Obesity increases the mortality of numerous types of cancer. Furthermore, children over 10 years of age who are obese at diagnosis of acute lymphoblastic leukemia (ALL) have twice the risk of relapse. We have found that obese mice transplanted with leukemia are more likely to relapse after treatment with chemotherapy. We further found that adipose tissue can protect ALL cells from chemotherapy in culture. But it is unclear whether a weight loss intervention after leukemia diagnosis will improve outcome.
A weight loss intervention by dietary modification in diet induced obese mice will decrease the ability of their adipose tissue explants to protect ALL cells from chemotherapy.
Diet-induced obese C57Bl/6 mice (n=7) were switched to a low-fat diet either 3 or 21 days prior to sacrifice at 20 weeks of age. Adipose tissue explants (100 ± 5 mg) from perirenal, visceral, and subcutaneous sites were collected and used in transwell co-cultures with 250 X103 8093 murine pre-B ALL cells. Explants from non-dieted obese mice and lean mice were used as controls. Viable ALL cells were quantified using trypan blue exclusion after a 3-day exposure to 15 nM daunorubicin or 5 nM of vincristine.
Dietary intervention significantly reduced body weights in the short (39.2 ± 2.4 grams; P= 0.014) and long (32 ± 2.9 grams; P=0.041) diet groups compared to obese mice (44.5 grams ± 2.6).
Leukemia cells were partially protected from daunorubicin by both visceral (21.5±15.7×103 viable cells, p=0.01) and perirenal (28.0±20.7×103, p=0.013) fat explants from obese mice, compared to cultures without adipose tissue (9.4±8.6×103). Fat explants from mice dieted for 3 days prior to collection showed similar protection of ALL cells from daunorubicin (not shown); however, fat explants from mice dieted for 21 days did not protect ALL cells from daunorubicin (visceral: 9.4±8.0×103, p=0.009; perirenal: 7.8±6.3×103, p=0.066 vs. obese).
Similar findings were obtained with vincristine. Leukemia cells were protected from vincristine significantly by visceral fat from obese mice (50.8±5.9×103, p=0.01) and marginally by perirenal and subcutaneous fat (93.8±139.1×103, p=0.06 and 113.4±143.7×103, p=0.07 respectively) compared to cultures without adipose tissue (12.4±11.7×103). While short dieting did not restore sensitivity to vincristine, long dieting of obese mice reduced explants leukemia protection to vincristine significantly in visceral (21.8±20.2×103, p=0.004) and marginally in perirenal (34.9±43.3×103, p=0.06) explants compared to the obese group.
Dietary intervention and weight loss in diet induced obese mice decreases the ability of adipose tissue ex vivo to protect ALL cells from daunorubicin and vincristine. These results could support a potential role for dietary intervention in improving leukemia outcome in obese patients.
No relevant conflicts of interest to declare.
Asterisk with author names denotes non-ASH members.