Abstract 3265: Thrombopoietin and megakaryocytes in breast cancer metastasis to bone

Abstract

Abstract Bone is one of the preferred sites for breast cancer cells to metastases. Once patients are diagnosed with skeletal metastases, the relative five-year survival rate falls from 90% to less than16%. Thrombocytosis is a sign of poor prognosis for survival, and thromboembolisms are one of the leading causes of death in all cancers patients. These conditions are due to high numbers and/or high platelet activity. Megakaryocytes (MKs) are responsible for platelet production, but also play a role in bone metabolism and skeletal homeostasis. We had determined in two mouse models of experimental metastasis (MDA-MB-231 in athymic mice, and 4T1.2 in Balb/c mice), that bone metastasis was associated with increased numbers of MKs. Under normal conditions MKs represent less than 1% of the total bone marrow cell population, but after analysis of the femurs of the mice with metastasis, we found at least a two-fold increase in the numbers of MKs present in the bone marrow in the MDA-MB-231mice. The Balb/c mice injected in the mammary glands with mouse 4T1.2 cells showed a four-fold increase in MKs in the spleen (extrameduallary hematopoiesis). Therefore we hypothesized that increased megakaryocytosis was linked to metastasis, and that decreasing the number of MKs would decrease metastasis. We transferred a thrombopoietin (TPO) expression deletion mutation to a Balb/c background and inoculated the mice with 4T1.2 cells. These TPO -/- mice showed approximately a 90% decrease in bone marrow MKs compared to the wild type mice. The numbers of blood platelets was also decreased by 90%. We tested our hypothesis by inoculation of 4T1.2LUC cells into the mammary gland, and then followed the course of the cancer and metastasis by luciferase imaging. Contrary to our hypothesis the TPO -/- mice developed metastasis to the bone more rapidly than the heterozygotes or wild type mice. Literature suggests that platelets interact with tumor cells to contribute to hematogenous metastasis and angiogenesis. In the TPO-/- mice with very few platelets, metastasis was more aggressive and developed more rapidly than in the wild type or the heterozygote mice. The next step will be to separate the role of the megakaryocytes from the platelets. This work was sponsored by the U.S. Army Medical Research and Materiel W81XWH-10-1-0253 Citation Format: Walter Jackson, Andrea M. Mastro, Donna M. Sosnoski. Thrombopoietin and megakaryocytes in breast cancer metastasis to bone. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3265. doi:10.1158/1538-7445.AM2015-3265