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1.
BMC Cancer ; 24(1): 294, 2024 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-38438903

RESUMO

BACKGROUND: IgG4, which plays a pivotal role in the progression of phenotypically diverse tumors, serves as a prognostic marker because of its influence on cancer immunity. Nevertheless, the functions of IgG4 in tongue squamous cell carcinoma (TSCC) remained to be identified. METHODS: To evaluate the significance of IgG4 expression in TSCC, we performed immunohistochemical analysis of patients with TSCC (n = 50) to evaluate the correlation of IgG4 expression with patients' clinicopathological features and prognoses. RESULTS: Higher IgG4 expression detected in TSCC tissues was associated with the less advanced mode of invasion (Yamamoto-Kohama [YK] 1-3) (P = 0.031) and with well-differentiated TSCC (P = 0.077). Kaplan-Meier analyses revealed that the higher IgG4 expression group exhibited better prognosis indicated by overall survival (OS) (P = 0.04) and recurrence-free survival (RFS) (P = 0.016). Univariate analysis of OS indicated that IgG4 expression was associated with longer OS (P = 0.061), and multivariate analysis of RFS revealed that IgG4 expression served as an independent prognostic factor for longer RFS (P = 0.005). CONCLUSION: These results indicate that relatively higher IgG4 levels serve as a favorable prognostic factor for TSCC.


Assuntos
Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Neoplasias Bucais , Neoplasias da Língua , Humanos , Carcinoma de Células Escamosas de Cabeça e Pescoço , Prognóstico , Imunoglobulina G
2.
Liver Int ; 44(2): 483-496, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38010940

RESUMO

OBJECTIVE: Hepatic overexpression of the thrombospondin 2 gene (THBS2) and elevated levels of circulating thrombospondin 2 (TSP2) have been observed in patients with chronic liver disease. This study aimed to identify the specific cells expressing THBS2/TSP2 in non-alcoholic fatty liver disease (NAFLD) and investigate the underlying mechanism behind THBS2/TSP2 upregulation. DESIGN: Comprehensive NAFLD liver gene datasets, including single-cell RNA sequencing (scRNA-seq), in-house NAFLD liver tissue, and LX-2 cells derived from human hepatic stellate cells (HSCs), were analysed using a combination of computational biology, genetic, immunological, and pharmacological approaches. RESULTS: Analysis of the genetic dataset revealed the presence of 1433 variable genes in patients with advanced fibrosis NAFLD, with THBS2 ranked among the top 2 genes. Quantitative polymerase chain reaction (qPCR) examination of NAFLD livers showed a significant correlation between THBS2 expression and fibrosis stage (r = .349, p < .001). In support of this, scRNA-seq data and in situ hybridization demonstrated that the THBS2 gene was highly expressed in HSCs of NAFLD patients with advanced fibrosis. Pathway analysis of the gene dataset revealed THBS2 expression to be associated with the transforming growth factor beta (TGFß) pathway and collagen gene activation. Moreover, the activation of LX-2 cells with TGFß increased THBS2/TSP2 and collagen expression independently of the TGFß-SMAD2/3 pathway. THBS2 gene knockdown significantly decreased collagen expression in LX-2 cells. CONCLUSIONS: THBS2/TSP2 is highly expressed in HSCs and plays a role in regulating fibrogenesis in NAFLD patients. THBS2/TSP2 may therefore represent a potential target for anti-fibrotic therapy in NAFLD.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Trombospondinas , Humanos , Hepatopatia Gordurosa não Alcoólica/complicações , Fígado/patologia , Fibrose , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo , Células Estreladas do Fígado/metabolismo , Colágeno/metabolismo , Cirrose Hepática/complicações
3.
Pathol Int ; 74(7): 387-393, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38787285

RESUMO

Leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5), a significant cancer stem cell marker in colorectal cancer (CRC), lacks lymph node (LN) expression studies. In this study, we identified LGR5 expression by RNAscope, a highly sensitive RNA in situ method, and analyzed its association with clinicopathological characteristics. Tissue microarrays were generated from primary tumors (PTs) and LN metastases in paraffin-embedded blocks of 38 CRC surgical resection materials. LGR5 expression by RNAscope was evaluated by dividing the expression levels into negative and positive expression. In all but two cases of LN metastasis, LGR5-positive dots were detected in tumor cells, and there was a wide range of LGR5-positive cells. More LGR5-positive dots were identified in the gland-forming region. Twenty-three cases were classified into a high LGR5-expression group, and 15 cases were classified into a low LGR5-expression group. In the high LGR5-expression group, the histological grade was lower than in the low LGR5-expression group (p = 0.0159), while necrosis was significantly more prevalent (p = 0.0326), and the tumor, node, metastasis stage was significantly lower (p = 0.0302). There was no association between LGR5 expression levels in LN metastases and LGR5 expression levels in PT tissue. LGR5 expression in LN metastases may influence prognosis. Further analysis may lead to new therapeutic strategies.


