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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Identifying the cellular origin of squamous skin tumors
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Identifying the cellular origin of squamous skin tumors

机译：确定鳞状皮肤肿瘤的细胞起源

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摘要

Squamous cell carcinoma (SCC) is the second most frequent skin cancer. The cellular origin of SCC remains controversial. Here, we used mouse genetics to determine the epidermal cell lineages at the origin of SCC. Using mice conditionally expressing a constitu-tively active KRas mutant (G12D) and an inducible CRE recombi-nase in different epidermal lineages, we activated Ras signaling in different cellular compartments of the skin epidermis and determined from which epidermal compartments Ras activation induces squamous tumor formation. Expression of mutant KRas in hair follicle bulge stem cells (SCs) and their immediate progeny (hair germ and outer root sheath), but not in their transient amplifying matrix cells, led to benign squamous skin tumor (papilloma). Expression of KRas~(G12D) in interfollicular epidermis also led to papilloma formation, demonstrating that squamous tumor initiation is not restricted to the hair follicle lineages. Whereas no malignant tumor was observed after KRas~(G12D) expression alone, expression of KRas~(G12D) combined with the loss of p53 induced invasive SCC. Our studies demonstrate that different epidermal lineages including bulge SC are competent to initiate papilloma formation and that multiple genetic hits in the context of oncogenic KRas are required for the development of invasive SCC.
机译：鳞状细胞癌（SCC）是第二常见的皮肤癌。 SCC的细胞起源仍然有争议。在这里，我们使用小鼠遗传学来确定SCC起源处的表皮细胞谱系。使用在不同表皮谱系中条件表达组成性活性KRas突变体（G12D）和可诱导的CRE重组酶的小鼠，我们激活了皮肤表皮不同细胞区室中的Ras信号传导，并确定了Ras激活从哪个表皮区室中诱导了鳞状肿瘤的形成。突变型KRas在毛囊隆突干细胞（SCs）及其直接后代（毛发胚和外根鞘）中表达，但在其瞬时扩增基质细胞中不表达，导致良性鳞状皮肤肿瘤（papilloma）。 KRas〜（G12D）在小泡间表皮中的表达也导致乳头状瘤的形成，表明鳞状肿瘤的起始并不局限于毛囊谱系。单独表达KRas〜（G12D）后未观察到恶性肿瘤，而表达KRas〜（G12D）与p53诱导的侵袭性SCC的丧失相结合。我们的研究表明，不同的表皮谱系（包括膨大的SC）都可以引发乳头瘤的形成，并且在致癌性KRas的背景下，多种遗传学突变是侵袭性SCC形成所必需的。

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  • 作者

    Gaelle Lapouge; Khalil Kass Youssef; Benoit Vokaer; Younes Achouri; Cindy Michaux; Panagiota A. Sotiropouloi; Cedric Blanpain;

  • 作者单位

    Institut de Recherche Interdisciplinaire en Biologie Humaine et Moleculaire, Universite Libre de Bruxelles, B-1070 Brussels, Belgium;

    Institut de Recherche Interdisciplinaire en Biologie Humaine et Moleculaire, Universite Libre de Bruxelles, B-1070 Brussels, Belgium;

    lnstitut d'lmmunologi Medicale, Universite Libre de Bruxelles, B-6041 Charleroi, Belgium;

    Universite Catholique de Louvain de Duve Institute, B-1200 Brussels, Belgium;

    Institut de Recherche Interdisciplinaire en Biologie Humaine et Moleculaire, Universite Libre de Bruxelles, B-1070 Brussels, Belgium;

    Institut de Recherche Interdisciplinaire en Biologie Humaine et Moleculaire, Universite Libre de Bruxelles, B-1070 Brussels, Belgium;

    Institut de Recherche Interdisciplinaire en Biologie Humaine et Moleculaire, Universite Libre de Bruxelles, B-1070 Brussels, Belgium;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
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  • 关键词

    cancer cell of origin; hair follicle stem cells;

    机译：起源的癌细胞;毛囊干细胞;

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