MUC1/sec-expressing tumors are rejected in vivo by a T cell-dependent mechanism and secrete high levels of CCL2.
MUC1/sec is a secreted form of the glycoprotein mucin 1 (MUC1). To characterize the role that MUC1 and MUC1/sec have in tumor progression, these genes were expressed in DA-3 mammary tumor cells. DA-3 cells and DA-3 cells expressing the transmembrane MUC1 gene (DA-3/TM) grow with similar kinetics in BALB/c mice. Surprisingly, DA-3 cells expressing and secreting MUC1/sec (DA-3/sec) fail to form tumors in vivo. The mechanism of rejection was evaluated using mice deficient in constituents of the immune system. All mice lacking IFN-gamma, NK, NKT, or macrophages formed DA-3/sec tumors that regressed shortly after implantation. However, progressively growing DA-3/sec tumors developed in mice devoid of T lymphocytes. The importance of T lymphocytes in the rejection of DA-3/sec tumors was further supported by detection of DA-3-specific CTL in mice challenged with the DA-3/sec tumor. Recruitment of appropriate APC and effector cells is an important first step in the tumor clearance. Indeed, DA-3/sec cells or cell supernatants recruited 3-4 times as many macrophages as DA-3/TM cells in vivo, suggesting that a secreted chemotactic product is produced from DA-3/sec cells. RNA and protein analysis of DA-3/sec cells revealed that several genes are up-regulated by MUC1/sec expression, including MCP-1 (CCL-2). These results suggest DA-3/sec cells are capable of recruiting immune cells, and that rejection of DA-3/sec tumors, although aided by cells of the innate immune response, is ultimately due to T cell-mediated events.
Grosso
Joseph F
JF
Department of Microbiology and Immunology, University of Miami School of Medicine, FL 33136, USA.
Herbert
Lynn M
LM
Owen
Jennifer L
JL
Lopez
Diana M
DM
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D000951:Antigens, Neoplasm / Q000276:immunology; D002351:Carrageenan / Q000494:pharmacology; D045744:Cell Line, Tumor / Q000378:metabolism; D018932:Chemokine CCL2 / Q000378:metabolism*; D002634:Chemotaxis, Leukocyte; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006084:Graft Rejection / Q000276:immunology*; D007153:Immunologic Deficiency Syndromes / Q000276:immunology; D007371:Interferon-gamma / Q000172:deficiency; D007694:Killer Cells, Natural / Q000276:immunology; D008212:Lymphocyte Depletion; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D015674:Mammary Neoplasms, Animal / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018396:Mucin-1 / Q000235:genetics / Q000502:physiology*; D009363:Neoplasm Proteins / Q000378:metabolism* / Q000502:physiology; D009368:Neoplasm Transplantation / Q000276:immunology; D020033:Protein Isoforms / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014162:Transfection
D000951:Antigens, Neoplasm; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D018396:Mucin-1; D009363:Neoplasm Proteins; D020033:Protein Isoforms; D007371:Interferon-gamma; D002351:Carrageenan