Expression of tumor invasion factors determines systemic engraftment and induction of humoral hypercalcemia in a mouse model of adult T-cell leukemia.
Infection with human T-cell leukemia virus type 1 (HTLV-1) leads sometimes to the development of adult T-cell lymphoma/leukemia (ATL), which is invariably fatal and often associated with humoral hypercalcemia of malignancy. The transformation of infected CD4 T cells and the pathogenesis of leukemia have been studied with great limitation in tissue culture and patients. To better understand the pathogenesis and perform preclinical drug studies, animal models of ATL are urgently needed. In mice, inoculation of HTLV-1 cell lines mostly leads to development of localized lymphomas. To develop an ATL animal model with leukemic spread of ATL cells, mouse strains with different well-defined immune deficiencies were inoculated intraperitoneally with different HTLV-1-infected cell lines (ACH.2, C8166, MT-2, MET-1). Inoculation of MET-1 cells into NOD/SCID mice provided the best model system for slowly developing T-cell leukemia with multiple organ involvement. In leukemic mice, an increase in serum calcium levels correlated with expression of receptor activator of nuclear factor kappa-light-chain-enhancer of activated B cells ligand on leukemic cells and secretion of parathyroid hormone-related protein and interleukin-6. In contrast to the other cell lines that did not spread systemically, MET-1 expressed both the adhesion molecules CD11a (LFA-1alpha) and CD49d (VLA-4alpha) and produced or induced expression of matrix metalloproteinases 1, 2, 3, and 9, thus underlining the importance of these molecules in the spread of adult T-cell leukemia cells. The MET-1/NOD/SCID model will be useful for developing interventions against invasion and spread of leukemic cells and subsequent humoral hypercalcemia of malignancy.
Parrula
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C
College of Veterinary Medicine, Department of Veterinary Biosciences, Ohio State University, 1925 Coffey Road, Columbus, OH 43210, USA.
Zimmerman
B
B
Nadella
P
P
Shu
S
S
Rosol
T
T
Fernandez
S
S
Lairmore
M
M
Niewiesk
S
S
D000818:Animals; D051926:Basigin / Q000276:immunology; D015153:Blotting, Western / Q000662:veterinary; D040881:CD11a Antigen / Q000276:immunology; D002460:Cell Line; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D006934:Hypercalcemia / Q000209:etiology* / Q000276:immunology; D007150:Immunohistochemistry / Q000662:veterinary; D039441:Integrin alpha4 / Q000276:immunology; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000276:immunology*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000276:immunology; D051379:Mice; D016688:Mice, Inbred NOD / Q000276:immunology*; D018345:Mice, Knockout; D016513:Mice, SCID / Q000276:immunology*; D044162:Parathyroid Hormone-Related Protein / Q000235:genetics / Q000276:immunology; D053245:RANK Ligand / Q000276:immunology; D012313:RNA / Q000737:chemistry / Q000235:genetics; D019707:Receptors, Chemokine / Q000235:genetics / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000662:veterinary
C497887:Bsg protein, mouse; D040881:CD11a Antigen; D044162:Parathyroid Hormone-Related Protein; D053245:RANK Ligand; D019707:Receptors, Chemokine; C505689:Tnfsf11 protein, mouse; C080633:macrophage inflammatory protein 1alpha receptor; D051926:Basigin; D039441:Integrin alpha4; D012313:RNA; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse