APC dosage effects in tumorigenesis and stem cell differentiation
APC dosage effects in tumorigenesis and stem cell differentiation
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DOI：
10.1387/ijdb.041807cg
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发表时间：
2004-01-01
影响因子：
0.7
通讯作者：
Fodde, R
中科院分区：
文献类型：
--
作者：
Gaspar, C;Fodde, R
众所周知，在发育中的动物中，信号分子(所谓的“形态因子”)的浓度梯度是组织和图案形成的。特别是，对果蝇和不同脊椎动物的研究表明，WNT、Hedgehog(HH)和转化生长因子-β(TGF-β)家族的梯度在肢体模式中起着关键作用。形态原通常在组织中心表达，可以在很长的范围内发挥作用，协调整个细胞领域的图案化。这些观察结果表明，暴露于不同浓度的这些扩散因子可能会引发不同的细胞反应。为了研究这些剂量依赖的Wnt/β-catenin信号转导效应，我们在小鼠APC基因座产生了几个亚型突变等位基因，并研究了它们在干细胞更新和分化以及肿瘤发生中的细胞和表型结果。结果清楚地表明，APC突变以剂量依赖的方式不同地影响干细胞的分化能力。同样，不同的APC突变(以及相应的Wnt信号剂量)在相应的小鼠模型中对肿瘤发生的易感性不同。这些结果对于理解Wnt通路缺陷引发肿瘤的分子和细胞基础具有重要意义。我们提出了一个模型，在该模型中，成体干细胞以组织特异性的β-连环蛋白水平为特征，以细胞增殖、分化和凋亡的阈值水平为特征。不同的APC突变会导致不同水平的β-连环蛋白信号转导，从而赋予不同组织不同程度的肿瘤易感性。因此，β-连环蛋白的剂量依赖效应不仅可能解释单一途径如何参与不同组织的发育和动态平衡，而且可能解释其在肿瘤发生中的多营养作用。
It is well established that concentration gradients of signaling molecules (the so-called "morphogens") organize and pattern tissues in developing animals. In particular, studies in Drosophila and different vertebrates have shown that gradients of the Wnt, Hedgehog (Hh) and transforming growth factor-beta (TGF-beta) families of morphogens play critical roles in limb patterning. Morphogens are often expressed in organizing centres and can act over a long range to coordinate the patterning of an entire field of cells. These observations imply that exposure to different concentrations of these diffusible factors may trigger differential cellular responses. In order to study these dosage-dependent Wnt/beta-catenin signaling effects, we have generated several hypomorphic mutant alleles at the mouse Apc locus and studied their cellular and phenotypic outcomes in stem cell renewal and differentiation, and in tumorigenesis. The results clearly show that Apc mutations differentially affect the capacity of stem cells to differentiate in a dosage-dependent fashion. Likewise, different Apc mutations (and the corresponding Wnt signaling dosages) confer different degrees of susceptibility to tumorigenesis in the corresponding mouse models. These results have implications for the understanding of the molecular and cellular basis of tumor initiation by defects in the Wnt pathway. We propose a model in which adult somatic stem cell compartments are characterized by tissue-speciffic beta-catenin threshold levels for cell proliferation, differentiation and apoptosis. Different APC mutations will result in different levels of beta-catenin signaling, thus conferring different degrees of tumor susceptibility in different tissues. Hence, beta-catenin dosage - dependent effects may not only explain how a single pathway is involved in the development and homeostasis of different tissues, but also its pleiotrophic role in tumorigenesis.