Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America.
PLoS One. 2011;6(8):e22446. doi: 10.1371/journal.pone.0022446. Epub 2011 Aug 10.
Expansion of Gr-1+/CD11b+ myeloid derived suppressor cells (MDSCs) is governed by the presence of increasingly metastatic, malignant primary tumors. Metastasis, not the primary tumor, is often the cause of mortality. This study sought to fully characterize the MDSC proteome in response to metastatic and non-metastatic mammary tumors using label-free mass spectrometry shotgun proteomics in a mouse model with tumor cell lines, 67NR and 4T1, derived from the same tumor. 67NR cells form only primary mammary tumors, whereas 4T1 cells readily metastasize to the lungs, lymph nodes, and blood. Overall analysis identified a total of 2825 protein groups with a 0.78% false discovery rate. Of the 2814 true identifications, 43 proteins were exclusive to the 67NR group, 153 were exclusive to the 4T1 group, and 2618 were shared. Among the shared cohort, 26 proteins were increased and 31 were decreased in the metastatic 4T1 cohort compared to non-metastatic 67NR controls after filtering. MDSCs selectively express proteins involved in the γ-glutamyl transferase, glutathione synthase pathways, CREB transcription factor signaling, and other pathways involved in platelet aggregation, as well as lipid and amino acid metabolism, in response to highly metastatic 4T1 tumors. Cell cycle regulation dominated protein pathways and ontological groups of the 67NR non-metastatic group. Not only does this study provide a starting point to identify potential biomarkers of metastasis expressed by MDSCs; it identifies critical pathways that are unique to non-metastatic and metastatic conditions. Therapeutic interventions aimed at these pathways in MDSC may offer a new route to control malignancy and metastasis.
Gr-1+/CD11b+ 髓系来源抑制细胞（MDSCs）的扩增受不断转移、恶性原发性肿瘤的存在所控制。转移而非原发性肿瘤往往是导致死亡的原因。本研究旨在使用无标签质谱shotgun 蛋白质组学，在具有肿瘤细胞系 67NR 和 4T1 的小鼠模型中，全面表征转移性和非转移性乳腺肿瘤对 MDSC 蛋白质组的影响，这两种细胞系均源自同一肿瘤。67NR 细胞仅形成原发性乳腺肿瘤，而 4T1 细胞则容易转移到肺部、淋巴结和血液中。总体分析共鉴定出 2825 个蛋白组，假发现率为 0.78%。在 2814 个真实鉴定中，有 43 个蛋白仅存在于 67NR 组，153 个蛋白仅存在于 4T1 组，2618 个蛋白是共有的。在共有的队列中，与非转移性 67NR 对照组相比，26 个蛋白在转移性 4T1 队列中增加，31 个蛋白减少。在高度转移性 4T1 肿瘤的刺激下，MDSC 选择性地表达参与 γ-谷氨酰转移酶、谷胱甘肽合酶途径、CREB 转录因子信号转导以及其他与血小板聚集以及脂质和氨基酸代谢相关的途径的蛋白。细胞周期调控主导着 67NR 非转移性组的蛋白途径和本体论组。本研究不仅为鉴定 MDSC 表达的潜在转移标志物提供了一个起点；还鉴定了非转移性和转移性条件下特有的关键途径。针对 MDSC 中这些途径的治疗干预可能为控制恶性肿瘤和转移提供新途径。