Assuntos
Biomarcadores Tumorais , Neoplasias Colorretais , Metástase Linfática , Receptores Acoplados a Proteínas G , Humanos , Neoplasias Colorretais/patologia , Neoplasias Colorretais/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/genética , Masculino , Feminino , Metástase Linfática/patologia , Pessoa de Meia-Idade , Idoso , Prognóstico , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/análise , Idoso de 80 Anos ou mais , Adulto , Linfonodos/patologia , Linfonodos/metabolismo
4.
BMC Cancer ; 23(1): 478, 2023 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-37237373

RESUMO

BACKGROUND: ADP-ribosylation factor-like protein 4 C (ARL4C) is a member of the ARF small GTP-binding protein subfamily. The ARL4C gene is highly expressed in colorectal cancer (CRC). ARL4C protein promotes cell motility, invasion, and proliferation. METHODS: We investigated the characteristics of ARL4C by comparing its expression at the invasion front and relationships with clinicopathological data using RNAscope, a highly sensitive RNA in situ method. RESULTS: In all cases, ARL4C expression was observed in cancer stromal cells and cancer cells. ARL4C expression in cancer cells was localized at the invasion front. In cancer stromal cells, ARL4C expression was significantly stronger in cases with high-grade tumor budding than in cases with low-grade tumor budding (P = 0.0002). Additionally, ARL4C expression was significantly increased in patients with high histological grade compared with those with low histological grade (P = 0.0227). Furthermore, ARL4C expression was significantly stronger in lesions with the epithelial-to-mesenchymal transition (EMT) phenotype compared with the non-EMT phenotype (P = 0.0289). In CRC cells, ARL4C expression was significantly stronger in cells that had the EMT phenotype compared with those with a non-EMT phenotype (P = 0.0366). ARL4C expression was significantly higher in cancer stromal cells than in CRC cells (P < 0.0001). CONCLUSION: Our analysis reinforces the possibility that ARL4C expression worsens the prognosis of patients with CRC. Further elucidation of the function of ARL4C is desired.


Assuntos
Transformação Celular Neoplásica , Neoplasias Colorretais , Humanos , Prognóstico , Fenótipo , Transformação Celular Neoplásica/genética , Neoplasias Colorretais/patologia , Transição Epitelial-Mesenquimal/genética , Regulação Neoplásica da Expressão Gênica , Movimento Celular/genética , Proliferação de Células/genética , Linhagem Celular Tumoral , Fatores de Ribosilação do ADP/genética , Fatores de Ribosilação do ADP/metabolismo
5.
Dig Dis Sci ; 67(6): 2134-2142, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-34081250

RESUMO

BACKGROUND: LGR5 is a promising stem cell marker in gastric pylorus, but there are few reports on its expression in human gastric corpus. AIMS: To investigate the involvement of LGR5 expression in gastric corpus ulcer regeneration in humans. METHODS: LGR5 expression was analyzed in five post-ESD ulcers during the healing process of regenerating epithelial cells of the gastric corpus. LGR5 expression was detected by mRNA in situ hybridization using an RNA scope kit. Immunohistochemistry of MUC6, HIK1083, and pepsinogen 1 (PG1) was performed to identify cell differentiation. RESULTS: We defined MUC6+/HIK1083-/PG1-, MUC6+/HIK1083+/PG1-, MUC6+/HIK1083+/PG1+, MUC6+/HIK1083-/PG1+, and MUC6-/HIK1083-/PG1+cells as pseudopyloric mucosa (PPM) phase 1 (PPM1), PPM phase 2 (PPM2), PPM phase 3 (PPM3), immature chief cells (ICC), and mature chief cells (MCC) in order from the ulcer center, respectively. In the regenerated mucosa around post-ESD ulcers, LGR5 expression was observed throughout the gland in PPM1-PPM3, but it was limited to the bottom of the gland in ICC and MCC. Furthermore, LGR5 expression was not identified in the normal gastric corpus. The H-score of PPM2 was significantly higher than that of PPM3 (P = 0.0313). The H-score of PPM3 was significantly higher than that of ICC (P = 0.0313). The LGR5 H-score was higher at the immature stage, which decreased gradually with progression of the differentiation stage. CONCLUSIONS: LGR5 expression appears to contribute to mucosal regeneration in the human gastric corpus. The application of LGR5 expression analysis to mucosal regeneration and fundic gland-type gastric tumors is expected.


