Mechanisms of Hyaluronan Signaling and Turnover in Prostate Cancer

描述（由申请人提供）：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并转化。正常情况下，其水平受到HA合酶（HAS）、透明质酸酶和特异性HA受体（如用于内吞作用的HA受体（HARE））的严格控制。HA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丰富。肿瘤细胞相关HA及其转换酶Hyal 1的定量可预测切除术后的浸润进展和生化复发。该建议的重点是确定HA合成和周转酶如何共同作用以影响基质形态和细胞通讯。假设是肿瘤细胞携带的表面HA通过促进HARE表达脉管系统中的停滞和/或肿瘤细胞进入淋巴和骨髓组织而增加转移效率。此外，如果Hyal 1存在，过量的肿瘤传播的HA可能加速肿瘤细胞内吞和/或内吞再循环，激活淋巴重塑。内吞再循环的速率决定生长因子和粘附受体的表面密度，从而影响肿瘤细胞运动性和转移性存活。在目标1中，选择用于诱导型HA合成或HA周转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。药理学试剂和体内敲低将用于检查HARE如何在宿主靶组织中发挥作用以调节前列腺肿瘤细胞定殖。这些策略还将确定HA信号传导和周转如何在治疗上靶向延迟或预防前列腺癌进展。目的2将通过比较肿瘤与HA代谢和HA信号传导的基质组分对淋巴管形态以及淋巴结和骨转移的影响来研究转移机制。将表征用于HA信号的递送和传播的分子形式，所述HA信号触发形态学变化以支持转移。目的3将追求新的观察，即升高Hyal 1，这是一种分泌和溶酶体酶，增加了前列腺肿瘤细胞的内吞再循环的速率，稳定选择其表达。工作假设是 Hyal 1通过调节囊泡运输的速率同时影响几种特定的信号传导途径，从而通过维持重要受体的表面呈递和通过将作为信号的HA的生物学上有效的消化产物再外化而促进肿瘤生长。它的自分泌作用，以及其对前列腺基质细胞的影响，将进行测试。

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.