Little is known about how megakaryocytes may affect metastasis beyond serving as a source of platelets. In this study, we explored the functional implications of megakaryocyte accumulation in the femurs of mice after injection of metastatic or non-metastatic breast cancer cells in 4T1.2 BALB/cJ and MDA-MB-231 nude mouse models. At bone metastatic sites, but not primary growth sites, tumor growth was associated with increased megakaryopoiesis in both model systems. In the orthotopic BALB/cJ model, extramedullary hematopoiesis occurred in the spleen, resulting in a four-fold increase in megakaryocytes. In support of the hypothesis that reducing megakaryocytes may reduce metastasis, we found that thrombopoietin-deficient mice exhibited a 90% relative decrease in megakaryocytes, yet they developed more aggressive metastasis than wild-type hosts. In human clinical specimens, we observed an increase in megakaryocytes in the bone marrow of 6/8 patients with metastatic breast cancer compared with age- and gender-matched controls. Taken together, our results suggested that an increase in megakaryocytes occurring in response to metastatic cells entering the bone marrow confers some measure of protection against metastasis, challenging present views on the role of megakaryocytes in this setting. Cancer Res; 77(8); 1942–54. ©2017 AACR.
Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).
- Received April 21, 2016.
- Revision received December 8, 2016.
- Accepted December 26, 2016.
- ©2017 American Association for Cancer Research.