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

前列腺癌(PCA)具有惊人的在骨骼中扩散、侵袭和存活的能力。 骨髓。一旦到了那里，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，它是如何维持的，以及DTC如何摆脱休眠仍是未知的。 像树突状细胞一样，造血干细胞(HSCs)在骨髓中基本上处于静止状态。HSC静止状态为 由骨髓中的一个区域调节，该区域被称为‘小生境’，由成骨细胞、内皮细胞和 其他要素。最近的研究表明，当HSCs与NICE表达的蛋白质结合时 成骨细胞(Annexin 2或Ax2)，它们增加其酪氨酸激酶受体Axl的表达(来自 希腊语中的anexelekto，意为不受控制)。因此，Ax1与生长停滞特异的6结合 (Gas6)，由成骨细胞在骨髓巢中分泌。在许多系统中，Gas6抑制细胞增殖，促进生存，并增加对化疗的耐药性。我们最近发现：(I)PCa DtCs在转移过程中以HSC壁龛为靶点(提交)(Ii)当PCa细胞与壁龛成骨细胞或壁龛成分(Ax2)结合时，它们增加Ax1的表达，(Iii)Gas6抑制PCa细胞的生长，(Iv)Gas6保护PCa细胞免受凋亡，(V)Gas6使PCa细胞对化疗产生抵抗。这些数据表明，一旦DTC进入利基市场， Gas6与其受体的相互作用调节DTCs的休眠和对 以增殖细胞为靶点的化疗。我们的中心假设是Gas6调节 前列腺癌骨转移的休眠拟议的目标将展示Gas6的程度 信号转导决定DCs在骨骼中是保持静止还是增殖 目的1：确定Gas6在多大程度上诱导肝星状细胞“巢”中的Pca细胞静止。 亚假说：生态位产生的Gas6是建立休眠所必需的。 目的2：明确Gas6自分泌产物在调节Pca在生态位休眠中的作用 次级假说：Pca自身表达Gas6，以一种自分泌的方式限制生长。我们 假设休眠是由维持这种活动的细胞建立的--但最终是 被经历转移性生长的细胞丢失。 目的3：明确Gas6信号在调节PCa化疗耐药中的作用 在HSC的“利基市场”。假说：处于休眠状态的前列腺癌细胞对化疗有抵抗力。

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.