Elevated regulatory T cells, surface and intracellular CTLA-4 expression and interleukin-17 in the lung cancer microenvironment in humans

Abstract

Regulatory T cells (Tregs) play an important role in the suppression of the immune response in lung cancer. Cytotoxic T-lymphocyte antigen 4 (CTLA-4) expressed on T lymphocytes is capable of downregulating cytotoxic T cells and is constitutively expressed on Tregs. Little is known about the population of Tregs with two forms of CTLA-4: surface (s) and intracellular (in) in the lung cancer environment. Th17 cells defined by production of IL-17 have pleiotropic functions in anticancer immune response. Our aim was to detect the elements of immune response regulation in lung cancer in three compartments: by analysis of bronchoalveolar lavage fluid (BALF) from the lung affected by cancer (clBALF), healthy symmetrical lung (hlBALF) and peripheral blood (PB) from the same patient. A total of 54 samples were collected. Tregs, (s)CTLA-4, (in)CTLA-4 were detected by flow cytometry with antibodies against CD4, CD25, Foxp3, CD127, CTLA-4, and concentration of IL-17 was estimated by ELISA. We observed a significantly higher proportion of Tregs in clBALF than in hlBALF or PB (8.5 vs. 5.0 vs. 5.1%, respectively, p < 0.05). The median proportion of (in)CTLA-4+ Tregs was higher in clBALF than in hlBALF or PB (89.0, 81.5, 56.0%, p < 0.05). IL-17 concentration was the highest in clBALF—6.6 pg/ml. We observed a significant correlation between the proportion of Tregs and (in)CTLA-4+ Tregs with IL-17A concentration in clBALF. We confirmed significant differences in the proportion of regulatory elements between cancerous lung and healthy lung and PB and the usefulness of BALF analysis in evaluation of immune response regulation in local lung cancer environment.

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Elevated systemic interleukin-7 in patients with colorectal cancer and individuals at high risk of cancer: association with lymph node involvement and tumor location in the right colon

Abstract

Interleukin (IL)-7 is a cytokine essential for protective immunity, and it is considered as a promising agent for cancer immunotherapy. Recent studies, however, appear to associate IL-7 with aggressiveness of solid tumors. The IL-7 has been less studied in colorectal cancer (CRC) and conditions associated with increased risk of CRC development. To explore IL-7 status in bowel diseases, it was measured immunofluorometrically in 431 individuals (110 with CRC) by using Luminex platform. A level of IL-7 in CRC patients was significantly higher than in controls, did not differ from those with adenomas, but was lower than in both active and inactive inflammatory bowel disease (IBD) cases. In CRC, IL-7 was higher in patients with lymph node and distant metastases and with tumors located in right colon. In adenomas, IL-7 elevation was associated exclusively with villous growth pattern, while in IBD, circulating IL-7 reflected clinical activity of Crohn's disease and ulcerative colitis. Systemic TNFα, IL-10, and PDGF-BB were independent predictors of circulating IL-7. In summary, our study is the first to demonstrate IL-7 elevation in CRC in association with metastatic disease and tumor location. Both associations should be considered when designing IL-7-based immunotherapies for CRC. Further studies on IL-7 functionality in CRC are necessary.

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Recurrent TP53 missense mutation in cancer patients of Arab descent