Assuntos
Neoplasias Gástricas , Úlcera Gástrica , Mucosa Gástrica/patologia , Humanos , Imuno-Histoquímica , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Neoplasias Gástricas/patologia , Úlcera Gástrica/patologia , Úlcera/patologia
6.
Histopathology ; 79(2): 227-237, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33590909

RESUMO

AIMS: Claudin 18 (CLDN18) is a member of the claudin family of cell surface proteins, which are widely expressed in epithelial cells and play a role in cell-cell adhesion. CLDN18 isoform 2 (CLDN18.2) is specifically expressed in gastric epithelial cells, and is frequently expressed at high levels in gastric adenocarcinoma. On the basis of this, zolbetuximab, a targeted monoclonal antibody, has been developed for patients with CLDN18.2-positive gastro-oesophageal adenocarcinoma. Colitis-associated colorectal adenocarcinomas (CACs) tend to lose intestinal markers and show aberrant gastric mucin expression. Furthermore, clinical trials of human epidermal growth factor receptor 2 (HER2) inhibitor therapy for colorectal carcinoma are ongoing. However, the expression profile of CLDN18.2 and HER2 has not been described in a series of human CACs. METHODS AND RESULTS: We performed immunohistochemistry for CLDN18 and HER2 on 56 consecutive CACs from 55 inflammatory bowel disease patients, and compared the expression profile with that of a control group of 56 sporadic colorectal adenocarcinomas (CRCs). CLDN18.1 expression and CLDN18.2 expression were validated by reverse transcription polymerase chain reaction (PCR) in paraffin-embedded CRC tissues. CLDN18 was positive in 27% (15/56) of CACs and in 5% (3/56) of sporadic CRCs (P = 0.004), and CLDN18-positive CACs were more likely to have lymph node metastasis than CLDN18-negative CACs (67% versus 36%; P = 0.017). CLDN18 expression was significantly associated with MUC5AC expression (P < 0.001) and loss of special AT-rich sequence-binding protein 2 expression (P = 0.005) in CACs. CLDN18.2 was expressed in CRCs that were immunoreactive for CLDN18. Only 4% of CACs were immunoreactive for HER2, and no differences were identified in sporadic CRCs. CONCLUSIONS: These findings suggest that certain CAC cases may be candidates for targeted zolbetuximab therapy.


Assuntos
Adenocarcinoma , Anticorpos Monoclonais/uso terapêutico , Claudinas/metabolismo , Colite , Neoplasias Colorretais , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/etiologia , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Colite/complicações , Colite/metabolismo , Colite/patologia , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/etiologia , Neoplasias Colorretais/patologia , Feminino , Humanos , Imuno-Histoquímica , Imunoterapia , Doenças Inflamatórias Intestinais/complicações , Doenças Inflamatórias Intestinais/metabolismo , Doenças Inflamatórias Intestinais/patologia , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos , Isoformas de Proteínas , Receptor ErbB-2
7.
BMC Cancer ; 21(1): 119, 2021 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-33541282

RESUMO

BACKGROUND: Leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5), a component of the Wnt receptor complex, is thought to lineage label gastric and intestinal stem cells. LGR5 expression is increased in colorectal carcinoma (CRC) compared to normal tissue. Colitis associated colorectal adenocarcinoma (CAC) often shows distinct morphologic and molecular phenotypes compared to sporadic cases. However, the expression profile of LGR5, and by extension the potential role of an intestinal stem cell phenotype, has not been well described in a series of human CAC. METHOD: RNA in situ hybridization (ISH) for LGR5 expression on 30 CACs (12 cases with conventional morphology and 18 cases with non-conventional type morphology) from 29 inflammatory bowel disease (IBD) patients was performed and compared the expression profile to a control group of 10 sporadic CRCs. Immunohistochemistry for beta-catenin and SATB2 was performed on the 30 CACs. RESULT: LGR5 was positive in 30% (9/30) of CAC cases and 90% (9/10) of sporadic CRCs (p = 0.002). A large majority (89%) of LGR5 positive CACs were of the conventional histologic type, and conventional type CAC showed a significantly higher LGR5 score (median 3.0; interquartile range 1.75-3.25) than non-conventional type CAC (median 1.5; interquartile range 1.00-2.00) (p = 0.034). CAC with conventional morphology did have a lower level of LGR5 expression than sporadic CRC. Sporadic CRCs showed a significantly higher LGR5 level score than non-conventional type CACs (p < 0.001). Nuclear translocation of beta-catenin was strongly associated with LGR5 expression (p = 0.003), however no significant association was identified between SATB2 expression and LGR5 expression status in CACs. CONCLUSION: These findings suggest that the wider spectrum of tumor morphology in CAC may be associated with absence of a LGR5-expressing intestinal stem cell phenotype.


