Senescent fibroblasts in melanoma initiation and progression: an integrated theoretical, experimental, and clinical approach.
Senescent fibroblasts in melanoma initiation and progression: an integrated theoretical, experimental, and clinical approach.
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DOI：
10.1158/0008-5472.can-13-1720
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发表时间：
2013-12-01
期刊：
影响因子：
11.2
通讯作者：
Anderson AR
中科院分区：
文献类型：
--
作者：
Kim E;Rebecca V;Fedorenko IV;Messina JL;Mathew R;Maria-Engler SS;Basanta D;Smalley KS;Anderson AR
我们提出了一项综合研究，以了解衰老成纤维细胞在推动黑色素瘤进展中的关键作用。基于混合细胞自动机范例，我们开发了一个正常皮肤的计算机模型。该模型侧重于调节角质形成细胞、黑素细胞和成纤维细胞（皮肤的关键成分）之间相互作用的关键细胞和微环境变量。该模型概括了正常的皮肤结构，并足够强大，以承受物理以及生化扰动。此外，该模型预测了皮肤微环境在黑色素瘤发生和发展中的重要作用。我们的体外实验表明，真皮成纤维细胞，这是在皮肤中的生长因子的重要来源，采用分泌表型，促进癌细胞的生长和入侵时，他们变得衰老。我们的共培养实验表明，衰老的成纤维细胞促进了非致瘤性黑素瘤细胞的生长，并增强了晚期黑素瘤细胞的侵袭力。受这些实验结果的启发，我们将衰老的成纤维细胞纳入我们的模型中，并表明衰老的成纤维细胞改变皮肤微环境，随后通过增强正常黑素细胞的生长和侵袭来改变皮肤结构。衰老成纤维细胞和早期黑素瘤细胞之间的相互作用导致黑素瘤的发生和发展。在衰老成纤维细胞产生的微环境因素中，蛋白酶被证明是从我们的模拟中促进黑色素瘤发展的关键促成因素之一。虽然不是直接验证，但我们也观察到人类组织学中黑色素瘤病变附近基质区域的蛋白水解活性增加。这使我们得出结论，衰老的成纤维细胞可能会产生一个促癌皮肤微环境，与突变的黑素细胞合作，推动黑色素瘤的发生和发展，因此应被视为一个潜在的未来治疗靶点。有趣的是，我们的模拟测试了基质靶向治疗的效果，这种治疗可以消除蛋白水解活性的影响，表明这种治疗可以有效地延迟黑色素瘤的发生和进展。
We present an integrated study to understand the key role of senescent fibroblasts in driving melanoma progression. Based on the hybrid cellular automata paradigm we developed an in silico model of normal skin. The model focuses on key cellular and microenvironmental variables that regulate interactions among keratinocytes, melanocytes and fibroblasts, key components of the skin. The model recapitulates normal skin structure, and is robust enough to withstand physical as well as biochemical perturbations. Furthermore, the model predicted the important role of the skin microenvironment in melanoma initiation and progression. Our in vitro experiments showed that dermal fibroblasts, which are an important source of growth factors in the skin, adopt a secretory phenotype that facilitates cancer cell growth and invasion when they become senescent. Our co-culture experiments showed that the senescent fibroblasts promoted the growth of non-tumorigenic melanoma cells and enhanced the invasion of advanced melanoma cells. Motivated by these experimental results, we incorporated senescent fibroblasts into our model and showed that senescent fibroblasts transform the skin microenvironment and subsequently change the skin architecture by enhancing the growth and invasion of normal melanocytes. The interaction between senescent fibroblasts and the early stage melanoma cells leads to melanoma initiation and progression. Of microenvironmental factors that senescent fibroblasts produce, proteases are shown to be one of key contributing factors that promoted melanoma development from our simulations. Although not a direct validation, we also observed increased proteolytic activity in stromal fields adjacent to melanoma lesions in human histology. This leads us to the conclusion that senescent fibroblasts may create a pro-oncogenic skin microenvironment that cooperates with mutant melanocytes to drive melanoma initiation and progression and should therefore be considered as a potential future therapeutic target. Interestingly, our simulations to test the effects of a stroma-targeting therapy that negates the influence of proteolytic activity showed that the treatment could be effective in delaying melanoma initiation and progression.