Browsing by Subject "tumor cell"

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Open Access
The cholesterol transporter ABCG1 links cholesterol homeostasis and tumour immunity
(Nature Publishing Group, 2015) Sag, D.; Cekic, C.; Wu, R.; Linden J.; Hedrick, C.C.
ATP-binding cassette transporter G1 (ABCG1) promotes cholesterol efflux from cells and regulates intracellular cholesterol homeostasis. Here we demonstrate a role of ABCG1 as a mediator of tumour immunity. Abcg1-/- mice have dramatically suppressed subcutaneous MB49-bladder carcinoma and B16-melanoma growth and prolonged survival. We show that reduced tumour growth in Abcg1-/- mice is myeloid cell intrinsic and is associated with a phenotypic shift of the macrophages from a tumour-promoting M2 to a tumour-fighting M1 within the tumour. Abcg1-/- macrophages exhibit an intrinsic bias towards M1 polarization with increased NF-κB activation and direct cytotoxicity for tumour cells in vitro. Overall, our study demonstrates that the absence of ABCG1 inhibits tumour growth through modulation of macrophage function within the tumour, and illustrates a link between cholesterol homeostasis and cancer. © 2015 Macmillan Publishers Limited. All rights reserved.
Open Access
Expression of CK-19 and CEA mRNA in peripheral blood of gastric cancer patients
(2010) Kutun, S.; Celik, A.; Cem Kockar, M.; Erkorkmaz, U.; Eroǧlu, A.; Cetin, A.; Erkosar, B.; Yakicier, C.
Aim: To investigate the clinical and pathological relevance of detection of circulating tumor cells (CTC) in the peripheral blood of gastric carcinoma patients before operation. Patients and Methods: Fifty patients with gastric adenocarcinoma were analysed prospectively. Patients were divided into two groups according to the extent of the tumor. Group I (unresectable) consisted of 22, and group II (resectable) consisted of 28 patients. Peripheral blood samples were collected pre-operatively from all 50 patients as well as from ten healthy controls and analyzed for carcinoembryonic antigen (CEA) and cytokeratin-19 (CK-19) messenger ribonucleic acids (mRNAs). Tumor localisation, stage, presence of signet cell formation, nodal metastases, serousal and lymphovascular invasion were recorded for all patients. Results: Expression of CK-19 was detected in 24 (48%), and CEA in 10 (20%) cases. Nine patients (40%) in group I and 15 (53.6%) in group II were positive for CK-19 expression. CEA expression was more frequent among group I patients (6 vs. 4 cases). There was no significant difference between the groups in the expression of CK-19 and CEA mRNA, tumor localisation, presence of signet formation, and presence and extent of nodal metastases. Patients with major vascular invasion (MVI) expressed significantly higher levels of CTC mRNA compared to those without MVI (p = 0.023 for CEA, and p = 0.009 for CK-19). The median 1 and 2-year survival was 9.5 and 10.5 months for group I, and 20 and 28.5 months for group II, respectively (p = 0.001). The mean survival was 6.7 months for patients with MVI, and 30.2 months for those without MVI (p = 0.0001). Conclusions: High levels of CTCs were observed in patients with MVI invasion, rather than other causes of unresectability. It can be suggested that expression of both CEA and CK-19 in the peripheral blood of gastric cancer patients are strong predictors of MVI and significantly worse survival rates. Copyright © Experimental Oncology, 2010.
Open Access
Myeloid expression of adenosine a2A receptor suppresses T and NK cell responses in the solid tumor microenvironment
(American Association for Cancer Research Inc., 2014) Cekic, C.; Day, Y.-J.; Sag, D.; Linden J.
High concentrations of adenosine in tumor microenvironments inhibit antitumor cytotoxic lymphocyte responses. Although T cells express inhibitory adenosine A2A receptors (A2AR) that suppress their activation and inhibit immune killing of tumors, a role for myeloid cell A2ARs in suppressing the immune response to tumors has yet to be investigated. In this study, we show that the growth of transplanted syngeneic B16F10 melanoma or Lewis lung carcinoma cells is slowed in Adora2af/f-LysMCre+/- mice, which selectively lack myeloid A2ARs. Reduced melanoma growth is associated with significant increases in MHCII and IL12 expression in tumor-associated macrophages and with >90% reductions in IL10 expression in tumor-associated macrophages, dendritic cells (DC), and Ly6C+ or Ly6G+ myeloid-derived suppressor cells (MDSC). Myeloid deletion of A2ARs significantly increases CD44 expression on tumor-associated T cells and natural killer (NK) cells. Depletion of CD8+ T cells or NK cells in tumor-bearing mice indicates that both cell types initially contribute to slowing melanoma growth in mice lacking myeloid A2A receptors, but tumor suppression mediated by CD8+ T cells is more persistent. Myeloid-selective A2AR deletion significantly reduces lung metastasis of melanomas that express luciferase (for in vivo tracking) and ovalbumin (as a model antigen). Reduced metastasis is associated with increased numbers and activation of NK cells and antigen-specific CD8+ T cells in lung in filtrates. Overall, the findings indicate that myeloid cell A2ARs have direct myelosuppressive effects that indirectly contribute to the suppression of T cells and NK cells in primary and metastatic tumor microenvironments. The results indicate that tumor-associated myeloid cells, including macrophages, DCs, and MDSCs all express immunosuppressive A2ARs that are potential targets of adenosine receptor blockers to enhance immune killing of tumors. ©2014 AACR.