Mechanisms That Regulate Dormancy of Disseminated Tumor Cells in the Bone Marrow

前列腺癌（PCa）具有惊人的扩散、侵袭和在骨中存活的能力 骨髓一旦到达那里，播散性肿瘤细胞（DTC）可能会休眠多年。如何休眠 DTC是如何建立的，如何保持，以及DTC如何从休眠中逃脱仍然是未知的。 造血干细胞（HSC），像DTC一样，在骨髓中大部分是静止的。HSC静止期是 由骨髓中称为“生态位”的区域调节，该区域由成骨细胞、内皮细胞和 其他元素。最近的研究表明，当HSC与小生境表达的蛋白质结合时， 成骨细胞（膜联蛋白2或AX 2），它们增加其酪氨酸激酶受体AXL的表达（从 希腊语“anexelekto”或“不受控制的”。随后，AXL与生长停滞特异性6 GAS 6，其由成骨细胞在骨髓龛中分泌。在许多系统中，GAS 6抑制细胞增殖，促进存活并增加对化疗的抗性。我们最近已经表明，（i）PCa DTC在转移期间靶向HSC龛（提交）（ii）当PCa细胞结合龛成骨细胞或龛的组分（AX 2）时，它们增加AXL的表达，（iii）GAS 6抑制PCa细胞生长，（iv）GAS 6保护PCa细胞免于凋亡，（v）GAS 6赋予PCa细胞对化疗的抗性。这些数据表明，一旦DTC进入利基市场， GAS 6及其受体之间的相互作用调节DTC的休眠和对 针对增殖细胞的化疗。我们的中心假设是GAS 6调节 PCa骨转移的休眠提出的目标将证明GAS 6 信号传导决定DTC在骨中是保持静止还是增殖 目的1：确定GAS 6诱导HSC“龛”中PCa细胞静止的程度。 亚假设：小生境产生的GAS 6是建立休眠所必需的。 目的2：明确GAS 6自分泌调节PCa休眠的作用 亚假设：PCa自身表达GAS 6，其以自分泌方式限制生长。我们 假设休眠是由维持这种活动的细胞建立的--但它最终 在转移生长过程中丢失的细胞。 目的3：明确GAS 6信号通路在PCa化疗耐药中的作用 在HSC的“利基”。亚假设：Doradine PCa细胞对化疗耐药。

Prostate cancers (PCa) have an astonishing ability to disseminate, invade and survive in the bone marrow. Once there, disseminated tumor cells (DTCs) may lie dormant for years. How dormancy of DTCs is established, how it is maintained, and how DTCs escape from dormancy remains unknown. Hematopoietic stem cells (HSCs), like DTCs, are largely quiescent In the marrow. HSC quiescence is regulated by a region in marrow termed the 'niche', that is comprised of osteoblasts, endothelial cells and other elements. Recent work demonstrates that when HSCs bind to proteins expressed by niche osteoblasts (annexin 2 or AX2), they increase their expression of the tyrosine kinase receptor AXL (from the Greek word 'anexelekto,' or uncontrolled). Sequentially, AXL binds to growth arrest-specific 6 (GAS6), which is secreted in the marrow niche by osteoblasts. In many systems GAS6 inhibits cellular proliferation, promotes survival and increases resistance to chemotherapy. We have recentiy show that; (i) PCa DTCs target the HSC niche during metastasis (submitted) (ii) when PCa cells bind to niche osteoblasts or components of the niche (AX2), they increase expression of AXL, (iii) GAS6 inhibits PCa cell growth, (iv) GAS6 protects PCa cells from apoptosis, (v) GAS6 confers resistance of PCa cells to chemotherapy. These data suggest that once DTCs enter the niche, interactions between GAS6 and its receptors regulates dormancy of DTCs and resistance to chemotherapies that target proliferating cells. Our central hypothesis is that GAS6 regulates dormancy of PCa bone metastases The proposed aims will demonstrate the extent to which GAS6 signaling determines whether DTCs remain quiescent or proliferate in bone Aim 1: Determine the extent to which GAS6 induces quiescence of PCa cells in the HSC 'niche'. Sub hypothesis: Niche produced GAS6 is essential for establishing dormancy. Aim 2: Define the role that autocrine production of GAS6 regulates dormancy of PCa in the niche Sub hypothesis: PCa themselves express GAS6 which limits growth in an autocrine fashion. We hypothesize that dormancy is established by cells that maintain this activity - but that it is eventually lost by cells that undergo metastatic growth. Aim 3: Define the role that GAS6 signaling plays in regulating resistance of PCa to chemotherapy in the HSC 'niche'. Sub hypothesis: Dormant PCa cells are resistant to chemotherapy.