Fluorescence imaging of multiple myeloma cells in a clinically relevant SCID/NOD in vivo model: biologic and clinical implications.
The in vivo preclinical testing of investigational therapies for multiple myeloma (MM) is hampered by the fact that models generated to recapitulate the development of diffuse skeletal lesions after i.v. injections of tumor cells do not allow for ready detection of the exact site(s) of lesions or for comprehensive monitoring of their progression. We therefore developed an in vivo MM model in severe combined immunodeficient/nonobese diabetic mice in which diffuse MM lesions developed after tail vein i.v. injection of human RPMI-8226/S MM cells stably transfected with a construct for green fluorescent protein (GFP). Using whole-body real-time fluorescence imaging to detect autofluorescent GFP(+) MM cells (and confirming the sensitivity and specificity of these findings both histologically and by flow cytometric detection of GFP(+) cells), we serially monitored, in a cohort of 75 mice, the development and progression of MM tumors. Their anatomical distribution and pathophysiological manifestations were consistent with the clinical course of MM in human patients, i.e., hallmarked by major involvement of the axial skeleton (e.g., spine, skull, and pelvis) and frequent development of paralysis secondary to spinal lesions without significant tumor spread to lungs, liver, spleen, or kidney. This model both recapitulates the diffuse bone disease of human MM and allows for serial whole-body visualization of its spatiotemporal progression. It therefore provides a valuable in vivo system to elucidate the molecular mechanisms underlying the marked osteotropism of MM, particularly for the axial skeleton, and for assessment of in vivo activity of novel anti-MM therapeutics.
Mitsiades
Constantine S
CS
Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA. Constantine_Mitsiades@dfci.harvard.edu
Mitsiades
Nicholas S
NS
Bronson
Ron T
RT
Chauhan
Dharminder
D
Munshi
Nikhil
N
Treon
Steven P
SP
Maxwell
Christopher A
CA
Pilarski
Linda
L
Hideshima
Teru
T
Hoffman
Robert M
RM
Anderson
Kenneth C
KC
D000818:Animals; D001853:Bone Marrow / Q000473:pathology; D005434:Flow Cytometry / Q000379:methods*; D005453:Fluorescence; D049452:Green Fluorescent Proteins; D006801:Humans; D008164:Luminescent Proteins / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D009368:Neoplasm Transplantation; D014162:Transfection; D014183:Transplantation, Heterologous
D008164:Luminescent Proteins; D049452:Green Fluorescent Proteins