The mechanisms responsible for the metastasis of breast cancer to bone remain ambiguous. While analyzing femur sections from mice that had been inoculated with metastatic MDA-MB-231 breast cancer cells, we saw an increased number of megakaryocytes (MKs) in the bone marrow. We hypothesized that either MKs aid in the growth of cancer cells by preparing a niche for the metastases or that the increase in MKs resulted from the altered microenvironment of the marrow due to the presence of cancer. MKs are the pre-cursors to platelets. Thrombocytosis, high platelet count, is a poor prognostic factor for metastasis; many cancer patients die from thromboembolisms. MKs also play a crucial role in bone metabolism and skeletal homeostasis.
Objectives: to determine (1) if the increase in MKs
precedes the growth of cancer cells in the bone; (2) the role that the cancer
cell-osteoblast/stromal interactions play in the increase in
megakaryopoiesis. For aim 1, we compared
MK numbers in the femurs of athymic mice inoculated with MDA-MB-231-luc intracardially
(metastasis) with those inoculated in the mammary gland (no metastasis). Serum was assayed for key MK maturation
factors thrombopoietin (TPO) and stromal-derived factor-1 (SDF-1). We found an increase
in MKs in femurs of mice with metastatic disease but not with localized growth.
The increase mirrored the increase in metastatic tumor burden. There was no
increase in platelet count, SDF-1, or TPO even when MK numbers were high. We
concluded that the cancer cells precede the increase of MKs in the bone marrow
in a xenograft model. Next we will use a syngeneic model of Balb/c with 4T1.2 cancer
cells that metastasize from the mammary gland. Finally, Balb/c mice lacking TPO and thus
having low MKs will be tested for metastasis. We will also add TPO to increase MKs
and determine how metastasis is affected. (Support: DOD W81XWH-10-0253)