Assuntos
Adenocarcinoma/patologia , Biomarcadores Tumorais/metabolismo , Carcinogênese/patologia , Colite/complicações , Neoplasias Colorretais/patologia , Receptores Acoplados a Proteínas G/metabolismo , Adenocarcinoma/etiologia , Adenocarcinoma/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Carcinogênese/metabolismo , Estudos de Casos e Controles , Neoplasias Colorretais/etiologia , Neoplasias Colorretais/metabolismo , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Receptores Acoplados a Proteínas G/genética , Taxa de Sobrevida
8.
BMC Cancer ; 21(1): 228, 2021 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-33676447

RESUMO

BACKGROUND: Leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5) is an important cancer stem cell marker in gastric cancer. However, no detailed studies are available on LGR5 expression in poorly differentiated gastric adenocarcinoma (PD-AC). Therefore, we investigated the relationship between LGR5 expression and clinicopathological data in PD-AC. METHODS: LGR5 mRNA expression levels were quantified in 41 PD-AC specimens using a highly sensitive RNAscope in situ hybridization technique. Epstein-Barr virus (EBV) infection was also detected by EBV in situ hybridization. RESULTS: LGR5 expression levels were measured in 38 of 41 PD-AC cases, and 17 cases were identified as LGR5 high. The frequency of EBV positivity tended to be higher in the LGR5-low group than in the LGR5-high group (P = 0.0764). Furthermore, the frequency of vascular invasion tended to be higher in the LGR5-high group than in the LGR5-low group (P = 0.0764). The overall survival of PD-AC patients in the LGR5-high group was significantly lower than in the LGR5-low group (log-rank test, P = 0.0108). The Cox proportional hazard regression model revealed that the LGR5-low group (HR = 0.29; 95% CI: 0.11-0.74; P = 0.01) showed independently better OS for PD-AC. CONCLUSIONS: Quantifying the levels of LGR5 expression may facilitate defining prognosis in Japanese patients with PD-AC. Further study of LGR5 in this context is warranted.


Assuntos
Adenocarcinoma/mortalidade , Biomarcadores Tumorais/metabolismo , Infecções por Vírus Epstein-Barr/epidemiologia , Receptores Acoplados a Proteínas G/metabolismo , Neoplasias Gástricas/mortalidade , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Adenocarcinoma/virologia , Idoso , Infecções por Vírus Epstein-Barr/diagnóstico , Infecções por Vírus Epstein-Barr/patologia , Infecções por Vírus Epstein-Barr/virologia , Feminino , Gastrectomia , Mucosa Gástrica/patologia , Mucosa Gástrica/cirurgia , Mucosa Gástrica/virologia , Herpesvirus Humano 4/isolamento & purificação , Humanos , Japão/epidemiologia , Estimativa de Kaplan-Meier , Masculino , Prognóstico , Estudos Retrospectivos , Neoplasias Gástricas/patologia , Neoplasias Gástricas/cirurgia , Neoplasias Gástricas/virologia
9.
BMC Pulm Med ; 21(1): 219, 2021 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-34246246

RESUMO

BACKGROUND: It is difficult to distinguish between multicentric Castleman's disease (MCD) and IgG4-related lung disease (IgG4-LD), an IgG4-related disease (IgG4-RD) in the lung. METHODS: We focused on IL-6, which is elevated in MCD, to distinguish between MCD and IgG4-LD by RNAscope, a highly sensitive RNA in situ method. Six cases of MCD and four cases of IgG4-LD were selected. RESULTS: In all cases of MCD and IgG4-LD, 10 or more IgG4-positive cells were found in one high-power field. All MCD cases were inconsistent with the pathological IgG4-related comprehensive diagnostic criteria, but 2 of 6 cases had an IgG4/IgG ratio greater than 40%. In all IgG4-LD cases, histological features were consistent with the pathological IgG4-RD comprehensive diagnostic criteria. IL-6 expression was observed in all MCD and IgG4-LD cases except for one IgG4-LD biopsy. IL-6-expressing cells were mainly identified in the stroma. Sites of IL-6 expression were not characteristic and were sparse. IL-6 expression tended to be higher in MCD compared with IgG4-LD. A positive correlation was found between the IL-6 H-score and serum IL-6 level. CONCLUSION: Differences in IL-6 expression may help distinguish between MCD and IgG4-LD. In addition, the presence of high IL-6 levels may help elucidate the pathological mechanisms of IgG4-LD.


