Metabotropic Glutamate Receptor 1 in African American Prostate Cancer

非裔美国人前列腺癌中的代谢型谷氨酸受体 1

• 批准号: 8675361
• 负责人: SHAHRIAR KOOCHEKPOUR
• 金额: $ 22.16万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8675361
• 关键词: African American; Age; Apoptosis; Benign; Biochemical; Bioenergetics; Biological; Biological Factors; Brain; Breast Melanoma; Cancer Biology; Cancer Cell Growth; Cancer Patient; Caucasians; Caucasoid Race; Cell Line; Cell Proliferation; Citric Acid Cycle; Clinical; Data; Development; Diagnostic; Environment; Epithelial Cells; Ethnic Origin; Family; GRM1 gene; Genetic; Gland; Gleason Grade for Prostate Cancer; Glutamate Receptor; Glutamates; Growth; Health; Health Services Accessibility; Healthcare Systems; In Vitro; Incidence; Indolent; Investigation; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of prostate; Measures; Metabolic; Metabotropic Glutamate Receptors; Molecular Target; Multivariate Analysis; Neoplasm Metastasis; Non-Essential Amino Acid; Oncogenic; Outcome; PC3 cell line; Patients; Penetrance; Phenotype; Play; Proliferating; Prostate; Prostate Cancer therapy; Prostate-Specific Antigen; Race; Radical Prostatectomy; Recurrence; Resistance; Risk Factors; Role; Serum; Signal Pathway; Signal Transduction; Signaling Molecule; Staging; Staining method; Stains; System; TNM; Testing; Time; Tissues; Transgenic Mice; Tumor Volume; Xenograft Model; base; burden of illness; cancer cell; cancer health disparity; caucasian American; cell motility; clinically significant; deprivation; ethnic difference; lipid biosynthesis; melanocyte; melanoma; member; men; metabotropic glutamate receptor type 1; migration; mortality; novel; outcome forecast; overexpression; prognostic; prostate cancer cell; racial difference; subcutaneous; tumor; tumor growth; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): Prostate cancer (PCa) presents with the greatest racial disparity of any cancer in the U.S., with an alarmingly high incidence and mortality rate among African Americans (AAs). AA men with PCa present with higher tumor volume, more advanced stage, higher Gleason grade, higher prostate-specific antigen (PSA), and worse prognosis than Caucasian Americans (CAs). The underlying reasons for such disproportionate ethnic differences may reflect genuine racial differences in cancer biology, socio-cultural differences, or access to health care systems. Recently, we discovered that serum glutamate levels positively correlate with PCa aggressiveness and Gleason score (e8 versus d6) in AAs and CAs. However, glutamate levels were higher in AAs, with primary or metastatic castrate-resistant (CR) PCa than in CAs. Glutamate deprivation or blockade with a glutamate receptor (i.e., GRM1) antagonist significantly decreased growth, migration and invasion and induced apoptosis in PCa cells. We also demonstrated a higher GRM1 expression in MDA-PCa2b (metastatic AA-PCa cell line) than in the E006AA (primary AA-PCa cell line). GRM1 overexpression increased E006AA cell proliferation, migration, and invasion. Our preliminary data show that GRM1 expression is higher in PCa tissues than in normal or benign glands in AAs. Based on these data, we hypothesized that GRM1 expression levels contribute to biological and clinical aggressiveness of PCa in AAs. Our hypothesis will be tested in the following Specific Aims: (1) to determine the association between tissue expression of GRM1 and clinicohistopathological predictors or prognosticators of PCa progression or aggressiveness in AAs; and (2) to determine the association between GRM1 expression levels and invasive and metastatic phenotypes in AA-PCa cells. Data generated from this exploratory study will define biological and/or clinicohistopathological significance or relevance of GRM1 expression in AA-PCa and may prove useful in discriminating clinically or biologically aggressive tumors from indolent (non-aggressive) tumors and minimizing PCa disparity in AAs.

描述(申请人提供)：前列腺癌(PCa)是美国所有癌症中种族差异最大的，在非裔美国人(AAs)中的发病率和死亡率高得惊人。AA组的肿瘤体积、分期、Gleason分级、前列腺特异性抗原(PSA)高于高加索裔美国人(CA)，预后较差。这种不成比例的种族差异的根本原因可能反映了癌症生物学上的真正种族差异、社会文化差异或获得医疗保健系统的机会。最近，我们发现血清谷氨酸水平与AAS和CA的PCa侵袭性和Gleason评分(e8和d6)呈正相关。然而，在患有原发或转移性去势抵抗(CR)Pca的AAS中，谷氨酸水平高于CA。剥夺谷氨酸或用谷氨酸受体拮抗剂(即GRM1)阻断可显著抑制PCa细胞的生长、迁移和侵袭，并诱导细胞凋亡。我们还发现，在转移性AA-PCA细胞系MDA-PCa2b中，GRM1的表达高于原代AA-PCA细胞系E006AA。GRM1过表达增加了E006AA细胞的增殖、迁移和侵袭。我们的初步数据显示，在AAS中，GRM1在PCa组织中的表达高于正常或良性腺体。基于这些数据，我们假设GRM1的表达水平有助于AAS中PCa的生物学和临床侵袭性。我们的假设将在以下特定目标中进行检验：(1)确定GRM1的组织表达与临床组织病理学指标或PCa进展或侵袭性的预测指标之间的关联；以及(2)确定GRM1的表达水平与AA-PCa细胞的侵袭和转移表型之间的关联。这项探索性研究产生的数据将确定GRM1在AA-PCa中的生物学和/或临床组织病理学意义或相关性，并可能被证明有助于区分临床或生物侵袭性肿瘤与惰性(非侵袭性)肿瘤，并将AA中的PCA差异降至最低。