Colorectal cancer cells induce lymphocyte apoptosis by an endothelial monocyte-activating polypeptide-II-dependent mechanism.
Endothelial monocyte-activating polypeptide-II (EMAP-II) was first isolated from cell growth medium conditioned by tumor cells, and is closely related or identical with the p43 component of the mammalian multisynthase complex. In its secreted form, EMAP-II has multiple cytokine-like activities in vitro, inducing procoagulant activity on the surface of endothelial cells, increasing expression of E- and P-selectins and TNF-R1, and directing migration of monocytes and neutrophils. EMAP-II has also been shown to induce apoptosis in endothelial cells, leading to the suggestion that it is a proinflammatory polypeptide with antiangiogenic activity. The role of secreted EMAP-II in tumors remains poorly understood, and we hypothesized that EMAP-II may play a role in immune evasion by tumor cells. We investigated its effects on lymphocytes, using recombinant protein, or colorectal cancer cell lines, as a source of native EMAP-II. Recombinant EMAP-II inhibits DNA synthesis and cell division, and induces apoptosis in mitogen-activated lymphocytes in PBMC preparations, and in Jurkat T cells. Native EMAP-II, released by or expressed on the surface of colorectal carcinoma cells, also induces activation of caspase 8 and apoptosis of PBLs and Jurkat cells, which are partially blocked by addition of Abs against EMAP-II. Thus, activated lymphocytes, along with proliferating endothelial cells, are targets for the cytotoxic activity of EMAP-II. Membrane-bound and soluble EMAP-II appear to play multiple roles in the tumor microenvironment, one of which is to assist in immune evasion.
Murray
J Clifford
JC
Wolfson Digestive Diseases Centre, University Hospital, School of Molecular Medical Sciences, University of Nottingham, Nottingham NG7 2UH, United Kingdom. cliff.murray@nott.ac.uk
Symonds
Peter
P
Ward
Wynne
W
Huggins
Mary
M
Tiga
Anna
A
Rice
Katherine
K
Heng
Yee M
YM
Todd
Ian
I
Robins
R Adrian
RA
D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D053181:Caspase 8; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D018920:Coculture Techniques; D015179:Colorectal Neoplasms / Q000737:chemistry / Q000378:metabolism* / Q000473:pathology; D016207:Cytokines / Q000494:pharmacology / Q000502:physiology*; D004247:DNA / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D004789:Enzyme Activation / Q000502:physiology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D006131:Growth Inhibitors / Q000494:pharmacology / Q000502:physiology; D019073:HT29 Cells; D006801:Humans; D007150:Immunohistochemistry; D019169:Jurkat Cells; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D016131:Lymphocyte Subsets / Q000166:cytology* / Q000473:pathology / Q000502:physiology*; D008565:Membrane Proteins / Q000502:physiology; D009363:Neoplasm Proteins / Q000494:pharmacology / Q000502:physiology*; D016601:RNA-Binding Proteins / Q000494:pharmacology / Q000502:physiology*; D011994:Recombinant Proteins / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D014407:Tumor Cells, Cultured
D016207:Cytokines; D006131:Growth Inhibitors; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D016601:RNA-Binding Proteins; D011994:Recombinant Proteins; C077219:small inducible cytokine subfamily E, member 1; D004247:DNA; C505530:CASP8 protein, human; D053181:Caspase 8; D020169:Caspases