Assuntos
Hiperplasia do Linfonodo Gigante/diagnóstico , Doença Relacionada a Imunoglobulina G4/diagnóstico , Interleucina-6/metabolismo , Pulmão/patologia , Adulto , Idoso , Biópsia , Hiperplasia do Linfonodo Gigante/metabolismo , Hiperplasia do Linfonodo Gigante/patologia , Diagnóstico Diferencial , Feminino , Humanos , Doença Relacionada a Imunoglobulina G4/metabolismo , Doença Relacionada a Imunoglobulina G4/patologia , Hibridização In Situ/métodos , Interleucina-6/genética , Japão , Pulmão/metabolismo , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
10.
Ann Diagn Pathol ; 52: 151739, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33862415

RESUMO

We investigated the expression of LGR5, the most robust and reliable known cancer stem cell (CSC) marker of colorectal cancer, and PD-L1 in tumor budding (TB), as well as clinicopathological features. Tissue microarrays (TMAs) were generated from TB samples from 32 stage II/III colorectal adenocarcinoma patients, and LGR5 expression in TMAs was evaluated by RNAscope, an extremely sensitive RNA in situ hybridization technique. LGR5 expression was significantly lower in the PD-L1-positive group than in the PD-L1-negative group (P = 0.0256). In the PD-L1-positive group, the tumor-infiltrating lymphocytes (TILs) score tended to be higher while the TNM stage was lower compared with the PD-L1 negative group (P = 0.0822 and P = 0.0765, respectively). There was no significant difference in Overall Survival between the PD-L1-positive and PD-L1-negative groups (log-rank test, P = 0.8218). This study showed that PD-L1-positive patients are a unique population with low LGR5 expression, and that LGR5-positive cells may be a promising therapeutic target in PD-L1-negative patients.


Assuntos
Adenocarcinoma/metabolismo , Antígeno B7-H1/metabolismo , Estadiamento de Neoplasias/métodos , Receptores Acoplados a Proteínas G/metabolismo , Adenocarcinoma/diagnóstico , Adenocarcinoma/mortalidade , Idoso , Estudos de Casos e Controles , Neoplasias Colorretais/patologia , Feminino , Humanos , Imuno-Histoquímica/métodos , Hibridização In Situ/métodos , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos do Interstício Tumoral/patologia , Masculino , Estadiamento de Neoplasias/estatística & dados numéricos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Prognóstico , RNA/genética , Análise Serial de Tecidos/métodos
11.
Cytokine ; 133: 155123, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32447247

RESUMO

We previously reported higher levels of C-C chemokine ligand (CCL) 1 in the bronchoalveolar lavage (BAL) fluid (BALF) of patients with sarcoidosis than in BALF of patients with immunoglobulin G4 (IgG4)-related disease (IgG4-RD), indicating that CCL1 might act as a marker of disease activity in sarcoidosis. Notably, less invasive sampling sources are desirable, as BAL cannot always be performed due to its inherent risk. In this study, we sought to decipher the correlation between serum levels of CCL1 and clinical characteristics of sarcoidosis. Serum samples were obtained from 44 patients with clinically confirmed sarcoidosis, 14 patients with IgG4-RD, and 14 healthy controls. The clinical and radiological findings were retrospectively evaluated. Serum levels of CCL1 were measured using a sandwich enzyme-linked immunosorbent assay. Serum levels of other 17 cytokines and chemokines were measured using a MILLIPLEX® MAP KIT and Luminex® magnetic beads. Serum levels of CCL1 were significantly higher in patients with sarcoidosis than in patients with IgG4-RD and healthy controls. Serum CCL1 was positively correlated with the degree of hilar lymph node swelling on chest computed tomography and serum levels of soluble interleukin 2 receptor. Positive correlations were also observed between serum CCL1 and total cell counts, lymphocyte counts in BALF, and serum T helper 1 mediators such as IP-10 and TNF-α in patients with sarcoidosis. Serum CCL1 levels were significantly elevated in sarcoidosis and correlated with clinical parameters of the disease. In addition, serum and BALF levels of CCL1 were positively correlated in a statistically significant manner. Although further research in this field is necessary, CCL1 might have the potential to be a reliable serological marker of disease activity in sarcoidosis.


Assuntos
Quimiocina CCL1/metabolismo , Doença Relacionada a Imunoglobulina G4/metabolismo , Imunoglobulina G/metabolismo , Sarcoidose/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Líquido da Lavagem Broncoalveolar , Feminino , Humanos , Ligantes , Masculino , Pessoa de Meia-Idade , Receptores de Interleucina-2/metabolismo , Estudos Retrospectivos , Adulto Jovem
12.
BMC Cancer ; 20(1): 319, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32293346

