Adipocytes impair leukemia treatment in mice.
Obesity is associated with increased cancer incidence and mortality. We have previously found that obesity in children is associated with a 50% increased recurrence of acute lymphoblastic leukemia (ALL) in high-risk patients. We have therefore developed novel in vivo and in vitro preclinical models to study the mechanism(s) of this association. Obesity increased relapse after monotherapy with vincristine (P = 0.03) in obese mice injected with syngeneic ALL cells. This occurred although the drug was dosed proportionally to body weight, equalizing blood and tissue drug levels. In coculture, 3T3-L1 adipocytes significantly impaired the antileukemia efficacy of vincristine, as well as three other chemotherapies (P < 0.05). Interestingly, this protection was independent of cell-cell contact, and it extended to human leukemia cell lines as well. Adipocytes prevented chemotherapy-induced apoptosis, and this was associated with increased expression of the two prosurvival signals Bcl-2 and Pim-2. These findings highlight the role of the adipocyte in fostering leukemia chemotherapy resistance, and may help explain the increased leukemia relapse rate in obese children and adults. Given the growing prevalence of obesity worldwide, these effects are likely to have increasing importance to cancer treatment.
Divisions of Endocrinology, Childrens Hospital Los Angeles, Los Angeles, CA, USA.
James W
JW
Behan
Jason P
JP
Yun
Marina P
MP
Proektor
Ehsan A
EA
Ehsanipour
Anna
A
Arutyunyan
Ara S
AS
Moses
Vassilios I
VI
Avramis
Stan G
SG
Louie
Anna
A
Butturini
Nora
N
Heisterkamp
Steven D
SD
Mittelman
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000473:pathology*; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D002450:Cell Communication / Q000502:physiology; D018920:Coculture Techniques; D019008:Drug Resistance, Neoplasm; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000473:pathology; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000473:pathology*; D014750:Vincristine / Q000494:pharmacology*
D000972:Antineoplastic Agents, Phytogenic; D014750:Vincristine