Articles de revues : « Muc expression »

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Kuznetsov, O. E., V. M. Tsyrkunov et S. Sh Kerimova. « Mucin expression in liver cancer ». Doklady of the National Academy of Sciences of Belarus 67, n^o 1 (4 mars 2023) : 59–65. http://dx.doi.org/10.29235/1561-8323-2023-67-1-59-65.

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Increasing incidence, difficulties in early diagnosis, and a high mortality rate in liver cancer (LC) determine the relevance of studying the mechanisms of its development. The aim of the work is to evaluate the expression of high molecular weight glycoproteins MUC-1, MUC-13 in liver cancer. The object of study is LC tissue samples of 65 patients from the archives and 34 blood serum samples from patients with morphologically confirmed LC. The age of subjects was 26– 97 years. The level of antibodies to MUC-1 and MUC-13 was studied by ELISA. The reference value ranges of MUC-1 (0.250 ± 0.10 ng/ml) and MUC-13 (0.321 ± 0.13 ng/ml) in the blood serum of healthy individuals were established. The concentration of antibodies to MUC-1 and MUC-13 in the blood serum in RP was significantly higher than that in practically healthy individuals. The concentration of MUC-1 and MUC-13 in the LC tumor tissue was higher than that in the blood serum of apparently healthy individuals and LC patients. With a confirmed LC diagnosis, the level of antibodies to MUC-1 in the blood serum, which exceeds 0.373 ng/ml, and the level of antibodies to MUC-13, which is more than 0.939 ng/ml, may indicate a high risk of a tumor process.

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Colecchia, Maurizio, Salvatore Lo Vullo, Patrizia Giannatempo, Daniele Raggi, Federica Perrone, Nicola Nicolai, Mario Catanzaro et al. « Frequent expression of androgen receptor (AR) on tumor cells of muscle-invasive (MIUC) and metastatic urothelial carcinoma (mUC) : Insights for clinical research. » Journal of Clinical Oncology 35, n^o 15_suppl (20 mai 2017) : e16019-e16019. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e16019.

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e16019 Background: Advanced UC treatment is being revolutionized by immunotherapy (IT). However, < 30% of patients (pts) will benefit from IT, and additional therapeutic targets are needed. Findings from analyses supporting an investigator-led, AR-based clinical research program are presented. Methods: From 09/2015, we collected the archival tissue blocks from pts who have been treated or consulted at our center and received platinum-based chemotherapy (CT) for MIUC or mUC. Immunohistochemistry (IHC) was performed on 3µm slides using mouse anti-human AR monoclonal Ab (Dako, clone AR441). ≥1% cutoff for AR+ IHC of tumor cells (TC) was used. AR-expressing pts were further stratified as follows: 1-5%, 5-25%, and 25-100%. Univariable (UVA) and multivariable (MVA) Cox models for overall survival (OS) were fitted, the latter adjusted for clinical stage (MIUC vs mUC), presence of visceral metastases, platinum CT type. OS was calculated from the date of first administration of CT. Exploratory PD-L1 co-expression, by TC or stroma (SP142 Ab, 1% cutoff), was analyzed in all pts. Results: 105 pts (46 MIUC and 59 mUC) had their tumor stained. 80 (76.2%) had bladder primary tumor, 85 (80.9%) had pure UC. 59 received cisplatin and 46 carboplatin. Overall, 37 pts (35.2%) had AR-expressing TC, 17 (16.2%) with ≥25% expression. Cox models were built on 93 pts with follow-up duration of ≥6 months. AR-expressing was equally distributed between MIUC and mUC pts (44.4% and 55.6%). On UVA, AR expression was not associated with OS, neither dichotomizing AR+/AR- pts (p = 0.477) nor after accounting for AR-positivity strata (p = 0.845). The same results were confirmed on MVA (p = 0.505 and p = 0.875). In AR+ vs. AR- pts, PD-L1 was equally expressed in the stroma (67.5 vs 57.9%) but less expressed by TC (39.4% vs 52%). Conclusions: AR is frequently expressed on TC of pts with MIUC and mUC, and AR expression does not seem to be associated with OS in these pts. AR pathway is worthy of clinical studies to synergistically act with anti-PD-L1 therapy. AR sequencing and FISH analysis in positive pts is ongoing, and a clinical program of a named-basis administration of antiandrogen therapy has started at our center.

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Shet, Tanuja, Sucheta Valsangar et Suhas Dhende. « Secretory Carcinoma of Breast : Pattern of MUC 2/MUC 4/MUC 6 Expression ». Breast Journal 19, n^o 2 (11 janvier 2013) : 222–24. http://dx.doi.org/10.1111/tbj.12085.

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Jiang, Zhipeng, Huashe Wang, Liang Li, Zehui Hou, Wei Liu, Taicheng Zhou, Yingru Li et Shuang Chen. « Analysis of TGCA data reveals genetic and epigenetic changes and biological function of MUC family genes in colorectal cancer ». Future Oncology 15, n^o 35 (décembre 2019) : 4031–43. http://dx.doi.org/10.2217/fon-2019-0363.

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Aim: Few studies focused on functions and regulatory networks of MUC family members in colorectal cancer based on comprehensive analysis of online database. Materials & methods: Copy number variation, methylation, pathway analysis and drug influence on MUC expression were analyzed based on The Cancer Genome Atlas and GTEx database. Results: Copy number variation analysis showed MUC heterozygous amplification and heterozygous deletion predominate. Methylation of MUC17, MUC12 and MUC4 were found related to gene expression. Function of MUC family genes mainly affects pathways such as apoptosis, cell cycle, DNA damage and EMT pathways. PLX4720, dabrafenib, gefitinib, afatinib and austocystin D can alter the expression of MUC gene. Conclusion: The genetic and epigenetic changes of MUC are related to the level of MUC expression in colorectal cancer.

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Treon, Steven P., Joseph A. Mollick, Mitsuyoshi Urashima, Gerrard Teoh, Dharminder Chauhan, Atsushi Ogata, Noopur Raje et al. « Muc-1 Core Protein Is Expressed on Multiple Myeloma Cells and Is Induced by Dexamethasone ». Blood 93, n^o 4 (15 février 1999) : 1287–98. http://dx.doi.org/10.1182/blood.v93.4.1287.

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Abstract Monoclonal antibodies (MoAbs) that selectively identify Muc-1 core protein (MoAbs DF3-P, VU-4H5) determinants were used to identify the Muc-1 glycoform present on 7 multiple myeloma (MM) cell lines, 5 MM patient plasma cells, 12 MM patient B cells, as well as 32 non-MM cell lines and normal hematopoietic cells. Flow cytometry studies demonstrated that all MM cell lines, MM patient plasma cells, and MM patient B cells expressed Muc-1 core protein epitopes. Circulating B cells from 4 normal donors also expressed Muc-1 core protein. In contrast, Muc-1 core protein was absent on 28 of 32 non-MM neoplastic cell lines, 17 of which expressed Muc-1. Splenic and tonsillar B cells, CD34+ stem cells, resting T cells, and bone marrow plasma cells obtained from normal donors both lacked Muc-1 glycoforms. We next studied the effects of estrogen, progesterone, and glucocorticoid receptor agonists and antagonists on Muc-1 expression, because consensus sequences for the response elements of these steroids are present on the Muc-1 gene promoter. These studies showed that dexamethasone (Dex) induced Muc-1 expression on MM cell lines, as determined by both flow cytometry and Western blot analyses. Dex also induced upregulation of Muc-1 on prostate and ovarian cancer cell lines. Time and dose-response studies demonstrated that Dex induced maximal cell surface Muc-1 expression by 24 hours at concentrations of 10−8 mol/L. Dex induced Muc-1 upregulation could be blocked with a 10-fold excess of the glucocorticoid receptor antagonist RU486, confirming that Dex was acting via the glucocorticoid receptor. No changes in Muc-1 expression were observed on MM cells treated with estrogen and progesterone receptor agonists and antagonists or with RU486. These studies provide the framework for targeting Muc-1 core protein in vaccination and serotherapy trials in MM. In addition, the finding that Muc-1 expression on MM cells can be augmented by Dex at pharmacologically achievable levels suggests their potential utility in enhancing treatments targeting Muc-1 in MM.

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Treon, Steven P., Joseph A. Mollick, Mitsuyoshi Urashima, Gerrard Teoh, Dharminder Chauhan, Atsushi Ogata, Noopur Raje et al. « Muc-1 Core Protein Is Expressed on Multiple Myeloma Cells and Is Induced by Dexamethasone ». Blood 93, n^o 4 (15 février 1999) : 1287–98. http://dx.doi.org/10.1182/blood.v93.4.1287.404k14_1287_1298.

