Prognostic Significance of Neuronal Differentiation of Cutaneous Melanoma

皮肤黑色素瘤神经元分化的预后意义

基本信息

批准号：
7587326
负责人：
Vijayasaradhi Setaluri
金额：
$ 16.54万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-03-15 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7587326
关键词：
American Joint Committee on Cancer Apoptosis Attention Biological Biological Markers Cell Cycle Arrest Cell Death Cell Differentiation process Cell Line Cell Proliferation Cell division Cells Chromosome Segregation Clinical Cutaneous Cutaneous Melanoma Cytokinesis Defect Dendrites Development Diagnosis Differentiation Antigens Disease Disease-Free Survival Early Diagnosis Exhibits Frequencies G2/M Arrest Gene Expression Genes Goals Growth In Vitro Investigation Lesion Malignant Neoplasms Melanoma Cell Metastatic Lesion Metastatic Melanoma Microtubule Stabilization Microtubule-Associated Protein 2 Microtubules Mitosis Mitotic Mitotic Spindle Apparatus Mitotic spindle Molecular Neoplasm Metastasis Neoplastic Melanocyte Neuronal Differentiation Neurons Outcome Pathway interactions Patients Phase Primary Neoplasm Prognostic Marker Proliferation Marker Property Proteins Radial Growth Phase Regression Analysis S-Phase Fraction Sentinel Lymph Node Series Skin Cancer Staging Staging System Stem cells Survival Analysis Testing Thick Vertical Growth Phase abstracting apoptotic protease-activating factor 1 cell type cohort interest melanoma mimicry minimally invasive molecular marker neoplastic cell nerve stem cell nestin protein novel marker overexpression precursor cell prognostic prognostic indicator relating to nervous system stem tumor tumor progression

项目摘要

DESCRIPTION (provided by applicant): Cutaneous melanoma is thought to progress through a series of distinct phases that include a non-invasive or minimally invasive radial growth phase and a vertical growth phase that acquires metastatic capacity. According to the widely accepted staging system, vertical thickness of primary tumor is the best predictor of the aggressiveness of melanoma. However, tumor thickness is not always a reliable parameter. Although a number of other clinical and biological parameters that influence melanoma progression have been identified, to date there are no molecular markers that can reliably predict aggressiveness of melanoma. Malignant melanoma is also known to exhibit molecular plasticity and transdifferentiate along several cellular pathways, including endothelial and neural cell types. Melanoma transdifferentiation seems to have biological and prognostic significance. We have investigated the effects of neuronal differentiation on melanoma tumor progression. We showed that the neuron-specific microtubule associated protein 2 (MAP2), a protein found primarily in the dendrites of post-mitotic, terminally differentiated neurons, is expressed abundantly in early invasive cutaneous primary melanoma lesions but present only less frequently or absent in metastatic lesions. MAP2 expression appears to be inversely correlated with tumor progression. The primary function of MAP2 is to stabilize microtubules. MAP2 alters the 'dynamic instability' of microtubules, a property critical for mitotic spindle formation and chromosome segregation. Therefore, we hypothesized that neuronal differentiation and activation of MAP2 gene expression in neoplastic melanocytes that are destined to divide rapidly, disrupts mitotic apparatus, inhibits cell proliferation and tumor progression. Retrospective immuno-histochemical and survival analysis of a small cohort showed that patients whose primary tumors were MAP2-positive had significantly longer disease-free survival than those with MAP2-negative melanoma. Investigation of the mechanisms that underlie the effects of MAP2 showed that overexpression of MAP2 in metastatic melanoma cells leads to stabilization of microtubules, G2-M arrest, growth inhibition followed by apoptosis. MAP2 expressing cells show mitotic spindle and cytokinesis defects similar to those seen in cells treated with microtubule-disrupting agents. Thus, ectopic activation of a neuronal differentiation gene in melanoma during early progression inhibits cell division and correlates with inhibition or delay of metastasis. The goal of this study is to test the hypothesis that expression of neuronal markers in cutaneous primary melanoma reduces tumor cell proliferative potential, increases the frequency of cell death and is associated with longer disease-free survival of patients. We propose to test and validate neuronal markers nestin, NEDD9 and MAP2 as a melanoma prognostics marker by investigating the association between MAP2 expression and a) markers for melanoma cell proliferation and apoptosis, and b) clinical outcome in patients diagnosed with melanoma. PUBLIC HEALTH RELEVANCE: Cutaneous melanoma is the deadliest form of skin cancer. If diagnosed early and treated appropriately before the cancer becomes aggressive, melanoma is often curable. However, there are no biological markers to reliably assess the aggressiveness of melanoma. The goal of this project is to assess the value of novel markers in predicting melanoma tumor aggressiveness.

