Prostate cancer cells commonly spread through the circulation, but few successfully generate metastatic foci in bone. Osteoclastic cellular activity has been proposed as an initiating event for skeletal
metastasis. Megakaryocytes (MKs) inhibit osteoclastogenesis, which could have an impact on
tumor establishment in bone. Given the location of mature MKs at vascular sinusoids, they may be the first cells to physically encounter
cancer cells as they enter the bone marrow. Identification of the interaction between MKs and
prostate cancer cells was the focus of this study. K562 (human MK precursors) and primary MKs derived from mouse bone marrow hematopoietic precursor cells potently suppressed prostate
carcinoma PC-3 cells in coculture. The inhibitory effects were specific to prostate
carcinoma cells and were enhanced by direct cell-cell contact. Flow cytometry for
propidium iodide (PI) and
annexin V supported a proapoptotic role for K562 cells in limiting PC-3 cells. Gene expression analysis revealed reduced
mRNA levels for
cyclin D1, whereas
mRNA levels of apoptosis-associated specklike
protein containing a CARD (ASC) and
death-associated protein kinase 1 (DAPK1) were increased in PC-3 cells after coculture with K562 cells. Recombinant
thrombopoietin (TPO) was used to expand MKs in the marrow and resulted in decreased skeletal lesion development after intracardiac
tumor inoculation. These novel findings suggest a potent inhibitory role of MKs in prostate
carcinoma cell growth in vitro and in vivo. This new finding, of an interaction of metastatic
tumors and hematopoietic cells during
tumor colonization in bone, ultimately will lead to improved therapeutic interventions for
prostate cancer patients.