Apc Restoration Promotes Cellular Differentiation and Reestablishes Crypt Homeostasis in Colorectal Cancer

被引：497

作者：

Dow, Lukas E. ^{[1
]}

O'Rourke, Kevin P. ^{[1
,2
]}

Simon, Janelle ^{[1
]}

Tschaharganeh, Darjus F. ^{[1
]}

van Es, Johan H. ^{[3
,4
]}

Clevers, Hans ^{[3
,4
]}

Lowe, Scott W. ^{[1
,5
]}

机构：

[1] Mem Sloan Kettering Canc Ctr, Canc Biol & Genet Program, New York, NY 10065 USA

[2] Weill Cornell Rockefeller Sloan Kettering Tri Ins, New York, NY 10065 USA

[3] Hubrecht Inst Dev Biol & Stem Cell Res, NL-3584 CT Utrecht, Netherlands

[4] Univ Med Ctr Utrecht, NL-3584 CT Utrecht, Netherlands

[5] Mem Sloan Kettering Canc Ctr, Howard Hughes Med Inst, New York, NY 10065 USA

来源：

CELL | 2015年 / 161卷 / 07期

基金：

英国医学研究理事会;

关键词：

MULTIPLE INTESTINAL NEOPLASIA; STEM-CELLS; TUMOR DORMANCY; ADENOMATOUS POLYPOSIS; WNT/BETA-CATENIN; MOUSE MODEL; HUMAN COLON; WNT; PROGRESSION; MUTATION;

D O I：

10.1016/j.cell.2015.05.033

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

The adenomatous polyposis coli (APC) tumor suppressor is mutated in the vast majority of human colorectal cancers (CRC) and leads to deregulated Wnt signaling. To determine whether Apc disruption is required for tumor maintenance, we developed a mouse model of CRC whereby Apc can be conditionally suppressed using a doxycycline-regulated shRNA. Apc suppression produces adenomas in both the small intestine and colon that, in the presence of Kras and p53 mutations, can progress to invasive carcinoma. In established tumors, Apc restoration drives rapid and widespread tumor-cell differentiation and sustained regression without relapse. Tumor regression is accompanied by the reestablishment of normal crypt-villus homeostasis, such that once aberrantly proliferating cells reacquire self-renewal and multi-lineage differentiation capability. Our study reveals that CRC cells can revert to functioning normal cells given appropriate signals and provide compelling in vivo validation of the Wnt pathway as a therapeutic target for treatment of CRC.

引用

页码：1539 / 1552

页数：14

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