Distinctive responsiveness to stromal signaling accompanies histologic grade programming of cancer cells.
Distinctive responsiveness to stromal signaling accompanies histologic grade programming of cancer cells.
复制标题
DOI：
10.1371/journal.pone.0020016
复制
发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Dairkee SH
中科院分区：
文献类型：
--
作者：
Luciani MG;Seok J;Sayeed A;Champion S;Goodson WH;Jeffrey SS;Xiao W;Mindrinos M;Davis RW;Dairkee SH
基质成分是促进癌细胞的生长、侵袭和扩散，还是抑制肿瘤病变进一步恶性进展，是肿瘤生物学中持续存在的难题。个体间异质性使肿瘤发生的动态图像概念化变得复杂。在后基因组时代，解开这种复杂性仍然是癌症生物学家的挑战。为了建立细胞串扰和不同的癌症侵袭性之间的功能关联，我们确定了恶性乳腺上皮细胞对基质信号传导的反应的特征。接近成纤维细胞导致107个探针的基因转录物改变>2倍，统称为成纤维细胞触发的肿瘤基因表达（FTExT）。与常规临床变量相比，FTExT分类器预测的中度和高度乳腺肿瘤患者远端复发的风险比具有显著性（数据集1，n = 258，HR - 2.11，95% CI 1.17-3.80，p值0.01;数据集2，n = 171，HR - 3.07，95% CI 1.21-7.83，p值0.01）。 以FTExT为代表的生物功能包括炎症信号传导、自由基清除、细胞死亡和细胞增殖。与在侵袭性原发性肿瘤中过表达的“增殖簇”基因不同，FTExT基因在这种情况下被独特地抑制。作为我们的相关发现的概念证明，其将基质-上皮串扰和肿瘤行为联系起来，我们显示了基质对细胞周期进展的肿瘤定义功能终点的影响的独特差异，以及对低级别与高级别癌细胞中治疗诱导的生长停滞和凋亡的抗性。因此，我们的实验数据揭示了“旁分泌协同性”的各个方面，这些方面完全取决于相互作用的肿瘤上皮的组织病理学定义的等级，并表明上皮对肿瘤微环境的反应是临床结果的决定性因素。在这种情况下，上皮-基质串扰的早期衰减可以改善易于临床挑战的病例的管理。
Whether stromal components facilitate growth, invasion, and dissemination of cancer cells or suppress neoplastic lesions from further malignant progression is a continuing conundrum in tumor biology. Conceptualizing a dynamic picture of tumorigenesis is complicated by inter-individual heterogeneity. In the post genomic era, unraveling such complexity remains a challenge for the cancer biologist. Towards establishing a functional association between cellular crosstalk and differential cancer aggressiveness, we identified a signature of malignant breast epithelial response to stromal signaling. Proximity to fibroblasts resulted in gene transcript alterations of >2-fold for 107 probes, collectively designated as Fibroblast Triggered Gene Expression in Tumor (FTExT). The hazard ratio predicted by the FTExT classifier for distant relapse in patients with intermediate and high grade breast tumors was significant compared to routine clinical variables (dataset 1, n = 258, HR – 2.11, 95% CI 1.17–3.80, p-value 0.01; dataset 2, n = 171, HR - 3.07, 95% CI 1.21–7.83, p-value 0.01). Biofunctions represented by FTExT included inflammatory signaling, free radical scavenging, cell death, and cell proliferation. Unlike genes of the ‘proliferation cluster’, which are overexpressed in aggressive primary tumors, FTExT genes were uniquely repressed in such cases. As proof of concept for our correlative findings, which link stromal-epithelial crosstalk and tumor behavior, we show a distinctive differential in stromal impact on prognosis-defining functional endpoints of cell cycle progression, and resistance to therapy-induced growth arrest and apoptosis in low vs. high grade cancer cells. Our experimental data thus reveal aspects of ‘paracrine cooperativity’ that are exclusively contingent upon the histopathologically defined grade of interacting tumor epithelium, and demonstrate that epithelial responsiveness to the tumor microenvironment is a deterministic factor underlying clinical outcome. In this light, early attenuation of epithelial-stromal crosstalk could improve the management of cases prone to be clinically challenging.
登录
查看更多内容
DOI：
10.1073/pnas.88.14.6028
发表时间：
1991-07-01
影响因子：
11.1
作者：
CORNIL, I;THEODORESCU, D;KERBEL, RS
通讯作者：
KERBEL, RS
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y
影响因子：
82.9
作者：
通讯作者：
--
影响因子：
6.5
作者：
Micke, Patrick;Kappert, Kai;Ostman, Arne
通讯作者：
Ostman, Arne
影响因子：
64.8
作者：
Karnoub, Antoine E.;Dash, Ajeeta B.;Weinberg, Robert A.
通讯作者：
Weinberg, Robert A.