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Monoclonal antibodies (MoAbs) that selectively identify Muc-1 core protein (MoAbs DF3-P, VU-4H5) determinants were used to identify the Muc-1 glycoform present on 7 multiple myeloma (MM) cell lines, 5 MM patient plasma cells, 12 MM patient B cells, as well as 32 non-MM cell lines and normal hematopoietic cells. Flow cytometry studies demonstrated that all MM cell lines, MM patient plasma cells, and MM patient B cells expressed Muc-1 core protein epitopes. Circulating B cells from 4 normal donors also expressed Muc-1 core protein. In contrast, Muc-1 core protein was absent on 28 of 32 non-MM neoplastic cell lines, 17 of which expressed Muc-1. Splenic and tonsillar B cells, CD34+ stem cells, resting T cells, and bone marrow plasma cells obtained from normal donors both lacked Muc-1 glycoforms. We next studied the effects of estrogen, progesterone, and glucocorticoid receptor agonists and antagonists on Muc-1 expression, because consensus sequences for the response elements of these steroids are present on the Muc-1 gene promoter. These studies showed that dexamethasone (Dex) induced Muc-1 expression on MM cell lines, as determined by both flow cytometry and Western blot analyses. Dex also induced upregulation of Muc-1 on prostate and ovarian cancer cell lines. Time and dose-response studies demonstrated that Dex induced maximal cell surface Muc-1 expression by 24 hours at concentrations of 10−8 mol/L. Dex induced Muc-1 upregulation could be blocked with a 10-fold excess of the glucocorticoid receptor antagonist RU486, confirming that Dex was acting via the glucocorticoid receptor. No changes in Muc-1 expression were observed on MM cells treated with estrogen and progesterone receptor agonists and antagonists or with RU486. These studies provide the framework for targeting Muc-1 core protein in vaccination and serotherapy trials in MM. In addition, the finding that Muc-1 expression on MM cells can be augmented by Dex at pharmacologically achievable levels suggests their potential utility in enhancing treatments targeting Muc-1 in MM.

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Braga, V. M., L. F. Pemberton, T. Duhig et S. J. Gendler. « Spatial and temporal expression of an epithelial mucin, Muc-1, during mouse development ». Development 115, n^o 2 (1 juin 1992) : 427–37. http://dx.doi.org/10.1242/dev.115.2.427.

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The Muc-1 mucin is found as a transmembrane protein in the apical surface of glandular epithelia. To provide insight into possible functions, we have assessed the timing of expression and the distribution of the Muc-1 protein during mouse embryogenesis using three different techniques: RT-PCR, northern blots and immunohistochemistry. Our results indicate that Muc-1 expression correlates with epithelial differentiation in stomach, pancreas, lung, trachea, kidney and salivary glands. Once started, Muc-1 synthesis continually increases with time, mainly due to epithelial area growth. Our data suggest that expression of the Muc-1 gene is under spatial and temporal control during organogenesis. Although Muc-1 is present in different organs, its expression is not induced systemically, but according to the particular onset of epithelial polarization and branching morphogenesis of each individual organ. It is of particular interest that Muc-1 protein can be detected lining the apical surfaces of the developing lumens when the epithelium of these organs is still undergoing folding and branching, and glandular activity has not yet started. We speculate that Muc-1 may participate in epithelial sheet differentiation/lumen formation during early development of the organs known to express it. This speculation is based on: (1) the detection of Muc-1 expression early during organogenesis, (2) the defined apical localization in different epithelia, (3) the decrease in cell-cell interactions when Muc-1 protein is highly expressed and (4) the possible interaction of its cytoplasmic tail with the actin cytoskeleton. However, it remains to be established using in vitro systems, whether the temporal and local expression of the Muc-1 gene coincident with the morphogenetic events described here is relevant for the process.

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Braga, V. M., et S. J. Gendler. « Modulation of Muc-1 mucin expression in the mouse uterus during the estrus cycle, early pregnancy and placentation ». Journal of Cell Science 105, n^o 2 (1 juin 1993) : 397–405. http://dx.doi.org/10.1242/jcs.105.2.397.

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The Muc-1 protein is an integral membrane protein that is expressed apically by simple secretory epithelia in many different organs. We present in this paper a study on Muc-1 protein expression in the mouse uterus during early pregnancy, placentation and the estrus cycle. Muc-1 immunopositive reaction is found in the decidua by day 8 of pregnancy onwards. The observed pattern was unusual, since Muc-1 protein was present in spherical cytoplasmic granules in granular metrial gland cells. Both the intracellular pattern of expression and the lymphoid origin of these cells were striking results. Muc-1 is thought to be an epithelial differentiation marker, and this is the first report of its expression by non-epithelial cells. Our results on Muc-1 expression in the uterus of cycling mice showed that higher levels of Muc-1 mRNA and protein correlate with higher levels of plasma estrogen in the estrus and proestrus phases. However, in ovariectomized mice without hormone replacement, the endometrium expressed high levels of this protein. These levels could not be substantially changed by estrogen, although progesterone reduced the levels of Muc-1 protein associated with the epithelium. These data together with the normal expression in the cycling mice suggest that progesterone might repress Muc-1 expression during the metestrus and diestrus phases. In cycling mice, when plasma progesterone is at its nadir and the estrogen level is elevated in estrus and proestrus phases, Muc-1 concentration would increase to its basal level, not because of estrogen stimulation, but due to lack of progesterone repression.(ABSTRACT TRUNCATED AT 250 WORDS)

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Brugger, Wolfram, Hans-Jörg Bühring, Frank Grünebach, Wichard Vogel, Sepp Kaul, Robert Müller, Tim H. Brümmendorf et al. « Expression of MUC-1 Epitopes on Normal Bone Marrow : Implications for the Detection of Micrometastatic Tumor Cells ». Journal of Clinical Oncology 17, n^o 5 (mai 1999) : 1535. http://dx.doi.org/10.1200/jco.1999.17.5.1535.

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PURPOSE: The expression of the carcinoma-associated mucin MUC-1 is thought to be restricted to epithelial cells and is used for micrometastatic tumor cell detection in patients with solid tumors, including those with breast cancer. Little is known, however, about the expression of MUC-1 epitopes in normal hematopoietic cells. MATERIALS AND METHODS: MUC-1 expression was analyzed by flow cytometry and immunocytology on bone marrow (BM) mononuclear cells and purified CD34+ cells from healthy volunteers, using different anti-MUC-1–specific monoclonal antibodies. In addition, Western blotting of MUC-1 proteins was performed. RESULTS: Surprisingly, 2% to 10% of normal human BM mononuclear cells expressed MUC-1, as defined by the anti–MUC-1 antibodies BM-2 (2E11), BM-7, 12H12, MAM-6, and HMFG-1. In contrast, two antibodies recognizing the BM-8 and the HMFG-2 epitopes of MUC-1 were not detected. MUC-1+ cells from normal BM consisted primarily of erythroblasts and normoblasts. In agreement with this, normal CD34+ cells cultured in vitro to differentiate into the erythroid lineage showed a strong MUC-1 expression on day 7 proerythroblasts. Western blotting of these cells confirmed that the reactive species is the known high molecular weight MUC-1 protein. CONCLUSION: Our data demonstrate that some MUC-1 epitopes are expressed on normal BM cells and particularly on cells of the erythroid lineage. Hence the application of anti–MUC-1 antibodies for disseminated tumor cell detection in BM or peripheral blood progenitor cells may provide false-positive results, and only carefully evaluated anti–MUC-1 antibodies (eg, HMFG-2) might be selected. Furthermore, MUC-1–targeted immunotherapy in cancer patients might be hampered by the suppression of erythropoiesis.

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Schmitt, Fernando C., Mónica B. Pereira et Celso A. Reis. « MUC 5 expression in breast carcinomas ». Human Pathology 30, n^o 10 (octobre 1999) : 1270–71. http://dx.doi.org/10.1016/s0046-8177(99)90052-7.

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Parry, G., J. Li, J. Stubbs, M. J. Bissell, C. Schmidhauser, A. P. Spicer et S. J. Gendler. « Studies of Muc-1 mucin expression and polarity in the mouse mammary gland demonstrate developmental regulation of Muc-1 glycosylation and establish the hormonal basis for mRNA expression ». Journal of Cell Science 101, n^o 1 (1 janvier 1992) : 191–99. http://dx.doi.org/10.1242/jcs.101.1.191.

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Muc-1 is a major mucin glycoprotein expressed on the surface of mammary epithelial cells. It has attracted considerable attention as it is expressed in an aberrant form on many breast tumor cells. Here we describe studies using a recently obtained cDNA probe of Muc-1 expression during lactogenic development in the mouse. Northern blot analysis demonstrated that Muc-1 is expressed at all stages of lactogenic development but its levels are increased very significantly during mid-pregnancy and into lactation. The basis of this was examined using CID-9 mammary epithelial cell cultures. It was found that in the presence of insulin Muc-1 mRNA levels were increased by both hydrocortisone and prolactin, with the combination of the three hormones supporting maximum expression. Muc-1 mRNA levels were also modulated by culturing cells on a basement-membrane-like extracellular matrix that promoted mRNA levels 5- to 10-fold above levels in cells cultured on plastic tissue culture dishes. Immunocytochemical studies using monoclonal antibodies to carbohydrate epitopes on Muc-1 demonstrated that while Muc-1 was found at all developmental stages, it became increasingly sialylated during the course of pregnancy and into lactation. Additionally, we found that while Muc-1 is tightly polarized to the apical surface of the epithelium of lactating and pregnant mice it exhibited a less-polarized distribution on a small proportion of ductal cells in virgin mice. We conclude that the expression of Muc-1 is regulated at several different levels and by a number of different factors. We speculate that this may reflect different functional roles for Muc-1 at different stages of mammary development.

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Xiao, Li-Jun, Shuang Zhao, En-Hong Zhao, Xin Zheng, Wen-Feng Gou, Ya-Nan Xing, Yasuo Takano et Hua-Chuan Zheng. « Clinicopathological and Prognostic Significance of MUC-2, MUC-4 and MUC-5AC Expression in Japanese Gastric Carcinomas ». Asian Pacific Journal of Cancer Prevention 13, n^o 12 (31 décembre 2012) : 6447–53. http://dx.doi.org/10.7314/apjcp.2012.13.12.6447.

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Budihastuti, Uki Retno, Sri Sulistyowati, Eriana Melinawati et Yohan Pamuji Marbun. « Mucin-1 expression in endometrium is higher in polycystic ovary syndrome than in normal women ». Universa Medicina 39, n^o 2 (20 mai 2020) : 74. http://dx.doi.org/10.18051/univmed.2020.v39.74-80.

