Metabotropic Glutamate Receptor 1 in African American Prostate Cancer

描述（由申请人提供）：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）中具有惊人的高发病率和死亡率。AA男性PCa患者的肿瘤体积、分期、Gleason分级、前列腺特异性抗原（PSA）和预后均高于美国白人（CA）。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，社会文化差异或获得医疗保健系统的真正种族差异。 最近，我们发现血清谷氨酸水平与前列腺癌的侵袭性和Gleason评分（e8与d 6）在AA和CA呈正相关。然而，谷氨酸水平较高的AA，原发性或转移性去势抵抗（CR）PCa比CA。谷氨酸剥夺或用谷氨酸受体阻断（即，GRM 1拮抗剂可显著抑制PCa细胞的生长、迁移和侵袭，并诱导细胞凋亡。我们还证明了在MDA-PCa 2b（转移性AA-PCa细胞系）中比在E006 AA（原代AA-PCa细胞系）中更高的GRM 1表达。GRM 1过表达增加E006 AA细胞的增殖、迁移和侵袭。我们的初步数据表明，GRM 1的表达是在前列腺癌组织高于正常或良性腺体的AA。 基于这些数据，我们假设GRM 1表达水平有助于AA中PCa的生物学和临床侵袭性。我们的假设将在以下特定目的中进行检验：（1）确定GRM 1的组织表达与AA中PCa进展或侵袭性的临床组织病理学预测因子或预测因子之间的关联;以及（2）确定GRM 1表达水平与AA-PCa细胞中侵袭性和转移性表型之间的关联。 本探索性研究产生的数据将确定AA-PCa中GRM 1表达的生物学和/或临床组织病理学意义或相关性，并可能证明可用于区分临床或生物学侵袭性肿瘤与惰性（非侵袭性）肿瘤，并最大限度地减少AA中的PCa差异。

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.