Abstract

Hereditary cancer comprises more than 10% of all breast cancer cases. Identification of germinal mutations enables the initiation of a preventive program that can include early detection or preventive treatment and may also have a major impact on cancer therapy. Several recurrent mutations were identified in the BRCA1/2 genes in Jewish populations however, in other ethnic groups in Israel, no recurrent mutations were identified to date. Our group established panel sequencing in cancer patients to identify recurrent, founder, and new mutations in the heterogeneous and diverse populations in Israel, We evaluated five breast cancer patients of Arab descent diagnosed with cancer before the age of 50 years and identified the previously described TP53 mutation, c.541C>T, R181C (rs587782596), in two women from unrelated Arab families. The two probands were diagnosed with breast cancer at a young age (27 and 34 years) and had significant family history spanning a wide range of tumors (breast cancer (BC), papillary thyroid cancer, glioblastoma multiform (GBM), colon cancer and leukemia). The R181C variant is expected to disrupt p53 at the ASPP2 binding domain but not the DNA binding domain and is defined by Clinvar as likely pathogenic and in HGMD as disease mutation. We further tested 85 unrelated Arab cancer patients and father of a BC carrier patient for TP53 c.541C>T using a real time polymerase chain reaction (RT-PCR) approach and identified four additional carriers, two with BC one with lung cancer, and the father of a BC carrier patient, diagnosed with GBM. Another carrier suffering from BC was identified using a Myriad panel, suggesting a recurrent mutation in this population with a frequency of 5/42 (11.9%) of our selected BC patients. We suggest testing Arab women with a breast cancer at a young age, Arab patients with multiple malignancies, or with suggestive family history for TP53 c.541C>T.

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The hereditary nature of small cell carcinoma of the ovary, hypercalcemic type: two new familial cases

Abstract

Small cell carcinoma of the ovary, hypercalcemic type, (SCCOHT) is the most common undifferentiated ovarian cancer in women aged under 40 years. SCCOHT is a monogenic disease, characterized by germline and somatic SMARCA4 mutations. Recent studies have stressed its morphological and clinical similarity to malignant rhabdoid tumours, which are usually caused by mutations in the related gene, SMARCB1. While familial tumours are rare, the incidence of germline mutations is relatively high, with up to 43% of SCCOHTs and 35% of rhabdoid tumours caused by germline mutations in SMARCA4 and SMARCB1, respectively. We report two new familial cases of SCCOHT. Affected members in both families and the associated tumours were found to carry SMARCA4 germline and somatic mutations, respectively, leading to loss of SMARCA4 protein expression in the tumours. Despite the rarity of familial SCCOHT, the high incidence of germline mutations is important to note, as without a family history of the disease, the hereditary nature of SCCOHT may be missed, especially if the mutation was inherited from the father or acquired de novo. The similarity between SCCOHT and rhabdoid tumours should be recognized, as infant carriers of SMARCA4 mutations may be at risk for these tumours in addition to SCCOHT.

http://ift.tt/2g6pU5l

Expression Levels of Warburg-Effect Related microRNAs Correlate with each Other and that of Histone Deacetylase Enzymes in Adult Hematological Malignancies with Emphasis on Acute Myeloid Leukemia

Abstract

Disruption of epigenetic regulation and characteristic metabolic alterations (known as the Warburg-effect) are well-known hallmarks of cancer. In our study we investigated the expression levels of microRNAs and histone deacetylase enzymes via RT-qPCR in bone marrow specimens of adult patients suffering from hematological malignancies (total cohort n = 40), especially acute myeloid leukemia (n = 27). The levels of the three examined Warburg-effect related microRNAs (miR-378*, miR-23b, miR-26a) positively correlated with each other and the oncogenic miR-155 and miR-125b, while negatively with the level of the tumorsuppressor miR-124. Significant relationships have been confirmed between the levels of SIRT6, HDAC4 and the microRNAs listed above. In NPM1-mutated AML (n = 6), the level of miR-125b was significantly lower than in the group of AML patients not carrying this mutation (n = 13) (p < 0.05). In M5 FAB type of AML (n = 5), the level of miR-124 was significantly higher compared to the M2 group (n = 7) (p < 0.05). In two cases of FAB M5 AML, the levels of SIRT6 and miR-26a increased during the first 4 weeks of treatment. In the total cohort, white blood cell count at the time of the diagnosis significantly correlated with the levels of HDAC4, SIRT6, miR-124 and miR-26a. Our results suggest that Warburg-effect related microRNAs may have important role in the pathogenesis of leukemia, and the potential oncogenic property of HDAC4 and SIRT6 cannot be excluded in hematological malignancies. Elevated level of miR-125b can contribute to adverse prognosis of AML without NPM1 mutation. The prevailment of the tumorsuppressor property of miR-124 may depend on the accompanying genetic alterations.

