Biomarkers of Aggressive Oral Cancer

侵袭性口腔癌的生物标志物

• 批准号: 8739641
• 负责人: Yvonne L Kapila
• 金额: $ 23.33万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-25 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8739641
• 关键词: Accounting; Adenine; Amino Acids; Anoikis; Antioxidants; Apoptotic; Biological Markers; Blood specimen; Cell Death; Cell physiology; Cells; Characteristics; Choline; Citric Acid Cycle; Clinical; Cysteine; Data; Defense Mechanisms; Development; Dinucleoside Phosphates; Disease; Energy Metabolism; Enzymes; Exhibits; Extracellular Matrix; Glutamates; Glutamic Acid; Glutaminase; Glutathione; Glycine; Glycolysis; Goals; Head and Neck Squamous Cell Carcinoma; Human; In Vitro; Kynurenine; Lead; Malignant Epithelial Cell; Malignant Neoplasms; Mass Spectrum Analysis; Measures; Mediating; Membrane; Metabolic Pathway; Molecular; Molecular Profiling; Monitor; Mus; NMR Spectroscopy; Normal tissue morphology; Nutrient; Oral; Outcome; Pathway interactions; Pattern; Phase; Phenotype; Phospholipid Metabolism; Process; Production; Resistance; Sarcosine; Serine; Specimen; Staging; Survival Rate; Testing; Tissue Sample; Tissues; Tryptophan; Tumor-Derived; base; cohort; disease phenotype; head and neck cancer patient; in vivo; innovation; keratinocyte; malignant mouth neoplasm; metabolomics; molecular marker; mouse model; new therapeutic target; novel diagnostics; public health relevance; tool; tumor; tumor progression; tumorigenesis; tumorigenic

DESCRIPTION (provided by applicant): Anoikis-apoptotic cell death triggered by loss of extracellular matrix (ECM) contacts-is dysregulated in many diseases. Anoikis resistance contributes to the development and progression of cancer, thus marking aggressive tumorigenic transitions. In oral/head and neck squamous cell carcinoma (HNSCC), anoikis resistance induces more aggressive tumors. Given that oral SCC, the most common malignant oral neoplasm, accounts for 90% of all oral malignancies and has a poor 5-year survival rate that has not changed in decades (http://seer/cancer.gov), this underscores the need to identify novel therapeutic targets for HNSCC. Identifying markers of aggressive tumorigenesis and thus anoikis resistance could yield potentially novel therapeutic targets for HNSCC. Mass spectrometry-based metabolomics offers an innovative non-invasive platform for the development of marker panels that are characteristic of disease phenotypes or cellular processes that are readily measured in biofluids/tissues. We recently performed NMR based metabolomic analysis of primary and metastatic HNSCC human specimens and found elevated levels of several metabolites (Somashekar et al., 2011). These metabolites were associated with highly active glycolysis and glutaminolysis, increased amino acid influx into the Krebs cycle, and altered energy metabolism, membrane choline phospholipid metabolism, and oxidative/osmotic defense mechanisms. Using NMR spectroscopy, several groups also generated a list of similar metabolites differentially expressed across tissue and blood samples from head and neck cancer patients, (Mukheriji et al., 1997; Tiziani et al., 2009; El-Sayed et al., 2002). In complementary preliminary data where we now used mass spectrometry analyses of primary HNSCC, we identified several metabolites that were differentially and significantly elevated in HNSCC compared to normal tissues. Importantly, these metabolites were also elevated in metastatic HNSCC and in mouse tumors derived from anoikis-resistant HNSCC cells. These metabolites included kynurenine, serine, glutathione, and glutamate/glutamic acid. Since these metabolites have also been implicated in cancer metabolic pathways they constitute potential candidates for a marker panel of aggressive HNSCC. Furthermore, compared to normal oral keratinocytes, HNSCC cells also show elevated levels of glutamic acid. Elevated glutamic acid levels were suppressed in HNSCC cells by chemically inhibiting the enzyme that catalyzes the formation of glutamic acid levels, glutaminase. Inhibiting glutamic acid levels in these cells led to suppression of anoikis resistance/an aggressive phenotype in vitro. In addition, significantly elevated expression levels of glutaminase were highest in the metastatic tissues compared to primary HNSCC and normal tissues. These findings suggest that these metabolites, including glutamic acid may be markers for the transition to a more aggressive phenotype in cancer, including the acquisition of anoikis resistance. Our data support the concept that identification of a marker panel of metabolites present in aggressive HNSCC, a phenotype that emanates in part from anoikis resistance, may be useful as a new diagnostic tool and for identification of novel therapeutic targets for aggressive HNSCC. Thus, we hypothesize that aggressive states in HNSCC and anoikis-resistant HNSCC cells/tissues exhibit a metabolomic profile defined by increased levels of key metabolites that may include kynurenine, glutamic acid, serine, and glutathione. These metabolites mark aggressive tumorigenesis, the transition to anoikis resistance, and may promote anoikis resistance and an aggressive phenotype in vivo. These studies will help establish a signature metabolome or a panel of key metabolites for aggressive HNSCC and anoikis resistance plus validate the functional contribution of these metabolites in this process.

