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2017 Cardiovascular Research Day Abstract Book

65 An obesity-generating

65 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. 81

66 Serum Amyloid A3 is a High Density Lipoprotein-associated Acute Phase Protein Maria De Beer, PhD 1 • Ailing Ji, PhD 2 • Victoria Noffsinger 2 • Preetha Shridas, PhD 2 • Frederick De Beer, MD 2 • Lisa Tannock, MD 2 • Nancy Webb, PhD 2 1Physiology, University of Kentucky • 2 Internal Medicine, University of Kentucky Faculty Acute phase serum amyloid (SAA) is a family of evolutionarily conserved, secreted proteins that exerts innate functions relevant to obesity and diabetes. In humans, two SAA isoforms (SAA1 and SAA2) are highly induced in the liver and extrahepatic tissues under the regulation of inflammatory cytokines. During severe inflammation, SAA1/2 levels can increase >1000-fold in plasma, where it is found associated with HDL. Mice produce an additional acute phase SAA, SAA3, which is thought to be produced mainly by adipocytes and macrophages and has not previously been found circulating on HDL. Objectives: The goal of this study was to investigate whether SAA3 serves as a third liver-derived, HDL-associated acute phase SAA in mice. Methods: Using isoform-specific oligonucleotide primers for qRT-PCR, we determined that SAA3 is transcriptionally induced to a similar extent (~2500-fold) compared to SAA1.1/2.1 (~6000-fold) in livers of C57BL/6 mice 19 hr after lipopolysaccharide (LPS) injection (100 µg/mouse). SAAs were also robustly induced in fat tissue (SAA1/2~100-fold; SAA3~400-fold). The analysis of primary mouse hepatocytes and in situ hybridization of mouse liver sections indicated that liver-derived SAAs are produced by hepatocytes and not other stromal cells, including Kupffer cells. All 3 SAA isoforms were detected in plasma of LPS-injected mice, although SAA3 levels were ~20% of SAA1/2. After separation by FPLC, virtually all of plasma SAA1/2 eluted with the HDL fraction, whereas ~15% of plasma SAA3 appeared to be lipid poor/free. HDL isolated from acute phase mouse plasma by density gradient ultracentrifugation was subjected to isoelectric focusing to determine the relative recovery of the various SAA isoforms. Whereas the bulk of plasma SAA1.1 was found in the d=1.063-1.21 fraction, only ~50% of SAA2.1 and ~10% of SAA3 was recovered after ultracentrifugation. These findings suggest that SAA3 may be more loosely associated with HDL compared to SAA1.1/2.1, which may give rise to lipid poor/free SAA3 that is susceptible to more rapid clearance in vivo. Conclusions: We conclude that SAA3 is a major hepatic acute phase SAA in mice that may produce systemic effects during inflammation. Future studies investigating SAA pathobiology in mice must take into account the previously under-studied SAA3. 82

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