September 21, 2009 — Having previously found that obesity in children 10 years and older is associated with a 50% increased recurrence of acute lymphoblastic leukemia, researchers now have a possible explanation for these relapses.
The underlying problem might be that adipocytes, or fat cells, provide a protective niche for leukemia cells during therapy, write investigators in a paper published online September 22 in Cancer Research.
"We were surprised to find leukemia cells in the fat tissue," said the study's senior author Steven D. Mittelman, MD, PhD, in a press statement. Dr. Mittelman is an assistant professor of pediatrics, physiology, and biophysics at the Keck School of Medicine, University of Southern California in Los Angeles.
Dr. Mittelman explained that, in their new study of mice with leukemia, obese mice had higher relapse rates than lean mice after treatment with the first-line chemotherapeutic agent vincristine.
Obesity evidently impaired the effect of vincristine; progressive leukemia developed in 7 of 12 obese mice treated with vincristine but in only 3 of 12 lean control mice (P = .03).
Notably, leukemia cells were visible in "fat pads" from the mice, write Dr. Mittelman and colleagues.
The investigators cultured the cells and found that, in vitro, they were still sensitive to vincristine. "These findings support the concept that adipose tissue can be a sanctuary site for leukemia during vincristine treatment," write the study authors.
"This study provides striking experimental support for the clinical observations that obesity is associated with poor prognosis in multiple cancers," said David Hockenbery, MD, who was not involved with the study. He is a member of the Fred Hutchinson Cancer Research Center and professor of internal medicine at the University of Washington in Seattle.
Clinical Implications
In effect, adiposity may cause vincristine to be underdosed in overweight children, suggest the authors, meaning that clinical outcome can be greatly affected. And underdosing could be worsened by the fact that chemotherapies are often capped to prevent dose-dependent toxicities. Thus, if a child's body surface area, which dictates dose, indicates a higher dose, a clinician might not administer it for fear of toxicities.
If obesity does in fact cause lower vincristine exposure in children (and not just mice), then pharmacokinetic experiments in obese patients will be needed to "rigorously address this issue," write the study authors.
The current study was inspired by research led by Los Angeles–based researchers at the city's Childrens' Hospital. In a cohort of 5420 children, including 262 obese children who were 10 years or older, obesity at the time of diagnosis independently increased relapse rates by about 50% (J Clin Oncol. 2007;25:2063-2069).
Or, Did the Chemo Get Absorbed by the Fat Tissue?
The researchers considered another explanation, aside from the idea of leukemia cells finding a safe haven in fat tissue, for the different outcomes of their obese and lean mice. Namely, the possibility that the chemotherapy (vincristine) might have accumulated in the adipose tissue to such a degree that it weakened the drug's effect on the leukemia cells.
However, that did not appear to be the explanation, the authors conclude. They found that vincristine accumulates in adipocytes more than in other cells, such as fibroblasts, but they also found that this did not affect drug levels in the leukemia cells.
Whatever the exact mechanics, there is an association between adiposity and increased morbidity from leukemia and other cancers (breast, colon, and prostate), note the authors. Understanding the association is crucial in any effort to prevent patient deaths. In pediatrics, adiposity is a significant problem, with 32% of American children overweight and 16% obese, note the authors.
The new findings complement other recent cancer research, say the authors, which has found that adipocytes impair the proliferation of normal hematopoietic cells and support the growth of malignant cells, including multiple myeloma cells.
The study was supported in part by a National Institute of Child Health and Development K12 Award and by the National Cancer Institute Centers for Transdisciplinary Research on Energetics and Cancer. The researchers have disclosed no relevant financial relationships.
Cancer Res. Published online before print September 22, 2009.
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