http://ift.tt/2g63aCp

Expression Levels of Warburg-Effect Related microRNAs Correlate with each Other and that of Histone Deacetylase Enzymes in Adult Hematological Malignancies with Emphasis on Acute Myeloid Leukemia

Abstract

Disruption of epigenetic regulation and characteristic metabolic alterations (known as the Warburg-effect) are well-known hallmarks of cancer. In our study we investigated the expression levels of microRNAs and histone deacetylase enzymes via RT-qPCR in bone marrow specimens of adult patients suffering from hematological malignancies (total cohort n = 40), especially acute myeloid leukemia (n = 27). The levels of the three examined Warburg-effect related microRNAs (miR-378*, miR-23b, miR-26a) positively correlated with each other and the oncogenic miR-155 and miR-125b, while negatively with the level of the tumorsuppressor miR-124. Significant relationships have been confirmed between the levels of SIRT6, HDAC4 and the microRNAs listed above. In NPM1-mutated AML (n = 6), the level of miR-125b was significantly lower than in the group of AML patients not carrying this mutation (n = 13) (p < 0.05). In M5 FAB type of AML (n = 5), the level of miR-124 was significantly higher compared to the M2 group (n = 7) (p < 0.05). In two cases of FAB M5 AML, the levels of SIRT6 and miR-26a increased during the first 4 weeks of treatment. In the total cohort, white blood cell count at the time of the diagnosis significantly correlated with the levels of HDAC4, SIRT6, miR-124 and miR-26a. Our results suggest that Warburg-effect related microRNAs may have important role in the pathogenesis of leukemia, and the potential oncogenic property of HDAC4 and SIRT6 cannot be excluded in hematological malignancies. Elevated level of miR-125b can contribute to adverse prognosis of AML without NPM1 mutation. The prevailment of the tumorsuppressor property of miR-124 may depend on the accompanying genetic alterations.

from Cancer via ola Kala on Inoreader http://ift.tt/2g63aCp
via IFTTT

Expression Levels of Warburg-Effect Related microRNAs Correlate with each Other and that of Histone Deacetylase Enzymes in Adult Hematological Malignancies with Emphasis on Acute Myeloid Leukemia

Abstract

Disruption of epigenetic regulation and characteristic metabolic alterations (known as the Warburg-effect) are well-known hallmarks of cancer. In our study we investigated the expression levels of microRNAs and histone deacetylase enzymes via RT-qPCR in bone marrow specimens of adult patients suffering from hematological malignancies (total cohort n = 40), especially acute myeloid leukemia (n = 27). The levels of the three examined Warburg-effect related microRNAs (miR-378*, miR-23b, miR-26a) positively correlated with each other and the oncogenic miR-155 and miR-125b, while negatively with the level of the tumorsuppressor miR-124. Significant relationships have been confirmed between the levels of SIRT6, HDAC4 and the microRNAs listed above. In NPM1-mutated AML (n = 6), the level of miR-125b was significantly lower than in the group of AML patients not carrying this mutation (n = 13) (p < 0.05). In M5 FAB type of AML (n = 5), the level of miR-124 was significantly higher compared to the M2 group (n = 7) (p < 0.05). In two cases of FAB M5 AML, the levels of SIRT6 and miR-26a increased during the first 4 weeks of treatment. In the total cohort, white blood cell count at the time of the diagnosis significantly correlated with the levels of HDAC4, SIRT6, miR-124 and miR-26a. Our results suggest that Warburg-effect related microRNAs may have important role in the pathogenesis of leukemia, and the potential oncogenic property of HDAC4 and SIRT6 cannot be excluded in hematological malignancies. Elevated level of miR-125b can contribute to adverse prognosis of AML without NPM1 mutation. The prevailment of the tumorsuppressor property of miR-124 may depend on the accompanying genetic alterations.

http://ift.tt/2g63aCp