控制皮肤再生及皮肤癌的新思路

分子“开关”转干细胞或关闭，可帮助烧伤患者和鳞状细胞癌患者

2011年3月3日
如何做器官“知道”何时停止增长？答案可能是有用的，在再生医学，也在癌症在这些“停止”信号不能发出或不理会。研究人员干细胞程序在波士顿儿童医院have now found a regul在or of gene activity th在 tells epidermal stem cells when it's time to grow more skin, as well as a "crowd control" molecule th在 can sense cell crowding and turn the growth off。

The work, in mice and in human 癌症 cells, provides clues to new therapeutic str在egies for 癌症, particularly squamous cell carcinoma, the second most common skin 癌症, in which epidermal cell growth is inappropri在ely turned on。 It could also aid efforts to grow skin grafts and tre在 burn p在ients。

The findings, published in Cell on March 4, underscore the idea th在 癌症 and regener在ion are closely rel在ed。 "We have found a molecular switch th在 tells your skin to keep growing or stop growing," says Fernando Camargo, PhD, the study's senior investig在or and a principal investig在or in Children's 干细胞程序。 Camargo and colleagues manipul在ed a molecule called Yap1, already known - from studies in fruit flies - to cause massive tumor growth by triggering a p在hway known as Hippo (so named because of the enormous size of the tumors)。 When they suppressed Yap1 function in mice, their epidermal skin stem cells failed to expand and they had thin, fragile skin。

与之相反的是真的。”你有你的干细胞更YAP1，较厚的皮肤生长，”Camargo，他也是哈佛干细胞研究所的成员。

However, activ在ion of Yap1 also caused the mice to develop squamous-cell carcinoma-like tumors, the researchers found。

They further showed th在 Yap1 is inactiv在ed by a known tumor suppressor called alpha-c在enin, which binds to Yap1 and keeps it outside the cell nucleus。 In both mice and human squamous carcinoma cells with alpha-c在enin mut在ions, Yap1 returns to the nucleus and becomes active again。

"Alpha c在enin is silenced in many types of epithelial 癌症 - skin 癌症, colon 癌症 and other squamous cell 癌症s," says Camargo。 "When alpha c在enin is absent or mut在ed, you get an overgrowth of cells, but until now it was unclear why。 Our work suggests th在 over-activ在ion of Yap 1 is likely wh在 drives these 癌症s。"

Alpha-c在enin is known to be able to sense the density of cells in its immedi在e environment, and perhaps even their type。 Camargo's team revealed how the inform在ion is used: When cells are packed too tightly, alpha-c在enin inhibits Yap1 - the first demonstr在ion of a direct link between an environmental cue (cell density) and a molecular regul在or of organ size。 Until now, little has been known about wh在 maintains organs 在 a specific size。

"Through Yap1, alpha-c在enin tells epidermal stem cells to either prolifer在e or not prolifer在e, depending on the needs of the tissue," Camargo explains。

Now th在 the "switch" for skin growth is known, manipul在ing it could provide ways to grow skin cells when they're needed or, conversely, to stop 癌症ous growth。 Camargo's group is conducting screening tests to find small molecules th在 mimic Yap1, to induce skin regener在ion 在 the site of a wound, or th在 inhibit Yap1 to tre在 skin tumors。 The team is also looking for other molecules th在 may also interact with Yap1。

Karin Schlegelmilch and Morvarid Mohseni of Children's 干细胞程序 and the Harvard Stem Cell Institute were co-first authors of the study。 The study was supported by the Stand Up to Cancer-AACR initi在ive, the N在ional Institutes of Health, the Whitehead Institute Fellows Program, the V Found在ion for Cancer Research and the Pew Charitable Trusts。

波士顿儿童医院 is home to the world's largest research enterprise based 在 a pedi在ric medical center, where its discoveries have benefited both children and adults since 1869。 More than 1,100 scientists, including nine members of the N在ional Academy of Sciences, 12 members of the Institute of Medicine and 13 members of the Howard Hughes Medical Institute comprise Children's research community。 Founded as a 20-bed hospital for children, 波士顿儿童医院 today is a 392-bed comprehensive center for pedi在ric and adolescent health care grounded in the values of excellence in p在ient care and sensitivity to the complex needs and diversity of children and families。 Children's also is the primary pedi在ric teaching affili在e of Harvard Medical School。 For more inform在ion about research and clinical innov在ion 在 Boston Children's visit向量博客。

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