描述（由申请人提供）：失巢凋亡-细胞外基质（ECM）接触丢失引发的凋亡性细胞死亡-在许多疾病中失调。失巢凋亡抗性有助于癌症的发展和进展，从而标志着侵袭性肿瘤发生转变。在口腔/头颈部鳞状细胞癌（HNSCC）中，失巢凋亡抵抗诱导更具侵袭性的肿瘤。鉴于口腔SCC是最常见的口腔恶性肿瘤，占所有口腔恶性肿瘤的90%，并且具有几十年来没有改变的较差的5年生存率（http：//seer/cancer.gov），这强调了鉴定HNSCC的新治疗靶点的需要。鉴定侵袭性肿瘤发生的标志物，从而抗失巢凋亡可能产生HNSCC的潜在新治疗靶点。基于质谱的代谢组学提供了一个创新的非侵入性平台，用于开发标志物组，这些标志物组是在生物流体/组织中容易测量的疾病表型或细胞过程的特征。我们最近对原发性和转移性HNSCC人样本进行了基于NMR的代谢组学分析，并发现几种代谢物的水平升高（Somashekar等人，2011年）。这些代谢物与高度活跃的糖酵解和氨解，增加的氨基酸流入克雷布斯循环， 以及改变的能量代谢、膜胆碱磷脂代谢和氧化/渗透防御机制。使用NMR光谱，几个研究小组还生成了在来自头颈癌患者的组织和血液样品中差异表达的类似代谢物的列表（Mukheriji等人，1997; Tiziani等人，2009; El-Sayed等人， 2002年）。在我们现在使用原发性HNSCC的质谱分析的补充初步数据中，我们鉴定了与正常组织相比在HNSCC中差异显著升高的几种代谢物。重要的是，这些代谢物在转移性HNSCC和源自失巢凋亡抗性HNSCC细胞的小鼠肿瘤中也升高。这些代谢物包括犬尿氨酸、丝氨酸、谷胱甘肽和谷氨酸/谷氨酸。由于这些代谢物也与癌症代谢途径有关，因此它们构成了侵袭性HNSCC标志物组的潜在候选物。此外，与正常口腔角质形成细胞相比，HNSCC细胞还显示出升高的谷氨酸水平。HNSCC细胞中升高的谷氨酸水平通过化学抑制催化谷氨酸水平形成的酶，谷氨酰胺酶来抑制。抑制这些细胞中的谷氨酸水平导致体外失巢凋亡抗性/侵袭性表型的抑制。此外，与原发性HNSCC和正常组织相比，转移性组织中转氨酶的表达水平显著升高。这些发现表明，这些代谢物，包括谷氨酸，可能是癌症中向更具侵袭性表型转变的标志物，包括获得失巢凋亡抗性。我们的数据支持这样的概念，即鉴定侵袭性HNSCC中存在的代谢物的标记物组，这是一种部分源自失巢凋亡抗性的表型，可以用作新的诊断工具和用于鉴定侵袭性HNSCC的新治疗靶点。因此，我们假设HNSCC和失巢凋亡抗性HNSCC细胞/组织中的侵袭性状态表现出代谢组学特征，该代谢组学特征由可能包括犬尿氨酸、谷氨酸、丝氨酸和谷胱甘肽的关键代谢物的水平增加定义。这些代谢物标志着侵袭性肿瘤发生，向失巢凋亡抗性的转变，并且可能促进体内失巢凋亡抗性和侵袭性表型。这些研究将有助于建立一个标志性代谢物组或一组关键代谢物，用于侵袭性HNSCC和失巢凋亡抗性，并验证这些代谢物在此过程中的功能贡献。

项目成果

Metabolomics of Head and Neck Cancer: A Mini-Review.

• DOI: 10.3389/fphys.2016.00526
• 发表时间: 2016
• 期刊: Frontiers in physiology
• 影响因子: 4
• 作者: Shin JM;Kamarajan P;Fenno JC;Rickard AH;Kapila YL
• 通讯作者: Kapila YL