GAS6/AXL Axis Regulates Prostate Cancer Invasion, Proliferation, and Survival in the Bone Marrow Niche

Abstract

Our recent studies have shown that annexin II, expressed on the cell surface of osteoblasts, plays an important role in the adhesion of hematopoietic stem cells (HSCs) to the endosteal niche. Similarly, prostate cancer (PCa) cells express the annexin II receptor and seem to use the stem cell niche for homing to the bone marrow. The role of the niche is thought to be the induction and sustenance of HSC dormancy. If metastatic PCa cells occupy a similar or the same ecological niche as HSCs, then it is likely that the initial role of the HSC niche will be to induce dormancy in metastatic cells. In this study, we demonstrate that the binding of PCa to annexin II induces the expression of the growth arrest-specific 6 (GAS6) receptors AXL, Sky, and Mer, which, in the hematopoietic system, induce dormancy. In addition, GAS6 produced by osteoblasts prevents PCa proliferation and protects PCa from chemotherapy-induced apoptosis. Our results suggest that the activation of GAS6 receptors on PCa in the bone marrow environment may play a critical role as a molecular switch, establishing metastatic tumor cell dormancy.

Proteomic Profiling of Androgen-independent Prostate Cancer Cell Lines Reveals a Role for Protein S during the Development of High Grade and Castration-resistant Prostate Cancer

“…We measured transcript levels of GAS6, a known homologue of PROS1, which has previously been linked to prostate cancer progression (45,46), on these xenografts and found its elevation in LuCaP 96AI cells (p Ͻ 0.05). Taken together, these results further support the involvement of PROS1 and GAS6 in the development of AIPC.…”

Bone marrow as a metastatic niche for disseminated tumor cells from solid tumors

“…For example, when osteoblasts are cocultured with prostate cancer cell line, PC3 cells, the secretion of growth arrest-specific 6 (GAS6) by the osteoblasts is significantly enhanced. 37 Interestingly, GAS6 inhibits the proliferation of PC3 cells, while preventing apoptosis. 37 In addition, when PC3 cells are inoculated into murine skeletal tissues, the expression of Axl, one of three receptors (Axl, Tyro3, Mer) for GAS6, is markedly increased.…”

“…37 Interestingly, GAS6 inhibits the proliferation of PC3 cells, while preventing apoptosis. 37 In addition, when PC3 cells are inoculated into murine skeletal tissues, the expression of Axl, one of three receptors (Axl, Tyro3, Mer) for GAS6, is markedly increased. 37 Along with this notion, in mice inoculated with prostate cancer cells, tumor growth is mainly observed in bones expressing low levels of GAS6 (forelimb), whereas tumors rarely grow in bones expressing abundant GAS6 (hindlimb).…”

“…37 In addition, when PC3 cells are inoculated into murine skeletal tissues, the expression of Axl, one of three receptors (Axl, Tyro3, Mer) for GAS6, is markedly increased. 37 Along with this notion, in mice inoculated with prostate cancer cells, tumor growth is mainly observed in bones expressing low levels of GAS6 (forelimb), whereas tumors rarely grow in bones expressing abundant GAS6 (hindlimb). 38 Moreover, PC3 and DU145 cells, which are proliferating in the bones, express relatively low levels of Axl, compared with when they are in a dormant state.…”

Homing of Cancer Cells to the Bone

“…Axl expression is correlated with metastasis and poor prognosis in a wide range of cancers such as breast cancer, prostate cancer, pancreatic cancer, ovarian cancer, renal cell carcinoma and esophageal adenocarcinoma [96][97][98][99][100]. Signaling through GAS-6 and its receptor Axl promotes invasion of prostate cancer cells towards the bone and regulates prostate cancer proliferation and survival [101].…”