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Background The polycystic ovary syndrome (PCOS) is caused by endocrine system dysfunction in women. MUCIN-1 (MUC-1) expression is found in endometrial tissues, which leads to implantation process dysfunction because of imbalance of trophoblast adhesion process. This study was conducted to compare endometrial MUC-1 expression between PCOS and normal women considering all existing external variables. Methods This cross-sectional study was conducted in General Hospital Dr. Moewardi Surakarta. Endometrial samples were obtained from 30 infertile PCOS women based on Rotterdam criteria, and 30 normal women. Life style and reproductive data such as age, menstrual problems, menstrual cycle, age at menarche, and BMI were collected. Subjects underwent endometrial biopsy in luteinizing hormone (LH) secretion phase LH + 5 days to LH + 10 days for immunohistochemistry (IHC) of MUC-1 expression. An independent-t and multiple linear regression test were used to analyze the data at significance level of p<0.05. Results Mean MUC-1 expression in the PCOS endometrium (49.66 ± 47.79) was significantly higher than in normal women (7.66 ± 14.55) (p=0.03). Multivariate linear regression model of life style and reproductive variables with MUC-1 showed that PCOS (b=29.54; 95% CI 9.57-49.49; p=0.004) and BMI (b= 29.99; 95% CI 5.91-54.07; p=0.001) significantly increase MUC-1 expression. PCOS (Beta=0.37) was more important than BMI (Beta=0.30) in increasing the MUC-1 expression. Conclusion Expression of MUC-1 levels in the PCOS endometrium was higher than in normal women. This suggests that MUC-1 contributes to the unexplained reproductive failure in PCOS.

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Batra, S. K., H. F. Kern, A. J. Worlock, R. S. Metzgar et M. A. Hollingsworth. « Transfection of the human Muc 1 mucin gene into a poorly differentiated human pancreatic tumor cell line, Panc1 : integration, expression and ultrastructural changes ». Journal of Cell Science 100, n^o 4 (1 décembre 1991) : 841–49. http://dx.doi.org/10.1242/jcs.100.4.841.

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Full-length cDNA for the human mucin Muc 1 gene under the control of the beta actin promoter was transfected into a morphologically poorly differentiated pancreatic tumor cell line, Panc 1, by the DEAE-dextran method. Integration of the foreign Muc 1 cDNA occurred at multiple sites in the genome of Panc 1. Northern blot analysis showed Muc 1 expression in cells transfected with the Muc 1 cDNA, but not in control cells transfected with vector alone or an antisense Muc 1 cDNA construct. Transfection of Panc 1 with Muc 1 cDNA did not cause any detectable alteration or rearrangements in the Muc 1 gene or cDNA. Western blot analysis of cell lysates from the transfected lines using a monoclonal antibody reactive with the Muc 1 protein (HMFG-2) demonstrated that Muc 1 protein expression correlated with the Northern blot data. Immunoperoxidase staining using HMFG-2 showed that Muc 1 protein was expressed in less than 5% of control Panc 1 cells, whereas greater than 95% of cells transfected with Muc 1 cDNA expressed the protein. Ultrastructural examination of Muc 1-transfected cells demonstrated the formation of dense core granules and increased amounts of rough endoplasmic reticulum.

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Ioannides, C. G., B. Fisk, K. R. Jerome, T. Irimura, J. T. Wharton et O. J. Finn. « Cytotoxic T cells from ovarian malignant tumors can recognize polymorphic epithelial mucin core peptides. » Journal of Immunology 151, n^o 7 (1 octobre 1993) : 3693–703. http://dx.doi.org/10.4049/jimmunol.151.7.3693.

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Abstract CTL isolated from tumor infiltrating lymphocytes/tumor associated lymphocytes (TAL) infiltrating ovarian tumors have been demonstrated to mediate lysis of tumor targets after in vitro culture. These effector cells are of particular interest as cellular probes to detect and define human tumor Ag and epitopes that stimulate cellular immunity to human tumors. Polymorphic epithelial mucin (PEM) core peptides are potential candidates as tumor specific Ag because of their preferential expression on epithelial tumors. We report here that ovarian CTL-TAL can recognize mucin (Muc-1) core peptide of PEM. Several ovarian CTL-TAL lines were developed that recognized in a non-MHC restricted fashion an Muc-1+ ovarian tumor, but not Muc-1-tumor. To define the specificity of these CTL-TAL and exclude cross-reactivity with other potential Ag, cytotoxicity experiments were performed using as targets EBV-transformed cell lines with an expression construct containing the Muc.1 cDNA. These ovarian CTL-TAL lysed mucin core-peptide transfected cells but not targets transfected with an expression construct containing a mucin frame-shift mutant cDNA as control. In addition, targets pulsed with short synthetic peptides composed of amino acids 1-14 of the Muc 1 core peptide repeat were also lysed by the same CTL-TAL. This lysis was inhibited by the mAb SM3 that recognize an epitope on the mucin core peptide. These results, which are a demonstration of a specific Ag recognized by ovarian CTL-TAL, may be of interest for specific immunotherapy of ovarian cancer.

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Alsamak, Fadi Fouad, Ahmed Sahib Abdulamir, Laila Khalid Mahdi, Khalid Alnaib et Fatimah Abu Bakar. « Association of Helicobacter pylori with colorectal cancer development ». Asian Biomedicine 4, n^o 4 (1 août 2010) : 609–18. http://dx.doi.org/10.2478/abm-2010-0077.

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Abstract Background: Helicobacter pylori (H. pylori) may be associated with colorectal cancer. However, the underlying mechanisms are still unclear. Objectives: Explore the serostatus of H. pylori cytotoxicity-associated gene A product (CagA) in patients with colorectal carcinoma, and assess the association of H. pylori with colorectal cancer via c-Myc and MUC-2 proteins at tumor tissues. Methods: H. pylori CagA IgG antibodies were screened using enzyme-linked immunosorbent assay (ELISA) in 30 patients with colorectal carcinoma and 30 cancer-free control subjects. Paraffin-embedded blocks were examined for the expression of c-Myc and MUC-2 protein by immunohistochemistry. Results: H. pylori CagA seropositivity increased significantly among colorectal cancer patients (p <0.05). The expression of c-Myc and MUC-2 in colorectal carcinoma patients was over-expressed (80%), and downexpressed (63%) in resection margins (p <0.05). c-Myc over-expression and MUC-2 down-expression were associated with CagA-positive rather than CagA-negative H. pylori patients. In 16 CagA seropositive vs. 14 CagA seronegative patients, the expression rate was 97.3% vs. 64.2% and 33.3% vs. 78.5% for cMyc and MUC-2, respectively. CagA IgG level was significantly higher in positive than in negative c-Myc patients (p= 0.036), and in negative than in positive MUC-2 patients (p= 0.044). c-Myc and MUC-2 were positively and inversely correlated with CagA IgG level (p <0.05). Conclusions: CagA-seropositive H. pylori is most probably associated with colorectal cancer development. Part of the underlying mechanism for such association might be via alterations in expression of MUC-2, which depletes the mucous protective layer in the colo-rectum, and c-Myc, which stimulates the growth of cancerous cells.

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Mall, Anwar S., Marilyn G. Tyler, Sam B. Ho, Jake E. J. Krige, Delawir Kahn, Wendy Spearman, Landon Myer et Dhirendra Govender. « The expression of MUC mucin in cholangiocarcinoma ». Pathology - Research and Practice 206, n^o 12 (décembre 2010) : 805–9. http://dx.doi.org/10.1016/j.prp.2010.08.004.

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Mikhaleva, L. M., R. A. Vandysheva, N. K. Shakhpazyan, E. D. Fedorov, A. E. Biryukov, K. Yu Midiber et V. V. Pechnikova. « Comparative assessment of the expression of Muc 2, Muc 5AC, and Muc 6 in serrated neoplasms of the colon ». Arkhiv patologii 81, n^o 2 (2019) : 10. http://dx.doi.org/10.17116/patol20198102110.

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Gibson, Joanna A., Hejin P. Hahn, Ali Shahsafaei et Robert D. Odze. « MUC Expression in Hyperplastic and Serrated Colonic Polyps ». American Journal of Surgical Pathology 35, n^o 5 (mai 2011) : 742–49. http://dx.doi.org/10.1097/pas.0b013e31821537a2.

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Shemirani, Nima, Vladimir Osipov, Alex Kolker, Pawjai Khampang et Joseph E. Kerschner. « Expression of mucin (MUC) genes in mucoepidermoid carcinoma ». Laryngoscope 121, n^o 1 (11 novembre 2010) : 167–70. http://dx.doi.org/10.1002/lary.21164.

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Baños-Lara, Ma Del Rocío, Boyang Piao et Antonieta Guerrero-Plata. « Differential Mucin Expression by Respiratory Syncytial Virus and Human Metapneumovirus Infection in Human Epithelial Cells ». Mediators of Inflammation 2015 (2015) : 1–7. http://dx.doi.org/10.1155/2015/347292.

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Mucins (MUC) constitute an important component of the inflammatory and innate immune response. However, the expression of these molecules by respiratory viral infections is still largely unknown. Respiratory syncytial virus (RSV) and human metapneumovirus (hMPV) are two close-related paramyxoviruses that can cause severe low respiratory tract disease in infants and young children worldwide. Currently, there is not vaccine available for neither virus. In this work, we explored the differential expression of MUC by RSV and hMPV in human epithelial cells. Our data indicate that the MUC expression by RSV and hMPV differs significantly, as we observed a stronger induction of MUC8, MUC15, MUC20, MUC21, and MUC22 by RSV infection while the expression of MUC1, MUC2, and MUC5B was dominated by the infection with hMPV. These results may contribute to the different immune response induced by these two respiratory viruses.

