Abstract
Disseminated tumor cells (DTCs) are believed to lie dormant in the marrow before they can be activated to form metastases. How DTCs become dormant in the marrow and how dormant DTCs escape dormancy remains unclear. Recent work has shown that prostate cancer (PCa) cell lines express the growth-arrest specific 6 (GAS6) receptors Axl, Tyro3, and Mer, and become growth arrested in response to GAS6. We therefore hypothesized that GAS6 signaling regulates the proliferative activity of DTCs in the marrow. To explore this possibility, in vivo studies were performed where it was observed that when Tyro3 expression levels exceed Axl expression, the PCa cells exhibit rapid growth. When when Axl levels predominate, PCa cells remain largely quiescent. These findings suggest that a balance between the expression of Axl and Tyro3 is associated with a molecular switch between a dormant and a proliferative phenotype in PCa metastases.
Highlights
Prostate cancer (PCa) cells have an astonishing ability to disseminate to the bone marrow
Expression of growth arrest specific 6 (GAS6) Receptors by PCa Cells Previously we showed that binding of PCa to annexin alters the expression of GAS6 receptors on PCa cell lines ([8])
We explored which of the GAS6 receptors are expressed by PCa cell lines under basal culture conditions
Summary
Prostate cancer (PCa) cells have an astonishing ability to disseminate to the bone marrow. Once there, disseminated tumor cells (DTCs) may lie dormant for years, undetected by standard clinical methods. HSCs normally reside in the bone marrow of adult mammals where their fate is tightly balanced between proliferation and quiescence [2,3,4,5]. HSC quiescence is regulated by microenvironmental controls derived from cellular ‘niches’ comprised predominately of osteoblasts, endothelial cells and other marrow elements [6]. One molecule that regulates HSC quiescence is growth arrest specific 6 (GAS6)[7] which in marrow is secreted by osteoblasts [8]. For HSCs, it appears that a balance between the expression of Axl, Tyro and Mer determines whether the cells remain quiescent or proliferate [14,15,16]
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