Role of Megakaryocytes in Breast Cancer Metastasis to Bone.

摘要

Hypothesis: megakaryocytes (MKs) contribute to the growth of metastatic breast cancer in the bone either by preparing a niche and/or by responding to the cytokines of the marrow resulting from the interaction of the cancer with cells of the marrow. We found that MKs increased in the femurs of mice bearing MDA-MB-231 human cancer. We compared MKs in femurs of nude mice inoculated with cancer cells into the mammary gland (non-metastasizing) with (intracardiac injection) bone metastasizing. Immunohistochemistry and counting of vonWillibrand factor+, multinucleated cells were used to determine MK numbers. Blood platelets, serum levels of thrombopoietin (TPO) and SDF-1 were measured. In another model, mouse mammary tumor cells (4T1.2 metastaic) or (67NR, non-metastatic) were injected into the mammary glands, and femurs and spleens assayed over time. The MK increased only in the metastatic model suggesting that the effect was local to the bone. However, the increase of MK was greatest in the spleen, extramedullary hematopoiesis. Results of an in vitro complementary study indicated that both osteoblasts and breast cancer cells together produced factor(s) that increase MK differentiation. In the meantime TPO-/- mouse embryos were regenerated and mice were backcrossed to Balb/c so that metastasis could be determined in MK deficient mice. The TPO-/- mice appear to be more susceptible to metastasis than the wildtype, with metastese appearing more quickly and spreading further after inoculation.