Mechanisms of Hyaluronan Signaling and Turnover in Prostate Cancer

描述（申请人提供）：基质重塑和间质上皮细胞通讯有助于前列腺癌的侵袭性进展。透明质酸（HA）是一种糖胺聚糖聚合物，在适合细胞增殖和运动时合成和翻转。正常情况下，其水平受到HA合成酶（HAS）、透明质酸酶和特定HA受体（如HA内吞作用受体（HARE））的严格控制。透明质酸在正常成人前列腺中可忽略不计，但在前列腺肿瘤和骨转移中含量丰富。肿瘤细胞相关HA及其转换酶Hyal1的定量检测可预测肿瘤的侵袭性进展和切除后的生化复发。该建议的重点是确定HA合成和周转酶如何共同影响基质形态和细胞通讯。假设是肿瘤细胞携带的表面透明质酸通过促进抑制表达hare的脉管系统和/或肿瘤细胞进入淋巴和骨髓组织来提高转移效率。此外，如果Hyal1存在，过量的瘤源性HA可能加速肿瘤细胞内吞和/或内吞循环，激活淋巴重塑。内吞循环率决定了生长因子和粘附受体的表面密度，从而影响肿瘤细胞的运动和转移生存。在目的1中，选择用于诱导HA合成或HA转换的肿瘤细胞将用于测试这些酶在前列腺生长和骨转移的临床相关小鼠模型中的各自作用。将使用药物和体内敲除来研究HARE如何在宿主靶组织中调节前列腺肿瘤细胞的定植。这些策略也将决定如何将血凝素信号传导和转换作为治疗目标来延缓或预防前列腺癌的进展。目的2将通过比较肿瘤与间质成分的HA代谢和HA信号对淋巴管形态、淋巴结和骨转移的影响来研究转移机制。分子格式的传递和传播的血凝素信号，触发形态学变化，以支持转移将被表征。Aim 3将继续进行新的观察，即升高的Hyal1（一种分泌酶和溶酶体酶）增加了稳定选择表达的前列腺肿瘤细胞的内吞循环率。工作假设是

DESCRIPTION (provided by applicant): Matrix remodeling and stromal-epithelial cellular communication contribute to aggressive progression of prostate cancer. Hyaluronan (HA), is a glycosaminoglycan polymer synthesized and turned over when appropriate for cell proliferation and motility. Normally, its levels are tightly controlled by HA synthase enzymes (HAS), hyaluronidases, and specific HA receptors such as the HA receptor for endocytosis (HARE). HA is negligible in normal adult prostate, but abundant in prostate tumors and bone metastases. Quantification of tumor cell associated HA and its turnover enzyme, Hyal1, predicts invasive progression and biochemical recurrence after resection. This proposal is focused on determining how the HA synthesis and turnover enzymes work together to influence matrix morphology and cell communication. The hypothesis is that surface HA borne by tumor cells increases metastatic efficiency by facilitating arrest in HARE-expressing vasculature and/or entry of the tumor cells into lymph and marrow tissue. In addition, excess tumor-borne HA may accelerate tumor cell endocytosis and/or endocytic recycling if Hyal1 is present, activating lymphatic remodeling. Rate of endocytic recycling determines the surface density of growth factor and adhesion receptors and thereby impacts tumor cell motility and metastatic survival. In aim 1, tumor cells selected for inducible HA synthesis or HA turnover will be used to test respective roles of these enzymes in clinically relevant mouse models of prostatic growth and bone metastasis. Pharmacological agents and in vivo knockdown will be used to examine how HARE functions in host target tissues to regulate prostate tumor cell colonization. These strategies will also determine how HA signaling and turnover may be therapeutically targeted to delay or prevent prostate cancer progression. Aim 2 will examine metastasis mechanisms by comparing the effects of tumor versus stromal components of HA metabolism and HA signaling on lymphatic vessel morphology, as well as lymph node and bone metastasis. The molecular format for delivery and propagation of the HA signals that trigger morphological changes to support metastasis will be characterized. Aim 3 will pursue the novel observation that elevated Hyal1, which is both a secreted and a lysosomal enzyme, increases the rate of endocytic recycling in the prostate tumor cells stably selected for its expression. The working hypothesis is that Hyal1 impacts several specific signaling pathways concurrently by modulating the rate of vesicular trafficking, thus contributing to tumor growth by maintaining surface presentation of important receptors and by re-externalizing biologically potent digestion products of HA that serve as signals. Its autocrine effects, as well as its impact on prostate stromal cells, will be tested.