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Li, Chao, Didi Zuo, Tao Liu, Libin Yin, Chenyao Li et Lei Wang. « Prognostic and Clinicopathological Significance of MUC Family Members in Colorectal Cancer : A Systematic Review and Meta-Analysis ». Gastroenterology Research and Practice 2019 (20 décembre 2019) : 1–16. http://dx.doi.org/10.1155/2019/2391670.

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Objective. To assess the association between MUC expression levels in colorectal cancer (CRC) tissues and prognosis and investigate the associations between MUC expression levels and CRC clinicopathological characteristics. Methods. The PubMed, Embase, Cochrane Library, and Web of Science databases were searched from inception through September 13, 2019, to identify studies investigating the association between MUC expression levels in CRC tissues and prognosis. Pooled hazard ratios (HRs) or odds ratio (ORs) with 95% confidence intervals (CIs) were used to evaluate associations between MUC expression levels and prognosis or clinicopathological characteristics, respectively. The heterogeneity between studies was assessed by the I2 values, whereas the likelihood of publication bias was assessed by Egger’s linear regression and Begg’s rank correlation test. Results. Among 33 included studies (n=6032 patients), there were no associations between combined MUC phenotype expression levels and overall survival (OS) or disease-free survival (DFS)/relapse-free survival (RFS) in patients with CRC. In subgroup analyses, the upregulated MUC1 expression (HR=1.50; 95% CI, 1.29–1.74; P<0.00001) was associated with poor OS. However, the upregulated MUC2 expression (HR=0.64; 95% CI, 0.52–0.79; P<0.00001) was associated with better OS. Furthermore, a high level of MUC1 expression (HR=1.99; 95% CI, 0.99–3.99; P=0.05) was associated with shorter DFS/RFS. However, patients with a low level of MUC2 tumors showed better DFS/RFS than patients with a high level of MUC2 tumors (HR=0.71; 95% CI, 0.49–1.04; P=0.08; P=0.0.009, I2=67%) and MUC5AC expression (HR=0.56; 95% CI, 0.38–0.82; P=0.003) was associated with longer DFS/RFS. In addition, a high level of MUC1 expression was associated with CRC in the rectum, deeper invasion, lymph node metastasis, distant metastasis, advanced tumor stage, and lymphatic invasion. A high level of MUC2 expression had a protective effect. High secretion of MUC5AC is associated with colon cancer compared with rectal cancer. Conclusion. The protein expression of MUC1 might be a poor biomarker in colorectal cancer and might play a role in tumor transformation and metastasis. However, the protein expression of MUC2 expression might have a protective effect. Furthermore, randomized controlled trials (RCTs) of large patients are needed to confirm the results.

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Banos-Lara, Rocio, et Maria Guerrero-Plata. « Differential mucins gene expression between respiratory human paramyxovirus infections (VIR5P.1142) ». Journal of Immunology 194, n^o 1_Supplement (1 mai 2015) : 148.10. http://dx.doi.org/10.4049/jimmunol.194.supp.148.10.

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Abstract Mucin (MUC) proteins are the main component of mucus and constitute part of the innate immune response. High production of mucins and mucus is characteristic in inflammatory lung diseases. Respiratory Syncytial Virus (RSV) and Human Metapneunovirus (hMPV) are RNA viruses belonging to the Paramyxoviridae family and represent the most important cause of severe lung diseases such as pneumonia and bronchiolitis in young children, the elderly and immunocompromised individuals. Although these viruses are close-related, the host immune response elicited by them is widely different. In this work we evaluated the lung gene expression of secreted (MUC2, MUC5AC, MUC5B, MUC8 and MUC19) and cell surface (MUC1, MUC3, MUC4, MUC13, MUC15, MUC16, MUC20, MUC21 and MUC22) mucins by qRTPCR in human epithelial cells infected with RSV or hMPV. Our data indicate that the MUC expression by RSV and hMPV differ significantly, as we observed a stronger induction of MUC8, MUC15, MUC20, MUC21 and MUC22 by RSV infection at 48 and 72 h than by hMPV. On the other hand, the expression of MUC2, MUC5B and MUC1 was dominated by the infection with hMPV at the same time points. No significant MUC5AC, MUC19, MUC3, or MUC13 expression was observed after any of the infections. Together, these data indicate that RSV appears to be a stronger inducer of MUC response than hMPV and suggest that MUC expression contribute to the differential immune response induced by these two major human respiratory viruses

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Kai, H., K. Yoshitake, A. Hisatsune, T. Kido, Y. Isohama, K. Takahama et T. Miyata. « Dexamethasone suppresses mucus production and MUC-2 and MUC-5AC gene expression by NCI-H292 cells ». American Journal of Physiology-Lung Cellular and Molecular Physiology 271, n^o 3 (1 septembre 1996) : L484—L488. http://dx.doi.org/10.1152/ajplung.1996.271.3.l484.

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Excessive production of airway mucus is a characteristic feature of many chronic inflammatory lung diseases. Although current pharmacological approaches to excessive mucus production are limited, glucocorticoids appear to be the most effective among a few useful drugs. The exact evidence for the effectiveness of glucocorticoids on mucus production has not been fully elucidated to date. The purpose of this study is to clarify the effect of dexamethasone on mucus production and mucin gene expression in a human pulmonary mucoepidermoid carcinoma cell line (NCI-H292). NCI-H292 cells produced hyaluronidase-resistant high-molecular-weight glycoconjugates (HMWG), which elute in the void volume on Sepharose CL-4B column chromatography. Dexamethasone significantly suppressed the basal production of [3H]glucosamine-or [3H]serine-labeled HMWG in NCI-H292 cells. In Northern blot analysis, dexamethasone attenuated steady-state mRNA levels of MUC-2 and MUC-5AC mucin genes. These data indicate that dexamethasone suppresses the basal production of HMWG and decreases steady-state mRNA levels of mucin genes in airway mucus-producing cancer cells.

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Gómez Rosso, A., ME Samar, RE Avila, I. Fonseca, G. Corball et RV Ferraris. « Expression of the membrane-associated mucin MUC-1 and its relationship with Ki67 in mucoepidermoid carcinoma of the salivary glands ». Revista de la Facultad de Odontología 32, n^o 3 (5 décembre 2022) : 10–18. http://dx.doi.org/10.25014/revfacodont271.2022.32.3.10.

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Background: Salivary gland tumors are rare and with different malignant potential. Immunohistochemistry is useful, especially Ki67, a marker of cell proliferation, for its prognostic information. On the other side, the mucin MUC-1 is overexpressed and loses its exclusively apical membranous localization and is aberrantly glycosylated in mucoepidermoid carcinoma of salivary glands. In the present work, we investigated the quantitative expression of tumor proliferative index and localization and overexpression of MUC-1 in the mucoepidermoid carcinoma of the human salivary glands, not studied is these organs, to determine their relationship with the histological grade and prognosis. Methods: H/E staining and immunohistochemistry with MUC-1 and Ki67 antibodies was performed on 10 cases. Results: The markings of the mucoepidermoid carcinoma depended on the histological grade; in low- grade tumors with MUC-1 only 10 to 25% of the cells were labeled, in contrast to high- grade tumors, with 75 to 90% labeled cells. They also differed in cell proliferation; in the low-grade tumors was 15% and in high-grade tumors it was greater than 30%. Conclusion: MUC-1 overexpression is significantly higher in high-grade mucoepidermoid carcinoma, as is Ki67 marking, results that are associated with tumor prognosis.

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Rubin, J. S., B. K. Bloor, I. R. Hart et P. R. Morgan. « muc-1 gene expression in head and neck squamous cell carcinomas ». Journal of Laryngology & ; Otology 114, n^o 10 (octobre 2000) : 772–76. http://dx.doi.org/10.1258/0022215001904121.

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Polymorphic epithelial mucin (PEM), the protein product of the gene muc-1, is a surface glycoprotein that is produced by a range of normal epithelial cells, but has been shown to be expressed at high levels in a range of adenocarcinomas. It has not been investigated extensively in head and neck related tissues, and not at all in head and neck squamous cell carcinomas (HNSCC). This immunohistochemical investigation using two monoclonal antibodies to muc-1 represents a baseline study of 18 HNSCC. In 13 cases, the glycoprotein was expressed at varying levels, usually in keratinizing foci. Although less prominent, expression was also present to some degree in nine of 23 control specimens of non-neoplastic mucosa, mostly at an epithelial level early in the parakeratinization process. Both antibodies showed a pattern of staining. The cellular basis for muc-1 expression is speculative at present and although it is at a lower level than in adenocarcinomas, it may help to provide further insight into epithelial cell differentiation in squamous cell carcinomas.

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Teruya-Feldstein, Julie, Gerard B. Donnelly, Andre Goy, Abhijith Hegde, Gouri Nanjangud, Jing Qin, Howard Thaler et al. « MUC-1 Mucin Protein Expression in B-cell Lymphomas ». Applied Immunohistochemistry & ; Molecular Morphology 11, n^o 1 (mars 2003) : 28–32. http://dx.doi.org/10.1097/00129039-200303000-00005.

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Kim, Kwang, Kyeong Woon Choi et Woo Yong Lee. « Clinicopathologic correlation with MUC expression in advanced gastric cancer ». Korean Journal of Clinical Oncology 14, n^o 2 (31 décembre 2018) : 89–94. http://dx.doi.org/10.14216/kjco.18016.