RESUMO

BACKGROUND: Leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5) is a promising intestinal stem cell and carcinoma stem cell marker. We examined the relationship between mismatch repair (MMR) protein deficiency and LGR5 expression in poorly differentiated (PD) colorectal carcinoma (CRC). METHODS: In 29 cases of PD-CRC, deficiencies in MMR proteins (MLH1, PMS2, MSH2, MSH6) and ß-catenin expression were identified by immunohistochemistry (IHC). LGR5 expression was examined by the RNAscope assay in tissue microarrays. RESULTS: LGR5 H-scores in MMR-deficient (MMR-D) cases were significantly lower than those in MMR-proficient (MMR-P) cases (P = 0.0033). Nuclear ß-catenin IHC scores in MMR-D cases were significantly lower than those in MMR-P cases (P = 0.0024). In all cases, there was a positive correlation between LGR5 H-score and nuclear ß-catenin IHC score (r = 0.6796, P < 0.001). Even in MMR-D and MMR-P cases, there was a positive correlation between LGR5 H-score and nuclear ß-catenin IHC score (r = 0.7180, P < 0.0085 and r = 0.6574, P < 0.003, respectively). MMR-D CRC cases showed low expression of LGR5, which may be due to low activation of the Wnt/ß-catenin signaling pathway. CONCLUSIONS: Our results reveal the relationship between LGR5 expression and MMR protein profiles in PD-CRC. A further study is warranted to confirm these findings.


Assuntos
Neoplasias Colorretais/genética , Reparo de Erro de Pareamento de DNA , Regulação para Baixo , Receptores Acoplados a Proteínas G/genética , Neoplasias Colorretais/metabolismo , Proteínas de Ligação a DNA/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Endonuclease PMS2 de Reparo de Erro de Pareamento/metabolismo , Proteína 1 Homóloga a MutL/metabolismo , Proteína 2 Homóloga a MutS/metabolismo , beta Catenina/metabolismo
13.
Ann Diagn Pathol ; 48: 151587, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32829068

RESUMO

Colon cancer stem cells (CSCs) are closely related to tumorigenesis and treatment response, and LGR5 is currently the most robust and reliable CSC marker in colorectal cancer (CRC). However, LGR5 expression in CRC tumor budding (TB) is not well understood. We examined the clinicopathological and prognostic significance of LGR5 in CRC TB. LGR5 expression was evaluated by RNAscope, a newly developed RNA in situ hybridization technique, using a tissue microarray consisting of 55 patient samples of TB in colon adenocarcinoma (CA) selected from the medical archives at our hospital. Patients were stratified into negative and positive LGR5 expression groups. Tumor-infiltrating lymphocytes (TILs) and histological grade were lower in the LGR5-positive group compared with the LGR5-negative group (P = .0407 and P = .0436, respectively). There was no significant difference in overall survival between the LGR5-positive group and the LGR5-negative group (log-rank test, P = .6931). LGR5 expression did not remain a predictor of prognosis in univariate analysis (OR = 0.84, 95% CI: 0.33-2.02, P = .6928). LGR5 expression may be affected by TILs, which have been demonstrated to be associated with worse prognosis in the budding area of CA and is an important potential marker of prognosis.


Assuntos
Adenocarcinoma/metabolismo , Neoplasias do Colo/patologia , Células-Tronco Neoplásicas/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Adenocarcinoma/diagnóstico , Idoso , Carcinogênese/metabolismo , Estudos de Casos e Controles , Feminino , Humanos , Hibridização In Situ/métodos , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos do Interstício Tumoral/patologia , Masculino , Estadiamento de Neoplasias , Células-Tronco Neoplásicas/patologia , Prognóstico , RNA/genética , Taxa de Sobrevida , Análise Serial de Tecidos/métodos
14.
Ann Diagn Pathol ; 46: 151491, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32163872

RESUMO

LGR5 is the most robust known stem cell marker for gastrointestinal tumors, but there are few reports in breast cancer. Triple negative breast cancer (TNBC) is the most malignant subtype of breast cancer, and thus identification of new cancer stem cell populations in TNBC may help to identify targeted therapies. LGR5 expression was evaluated by RNAscope, a newly developed RNA in situ hybridization technique, using a tissue microarray consisting of 43 patient samples of TNBC selected from the medical archives at our hospital. Patients were stratified into negative and positive LGR5 expression groups. Tumor necrosis was greater in the LGR5-positive group compared with the LGR5-negative group (P = .026). Mitosis tended to show a high value in the LGR5-positive group compared with the LGR5-negative group (P = .0831), while stage tended to show a high stage in the LGR5-positive group compared with the LGR5-negative group (P = .0617). Cox proportional hazards models revealed that the LGR5-positive group (overall survival (OS) = 2.12; 95% CI: 2.12-2.12; P = 0.1575) had no relationship with OS. LGR5 expression is associated with tumor necrosis of TNBC and suggested higher malignant potential.


