Abstract 1167: Osteolysis, splenic and hepatic extramedullary hematopoiesis, MDSCs, tumor growth, and metastases by orthotopic mammary tumors are increased by alcohol consumption and fatty diets
Authors: Dusad Anand , Khadge Saraswoti , Thiele Geoffrey M. , Duryee Michael J. , Britton Holly C. , Klassen Lynell W. , Dafferner Alicia J. , Farrell Tracy , McGuire Timothy R. , Hunter Carlos D. , Easterling Karen C. , O'Kane Karen J. , Sharp John Graham , Talmadge James E. 
Published: May 2015

Abstract
Fatty diets can induce low-grade inflammation that we report is increased by chronic alcohol consumption (CAC). CAC as 16.6% of total calories when administered in combination with the Lieber-DeCarli high-fat diet increases inflammation included hepatic and splenic extramedullary hematopoiesis (EMH) as assessed by flow cytometry, immunohistochemistry and a colony forming unit-granulocyte macrophage (CFU-GM) assay. Further, an increased number of hepatic myeloid derived suppressor cells (MDSCs) CD11b+Gr1+ cells that were predominantly Ly6cbr are observed. The increase in MDSCs is associated with an increased number of hepatic non-parenchymal cells including adipocytes (Oil Red O). Consistent with the increased number of hepatic MDSCs and EMH is a decrease in bone marrow cellularity and progenitor cells measured by flow cytometry (Lin-CD11b-Gr1-Sca-1+) and CFU-GM/femur. Unexpectedly, we observed demineralization and osteolytic lesions by micro computed tomography (micro CT) in all bones examined including femur, tibia, fibula and vertebral column that was associated with osteoclast activity (Trap+). Osteolysis was most notable in the fibula and vertebral spurs associated with osteoclast channels, and the demineralization appeared to be associated with areas of active myelopoiesis. The low grade, chronic inflammation associated with the Lieber-DeCarli fatty diet and CAC accelerated the induction of orthotopic 4T1 mammary tumors, resulting in extensive bone osteolysis, demineralization and increased metastases at aberrant sites including splenic, cardiac, hepatic, and extensive lymph node foci in addition to peritoneal and pleural effusions. The latter were haemorrhagic with a predominant nucleated cell infiltrate composed of bands, segs and myelocytes, supporting EMH. These results support the suggestion that a high-fat diet and CAC together increase tumor induction, metastasis and pathology in association with MDSC mobilization, expansion and EMH resulting in increased numbers of osteoclasts, associated bone demineralization and suppression of T-cell frequency and function. These results support the development of combination therapy strategies incorporating multiple molecular therapeutics that inhibit OCs, MDSCs and their associated mediators.
Citation Format: Anand Dusad, Saraswoti Khadge, Geoffrey M. Thiele, Michael J. Duryee, Holly C. Britton, Lynell W. Klassen, Alicia J. Dafferner, Tracy Farrell, Timothy R. McGuire, Carlos D. Hunter, Karen C. Easterling, Karen J. O'Kane, John Graham Sharp, James E. Talmadge. Osteolysis, splenic and hepatic extramedullary hematopoiesis, MDSCs, tumor growth, and metastases by orthotopic mammary tumors are increased by alcohol consumption and fatty diets. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1167. doi:10.1158/1538-7445.AM2014-1167