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Kim, Hyunho, In-Ho Kim et Kwangil Yim. « The clinical prognostic impact of APOBEC3B protein expression in metastatic urothelial carcinoma. » Journal of Clinical Oncology 38, n^o 6_suppl (20 février 2020) : 544. http://dx.doi.org/10.1200/jco.2020.38.6_suppl.544.

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544 Background: APOBEC3 enzymes function as a carcinogenic mutagens resulting in substitution of Cytosine to Thymine or Guanine in tCw motif. Mutation signature in urothelial (UC) carcinoma is mediated by APOBEC3 more than smoking which is well known as a risk factor. This study aimed to explore the association of APOBEC3 expression with survival in metastatic UC (mUC). Methods: We examined 94 patients treated with gemcitabine plus platinum chemotherapy for mUC. APOBEC3A and 3B protein expression was measured using immunohistochemistry from archived formalin-fixed paraffin-embedded tissue which was obtained before chemotherapy. Immunohistochemistry results were evaluated by H-score. The cutoff levels of APOBEC3A and 3B expression were calculated with time dependent ROC analysis. Results: APOBEC3B high expression exhibited longer overall survival (OS) and progression-free survival (PFS) than low expression (median OS: 16 months vs 9 months, p=0.032; median PFS: 7 months vs 4 months, p=0.017). APOBEC3A high expression was associated with longer OS (median OS: 13 months vs 9 months, p=0.036; median PFS: 6 months vs 4 months, p=0.405). Disease control (CR/PR/SD) rate (DCR) was higher in APOBEC3B high group than low group (DCR, 79.4% and 57.1%, respectively, p=0.045). Mean H-score of APOBEC3B was higher in disease control group than progressive disease group (mean H-score, 125.3 vs 101.3, p=0.029). APOBEC3A expression was not correlated with chemotherapy response. There was not a significant correlation between APOBEC3A and APOBEC3B (Spearman correlation coefficient=0.111, p=0.319). Conclusions: mUC with APOBEC3B high expression may be associated with better response from gemcitabine plus platinum chemotherapy and longer overall survival. Further functional studies are warranted to clarify the clinical significance of APOBEC3B protein expression in mUC.

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Gómez Rosso, Araceli, María Elena Samar, Ávila Rodolfo, Luis Ferraris, Ismael Fonseca et Javier Fernández. « Pleomorphic adenoma of the lacrimal gland : atypical location of a salivary tumor ». Revista de la Facultad de Odontología 30, n^o 3 (8 décembre 2020) : 20–28. http://dx.doi.org/10.25014/revfacodont271.2020.30.3.20.

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Introduction: In daily ophthalmological practice, lacrimal gland tumors are rare. They represent 5 to 7.5% of all intraorbital tumors. The most common epithelial tumor of this gland is the pleomorphic adenoma, with a percentage of 25 to 50% of its tumor lesions. Objective: In this communication we presented a case of lacrimal gland pleomorphic adenoma and study the expression of Ki67 and the location and expression of MUC-1 and its correlation with tumor prognosis. We also carried out a retrospective descriptive study of the literature on the subject published between 1951 and 2020, using the MEDLINE database. Material and methods: The surgical piece examined, was processed according to the paraffin embedding technique, was performed with a histopathological diagnosis of pleomorphic lacrimal gland adenoma. Histological sections were stained with Hematoxylin / Eosin. Immunostaining with Ki67 and MUC-1 was performed with the DAKO LSAB + kit. Results: The diagnosis of hypercellular pleomorphic adenoma with areas of the remaining lacrimal gland was made. Ki67 labeling was low (≤15%). MUC-1 expression was intense, situated to the apical cell membrane of approximately 10% epitheliocytes from pseudoductal and cystic structures.Conclusions: Through histopathological evaluation, the correlation of Ki67 expression and the location and expression of MUC1, we verified that it is a non-recurrent pleomorphic adenoma without malignant transformation.

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Gupta, Shilpa, Martine C. Maculaitis, Andrew Bernstein, Anna Boudoures, Marija Tesic-Schnell, Brian S. Seal, Emily Mulvihill et Yunes Doleh. « Real-world adoption of PD-L1 testing in metastatic urothelial carcinoma. » Journal of Clinical Oncology 38, n^o 15_suppl (20 mai 2020) : e19184-e19184. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e19184.

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e19184 Background: The role of PD-L1 testing in locally advanced (LA) or metastatic urothelial carcinoma (mUC) is not currently well-defined, except in cisplatin-ineligible patients (pts). IMVigor130 trial data are the first to suggest cisplatin-eligible PD-L1 positive pts may also benefit from immunotherapy (IO) (ESMO LBA14_PR, 2019). As clinical data accumulate on the influence of PD-L1 expression on LA/mUC pt outcomes with IO, we assessed medical oncologists’ (ONCs) PD-L1 testing perceptions and practices. Methods: ONCs completed a longitudinal, online self-report survey fielded from August 22 to September 23, 2019, prior to release of IMVigor130 data. Baseline results are reported. Descriptive statistics and bivariate comparisons by practice setting were conducted. Results: ONCs (N = 203) had a mean of 15 years in practice; a majority (64%) practice in the community. ONCs tested most LA/mUC pts, but initiated treatment for about a third before receiving results (Table). Half believe PD-L1 testing in LA/mUC will increase over time; this view was more common for ONCs who do not (n = 55) vs. do (n = 148) order PD-L1 testing as standard for LA/mUC pts (55% vs. 49%). Most ONCs reported that pts in an IO + chemotherapy trial arm should be stratified by PD-L1 status (74%), but not platinum agent (69%). Common barriers to more LA/mUC pts (n = 92) getting a PD-L1 test were limited biopsy sample (54%), lack of influence on treatment decisions (54%), and treatment initiation urgency (30%). ONCs varied little by practice setting. Conclusions: PD-L1 testing has been adopted by ONCs for most of their LA/mUC pts. However, ONCs report limited biopsy sample and lack of influence on treatment decisions as barriers to testing more LA/mUC pts, supporting their initiation of therapy prior to receipt of results and desire for trial data to be stratified by PD-L1 status. Results suggest PD-L1 expression is not yet a key driver in treatment decisions. Given the variability in self-reported responses, results should be interpreted with this limitation in mind. [Table: see text]

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Batra, Surinder K., Richard S. Metzgar et Michael A. Hollingsworth. « Human Muc 1 Mucin Gene Expression in the Fetal Pancreas ». Pancreas 7, n^o 3 (mai 1992) : 391–93. http://dx.doi.org/10.1097/00006676-199205000-00018.

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Tsukashita, Shizuki, Ryoji Kushima, Masamichi Bamba, Hiroyuki Sugihara et Takanori Hattori. « MUC gene expression and histogenesis of adenocarcinoma of the stomach ». International Journal of Cancer 94, n^o 2 (2001) : 166–70. http://dx.doi.org/10.1002/ijc.1460.

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TERADA, TADASHI, TETSUO OHTA, MOTOKO SASAKI, YASUNI NAKANUMA et YOUNG S. KIM. « EXPRESSION OF MUC APOMUCINS IN NORMAL PANCREAS AND PANCREATIC TUMOURS ». Journal of Pathology 180, n^o 2 (octobre 1996) : 160–65. http://dx.doi.org/10.1002/(sici)1096-9896(199610)180:2<160 ::aid-path625>3.0.co;2-a.

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Montoya, Carlos A., Pascal Leterme, Véronique Romé, Stephen Beebe, Jean Claustre et Jean-Paul Lallès. « Phaseolin from Phaseolus vulgaris bean modulates gut mucin flow and gene expression in rats ». British Journal of Nutrition 104, n^o 12 (2 août 2010) : 1740–47. http://dx.doi.org/10.1017/s0007114510002813.

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Dietary protein might modulate mucin flow and intestinal mucin gene expression. Since unheated phaseolin from Phaseolus vulgaris bean is resistant to digestion and increases gut endogenous protein losses, we hypothesised that unheated phaseolin influences mucin flow and gene expression, and that phaseolin heat treatment reverses these effects. The hypothesis was tested using a control diet containing casein as the sole protein source and three other diets with casein being replaced by 33 and 67 % of unheated and 67 % of heated phaseolin. The rats were fed for 6 d and euthanised. Digesta and faeces were collected for determining digestibility and mucin flow. Gut tissues were collected for mucin (Muc1, Muc2, Muc3 and Muc4) and Trefoil factor 3 (Tff3) gene expressions. Colonic mucin flow decreased linearly with increasing the dietary level of unheated phaseolin (P < 0·05). Unheated phaseolin increased N flow in ileum, colon and faeces (P < 0·05), and reduced apparent N digestibility linearly (P < 0·01). Heat treatment reversed all these changes (P < 0·05 to < 0·001), except mucin flow. The expressions of Muc mRNA in gut tissues were influenced by dietary phaseolin level (ileum and colon: Muc3 and Muc4) and thermal treatment (ileum: Muc2; colon: Muc2, Muc3, Muc4 and Tff3) (P < 0·05 to 0·001). In conclusion, phaseolin modulates mucin flow and Muc gene expression along the intestines differentially.

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Ulu, Yuksel, Seza Tetikkurt, Ugur Izol et Yunus Donder. « Evaluation of MUC-1, MUC-4, CDX-2 and OCT-1 expression profiles in gastric carcinomas and precancerous lesions ». Annals of Medical Research 26, n^o 12 (2019) : 2908. http://dx.doi.org/10.5455/annalsmedres.2019.08.461.

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Lohova, Elizabeta, et Mara Pilmane. « Expression of MUC-2, MUC-6, NAPE-PLD, IL-6 and IL-13 in Healthy and Metaplastic Bronchial Epithelium ». Diseases 11, n^o 1 (27 décembre 2022) : 5. http://dx.doi.org/10.3390/diseases11010005.

