Role of Megakaryocytes in Breast Cancer Metastasis to Bone

Abstract

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 nonmetastatic 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.

Hepatic thrombopoietin gene silencing reduces platelet count and breast cancer progression in transgenic MMTV-PyMT mice

“…53 In addition, TPOdeficient mice, which are hemostatically compromised, exhibited more aggressive bone metastases in the syngeneic 4T1.2 breast cancer model. 54 Meanwhile, others have reported a reduced number of lung metastases of IV injected tumor cells in mice with experimental thrombocytopenia-associated hemostasis impairment. 38,55 Another study demonstrated that select chemotherapies are more effective in thrombocytopenic mice.…”

The Novel Association of Circulating Tumor Cells and Circulating Megakaryocytes with Prostate Cancer Prognosis

“…To support this, megakaryocytes have been reported to increase their number in response to cancer bone metastasis and inhibit prostate and breast cancer cell growth both in vitro and in vivo (48)(49)(50). Although the prognostic value and biological functions of megakaryocytes in cancer development and progression need to be further investigated, models that analyze the number difference between CTCs and megakaryocytes should be developed to make an efficient biomarker for survival prediction for patients with mCRPCs and potentially for other cancers as well.…”

Molecular principles of metastasis: a hallmark of cancer revisited

“…190 However, this belief has been challenged by showing that an increase in megakaryocytes confers some measure of protection against metastasis. 199 In addition, neutrophils in circulation have been found to inhibit metastasis. 6,200 Blood sampling in 70 women with advanced-stage breast cancer showed a CTC-immune cell association.…”