Assuntos
Biomarcadores Tumorais/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Adulto , Idoso , Feminino , Humanos , Pessoa de Meia-Idade , Estudos Retrospectivos
15.
Mod Pathol ; 32(6): 884-892, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30710095

RESUMO

The special AT-rich sequence binding protein 2 (SATB2) is a sensitive and specific diagnostic marker for colorectal adenocarcinoma and reduced expression of SATB2 is associated with a poor prognosis. Colitis-associated colorectal adenocarcinoma often shows distinct morphologic and molecular phenotypes compared to sporadic cases. However, the SATB2 expression profile in colitis-associated carcinoma has not been defined. We performed immunohistochemistry for SATB2 as well as CDX2, MUC5AC, MUC6 and mismatch repair proteins on 60 consecutive colitis-associated carcinomas from 58 inflammatory bowel disease patients and compared the expression profile to a control group of 32 sporadic colorectal carcinomas. Only 26 (43%) colitis-associated carcinomas expressed SATB2, compared to 29 (91%) sporadic colorectal carcinomas (p < 0.0001). MUC5AC expression was more frequently observed in colitis-associated carcinomas than sporadic colorectal caracinomas (52% and 25% respectively; p = 0.013). Eight (13%) cases of colitis-associated carcinoma showed loss of CDX2 expression, which was retained in all of the sporadic controls (p = 0.047). In colitis-associated carcinoma, 50% of SATB2 negative cases had lymph node metastasis compared to only 15% of SATB2 positive cases (p = 0.007). Loss of SATB2 was particularly frequent in mucinous-type tumors, occurring in 83% of these cases. There was no significant association between SATB2 expression and mismatch repair protein status. These data show that the immunoprofile of colitis-associated carcinoma is different than that seen in sporadic cases. In particular, SATB2 is significantly less sensitive in colitis-associated carcinoma and it should be interpreted cautiously as a marker of colorectal origin in colitis patients. The association between loss of SATB2 and lymph node metastasis suggests that it may have similar prognostic value in the setting of inflammatory bowel disease as in sporadic cases.


Assuntos
Adenocarcinoma/metabolismo , Biomarcadores Tumorais/análise , Colite/complicações , Neoplasias Colorretais/metabolismo , Proteínas de Ligação à Região de Interação com a Matriz/biossíntese , Fatores de Transcrição/biossíntese , Adenocarcinoma/etiologia , Adenocarcinoma/patologia , Adulto , Idoso , Neoplasias Colorretais/etiologia , Neoplasias Colorretais/patologia , Feminino , Humanos , Masculino , Proteínas de Ligação à Região de Interação com a Matriz/análise , Pessoa de Meia-Idade , Mucinas/biossíntese , Fatores de Transcrição/análise
16.
Cytokine ; 120: 125-129, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31063909

RESUMO

BACKGROUND: We previously reported that the cytokine profiles in the bronchoalveolar lavage fluid (BALF) of IgG4-related respiratory disease (IgG4-RRD) more closely resemble the T-helper (Th) 2 response than sarcoidosis. The present study aimed to assess the chemokines in the BALF of IgG4-RRD and sarcoidosis in order to evaluate any possible associations between these chemokines and other markers. METHODS: We examined 12 chemokines using a MILLIPLEX® MAP Kit (Millipore, Darmstadt, Germany) in the same BALF samples of the same 44 patients (IgG4-RRD, n = 11; sarcoidosis, n = 33) in which we had previously evaluated the cytokines. RESULTS: The levels of CC-chemokine ligand (CCL)26 in the BALF of IgG4-RRD patients (median 24.5, range 3.1-401.1 pg/mL) were significantly higher than those in the BALF of sarcoidosis patients (median 3.1, range 3.1-155.6 pg/mL, p < 0.05). Interestingly, the BALF levels of CCL1 in the sarcoidosis patients (median 13.1, range 0.1-106.9 pg/mL) were significantly higher than those of the IgG4-RRD patients (median 9.8, range 0.1-14.7 pg/mL, p < 0.05). Furthermore, the CCL1 levels in the BALF were correlated with the total cell count (ρ = 0.539, p < 0.001), lymphocyte fraction (R = 0.406, P < 0.05), lymphocyte count (R = 0.686, P < 0.001), TNF-α level, (R = 0.748, P < 0.001), and IL-2 level (R = 0.757, P < 0.001) in the BALF of sarcoidosis patients. CONCLUSIONS: CCL1 might reflect disease activity and its involvement in the pathogenesis of sarcoidosis might be more closely related to Th1 than to Th2.


Assuntos
Líquido da Lavagem Broncoalveolar/química , Quimiocina CCL1/metabolismo , Quimiocinas/metabolismo , Imunoglobulina G/imunologia , Doenças Respiratórias/imunologia , Sarcoidose/imunologia , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
17.
Ann Diagn Pathol ; 40: 161-165, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31100646

RESUMO

Colon cancer stem cells (CSCs) are closely related to tumorigenesis and treatment response, and LGR5 is currently the most robust and reliable CSC marker in colorectal cancer (CRC). However, LGR5 expression in CRC tumor budding (TB) is not well understood. We examined the clinicopathological and prognostic significance of LGR5 in CRC TB. LGR5 expression was evaluated by RNAscope, a newly developed RNA in situ hybridization technique, using a tissue microarray consisting of 55 patient samples of TB in colon adenocarcinoma (CA) selected from the medical archives at our hospital. Patients were stratified into negative and positive LGR5 expression groups. Inflammatory cell infiltration was weaker and histological grade was lower in the LGR5-positive group compared with the LGR5-negative group (P = 0.0407 and P = 0.0436, respectively). There was a significant difference in OS between the LGR5-positive group and LGR5-negative group (log-rank test, P = 0.0088). Cox proportional hazards models revealed that the LGR5-positive group (Overall survival (OS) = 0.37, 95% CI: 0.17-0.79, P = 0.0101) had better OS. LGR5 expression may be affected by inflammatory cell infiltration in the budding area of CA and is an important potential marker of prognosis.


