Multi-cancer computational analysis reveals invasion-associated variant of desmoplastic reaction involving INHBA, THBS2 and COL11A1.
Multi-cancer computational analysis reveals invasion-associated variant of desmoplastic reaction involving INHBA, THBS2 and COL11A1.
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DOI：
10.1186/1755-8794-3-51
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发表时间：
2010-11-03
影响因子：
2.7
通讯作者：
Anastassiou D
中科院分区：
文献类型：
--
作者：
Kim H;Watkinson J;Varadan V;Anastassiou D
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是未知的。这项研究确定了一种与入侵相关的基因特征，揭示了这些机制。我们使用一种新的计算方法来分析来自多种癌症的数据，该方法确定了一组基因，这些基因的协调过表达表明存在一种特定的表型，在这种情况下是晚期癌症。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，对应于基质结缔组织增生反应的特定变体，存在于超过每种癌症特异性侵袭性转移阈值的大量样本中，表明相应的生物学机制在该点被触发。例如，这个阈值在卵巢癌的IIIc期和结直肠癌的II期达到。因此，它的存在表明已经达到了相应的阶段。它有几个特点，如协调过表达特定的胶原，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侵袭促进了细胞外基质中蛋白水解的改变。在所有癌症中，INHBA信号的显著存在强烈提示以激活素a诱导TGF-β信号传导为中心的生物学机制，因为激活素a是由INHBA同型二聚体组成的TGF-β超家族的成员。此外，我们在至少一个乳腺癌数据集中确定了该特征可以预测新辅助治疗的反应。因此，这些结果可用于开发高特异性的生物标志物，用于检测癌症侵袭和预测对新辅助治疗的反应，以及针对相应生物学机制的潜在多癌转移抑制治疗。
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.
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影响因子：
--
作者：
Schmalbach, CE;Chepeha, DB;Hanash, S
通讯作者：
Hanash, S
DOI：
10.1111/j.1749-6632.2008.03757.x
发表时间：
2009-01-01
期刊：
CHALLENGES OF SYSTEMS BIOLOGY: COMMUNITY EFFORTS TO HARNESS BIOLOGICAL COMPLEXITY
影响因子：
--
作者：
Watkinson, John;Liang, Kuo-ching;Anastassiou, Dimitris
通讯作者：
Anastassiou, Dimitris
影响因子：
4
作者：
Stover, Daniel G.;Bierie, Brian;Moses, Harold L.
通讯作者：
Moses, Harold L.
影响因子：
9.8
作者：
Bignotti, Eliana;Tassi, Renata A.;Santin, Alessandro D.
通讯作者：
Santin, Alessandro D.
影响因子：
82.9
作者：
Farmer, Pierre;Bonnefoi, Herve;Delorenzi, Mauro
通讯作者：
Delorenzi, Mauro