描述（由申请人提供）：皮肤黑色素瘤被认为经历一系列不同的阶段，包括非侵入性或微创径向生长阶段和获得转移能力的垂直生长阶段。根据广泛接受的分期系统，原发肿瘤的垂直厚度是黑色素瘤侵袭性的最佳预测指标。然而，肿瘤厚度并不总是可靠的参数。尽管已经确定了影响黑色素瘤进展的许多其他临床和生物学参数，但迄今为止还没有可以可靠预测黑色素瘤侵袭性的分子标记。恶性黑色素瘤还表现出分子可塑性，并沿着多种细胞途径转分化，包括内皮细胞和神经细胞类型。黑色素瘤转分化似乎具有生物学和预后意义。我们研究了神经元分化对黑色素瘤进展的影响。我们发现，神经元特异性微管相关蛋白 2 (MAP2) 是一种主要存在于有丝分裂后终末分化神经元树突中的蛋白质，在早期侵袭性皮肤原发性黑色素瘤病变中大量表达，但在转移性黑色素瘤病变中出现频率较低或不存在。病变。 MAP2 表达似乎与肿瘤进展呈负相关。 MAP2 的主要功能是稳定微管。 MAP2 改变微管的“动态不稳定性”，这是有丝分裂纺锤体形成和染色体分离的关键特性。因此，我们假设肿瘤性黑素细胞中的神经元分化和 MAP2 基因表达的激活注定会快速分裂，破坏有丝分裂装置，抑制细胞增殖和肿瘤进展。一个小队列的回顾性免疫组织化学和生存分析表明，原发肿瘤为 MAP2 阳性的患者比 MAP2 阴性黑色素瘤患者的无病生存期显着更长。对 MAP2 作用机制的研究表明，转移性黑色素瘤细胞中 MAP2 的过度表达会导致微管稳定、G2-M 期停滞、生长抑制以及随后的细胞凋亡。表达 MAP2 的细胞表现出有丝分裂纺锤体和胞质分裂缺陷，与用微管破坏剂处理的细胞中所见的缺陷相似。因此，黑色素瘤早期进展过程中神经元分化基因的异位激活会抑制细胞分裂，并与抑制或延迟转移相关。本研究的目的是检验以下假设：皮肤原发性黑色素瘤中神经元标记物的表达会降低肿瘤细胞的增殖潜力，增加细胞死亡的频率，并与患者较长的无病生存期相关。我们建议通过研究 MAP2 表达与 a) 黑色素瘤细胞增殖和凋亡的标记物以及 b) 诊断为黑色素瘤的患者的临床结果之间的关联来测试和验证神经元标记物巢蛋白、NEDD9 和 MAP2 作为黑色素瘤预后标记物。公共卫生相关性：皮肤黑色素瘤是最致命的皮肤癌。如果在癌症变得具有侵袭性之前尽早诊断并进行适当治疗，黑色素瘤通常是可以治愈的。然而，没有生物标志物可以可靠地评估黑色素瘤的侵袭性。该项目的目标是评估新型标记物在预测黑色素瘤侵袭性方面的价值。