increase in PGE2 production and cell proliferation. Acid-induced mPGES1 expression depends on activation of NOX5-S and NF-κB1 p50. Microsomal PGES1 may be a potential target to prevent or treat EA.
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Adenocarcinoma/metabolismo , Esófago de Barrett/metabolismo , Neoplasias Esofágicas/metabolismo , Oxidorreductasas Intramoleculares/biosíntesis , Proteínas de la Membrana/metabolismo , NADPH Oxidasas/metabolismo , Subunidad p50 de NF-kappa B/metabolismo , Adenocarcinoma/enzimología , Adenocarcinoma/genética , Adenocarcinoma/patología , Esófago de Barrett/enzimología , Esófago de Barrett/genética , Esófago de Barrett/patología , Sitios de Unión , Línea Celular , Línea Celular Tumoral , Proliferación Celular , Dinoprostona/genética , Dinoprostona/metabolismo , Progresión de la Enfermedad , Neoplasias Esofágicas/enzimología , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patología , Regulación Neoplásica de la Expresión Génica , Humanos , Oxidorreductasas Intramoleculares/genética , Oxidorreductasas Intramoleculares/metabolismo , Proteínas de la Membrana/genética , NADPH Oxidasa 5 , NADPH Oxidasas/genética , Subunidad p50 de NF-kappa B/genética , Regiones Promotoras Genéticas , Prostaglandina-E Sintasas , Regulación hacia ArribaRESUMEN
Bile reflux is a risk factor in the development of intestinal metaplasia in the stomach and is believed to function as an initiator of gastric carcinogenesis. However, whether the G protein-coupled bile acid receptor TGR5 is expressed in this tumor is not known. In this study, we determined the expression of TGR5 in gastric adenocarcinoma and examined the role of TGR5 in cell proliferation. Strong TGR5 staining was present in 12% of cases of intestinal metaplasia but in no cases of normal gastric epithelium (P < 0.01). Moderate to strong TGR5 membranous and cytoplasmic staining was present in 52% of the intestinal but in only 25% of the diffuse subtype of adenocarcinomas (P < 0.001). Kaplan-Meier univariate survival analysis revealed that moderate to strong TGR5 staining was associated with decreased patient survival (P < 0.05). Treatment with taurodeoxycholic acid (TDCA, a bile acid) significantly increased thymidine incorporation in the AGS gastric adenocarcinoma cell line, suggesting that bile acids may increase cell proliferation. This increase was significantly decreased by knockdown of TGR5 with TGR5 small-interfering RNA (siRNA). In addition, overexpression of TGR5 significantly enhanced TDCA-induced increases in thymidine incorporation. TGR5 is coupled with G(q)α and Gα(i-3) proteins. TDCA-induced increase in thymidine incorporation was significantly decreased by knockdown of G(q)α and Gα(i-3) with their siRNAs. We conclude that TGR5 is overexpressed in most gastric intestinal-type adenocarcinomas, and moderate to strong TGR5 staining is associated with decreased patient survival in all gastric adenocarcinomas. Bile acids increase cell proliferation via activation of TGR5 receptors and G(q)α and Gα(i-3) proteins.