Center for Computational Biology and Bioinformatics and Department of Electrical Engineering, Columbia University, New York, NY, USA.
BMC Med Genomics. 2010 Nov 3;3:51. doi: 10.1186/1755-8794-3-51.
Despite extensive research, the details of the biological mechanisms by which cancer cells acquire motility and invasiveness are largely unknown. This study identifies an invasion associated gene signature shedding light on these mechanisms.
We analyze data from multiple cancers using a novel computational method identifying sets of genes whose coordinated overexpression indicates the presence of a particular phenotype, in this case high-stage cancer.
We conclude that there is one shared "core" metastasis-associated gene expression signature corresponding to a specific variant of stromal desmoplastic reaction, present in a large subset of samples that have exceeded a threshold of invasive transition specific to each cancer, indicating that the corresponding biological mechanism is triggered at that point. For example this threshold is reached at stage IIIc in ovarian cancer and at stage II in colorectal cancer. Therefore, its presence indicates that the corresponding stage has been reached. It has several features, such as coordinated overexpression of particular collagens, mainly COL11A1 and other genes, mainly THBS2 and INHBA. The composition of the overexpressed genes indicates invasion-facilitating altered proteolysis in the extracellular matrix. The prominent presence in the signature of INHBA in all cancers strongly suggests a biological mechanism centered on activin A induced TGF-β signaling, because activin A is a member of the TGF-β superfamily consisting of an INHBA homodimer. Furthermore, we establish that the signature is predictive of neoadjuvant therapy response in at least one breast cancer data set.
Therefore, these results can be used for developing high specificity biomarkers sensing cancer invasion and predicting response to neoadjuvant therapy, as well as potential multi-cancer metastasis inhibiting therapeutics targeting the corresponding biological mechanism.
尽管进行了广泛的研究，但癌细胞获得运动性和侵袭性的生物学机制的细节在很大程度上仍不清楚。本研究确定了一个与侵袭相关的基因特征，揭示了这些机制。
我们使用一种新的计算方法分析了来自多种癌症的数据，该方法确定了一组基因的集合，这些基因的协调过表达表明存在特定表型，在这种情况下为高阶段癌症。
我们得出的结论是，存在一个共享的“核心”转移相关基因表达特征，对应于特定变体的基质纤维母细胞反应，存在于大量超过每个癌症特有的侵袭性过渡阈值的样本中，表明相应的生物学机制在该点被触发。例如，在卵巢癌中，该阈值在 IIIc 期达到，在结直肠癌中在 II 期达到。因此，其存在表明相应的阶段已经达到。它具有几个特征，例如特定胶原蛋白的协调过表达，主要是 COL11A1 和其他基因，主要是 THBS2 和 INHBA。过表达基因的组成表明细胞外基质中促进侵袭的改变性蛋白水解。该签名中 INHBA 的突出存在强烈表明了一种以激活素 A 诱导的 TGF-β信号为中心的生物学机制，因为激活素 A 是 TGF-β超家族的成员，由 INHBA 同源二聚体组成。此外，我们确定该特征可预测至少一个乳腺癌数据集的新辅助治疗反应。
因此，这些结果可用于开发用于检测癌症侵袭并预测新辅助治疗反应的高特异性生物标志物，以及针对相应生物学机制的潜在多癌症转移抑制治疗。
