HYALURONAN TURNOVER IN PROSTATE CANCER

前列腺癌中的透明质酸周转率

• 批准号: 8360446
• 负责人: Melanie A Simpson
• 金额: $ 7.35万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8360446
• 关键词: Antibodies; Bone Tissue; CD44 Antigens; CD44 gene; Cadherins; Cancer Etiology; Cancer Patient; Cell Adhesion; Cessation of life; Cleaved cell; Clinical; Complex; Data; Development; Endocytosis; Endothelial Cells; Enzymes; Frequencies; Funding; Glycosaminoglycans; Goals; Grant; Growth; Hyaluronan; Hyaluronidase; Injection of therapeutic agent; Intake; Integrins; Ligation; Liver; Lymph; Lymphatic; Malignant neoplasm of prostate; Marrow; Metastatic Neoplasm to the Bone; Monitor; Mus; National Center for Research Resources; Nebraska; Neoplasm Metastasis; Outcome; Pathway interactions; Polymers; Principal Investigator; Process; Production; Prostate; Prostatic Neoplasms; Recycling; Relative (related person); Research; Research Infrastructure; Resources; Signal Transduction; Source; Stromal Cells; Surface; System; Tissues; United States National Institutes of Health; adhesion receptor; bone; cell growth; cell motility; cost; density; extracellular; hyaluronan synthase 1; imaging modality; innovation; lymph nodes; men; metastatic process; mortality; neoplastic cell; novel; outcome forecast; preference; receptor; response; tumor; tumor growth; uptake

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Prostate cancer is the second leading cause of cancer death in U.S. men. Over 80% of mortality results from complications of bone metastasis. Our lab studies mechanisms by which extracellular components regulate tumor development and metastatic dissemination. Our upcoming R01 application centers on hyaluronan (HA), a polymeric glycosaminoglycan essential for cell growth and migration in development. HA is negligible in normal prostate, but abundant in prostate tumors and bone metastases. Quantification of tumor-associated HA and its turnover enzyme, Hyal1, predicts invasive progression and provides a clinical readout for prostate cancer patient prognosis. Tumor-associated HA polymers are synthesized by HA synthases (HAS) and cleaved by hyaluronidases (i.e.; Hyal1). Response to HA at the cellular and tissue level is controlled by HA size and by specific distribution of HA receptors such as CD44 and the HA receptor for endocytosis (HARE). Our hypothesis for this application is built on three key results from our previous data: (1) exogenous HA has no effect on tumor cells, while induced endogenous HA production lowers surface expression of integrins, and cadherins, which reduces growth rate and motility of tumor cells; (2) induced expression of Hyal1, which is both a secreted and a lysosomal enzyme, increases the rate of endocytic HA intake in tumor cells; and (3) systemic administration of an antibody against HARE, found in endothelial cells of liver, lymph node and bone, blocks spontaneous metastasis of prostate tumor cells in mice. From these observations, we postulate 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, we suggest excess tumor-borne HA can accelerate tumor cell endocytosis and/or endocytic recycling if Hyal1 is present, activating lymphatic remodeling. Rate of endocytic recycling determines the surface density of cell adhesion receptors and thereby impacts tumor cell motility and metastatic survival. This hypothesis is novel, innovative and parsimonious: no previous explanation has incorporated the complex actions of HA in tumor growth and metastasis under the common process of endocytosis, triggered by distinct receptor classes on tumor cells versus stromal cells, leading to different but concurrent outcomes. Positively defining these unique mechanisms could open avenues of therapy through antagonism of endocytic uptake or recycling pathways more heavily relied upon by tumor cells. Our goal in the bridge funding period is to collect additional preliminary data to support the following aims: Aim 1: Determine how HA controls lymphatic navigation and bone metastasis. HA is a likely factor in metastatic preference of prostate tumor cells, while Hyal1 is important for metastasis initiation. We know the size and quantity of HA polymers, on which HA receptor ligation depends, are determined by the relative expression of HAS and Hyal1 enzymes. HARE is not expressed in prostate, but is present on endothelial cells in lymph node and bone, tissues to which HA-enveloped tumor cells show increased frequency of metastasis. We have inducible systems that allow us to stimulate or inhibit either HAS or Hyal1 in an experimentally controlled fashion and we have developed non-invasive near-infrared imaging methods for monitoring tumor growth in mice. We will use orthotopic and intracardiac injection in mice to quantify effects of HA, Hyal1 and HARE manipulation on the metastatic process

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 前列腺癌是美国男性癌症死亡的第二大原因。 超过80%的死亡率是由于骨转移的并发症。 我们的实验室研究细胞外成分调节肿瘤发展和转移扩散的机制。 我们即将推出的R 01应用集中在透明质酸（HA），一种对细胞生长和发育中的迁移至关重要的聚合糖胺聚糖。 HA在正常前列腺中可忽略不计，但在前列腺肿瘤和骨转移中丰富。 肿瘤相关HA及其转换酶Hyal 1的定量可预测侵袭性进展，并为前列腺癌患者预后提供临床读数。 肿瘤相关HA聚合物由HA酶（HAS）合成并由透明质酸酶（即; Hyal 1）。 在细胞和组织水平上对HA的反应受HA大小和HA受体如CD 44和内吞作用HA受体（HARE）的特异性分布控制。 我们对这一应用的假设建立在我们以前数据的三个关键结果上：（1）外源性HA对肿瘤细胞没有影响，而诱导的内源性HA产生降低了整合素和钙粘蛋白的表面表达，这降低了肿瘤细胞的生长速率和运动性;（2）Hyal 1的诱导表达，Hyal 1既是分泌酶又是溶酶体酶，增加了肿瘤细胞内吞HA的摄入速率;和（3）全身施用在肝、淋巴结和骨的内皮细胞中发现的抗HARE的抗体，阻断小鼠中前列腺肿瘤细胞的自发转移。 从这些观察结果，我们推测，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，我们认为，如果Hyal 1存在，过量的肿瘤传播的HA可以加速肿瘤细胞的内吞和/或内吞再循环，激活淋巴重塑。 内吞再循环的速率决定细胞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。 这一假说是新颖的、创新的和简约的：没有先前的解释将HA在肿瘤生长和转移中的复杂作用纳入内吞作用的共同过程中，内吞作用由肿瘤细胞与基质细胞上的不同受体类别触发，导致不同但同时发生的结果。 明确定义这些独特的机制可以通过拮抗肿瘤细胞更严重依赖的内吞摄取或再循环途径开辟治疗途径。 我们在过渡资助期间的目标是收集更多的初步数据，以支持以下目标： 目的1：确定HA如何控制淋巴导航和骨转移。HA可能是前列腺肿瘤细胞转移偏好的一个因素，而Hyal 1对转移启动很重要。 我们知道HA受体连接所依赖的HA聚合物的大小和数量由HAS和Hyal 1酶的相对表达决定。 HARE在前列腺中不表达，但存在于淋巴结和骨中的内皮细胞上，HA包膜的肿瘤细胞显示出转移频率增加的组织。 我们拥有诱导系统，使我们能够以实验控制的方式刺激或抑制HAS或Hyal 1，并且我们已经开发出非侵入性近红外成像方法来监测小鼠肿瘤的生长。 我们将在小鼠中使用原位和心内注射来量化HA、Hyal 1和HARE操作对转移过程的影响。