Immunodeficient mouse strains display marked variability in growth of human melanoma lung metastases.
OBJECTIVE
Immunodeficient mice serve as critical hosts for transplantation of xenogeneic cells for in vivo analysis of various biological processes. Because investigators typically select one or two immunodeficient mouse strains as recipients, no comprehensive study has been published documenting differences in human tumor engraftment. Taking advantage of the increased metastatic potential of RhoC-expressing human (A375) melanoma cells, we evaluate four immunodeficient mouse strains: severe combined immunodeficiency (scid), nonobese diabetic (NOD)-scid, NOD-scid beta2m(null), and NOD-scid IL2Rgamma(null) as xenograft tumor recipients.


METHODS
Bioluminescence, magnetic resonance imaging, and histopathology were used to monitor serial tumor growth. Natural killer (NK) cell function was examined in each mouse strain using standard (51)Chromium release assays.


RESULTS
Melanoma metastases growth is delayed and variable in scid and NOD-scid mice. In contrast, NOD-scid beta2m(null) and NOD-scid IL2Rgamma(null) mice show rapid tumor engraftment, although tumor growth is variable in NOD-scid beta2m(null) mice. NK cells were detected in all strains except NOD-scid IL2Rgamma(null), and in vitro activated scid, NOD-scid, and NOD-scid beta2m(null) NK cells kill human melanoma lines and primary melanoma cells. Expression of human NKG2D ligands MHC class I chain-related A and B molecules renders melanoma susceptible to murine NK cell-mediated cytotoxicity and killing is inhibited by antibody blockade of murine NKG2D.


CONCLUSIONS
Murine NKG2D recognition of MICA/B is an important receptor-ligand interaction used by NK cells in immunodeficient strains to limit engraftment of human tumors. The absolute NK deficiency in NOD-scid IL2Rgamma(null) animals makes this strain an excellent recipient of melanoma and potentially other human malignancies.
Carreno
Beatriz M
BM
Department of Medicine, Washington University School of Medicine, St Louis, MO 63110, USA. bcarreno@wustl.edu
Garbow
Joel R
JR
Kolar
Grant R
GR
Jackson
Erin N
EN
Engelbach
John A
JA
Becker-Hapak
Michelle
M
Carayannopoulos
Leonidas N
LN
Piwnica-Worms
David
D
Linette
Gerald P
GP
D000818:Animals; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D005434:Flow Cytometry; D058851:GPI-Linked Proteins; D006085:Graft Survival; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D053631:Interleukin Receptor Common gamma Subunit / Q000235:genetics / Q000378:metabolism; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000556:secondary*; D008546:Melanoma, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014183:Transplantation, Heterologous; D047368:Tumor Burden; D020741:rho GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D000075024:rhoC GTP-Binding Protein
D058851:GPI-Linked Proteins; D015395:Histocompatibility Antigens Class I; C507942:Il2rg protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D053631:Interleukin Receptor Common gamma Subunit; C099187:MHC class I-related chain A; C098080:MICB antigen; D011993:Recombinant Fusion Proteins; C423230:ULBP2 protein, human; D008156:Luciferases; C066690:RHOC protein, human; D020741:rho GTP-Binding Proteins; D000075024:rhoC GTP-Binding Protein