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Background: The normal tissue structure of the respiratory system is necessary to provide adequate protection of the airways and lungs. Prolonged exposure to trigger factors can result in adaptive mechanism activation and lead to the development of chronic pulmonary diseases or even dysplastic changes. Materials and methods: Respiratory system material with a pseudostratified ciliated epithelium was obtained from 12 patients (aged 16 to 95), and material with a stratified squamosa epithelium was obtained from six patients (aged 23 to 93). Routine staining was performed, and an immunohistochemistry was conducted for MUC-2, MUC-6, NAPE-PLD, IL-6 and IL-13. Results: Inflammatory processes were not detected in any of the specimens. A number of correlations were identified, with the most important being a strong positive correlation for IL-13 between the alveolar epithelium and alveolar macrophages and a strong positive correlation for IL-6 between the alveolar epithelium and alveolar macrophages in the stratified squamous epithelium group. We also detected a statistically significant difference in IL-6 in alveolar macrophages. Conclusion: There were no signs of dysplastic changes in either group. Increased secretion of IL-13 in the stratified squamous epithelium group shows its involvement in metaplastic changes in the bronchial epithelium. The secretion of atypical factors by hyaline cartilage demonstrates its plasticity and adaptability.

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Bódi, Nikolett, Lalitha Chandrakumar, Afnan al Doghmi, Diána Mezei, Zita Szalai, Bence Pál Barta, János Balázs et Mária Bagyánszki. « Intestinal Region-Specific and Layer-Dependent Induction of TNFα in Rats with Streptozotocin-Induced Diabetes and after Insulin Replacement ». Cells 10, n^o 9 (13 septembre 2021) : 2410. http://dx.doi.org/10.3390/cells10092410.

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Tumour necrosis factor alpha (TNFα) is essential in neuroinflammatory modulation. Therefore, the goal of this study is to reveal the effects of chronic hyperglycaemia and insulin treatment on TNFα expression in different gut segments and intestinal wall layers. TNFα expression was mapped by fluorescent immunohistochemistry and quantitative immunogold electron microscopy in myenteric ganglia of duodenum, ileum and colon. Tissue TNFα levels were measured by enzyme-linked immunosorbent assays in muscle/myenteric plexus-containing (MUSCLE-MP) and mucosa/submucosa/submucous plexus-containing (MUC-SUBMUC-SP) homogenates. Increasing density of TNFα-labelling gold particles is observed in myenteric ganglia from proximal to distal segments and TNFα tissue levels are much more elevated in MUSCLE-MP homogenates than in MUC-SUBMUC-SP samples in healthy controls. In the diabetics, the number of TNFα gold labels is significantly increased in the duodenum, decreased in the colon and remained unchanged in the ileal ganglia, while insulin does not prevent these diabetes-related TNFα changes. TNFα tissue concentration is also increased in MUSCLE-MP homogenates of diabetic duodenum, while decreased in MUC-SUBMUC-SP samples of diabetic ileum and colon. These findings support that type 1 diabetes has region-specific and intestinal layer-dependent effects on TNFα expression, contributing to the regional damage of myenteric neurons and their intestinal milieu.

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Apolo, Andrea B., Jeffrey R. Infante, Omid Hamid, Manish R. Patel, Ding Wang, Karen Kelly, Anthony E. Mega et al. « Safety, clinical activity, and PD-L1 expression of avelumab (MSB0010718C), an anti-PD-L1 antibody, in patients with metastatic urothelial carcinoma from the JAVELIN Solid Tumor phase Ib trial. » Journal of Clinical Oncology 34, n^o 2_suppl (10 janvier 2016) : 367. http://dx.doi.org/10.1200/jco.2016.34.2_suppl.367.

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367 Background: Avelumab* (MSB0010718C) is a fully human anti-PD-L1 IgG1 antibody being investigated in multiple clinical trials. We report safety and clinical activity of avelumab as a second-line therapy in patients (pts) with metastatic urothelial carcinoma (mUC) based on level of PD-L1 expression (NCT01772004). Methods: Pts with mUC unselected for PD-L1 expression received avelumab at 10 mg/kg Q2W by IV infusion until confirmed progression, unacceptable toxicity, or any criterion for withdrawal occurred. Tumors were assessed every 6 wks (RECIST 1.1). Best overall response rate (ORR) and progression-free survival (PFS) were evaluated. Adverse events (AEs) were graded by NCI-CTCAE v4.0. PD-L1 expression was assessed by immunohistochemistry. Results: As of 19 Mar 2015, 44 pts (30 men, 14 women) with mUC were treated with avelumab (median 13 wks [range 2-28]) and followed for a median of 3.5 mo (range 3.0-5.0). Median age was 68y (range 30-84), ECOG performance status was 0 (43.2%) or 1 (56.8%), and pts had received a median of 2 prior therapies (range 1- ≥ 4). Treatment-related treatment-emergent AEs (TR-TEAEs) of any grade occurred in 26 pts (59.1%); those occurring ≥ 10% were grade 1/2 infusion-related reactions (8 [18.2%]) and fatigue (7 [15.9%]). One pt had grade 3 asthenia. There were no treatment-related deaths. ORR was 15.9% (7 pts; 95% CI: 6.6, 30.1) with 1 CR and 6 PRs; 6 responses were ongoing at data cutoff. Stable disease (SD) was observed in 19 pts (42.3%) and disease-control rate (CR+PR+SD) was 59.1%. PD-L1 expression was evaluable in 32 pts. Using a ≥ 5% cutoff (10/32 [31.3%] were PD-L1+), ORR was 40.0% in PD-L1+ pts (4/10) vs 9.1% in PD-L1– pts (2/22; p= 0.060). PFS rate at 12 wks was 70.0% (95% CI: 32.9, 89.2) in PD-L1+ pts vs 45.5% (95% CI 22.7, 65.8) in PD-L1− pts. Conclusions: Avelumabshowed an acceptable safety profile and had clinical activity in pts with mUC. There was a trend towards higher ORR and prolonged PFS rate at 12 wks in pts with PD-L1+ mUC. Further analyses of PD-L1 expression and clinical activity of avelumab in UC are ongoing. *Proposed INN. Clinical trial information: NCT01772004.

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Sharma, Padmanee, Margaret K. Callahan, Petri Bono, Joseph W. Kim, Pavlina Spiliopoulou, Emiliano Calvo, Rathi Narayana Pillai et al. « Nivolumab monotherapy in metastatic urothelial carcinoma : Longer-term efficacy and safety results from the CheckMate 032 study. » Journal of Clinical Oncology 36, n^o 6_suppl (20 février 2018) : 414. http://dx.doi.org/10.1200/jco.2018.36.6_suppl.414.

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414 Background: Nivolumab has shown efficacy and acceptable safety in 2 open-label, multicenter studies (CheckMate 032 and 275) and is approved for patients (pts) with metastatic urothelial carcinoma (mUC) after ≥1 platinum-based therapy. Here we report longer-term efficacy and safety results for pts with mUC in the phase 1/2 CheckMate 032 study who received nivolumab monotherapy based on > 2 years of follow-up. Methods: Pts with mUC, regardless of programmed death-1 ligand 1 (PD-L1) expression status, received nivolumab 3 mg/kg intravenously every 2 weeks until progression or discontinuation. Tumor PD-L1 membrane expression was assessed with Dako PD-L1 immunohistochemical staining. Primary endpoint: objective response rate (ORR; RECIST 1.1); other endpoints: safety, progression-free survival (PFS), overall survival (OS), and duration of response. Results: Of 78 treated pts (median age 65.5 years; range, 31-85), 52 (66.7%) had received ≥2 prior therapies. At a minimum follow-up of 24 months, 11 pts (14.1%) remain on treatment. Treatment discontinuation was mainly due to disease progression (52 pts [66.7%]). Tumor PD-L1 expression was evaluable in 68 pts (87.2%); 26 (38.2%) pts had ≥1% and 42 (61.8%) had < 1% expression. The table shows overall efficacy. Updated ORR was 25.6%, with 1 additional complete response (CR) achieved for a CR rate of 8%. Median duration of response was not reached. ORR, 1- and 2-year PFS and OS rates were similar between the PD-L1 < 1% and > 1% subsets. Grade 3 or 4 treatment-related adverse events (TRAEs) occurred in 22 pts (28.2%); most frequent were ↑lipase (6.4%), ↑amylase (5.1%), and maculopapular rash (3.8%). One pt had a grade 5 TRAE (pneumonitis). Conclusions: Nivolumab showed clinically meaningful, durable efficacy with promising long-term survival regardless of PD-L1 expression, and no new toxicity signals with longer-term follow-up in previously treated pts with mUC. Clinical trial information: NCT01928394. [Table: see text]

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Gomez De Liano Lista, Alfonso, Georgia Anguera, Emilio Esteban, Ovidio Fernandez Calvo, Iciar García-Carbonero, Xavier Garcia del Muro, Iria González Maeso et al. « AUREA study : Atezolizumab (Atezo) combined with split-dose gemcitabine plus cisplatin (s-GC) in locally advanced or metastatic urothelial cancer (LA/mUC) : A SOGUG study. » Journal of Clinical Oncology 39, n^o 15_suppl (20 mai 2021) : TPS4589. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.tps4589.