Assuntos
Adenocarcinoma/patologia , Neoplasias do Colo/patologia , Neoplasias Colorretais/patologia , Receptores Acoplados a Proteínas G/metabolismo , Adenocarcinoma/diagnóstico , Adenocarcinoma/metabolismo , Idoso , Carcinogênese , Colo/patologia , Neoplasias do Colo/diagnóstico , Neoplasias do Colo/metabolismo , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/metabolismo , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Prognóstico , Modelos de Riscos Proporcionais , Receptores Acoplados a Proteínas G/genética
18.
Histopathology ; 73(1): 38-48, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29469192

RESUMO

AIMS: GATA6 is known to play a role in lung development. However, its role in the carcinogenesis of lung cancer is not well studied. The aim of this study was to analyse GATA6 expression in lung adenocarcinomas (LAs) by immunohistochemistry (IHC) in order to define its association with clinicopathological characteristics. METHODS AND RESULTS: IHC analysis of GATA6 was performed with tissue microarray slides containing 348 LAs. The association between GATA6 expression and clinicopathological parameters was evaluated. GATA6 expression in epithelial tumours other than lung cancer was also evaluated. GATA6 expression was found in 47 LAs (13.5%). This occurred more frequently in younger patients (P = 0.005), and was associated with the absence of lymph node metastasis (P =0.024), well-differentiated to moderately differentiated tumours (P < 0.001), the absence of lymphatic invasion (P = 0.020), and the absence of vascular invasion (P = 0.011). GATA6 expression was associated with mucin production (P < 0.001), the invasive mucinous adenocarcinoma subtype (P < 0.001), KRAS mutations (P = 0.026), expression of MUC2 (P < 0.001), CDX2 (P = 0.049), and MUC5AC (P < 0.001), and absence of expression of TTF-1 (P = 0.002). GATA6 expression was also associated with hepatocyte nuclear factor 4α (HNF4α) expression (P < 0.001). GATA6 expression tended to indicate better prognoses, whereas patients with HNF4α expression had significantly worse prognoses (P = 0.033). Of 270 tumours other than lung cancer, 110 expressed GATA6. CONCLUSIONS: These findings suggest that GATA6 might interact with HNF4α and contribute to the development of mucinous-type LAs.


Assuntos
Adenocarcinoma/patologia , Fator de Transcrição GATA6/metabolismo , Fator 4 Nuclear de Hepatócito/biossíntese , Neoplasias Pulmonares/patologia , Proteínas Proto-Oncogênicas p21(ras)/genética , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma de Pulmão , Adenocarcinoma Mucinoso/patologia , Idoso , Biomarcadores Tumorais/análise , Feminino , História do Século XVII , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Masculino , Mutação , Prognóstico
19.
Pathol Int ; 2018 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-30043418

RESUMO

LGR5 is expressed in various tumors and has been identified as a putative intestinal stem cell marker. Here we investigated LGR5 expression in colorectal neuroendocrine neoplasms and analyzed the correlation with pathological characteristics. We evaluated the clinicopathological features of 8 neuroendocrine tumor (NET) grade 1 (NET G1), 4 NET Grade 2 (NET G2), and 8 NET Grade 3 (NET G3; also termed neuroendocrine carcinoma, or NEC) cases. We examined LGR5 expression using an RNAscope, a newly developed RNA in situ hybridization technique, with a tissue microarray of the neuroendocrine neoplasm samples. LGR5 staining in individual tumor cells was semi-quantitatively scored using an H-score scale. We also performed a combination of LGR5 RNA in situ hybridization and synaptophysin immunohistochemistry. All cases contained tumor cells with some LGR5-positive dots. For all cases, H-scores showed a positive correlation with nuclear beta-catenin expression. In the NEC group, there was a strong positive correlation between H-score and beta-catenin expression. Our findings suggest that LGR5 may serve as a stem cell marker in NEC, as is the case in colon adenocarcinoma. The positive correlation between H-score and beta-catenin expression suggests that LGR5 expression might be affected by beta-catenin expression in neuroendocrine neoplasms and especially in NEC.

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