2017 Cardiovascular Research Day Abstract Book

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An obesity-generating diet drives the cancer stem cell phenotype and glioblastoma
progression.
Daniel J Silver, PhD 1 • Gustavo A Roversi 1 • Anthony Gromovsky 1 • J Mark Brown, PhD 1 • Justin
D Lathia, PhD 1
1Cellular and Molecular Medicine, Cleveland Clinic
Staff
Glioblastoma (GBM) is the most prevalent and lethal brain cancer. The disease occurs in two to
three per 100,000 adults annually and accounts for approximately half of all brain cancers. While
there are no known causes for GBM, obesity is an established risk factor for cancer in general.
Recent work confirmed that overweight and obese women are at greater risk of developing glioma
compared to women of healthy body weight. This finding represents a major change in the
consideration of body mass for brain cancer patients, a factor that has been largely ignored in the
clinic. Furthermore, it is well-established that consumption of a Western-pattern diet leads to
increased rates of obesity. For these reasons, we hypothesized that obesity accelerates GBM
progression by driving tumor cell proliferation and/or cancer stem cell enrichment. We have tested
this hypothesis in vivo using three syngeneic glioma models transplanted into the brains of
immune-competent C57BL/6 mice. Mice were maintained on either an obesity-generating, high-fat
diet (HFD) or a standard rodent chow diet. Tumor-bearing mice fed the HFD succumbed to disease
nearly two-fold faster than those fed the chow diet. For example, mice transplanted with the GL261
syngeneic glioma model and maintained on HFD were culled, on average, 16 days earlier than those
maintained on chow. Furthermore, we noted a nearly three-fold increase in the frequency of tumor
generation in obese animals compared to lean, suggesting that systemic obesity enriches for a
tumor-initiating cancer stem cell population in the brain. Tumor cells treated directly with oleic
acid or linoleic acid in vitro demonstrated increased viability and enhanced sphere formation
compared to vehicle controls. These data indicated that certain lipid components of the obesitygenerating
diet were sufficient to drive tumor cell proliferation and the emergence of the cancer
stem cell state. In order to identify the set of lipid species contributing to accelerated disease
progression, we profiled the major lipids present in tumors of obese mice compared to tumors of
lean mice using untargeted lipidomics. This analysis revealed four putative oncogenic lipids. These
species were robustly expressed in tumors resected from obese mice compared to tumors resected
from lean mice. We have additionally identified two potentially tumor-suppressive lipids that were
expressed strongly in the contralateral hemisphere of lean mice compared to tumors resected from
either lean or obese mice. This work confirms a shift in the lipid profile of tumors developing in the
brains of the obese mice and suggests that select lipid species may directly drive the increased
tumor cell proliferation and enhancement in the cancer stem cell compartment that we observe in
vivo.
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