Biomarkers of residual disease, disseminated tumor cells, and metastases in the MMTV-PyMT breast cancer model.
Biomarkers of residual disease, disseminated tumor cells, and metastases in the MMTV-PyMT breast cancer model.
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DOI：
10.1371/journal.pone.0058183
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Kouros-Mehr H
中科院分区：
文献类型：
--
作者：
Franci C;Zhou J;Jiang Z;Modrusan Z;Good Z;Jackson E;Kouros-Mehr H
癌症转移部分地由源自原发性肿瘤的播散性肿瘤细胞和治疗后持续存在的残留疾病引起。微转移，播散性肿瘤和残留疾病的生物标志物的鉴定可能会产生新的工具，用于早期检测和治疗这些疾病状态之前，他们发展成转移和复发性肿瘤。在这里，我们描述了MMTV-PyMT乳腺癌模型中肺中播散性肿瘤细胞、肺转移和残留肿瘤细胞的分子谱。将MMTV-PyMT小鼠与肌动蛋白-GFP小鼠交配，并将来自青春期MMTV-PyMT的局灶性增生病变;将肌动蛋白-GFP小鼠原位移植到FVB/n小鼠中以追踪单个肿瘤病灶。用TAC化疗（多西他赛、多柔比星、环磷酰胺）治疗荷瘤小鼠，并通过mRNA微阵列分析对残留和复发的肿瘤细胞进行分选和分析。数据分析显示残留肿瘤中Jak/Stat途径、Notch途径和表观遗传调节因子的富集。Stat 1在残留肿瘤细胞的DNA损伤抗性群体中显著上调，并且在未治疗的肿瘤中鉴定了预先存在的Stat 1亚群。还从MMTV-PyMT移植小鼠中分选来自腺瘤、癌、肺播散性肿瘤细胞和肺转移的肿瘤细胞，并通过mRNA微阵列进行分析。尽管播散性肿瘤细胞在mRNA水平上与癌细胞相似，但肺转移瘤的基因型与播散性细胞和原发性肿瘤非常不同。肺转移瘤富含许多染色质修饰基因和干细胞相关基因。H3 K4和H3 K9的组蛋白分析表明，肺转移癌在恶性进展过程中已被重编程。这些数据确定了残留肿瘤细胞和播散肿瘤细胞的新生物标志物，并涉及可能介导治疗后转移形成和肿瘤复发的途径。
Cancer metastases arise in part from disseminated tumor cells originating from the primary tumor and from residual disease persisting after therapy. The identification of biomarkers on micro-metastases, disseminated tumors, and residual disease may yield novel tools for early detection and treatment of these disease states prior to their development into metastases and recurrent tumors. Here we describe the molecular profiling of disseminated tumor cells in lungs, lung metastases, and residual tumor cells in the MMTV-PyMT breast cancer model. MMTV-PyMT mice were bred with actin-GFP mice, and focal hyperplastic lesions from pubertal MMTV-PyMT;actin-GFP mice were orthotopically transplanted into FVB/n mice to track single tumor foci. Tumor-bearing mice were treated with TAC chemotherapy (docetaxel, doxorubicin, cyclophosphamide), and residual and relapsed tumor cells were sorted and profiled by mRNA microarray analysis. Data analysis revealed enrichment of the Jak/Stat pathway, Notch pathway, and epigenetic regulators in residual tumors. Stat1 was significantly up-regulated in a DNA-damage-resistant population of residual tumor cells, and a pre-existing Stat1 sub-population was identified in untreated tumors. Tumor cells from adenomas, carcinomas, lung disseminated tumor cells, and lung metastases were also sorted from MMTV-PyMT transplant mice and profiled by mRNA microarray. Whereas disseminated tumors cells appeared similar to carcinoma cells at the mRNA level, lung metastases were genotypically very different from disseminated cells and primary tumors. Lung metastases were enriched for a number of chromatin-modifying genes and stem cell-associated genes. Histone analysis of H3K4 and H3K9 suggested that lung metastases had been reprogrammed during malignant progression. These data identify novel biomarkers of residual tumor cells and disseminated tumor cells and implicate pathways that may mediate metastasis formation and tumor relapse after therapy.
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影响因子：
64.8
作者：
通讯作者：
--
影响因子：
12.3
作者：
Herschkowitz JI;Simin K;Weigman VJ;Mikaelian I;Usary J;Hu Z;Rasmussen KE;Jones LP;Assefnia S;Chandrasekharan S;Backlund MG;Yin Y;Khramtsov AI;Bastein R;Quackenbush J;Glazer RI;Brown PH;Green JE;Kopelovich L;Furth PA;Palazzo JP;Olopade OI;Bernard PS;Churchill GA;Van Dyke T;Perou CM
通讯作者：
Perou CM
影响因子：
6.2
作者：
Hall, Carolyn;Krishnamurthy, Savitri;Lucci, Anthony
通讯作者：
Lucci, Anthony
影响因子：
10.5
作者：
Ancrile, Brooke;Lim, Kian-Huat;Counter, Christopher M.
通讯作者：
Counter, Christopher M.
影响因子：
5.3
作者：
GUY, CT;CARDIFF, RD;MULLER, WJ
通讯作者：
MULLER, WJ