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）：anoiki -由细胞外基质（ECM）接触丢失引发的凋亡细胞死亡-在许多疾病中失调。Anoikis的耐药性有助于癌症的发展和进展，从而标志着侵袭性肿瘤的转变。在口腔/头颈部鳞状细胞癌（HNSCC）中，anoikis耐药诱导更具侵袭性的肿瘤。口腔鳞状细胞癌是最常见的口腔恶性肿瘤，占所有口腔恶性肿瘤的90%，其5年生存率很低，几十年来一直没有改变（http://seer/cancer.gov），这强调了寻找新的治疗靶点的必要性。识别侵袭性肿瘤发生的标记物，从而产生耐药，可以为HNSCC提供潜在的新治疗靶点。基于质谱的代谢组学为开发具有疾病表型或细胞过程特征的标记板提供了一个创新的非侵入性平台，这些标记板易于在生物流体/组织中测量。我们最近对原发性和转移性HNSCC人类标本进行了基于核磁共振的代谢组学分析，发现几种代谢物水平升高（Somashekar et al., 2011）。这些代谢物与高活性的糖酵解和谷氨酰胺解有关，增加了进入克雷布斯循环的氨基酸，

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