Stromal responses among carcinomas--response.
Stromal responses among carcinomas--response.
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癌症间的基质反应——反应。
DOI：
10.1158/1078-0432.ccr-13-3238
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发表时间：
2014
期刊：
影响因子：
--
通讯作者：
Chen,JuliaL
中科院分区：
文献类型：
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作者：
West,RobertB;vandeRijn,Matt;Chen,JuliaL
我们感谢作者对我们关于基质信号的临床相关性的研究感兴趣(1)。我们很高兴地看到，自从我们在2005年的出版物(2)中描述了间质签名的临床变异以来，由基因表达谱所定义的间质签名领域在癌症中是如何增长的。随后，其他人发现了这种韧带样型纤维瘤病(DTF)特征的轻微差异，这些差异似乎可归因于每个实验室使用的平台(3，4)。Triulzi和他的同事提出了一种可能性，即乳腺癌和卵巢癌的DTF签名与预后的不同相关性可能是由于分期，因为通常情况下，当发现时，乳腺癌的分期可能低于卵巢。我们之前的一项研究的数据似乎并不支持这一点。我们之前已经观察了乳腺癌DTF信号与分期的相关性。在我们2008年的研究中(5)，通过基因表达谱分析和免疫组织化学方法观察了561例乳腺癌病例和745例乳腺癌病例，我们发现DTF签名的存在与乳腺癌的分期之间没有统计学意义上的差异。然而，我们同意现有的预后预测指标(或传统的临床病理特征)对间质信号有相反的影响。例如，在我们2009年的CCR文章(6)中，我们证明了我们描述的结肠刺激因子1(CSF1)巨噬细胞特征与已知的预测不良预后的特征(高级别、ER/PR阴性、P53突变状态)相关。然而，当我们将分析局限于雌激素受体(ER)阴性的癌症时，有一种趋势是CSF1签名与提高存活率相关。这些发现与越来越多的基因组证据相一致，表明一个器官系统中有许多可重复发生的癌症亚型，如果将所有病例放在一起研究，任何一种特征，如ER状态或间质信号，都可能与良好的结果相关，但如果只检查特定的亚型，也可能与不良结果相关。例如，ER阳性通常与良好的预后相关，当观察患者存活超过10年的病例时，HR大于1(7)。虽然肿瘤亚型在间质信号上的差异是有趣的和临床相关的，但我们认为这些信号的潜在生物学最终更重要，甚至更重要，因为我们现在已经表明，DTF信号存在于许多不同类型的癌症中。最终，我们认为这些信号对于它们在识别新的治疗靶点和了解癌症病因方面对癌症的潜在影响是重要的。后一点显然很重要，正如我们在2009年对导管原位癌的研究(8)中显示的那样，DTF征象出现在癌的侵袭前期，这表明间质征象早在肿瘤侵入间质之前就出现了。这一发现提出了DTF间质信号在癌症发生中发挥作用的可能性。其他有模型系统的人已经证明，改变间质基因的表达可以诱导肿瘤发生。DTF信号在癌症早期(侵袭前)和晚期(至少在乳房，可能在其他方面)的存在表明，间质在癌症生物学中具有基础作用。我们认为我们都同意间质信号与临床相关，是确定癌症治疗目标和预防策略目标的有前途的研究领域。
We thank the authors for their interest in our study on the clinical relevance of stromal signatures (1). We have been delighted to see how the field of stromal signatures, as defined by gene expression profiling, in cancer has grown since our description of clinical variation in stromal signatures in our 2005 publication (2). Others, subsequently, have identified slight variations on this desmoid type fibromatosis (DTF) signature, and the differences seem attributable to the platforms used by each laboratory (3, 4). Triulzi and colleagues raise the possibility that the different correlation with outcome seen for the DTF signature in breast versus ovarian carcinoma may be due to stage, as in general, breast may be lower stage than ovarian, when discovered. Data from one of our prior studies do not seem to support that. We have previously looked at the correlation of the DTF signatures in breast cancer with stage. In our study in 2008 (5), looking at 561 breast cancer cases by gene expression profiling and 745 cases by immunohistochemistry, we found no statistically significant difference between the presence of the DTF signature and the stage of the breast cancer. However, we agree that existing outcome predictors (or traditional clinicopathologic features) can have opposite effects with regard to stromal signatures. For example, in our 2009 CCR article (6), we demonstrated that the colonystimulating factor 1 (CSF1) macrophage signature that we described had a correlation with features known to predict poor outcome (high grade, ER/PR negativity, p53 mutation status). However, when we restricted the analysis to estrogen receptor (ER)–negative cancers, there was a trend for the CSF1 signature to correlate with improved survival. These findings are consistent with the growing large body of genomic evidence to suggest that there are many reproducible subtypes of cancer within an organ system and that any one feature, like ER status or stromal signature, may correlate with good outcome if all cases are studied together, but may also correlate with bad outcome if only a specific subtypes is examined. For example, ER positivity that is generally associated with good outcome has a HR greater than 1 when looking at cases with patient survival over 10 years (7). Although the findings of tumor subtype differences in stromal signatures are interesting and clinically relevant, we think that the underlying biology of these signatures is ultimately more significant and even more so as we have now shown that the DTF signature is present in many different types of cancer. Ultimately, we think that these signatures are important for their potential impact on cancer in terms of identifying new therapeutic targets and understanding cancer etiology. The latter point is clearly important as we have shown in our 2009 study of ductal carcinoma in situ (8) that the DTF signature is present in preinvasive stages of cancer, suggesting that stromal signatures arise well before the neoplasia invades into the stromal. This finding raises the possibility that the DTF stromal signature plays a role in carcinogenesis. Others with model systems have demonstrated that altering stroma gene expression can induce neoplasia. The presence of the DTF signature at early (preinvasive) and late stages of cancer (at least in breast, possibility others) suggests that there is a fundamental role of the stroma in cancer biology. We think we can all agree that stromal signatures are clinically relevant and are promising areas of research to identify cancer treatment targets and targets for prevention strategies.