Not All Wnt Activation Is Equal: Ligand-Dependent versus Ligand-Independent Wnt Activation in Colorectal Cancer.
Not All Wnt Activation Is Equal: Ligand-Dependent versus Ligand-Independent Wnt Activation in Colorectal Cancer.
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DOI：
10.3390/cancers12113355
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发表时间：
2020-11-13
期刊：
影响因子：
5.2
通讯作者：
Leedham SJ
中科院分区：
文献类型：
--
作者：
Kleeman SO;Leedham SJ
结直肠癌是癌症相关死亡的第三大常见原因。大多数结直肠癌患者的 Wnt 信号通路由基因突变激活。已经描述了许多不同类型的 Wnt 通路突变：一些突变增加了肿瘤细胞对基质细胞产生的 Wnt 配体的敏感性（配体依赖性），而另一些则驱动通路的下游激活（配体非依赖性）。配体依赖性肿瘤特别令人感兴趣，因为有许多新兴的治疗选择，例如豪猪抑制剂，可以专门针对这些肿瘤。在这篇综述中，我们讨论了关于这些不同类型的 Wnt 激活突变的已知信息。我们建议，配体依赖性肿瘤应被视为结直肠癌的一个单独的子集，具有自己的生物标志物、预后和靶向治疗。 Wnt 信号传导在结直肠肿瘤中普遍被激活，并且在 APC、CTNNB1、RNF43 和 R-spondin (RSPO2/3) 等基因中发现了驱动突变。腺瘤性大肠杆菌 (APC) 和 CTNNB1 突变导致下游组成型激活（配体无关），而 RNF43 和 RSPO 突变需要外源 Wnt 配体来激活信号传导（配体依赖）。在这里，我们提供的证据表明这些突变并不等同，并且配体依赖性和配体非依赖性肿瘤在潜在的 Wnt 生物学、分子发病机制、形态和预后方面存在差异。这些不重叠的特征可用于开发配体依赖性肿瘤的生物标志物和靶向治疗，包括豪猪抑制剂、抗 RSPO3 抗体和天冬酰胺酶。越来越多的证据表明，这些疗法可能与配体依赖性肿瘤的免疫疗法产生协同作用。总之，我们认为配体依赖性肿瘤是结直肠癌中一个未被充分认识的独立疾病实体。
Colorectal cancer is the third most common cause of cancer-related deaths. The Wnt signaling pathway is activated by genetic mutations in most patients with colorectal cancer. A number of different types of Wnt pathway mutation have been described: some increase the sensitivity of tumor cells to Wnt ligands produced by stromal cells (ligand-dependent), while others drive downstream activation of the pathway (ligand-independent). Ligand-dependent tumors are of particular interest as there are a number of emerging treatment options, such as porcupine inhibitors, that can specifically target these tumors. In this review, we discuss what is known about these different types of Wnt activating mutations. We propose that ligand-dependent tumors should be viewed as a separate subset of colorectal cancer with its own biomarkers, prognosis and targeted therapies. Wnt signaling is ubiquitously activated in colorectal tumors and driver mutations are identified in genes such as APC, CTNNB1, RNF43 and R-spondin (RSPO2/3). Adenomatous polyposis coli (APC) and CTNNB1 mutations lead to downstream constitutive activation (ligand-independent), while RNF43 and RSPO mutations require exogenous Wnt ligand to activate signaling (ligand-dependent). Here, we present evidence that these mutations are not equivalent and that ligand-dependent and ligand-independent tumors differ in terms of underlying Wnt biology, molecular pathogenesis, morphology and prognosis. These non-overlapping characteristics can be harnessed to develop biomarkers and targeted treatments for ligand-dependent tumors, including porcupine inhibitors, anti-RSPO3 antibodies and asparaginase. There is emerging evidence that these therapies may synergize with immunotherapy in ligand-dependent tumors. In summary, we propose that ligand-dependent tumors are an underappreciated separate disease entity in colorectal cancer.
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影响因子：
56.9
作者：
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通讯作者：
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影响因子：
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作者：
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DOI：
10.1530/joe-18-0153
发表时间：
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期刊：
The Journal of endocrinology
影响因子：
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7.5
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Hoey T