Mechanisms of cancer cell chemotaxis in perineural invasion

神经周围侵袭中癌细胞趋化机制

• 批准号: 8083765
• 负责人: Richard J Wong
• 金额: $ 37万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8083765
• 关键词: Apoptotic; Archives; Behavior; Biological Assay; Cell Line; Cells; Characteristics; Chemicals; Chemotaxis; Clinical; Colorectal Cancer; Dictyostelium; Dictyostelium discoideum; Disease; Event; Family; Functional disorder; Genetic Polymorphism; Guanosine Triphosphate Phosphohydrolases; Head and Neck Cancer; Human; Image; In Vitro; Incidence; Invaded; Investigation; Laboratories; Lead; Leukocytes; Life; MEKs; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Malignant neoplasm of pancreas; Mediating; Methods; Modeling; Molecular; Motor; Mus; Mutation; Nerve; Neuraxis; Neurons; Non-Malignant; Oncogenic; Operative Surgical Procedures; PTEN gene; Pancreas; Pathologic; Pathology; Pathway interactions; Patients; Phenotype; Physarum polycephalum; Positioning Attribute; Process; Prostate; Proteins; Receptor Activation; Receptor Protein-Tyrosine Kinases; Recurrence; Resected; Role; Sensory; Site; Specimen; System; Techniques; Time; Work; base; cancer cell; cell motility; clinically relevant; clinically significant; enhancing factor; in vivo; in vivo Model; matrigel; migration; neurotrophic factor; novel; novel therapeutic intervention; pancreatic cancer cells; perineural; prevent; proto-oncogene protein c-ret; receptor expression; relating to nervous system; response; rho; sciatic nerve; theories; tumor; tumor progression

DESCRIPTION (provided by applicant): The ability of selected cancers to invade in, around, and along nerves is a well described event termed perineural invasion (PNI). PNI has repeatedly been shown to be an adverse pathologic finding, heralding more aggressive local disease, higher recurrence rates, and worsened survival. Despite widespread recognition of the clinical significance of PNI, its mechanisms remain poorly understood. We recently demonstrated the critical role of cancer cell chemotaxis (external gradient sensing and directional migration) towards glial-derived neurotrophic factor (GDNF) and activation of the RET tyrosine kinase receptor as a key mechanism for PNI. Mechanisms of chemotaxis have been previously defined primarily in the non-malignant systems of dictyostelium discoideum (slime mold) and leukocytes. However, chemotactic mechanisms have not been as well defined in cancer cells. Interestingly, pathways associated with chemotaxis in dictyostelium and leukocytes are frequently aberrant in cancer. These include tyrosine kinase receptor activity, PI3K activity, Rho family (Cdc42, Rac1, RhoA) GTPase and Ras GTPase activity. GDNF has been shown to activate each of these factors in pancreatic cancer cells. We will elucidate the relationship between oncogenic activation of these factors and their chemotactic response to GDNF, in the clinically important context of PNI. Our central hypothesis is that the dysregulation of these factors in some cancers may promote chemotaxis towards GDNF, leading to PNI. We will define the oncogenic characteristics that promote a neural invasive phenotype. We will define the roles of these pathways in PNI using a combination of techniques including: single cell live time-lapse imaging, an in vitro Matrigel model of PNI that assesses interactions between nerves and cancer cells, an in vivo murine sciatic nerve model of PNI, and studies of surgically resected human cancers. The combination of these methods will position us to achieve three Aims: 1. Identify putative mechanisms of cancer cell chemotaxis towards GDNF. We will focus on: (a) RET-GFR1 receptor expression, and the RET G681S polymorphism, (b) PI3K/PTEN activity and the p1101 H1047R and E545K mutations, (c) Rho family (Cdc42, Rac1, RhoA) and Ras GTPase activity. 2. Define the role of chemotactic mechanisms in models of cancer cell PNI. Using in vitro and in vivo models, we will correlate modulation of the factors in Aim 1 with changes in PNI phenotype. 3. Validate identified chemotactic mechanisms in human cancers. We will use surgical specimens for molecular, pathologic, and clinical correlations to validate the identified factors from Aims 1 & 2. This proposal will allow us to (1) define mechanisms of cancer cell chemotaxis in perineural invasion, (2) predict PNI behavior based on an assessment of cancer cell characteristics, (3) identify novel targets for therapy by chemotactic inhibition, and (4) introduce a novel therapeutic approach in targeting a cancer's interactions with its microenvironment to modify its behavior, rather than targeting its viability. PUBLIC HEALTH RELEVANCE: Some cancers have the ability to invade along nerves, an ominous event that causes nerve dysfunction and makes the cancer more difficult to eradicate. Our laboratory has determined that this process of perineural invasion is driven by the active migration of cancer cells towards a protein secreted by nerve cells in a process called chemotaxis. Our proposal will investigate how mechanisms of chemotaxis by cancer cells may specifically lead to perineural invasion. Results from this work may allow clinicians to identify patients with cancers that are likely to invade along nerves, and ultimately develop novel therapies to prevent this type of cancer progression.

