Evidence for a non-stochastic two-field hypothesis for persistent skin cancer risk.
Evidence for a non-stochastic two-field hypothesis for persistent skin cancer risk.
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DOI：
10.1038/s41598-020-75864-2
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发表时间：
2020-11-05
影响因子：
4.6
通讯作者：
Kim YL
中科院分区：
文献类型：
--
作者：
Konger RL;Ren L;Sahu RP;Derr-Yellin E;Kim YL
随着致癌物的反复暴露，个体肿瘤通过克隆扩张和进化的逐步过程在基因突变的领域中发展。一旦建立，这个“癌症领域”在没有持续接触致癌物质的情况下持续存在，导致癌症发展的持续风险。使用生物成像方法，我们先前证明了在紫外线照射停止后，以炎性血管生成为特征的真皮癌前病变区域持续存在，并准确地预测了未来上覆表皮肿瘤的形成。在紫外线治疗后，其他人观察到P53免疫阳性细胞的斑块随机存在于整个表皮干细胞群体中。然而，这些研究是通过随机活组织检查完成的，引入了抽样偏差。我们现在发现，P53+的表皮细胞不是随机分布的，而是仅在覆盖这个多焦点真皮区域的区域中浓缩。此外，我们还表明真皮场的特征是衰老的表型。我们认为，在没有外源性致癌物或促进剂的情况下，上覆上皮癌化场的持续需要一个由驱动上覆表皮癌变场持续的真皮衰老场组成的双场复合体。这些观察结果挑战了目前的模型，这些模型认为，在没有持续致癌物暴露的情况下，癌症风险的持续只是随机排列、长寿但处于休眠状态的上皮克隆干细胞突变的函数。这里提出的模型可以为停止致癌暴露后癌症风险如何持续提供新的见解。
With recurring carcinogen exposures, individual tumors develop in a field of genetic mutations through a stepwise process of clonal expansion and evolution. Once established, this “cancer field” persists in the absence of continued carcinogen exposures, resulting in a sustained risk for cancer development. Using a bioimaging approach, we previously demonstrated that a dermal premalignant field characterized by inflammatory angiogenesis persists following the cessation of ultraviolet light exposures and accurately predicts future overlying epidermal tumor formation. Following ultraviolet light treatments, others have observed that patches of p53 immunopositive cells persist stochastically throughout the epidermal stem cell population. However, these studies were done by random biopsies, introducing sampling bias. We now show that, rather than being randomly distributed, p53+ epidermal cells are enriched only in areas overlying this multi-focal dermal field. Moreover, we also show that the dermal field is characterized by a senescent phenotype. We propose that persistence of the overlying epithelial cancerization field in the absence of exogenous carcinogens or promoters requires a two-field composite consisting of a dermal senescent field driving the persistence of the overlying epidermal cancer field. These observations challenge current models that suggest that persistence of cancer risk in the absence of continued carcinogen exposures is simply a function of stochastically arranged, long-lived but dormant epithelial clonal stem cells mutants. The model proposed here could provide new insights into how cancer risk persists following cessation of carcinogenic exposures.
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影响因子：
64.8
作者：
Baker DJ;Childs BG;Durik M;Wijers ME;Sieben CJ;Zhong J;Saltness RA;Jeganathan KB;Verzosa GC;Pezeshki A;Khazaie K;Miller JD;van Deursen JM
通讯作者：
van Deursen JM
影响因子：
64.5
作者：
Hu B;Castillo E;Harewood L;Ostano P;Reymond A;Dummer R;Raffoul W;Hoetzenecker W;Hofbauer GF;Dotto GP
通讯作者：
Dotto GP
影响因子：
64.8
作者：
Kang, Tae-Won;Yevsa, Tetyana;Zender, Lars
通讯作者：
Zender, Lars
DOI：
10.1073/pnas.211053698
发表时间：
2001-10-09
影响因子：
11.1
作者：
Krtolica, A;Parrinello, S;Campisi, J
通讯作者：
Campisi, J
影响因子：
21.3
作者：
Procopio MG;Laszlo C;Al Labban D;Kim DE;Bordignon P;Jo SH;Goruppi S;Menietti E;Ostano P;Ala U;Provero P;Hoetzenecker W;Neel V;Kilarski WW;Swartz MA;Brisken C;Lefort K;Dotto GP
通讯作者：
Dotto GP