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TPS4589 Background: First-line cisplatin-based chemotherapy (70 mg/m2) is the standard of care for LA/mUC patients (pts). However, about 50% will be ineligible for Cisplatin according to Galsky´s criteria. Moreover, a significant proportion of cisplatin-fit pts will receive carboplatin based on physician criteria. s-GC represents a feasible alternative in such situations, and could improve response rate compared to carboplatin regimens. Atezo is a programmed death-ligand 1 (PD-L1) inhibitor that is approved as first line treatment for cisplatin-ineligible LA/mUC pts with PD-L1 expression ≥5% (Ventana SP142). We present the study design of a phase II single arm trial of Atezo +s-GC in previously untreated pts with LA/mUC (NCT04602078). Methods: This single arm, open-label, multicenter study evaluates the efficacy and safety of Atezo +s-GC in previously untreated pts with LA/mUC. 66 pts will be enrolled and receive s-GC x 6 cycles (Cisplatin 35mg/m2 + Gemcitabine 1000mg/m2 on days 1 and 8 Q3W) and Atezo (1200 mg IV Q3W), followed by Atezo (1200 mg IV Q3W) until disease progression, toxicity or absence of clinical benefit. Eligibility criteria include histologically confirmed unresectable LA/mUC, measurable disease per RECIST 1.1 and adequate organ and marrow. Pts must be unfit for full cisplatin dose based on: age > 70 years, PS ECOG 0-2, creatinine Clearance >30 and <60 mL/min per Cockroft-Gault formula or by 24-hour urine collection. Other reasons for cisplatin ineligibility as considered by investigator, including those uncovered by Galsky´s criteria, will be allowed, prior discussion with PI. Exclusion criteria include prior systemic therapy for LA/mUC (adjuvant/neoadjuvant allowed if finished > 12 months prior to inclusion), prior autoimmune disease and uncontrolled significant illnesses. The primary endpoint is ORR per RECIST 1.1 assessed by investigator; the secondary endpoints are DoR, OS, PFS and safety. Biomarker analysis, including PD-L1 expression and microbiome relationship, will be an exploratory objective. The first two patients were enrolled in February 2021. Clinical trial information: NCT04602078.

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Fehlings, Michael, Leesun Kim, Xiangnan Guan, Kobe Yuen, Alireza Tafazzol, Shomyseh Sanjabi, Oliver A. Zill et al. « Single-cell analysis reveals clonally expanded tumor-associated CD57⁺ CD8 T cells are enriched in the periphery of patients with metastatic urothelial cancer responding to PD-L1 blockade ». Journal for ImmunoTherapy of Cancer 10, n^o 8 (août 2022) : e004759. http://dx.doi.org/10.1136/jitc-2022-004759.

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BackgroundA growing body of evidence suggests that T-cell responses against neoantigens are critical regulators of response to immune checkpoint blockade. We previously showed that circulating neoantigen-specific CD8 T cells in patients with lung cancer responding to anti-Programmed death-ligand 1 (PD-L1) (atezolizumab) exhibit a unique phenotype with high expression of CD57, CD244, and KLRG1. Here, we extended our analysis on neoantigen-specific CD8 T cells to patients with metastatic urothelial cancer (mUC) and further profiled total CD8 T cells to identify blood-based predictive biomarkers of response to atezolizumab.MethodsWe identified tumor neoantigens from 20 patients with mUC and profiled their peripheral CD8 T cells using highly multiplexed combinatorial tetramer staining. Another set of patients with mUC treated with atezolizumab (n=30) or chemotherapy (n=40) were selected to profile peripheral CD8 T cells by mass cytometry. Using single-cell transcriptional analysis (single-cell RNA sequencing (scRNA-seq)), together with CITE-seq (cellular indexing of transcriptomes and epitopes by sequencing) and paired T-cell receptor (TCR) sequencing, we further characterized peripheral CD8 T cells in a subset of patients (n=16).ResultsHigh frequency of CD57 was observed in neoantigen-specific CD8 T cells in patients with mUC responding to atezolizumab. Extending these findings to bulk CD8 T cells, we found higher frequency of CD57 expressing CD8 T cells before treatment in patients responding to atezolizumab (n=20, p<0.01) but not to chemotherapy. These findings were corroborated in a validation cohort (n=30, p<0.01) and notably were independent of known biomarkers of response. scRNA-seq analysis identified a clonally expanded cluster enriched within CD57+ CD8 T cells in responding patients characterized by higher expression of genes associated with activation, cytotoxicity, and tissue-resident memory markers. Furthermore, compared with CD57− CD8 T cells, TCRs of CD57+ CD8 T cells showed increased overlap with the TCR repertoire of tumor-infiltrating T cells.ConclusionsCollectively, we show high frequencies of CD57 among neoantigen-specific and bulk CD8 T cells in patients responding to atezolizumab. The TCR repertoire overlap between peripheral CD57+ CD8 T cells and tumor-infiltrating lymphocytes suggest that accumulation of peripheral CD57+ CD8 T cells is reflective of an ongoing antitumor T-cell response. Our findings provide evidence and rationale for using circulating CD8 T cells expressing CD57 as a readily accessible blood-based biomarker for selecting patients with mUC for atezolizumab therapy.

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Rahardja, Fanny, Dwi Prasetyo, Muhammad N. Shahib et Susy Tjahjani. « The Influence of Lactobacillus Acidophilus on MUC1, GAL-3, IL-1β and IL-17 Gene Expression in BALB/c Mice Stomach ». Open Microbiology Journal 15, n^o 1 (14 juillet 2021) : 67–71. http://dx.doi.org/10.2174/1874285802115010067.

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Background and Objective: Lactobacillus acidophilus has been widely used for the management of gastrointestinal carcinoma owing to its immunomodulation effect; however, the role of L. acidophilus and its specific mechanism of action in the stomach is not fully comprehended. The present study evaluated the expression profile of MUC-1, GAL-3, IL -1β, and IL-17 in the L. acidophilus treated mice stomach. Methods: The study was conducted utilizing three groups of mice, 6 mice for each group, administered with different doses of L. acidophilus and a control group treated with normal saline. The results were analyzed with the Mann-Whitney Test. Results: The results demonstrated that L. acidophilus elevated IL-1β insignificantly and inhibited the expression of IL-17. The MUC-1 expression is influenced by L. acidophilus and inversely proportional to GAL-3 expression. Conclusion: Lactobacillus acidophilus plays a prominent role against inflammatory responses and has a potential in the treatment of gastrointestinal cancer.

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Huddart, Robert A., Arlene O. Siefker-Radtke, Arjun Vasant Balar, Mehmet Asim Bilen, Thomas Powles, Aristotelis Bamias, Daniel Castellano et al. « PIVOT-10 : A phase II study of bempegaldesleukin (NKTR-214) in combination with nivolumab (NIVO) in cisplatin (cis) ineligible patients with previously untreated locally advanced or metastatic urothelial cancer (mUC). » Journal of Clinical Oncology 38, n^o 6_suppl (20 février 2020) : TPS589. http://dx.doi.org/10.1200/jco.2020.38.6_suppl.tps589.

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TPS589 Background: Checkpoint inhibitors can achieve durable responses in cis-ineligible 1L mUC. However, use is restricted to patients whose tumors are PD-L1 high. Approximately 70% of cis-ineligible patients have tumors with low PD-L1 expression, leaving a significant proportion of 1L mUC patients in need of new treatment options. Bempegaldesleukin (BEMPEG; NKTR-214) is a CD122-preferential IL-2 pathway agonist designed to provide sustained signaling through the IL-2 βγ receptor. NIVO is an anti-PD-1 antibody that is approved for treatment in several types of cancers, including 2L mUC after treatment with a platinum agent. Early BEMPEG plus NIVO data in 1L mUC (cis-eligible and -ineligible) patients found an objective response rate (ORR) of 48% (13/27) in the efficacy evaluable population (defined as having undergone at least one post-baseline scan) and a CR rate of 19%, prompting this further exploration of BEMPEG plus NIVO in a phase 2 study (Siefker-Radke, 2019). Methods: This Phase 2 multi-national trial evaluates BEMPEG plus NIVO in previously untreated patients with cis-ineligible mUC. Eligibility also requires tumor tissue be analyzed by central laboratory to document PD-L1 status. Approximately 205 patients will be enrolled. BEMPEG (0.006 mg/kg) and NIVO (360 mg) are given intravenously (IV) on Day 1 of each 3-week cycle. The primary endpoint is ORR assessed per RECIST 1.1 by blinded independent central review (BICR) in patients with low PD-L1 expression (defined as Combined Positive Score [CPS] < 10). Secondary endpoints include ORR and duration of response in all treated patients, safety, and tolerability. Tumor and blood samples will be collected for biomarker analyses. Enrollment is ongoing. Clinical trial information: NCT03785925.

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Yoo, Kyo-Sang, Ho Soon Choi, Dae Won Jun, Hang Lak Lee, Oh Young Lee, Byung Chul Yoon, Kyeong Geun Lee, Seung Sam Paik, Yong Seok Kim et Jin Lee. « MUC Expression in Gallbladder Epithelial Tissues in Cholesterol-Associated Gallbladder Disease ». Gut and Liver 10, n^o 5 (15 septembre 2016) : 851–58. http://dx.doi.org/10.5009/gnl15600.

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Wegner, Carole C., Xinhui Zhou, Zhi-Ming Ding, Macus T. Kuo et Daniel D. Carson. « Tyrosine kinase inhibition decreases Muc-1 expression in mouse epithelial cells ». Journal of Cellular Physiology 170, n^o 2 (février 1997) : 200–208. http://dx.doi.org/10.1002/(sici)1097-4652(199702)170:2<200 ::aid-jcp12>3.0.co;2-l.