描述（由申请人提供）：选定的癌症在神经内、周围和沿着神经侵袭的能力是一种被充分描述的事件，称为神经周侵袭（PNI）。PNI已多次被证明是一种不良病理发现，预示着局部疾病更具侵袭性、复发率更高和生存率更差。 尽管PNI的临床意义得到广泛认可，但其机制仍知之甚少。我们最近证明了癌细胞趋化性（外部梯度感应和定向迁移）对胶质源性神经营养因子（GDNF）和激活RET酪氨酸激酶受体作为PNI的关键机制的关键作用。 趋化性的机制以前已被定义主要是在非恶性系统的盘状网柄霉（黏菌）和白细胞。然而，在癌细胞中，趋化机制还没有被很好地定义。有趣的是，与网骨细胞和白细胞中的趋化性相关的途径在癌症中经常异常。这些包括酪氨酸激酶受体活性、PI 3 K活性、Rho家族（Cdc 42、Rac 1、RhoA）GT3和Ras GT3活性。GDNF已被证明可以激活胰腺癌细胞中的每一种因子。我们将阐明这些因素的致癌激活和它们对GDNF的趋化反应之间的关系，在临床上重要的背景下PNI。 我们的中心假设是，在某些癌症中这些因子的失调可能会促进对GDNF的趋化性，导致PNI。我们将定义促进神经侵袭表型的致癌特征。我们将使用以下技术的组合来定义这些通路在PNI中的作用：单细胞实时延时成像，评估神经和癌细胞之间相互作用的PNI的体外Matrigel模型，PNI的体内鼠坐骨神经模型，以及手术切除的人类癌症的研究。这些方法的结合将使我们能够实现三个目标：1。确定癌细胞对GDNF的趋化性的假定机制。我们将重点关注：（a）RET-GFR 1受体表达和RET G681 S多态性，（B）PI 3 K/PTEN活性和p1101 H1047 R和E545 K突变，（c）Rho家族（Cdc 42、Rac 1、RhoA）和Ras GT3活性。2.定义趋化机制在癌细胞PNI模型中的作用。使用体外和体内模型，我们将关联目标1中的因子的调制与PNI表型的变化。3.在人类癌症中发现了趋化机制。我们将使用手术标本进行分子、病理和临床相关性研究，以验证目标1和2中确定的因素。这一提议将使我们能够（1）定义癌细胞在神经周围侵袭中的趋化性机制，（2）基于对癌细胞特征的评估预测PNI行为，（3）通过趋化性抑制识别新的治疗靶点，以及（4）引入一种新的治疗方法，靶向癌症与其微环境的相互作用以改变其行为，而不是靶向其生存能力。 公共卫生相关性： 一些癌症有能力沿着沿着神经侵入，这是一种不祥的事件，会导致神经功能障碍，使癌症更难以根除。我们的实验室已经确定，这种神经周围侵袭的过程是由癌细胞在一种称为趋化性的过程中向神经细胞分泌的蛋白质主动迁移驱动的。我们的建议将探讨癌细胞的趋化机制如何可能导致神经周围的入侵。这项工作的结果可能使临床医生能够识别出可能沿着沿着神经侵入的癌症患者，并最终开发出新的疗法来预防这种类型的癌症进展。