RESUMO
Loss of major histocompatibility complex class II (MHC II) expression is associated with poor patient outcome in diffuse large B-cell lymphoma (DLBCL). As MHC II molecules are lost with plasmacytic differentiation in normal cells, we asked whether MHC II loss in DLBCL is associated with an altered differentiation state. We used gene expression profiling, quantum dots, and immunohistochemistry to study the relationship between MHC II and plasma cell markers in DLBCL and plasmablastic lymphoma (PBL). Results demonstrate that MHC II(-) DLBCL immunophenotypically overlap with PBL and demonstrate an inverse correlation between MHC II and plasma cell markers MUM1, PRDM1/Blimp1, and XBP1s. In addition, MHC II expression is significantly higher in germinal center-DLBCL than activated B cell-DLBCL. A minor subset of cases with an unusual pattern of mislocalized punctate MHC II staining and intermediate levels of mRNA is also described. Finally, we show that PBL is negative for MHC II. The results imply a spectrum of MHC II expression that is more frequently diminished in tumors derived from B cells at the later stages of differentiation (with complete loss in PBL). Our observations provide a possible unifying concept that may contribute to the poor outcome reported in all MHC II(-) B-cell tumors.
Assuntos
Diferenciação Celular/genética , Antígenos de Histocompatibilidade Classe II/genética , Linfoma Difuso de Grandes Células B/genética , Plasmócitos/metabolismo , Análise de Variância , Antígenos CD20/genética , Antígenos CD20/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Antígenos HLA-DR/genética , Antígenos HLA-DR/metabolismo , Antígenos de Histocompatibilidade Classe II/metabolismo , Humanos , Imuno-Histoquímica , Fatores Reguladores de Interferon/genética , Fatores Reguladores de Interferon/metabolismo , Linfoma de Células B/genética , Linfoma de Células B/metabolismo , Linfoma Difuso de Grandes Células B/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Plasmócitos/patologia , Fator 1 de Ligação ao Domínio I Regulador Positivo , Fatores de Transcrição de Fator Regulador X , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteína 1 de Ligação a X-BoxRESUMO
While the acquisition of invasiveness is a critical step in early stage breast carcinomas (DCIS), no established molecular markers reliably identify tumor progression. The metastasis gene osteopontin is subject to alternative splicing, which yields 3 messages, osteopontin-a, osteopontin-b and osteopontin-c. Osteopontin-c is selectively expressed in invasive, but not in noninvasive, breast tumor cell lines, and it effectively supports anchorage independence. We evaluated osteopontin-c as a biomarker. The RNA message for osteopontin-c was present in 16 of 20 breast cancers (80%), but was undetectable in 22 normal specimens obtained from reduction mammoplasty. In contrast, osteopontin-a RNA was expressed at various levels in all 20 breast cancers, 11 tumor-surrounding tissues and 21 normal samples. The splice variant osteopontin-b was present at barely detectable levels in 18 of 20 cancers and in 6 of 22 normal breasts. By immunohistochemistry, 66 of 69 normal breasts were negative, while 3 showed low level staining. Among the breast cancers, 43 of 56 cores (77%) stained positive for osteopontin-c. When correlated with tumor grade, the staining for osteopontin-c increased from grade 1 to grade 3. In a total of 178 breast specimens analyzed, osteopontin-c was present in 78% of cancers, 36% of surrounding tissues and 0% of normal tissues. Furthermore, osteopontin-c detects a higher fraction of breast cancers than estrogen receptor (ER), progesterone receptor or HER2. In conjunction, osteopontin-c, ER and HER2 reliably predict grade 2-3 breast cancer. Hence, osteopontin-c is a diagnostic and prognostic marker that may have value in a diagnostic panel together with conventional breast cancer markers.
Assuntos
Processamento Alternativo , Neoplasias da Mama/metabolismo , Osteopontina/metabolismo , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Mama/metabolismo , Mama/patologia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/patologia , Estudos de Casos e Controles , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Técnicas Imunoenzimáticas , Pessoa de Meia-Idade , Invasividade Neoplásica/patologia , Estadiamento de Neoplasias , Osteopontina/genética , Prognóstico , Isoformas de Proteínas , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
BACKGROUND: The PI3K/AKT/mTOR pathway is central to prostate cancer progression. A preliminary investigation of immuno-histochemical expression of mammalian target of rapamycin (mTOR) pathway markers was undertaken to identify patterns of expression in prostate tissue. METHODS: Immunohistochemistry was performed on a custom-made prostate tissue array. Mean long scores and variability of long scores for each marker were recorded for normal lumenal cells, prostate intraepithelial neoplasia (PIN), and cancer. RESULTS: Expression of PTEN decreased and mTOR signaling pathway markers increased in PIN and in cancer as compared to normal cells in the majority of samples. Overexpression of 4E-BP1 and p-4E-BP1 was observed in PIN and cancer. However, in cancer, the overexpression of 4E-BP1 was significantly higher than with any other marker. DISCUSSION: Results suggest that 4E-BP1 overexpression is strongly associated with prostate cancer, especially when combined with PTEN and mTOR expression data. Hierarchical clustering analysis utilizing PTEN, mTOR, and 4E-BP1 separated normal from cancer cell populations in most cases.