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Lopez-Beltran, Antonio, Alessia Cimadamore, Ana Blanca, Francesco Massari, Nuno Vau, Marina Scarpelli, Liang Cheng et Rodolfo Montironi. « Immune Checkpoint Inhibitors for the Treatment of Bladder Cancer ». Cancers 13, n^o 1 (3 janvier 2021) : 131. http://dx.doi.org/10.3390/cancers13010131.

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A number of immune checkpoint inhibitors (ICIs) have been approved as first-line therapy in case of cisplatin-ineligible patients or as second-line therapy for patients with metastatic urothelial carcinoma (mUC) of the bladder. About 30% of patients with mUC will respond to ICIs immunotherapy. Programmed death-ligand 1 (PD-L1) expression detected by immunohistochemistry seems to predict response to immune checkpoint inhibitors in patients with mUC as supported by the objective response rate (ORR) and overall survival (OS) associated with the response observed in most clinical trials. Pembrolizumab, an anti-PD-1 antibody, demonstrated better OS respective to chemotherapy in a randomized phase 3 study for second-line treatment of mUC. Nivolumab, a PD-1 antibody, also demonstrated an OS benefit when compared to controls. Atezolizumab, Durvalumab, and Avelumab antibodies targeting PD-L1 have also received approval as second-line treatments for mUC with durable response for more than 1 year in selected patients. Atezolizumab and Pembrolizumab also received approval for first-line treatment of patients that are ineligible for cisplatin. A focus on the utility of ICIs in the adjuvant or neoadjuvant setting, or as combination with chemotherapy, is the basis of some ongoing trials. The identification of a clinically useful biomarker, single or in association, to determine the optimal ICIs treatment for patients with mUC is very much needed as emphasized by the current literature. In this review, we examined relevant clinical trial results with ICIs in patients with mUC alone or as part of drug combinations; emphasis is also placed on the adjuvant and neoadjuvant setting. The current landscape of selected biomarkers of response to ICIs including anti-PD-L1 immunohistochemistry is also briefly reviewed.

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Gupta, Shilpa, Guru Sonpavde, Petros Grivas, Andrea B. Apolo, Elizabeth R. Plimack, Thomas W. Flaig, Noah M. Hahn et al. « Defining “platinum-ineligible” patients with metastatic urothelial cancer (mUC). » Journal of Clinical Oncology 37, n^o 7_suppl (1 mars 2019) : 451. http://dx.doi.org/10.1200/jco.2019.37.7_suppl.451.

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451 Background: Patients (pts) with mUC who are ineligible to receive cisplatin have limited treatment options. Pembrolizumab and atezolizumab were approved as 1st-line therapy in these pts, but their use is now restricted in pts with tumors with high PD-L1 expression, or platinum-ineligible. “Platinum-ineligible” mUC (cisplatin and carboplatin ineligible), remains undefined, and a clear definition is needed for determining treatment and clinical trial eligibility. Methods: We surveyed 56 genitourinary medical oncologists in the US using an online tool consisting of several clinical parameters (Round 1) and based on the responses, we refined the survey (Round 2) and then compiled the responses to generate a consensus definition. Results: Responses were received from 43/56 (77%) of those surveyed in Round 1 and 44/56 (78.5%) in Round 2. Based on the results shown in the Table, we recommend 1 of the following 5 parameters be used to define "platinum-ineligible” mUC: ECOG PS > 3; Cr Cl < 30 ml/min; Peripheral neuropathy > 3; NYHA Heart Failure Class > 3; ECOG PS 2 and Cr Cl < 30 ml/min. Conclusions: “Platinum-ineligible” mUC is a new and undefined category with a substantial definition variability among investigators. Results from consensus definition are proposed for standardization of this mUC category. [Table: see text]

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Labriola, Matthew, Jason Zhu, Sachica Cheris, Xin Liu, Kathryn Perkinson, Zuowei Su, Shannon McCall et al. « Concordance between PD-L1 assays for metastatic renal cell carcinoma (mRCC) and metastatic urothelial carcinoma (mUC). » Journal of Clinical Oncology 37, n^o 15_suppl (20 mai 2019) : e14259-e14259. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e14259.

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e14259 Background: Immune checkpoint inhibitors (ICIs) are standard of care for mRCC and mUC patients (pts). PD-L1 status is gaining importance as a predictive biomarker, particularly for cisplatin-ineligible mUC. PD-L1 positivity is defined differently by PD-L1 assay and tumor type, with limited concordance studies. Given real-world limitations in PD-L1 testing, assay concordance studies are needed to distinguish positive (pos)/negative (neg) results and treatment selection. We compared Dako 28–8 and Ventana SP142 assays in mRCC and Dako 22C3 and Ventana SP263 assays in mUC. Methods: 32 pts with mRCC and 18 pts with mUC who had received ICI therapy at Duke Cancer Institute were identified. FFPE archival tumor samples for pts with mRCC were evaluated with Dako 28–8 and Ventana SP142 PD-L1 immunohistochemistry (IHC) assays. For pts with mUC, FFPE archival tumor samples were evaluated with Dako 22C3 and Ventana SP263 PD-L1 IHC assays. Scoring was validated by two pathologists using the scoring system for each assay. PD-L1 status was subsequently correlated to best RECIST response (objective response rate (ORR) defined as stable disease or better). Results: Tissue was obtained from primary tissue in 72% of mRCC cases and in 61% of mUC cases, with remainder from metastatic biopsies. The majority of mRCC cases (29/32, 91%) were concordant between Dako 28-8 and Ventana SP142 assays (8 cases pos and 21 cases neg), with 3 discordant cases (1 case pos for Dako 28-8 but neg for Ventana SP142 and 2 cases neg for Dako 28-8 but pos for Ventana SP142), all from primary tissue. The majority of mUC cases (17/18, 94%) were also concordant between Dako 22C3 and Ventana SP263 assays (2 pos cases and 15 neg cases), with 1 indeterminate Dako 22C3 test on a metastatic biopsy due to background lymph node. In mRCC, the ORR for PD-L1 pos cases was 45% (5/11) versus 33% (8/24) for PD-L1 neg cases. In mUC, the ORR for PD-L1 positive cases was 50% (1/2) versus 31% (5/16) for PD-L1 neg cases. Conclusions: There was strong concordance between the clinically meaningful PD-L1 assays chosen for comparison in both mRCC and mUC. mUC results were limited by low PD-L1 expression in this cohort. Although PD-L1 status does not fully predict for response to ICIs, this suggests that PD-L1 testing could be used interchangeably for the majority of cases when selecting ICI treatment in mRCC and mUC.

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Warde, Kate, Yi-Jan Lim, Felix Beuschlein, Constanze Hantel et Michael Conall Dennedy. « Investigating the Role of Cholesterol and Lipid Trafficking in Mitotane Resistance in Adrenocortical Carcinoma ». Journal of the Endocrine Society 5, Supplement_1 (1 mai 2021) : A70. http://dx.doi.org/10.1210/jendso/bvab048.141.

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Abstract Introduction: Adrenocortical Carcinoma (ACC) is a rare aggressive cancer which carries a poor prognosis. Adjuvant mitotane improves survival but is limited by poor response rates and resistance following tumour recurrence. Mitotane’s efficacy has been attributed to intracellular accumulation of toxic free cholesterol (FC) predominantly through inhibition of cholesterol storage through SOAT1. Yet SOAT1 specific inhibitors demonstrate inferior efficacy to mitotane in inducing ACC cell death. We hypothesize that mitotane’s efficacy to induce toxic FC accumulation in ACC cells is also mediated through enhanced breakdown of stored cholesterol within intracellular lipid droplets (LDs). Methodology: ATCC-H295R (mitotane sensitive) and MUC-1 (mitotane resistant) ACC cells were evaluated for neutral lipid content using BODIPY493/503 under baseline and cholesterol loaded conditions using Amnis ImageStream, additionally cells were treated with mitotane (H295R - 20, 40, 50µM; MUC1 - 50, 100, 200µM) for 6hr. Analysis of LDs using CE-BODIPY and FA-BODIPY identified cholesterol ester (CE) and triacylglycerol (TAG)-containing LDs, respectively. Lipid droplet-associated proteins (LDAPs) Perilipin (PLIN) 1–4 and hormone sensitive lipase (HSL) were evaluated using western blotting and PCR. Lipid uptake receptors; SRB1, LDLR, LRP1 and CD36 were measured by flow cytometry. Results: Mitotane treatment, within therapeutic range, decreased staining for LDs significantly in H295R. This was also reflected by decreased expression of LDAPs, PLIN1 and PLIN3. The decrease in H295R LDs was associated with increased activation of HSL (pHSL and LIPE). However, this effect was only evident in MUC-1 at supratherapeutic mitotane (200µM). H295R and MUC-1 demonstrated similar overall LD numbers at baseline and under cholesterol supplementation. Expression of PLIN3 was high in both cell lines, while PLIN1, PLIN2 and PLIN4 demonstrated distinct LD profiles in each. Investigation of LD content showed that H295R preferentially store CEs while MUC-1 store only TAG, irrespective of cholesterol-loading. Mitotane treatment significantly reduces both CE and TAG LDs in H295R and MUC-1. Expression of lipid uptake receptors also demonstrated significant variability between cell lines including SRB1 and LRP1. Conclusion: We highlight that lipolysis through LD breakdown and activation of HSL represents a putative additional mechanism for mitotane induced FC cytotoxicity in ACC. We also demonstrate significant differences in cholesterol handling and LDAPs between mitotane sensitive and mitotane resistant models, in particular, the absence of CE LDs in MUC-1. We therefore propose a mechanism of resistance to mitotane through absent CE storage. Further understanding of cholesterol and lipid handling in ACC offers novel therapeutic exploitation, especially in the setting of mitotane resistant disease.

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