Apc restoration promotes cellular differentiation and reestablishes crypt homeostasis in colorectal cancer Journal Article
| Authors: | Dow, L. E.; O'Rourke, K. P.; Simon, J.; Tschaharganeh, D. F.; van Es, J. H.; Clevers, H.; Lowe, S. W. |
| Article Title: | Apc restoration promotes cellular differentiation and reestablishes crypt homeostasis in colorectal cancer |
| Abstract: | 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 re-establishment 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. © 2015 Elsevier Inc. |
| Keywords: | controlled study; gene mutation; gene deletion; nonhuman; colorectal cancer; cell proliferation; mouse; animal tissue; gene expression; animal experiment; animal model; cell renewal; in vivo study; cell differentiation; tumor regression; protein p53; carcinogenesis; alkaline phosphatase; cancer regression; cytokeratin 20; invasive carcinoma; gene silencing; doxycycline; k ras protein; small intestine; intestine function; short hairpin rna; apc protein; intestine crypt; wnt; colon adenoma; intestine polyp; polyposis; protein homeostasis; enzyme repression; apc; shrna; wnt signaling pathway; fap; priority journal; article |
| Journal Title: | Cell |
| Volume: | 161 |
| Issue: | 7 |
| ISSN: | 0092-8674 |
| Publisher: | Cell Press |
| Date Published: | 2015-06-18 |
| Start Page: | 1539 |
| End Page: | 1552 |
| Language: | English |
| DOI: | 10.1016/j.cell.2015.05.033 |
| PROVIDER: | scopus |
| PMCID: | PMC4475279 |
| PUBMED: | 26091037 |
| DOI/URL: | |
| Notes: | Export Date: 3 August 2015 -- Source: Scopus |
Altmetric
Citation Impact
BMJ Impact Analytics
MSK Authors
Related MSK Work