| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
From the Department of Pathology,* University of Southern California Keck School of Medicine, Los Angeles; and the Department of Biological Sciences, Program in Molecular and Computational Biology, University of Southern California, Los Angeles, California
Individuals with heterozygous germline adenomatous polyposis coli (APC) mutations or familial adenomatous polyposis (FAP) are born with normal appearing colons but later develop hundreds to thousands of polyps. Tumor progression apparently starts after somatic loss of the normal APC allele, but germline APC mutations may potentially alter niche stem cell survival through dominant-negative interactions or haploinsufficiency. Although morphologically occult, altered stem cell turnover or clonal evolution rates may be detected by measuring the diversity of crypt sequences, with greater diversity expected with longer lived stem cell lineages. Methylation pattern diversity (numbers of unique patterns per crypt) was higher in normal appearing crypts from four of five FAP colons compared to six non-FAP colons and one attenuated FAP colon. Simulations indicate higher FAP crypt diversity is consistent with slower clonal evolution from enhanced stem cell survival, either through increased stem cell numbers or decreased stem cell lineage extinction, which is predicted to increase progression rates to cancer. Enhanced stem cell survival was associated with APC mutations that remove some but not all catenin-binding repeats. Therefore, some APC mutations may be common in colorectal cancers because they confer occult pretumor "caretaker" and "gatekeeper" defects. FAP crypts accumulate more alterations from slower stem cell clonal evolution rather than increased error rates. In non-FAP crypts, enhanced stem cell survival conferred by somatic heterozygous APC mutations would favor fixation through occult clonal niche expansions. Heterozygous APC mutations may change stem cell survival during colorectal pretumor progression.
This article has been cited by other articles:
 |
|
 |
|
  B. M. Boman and E. Huang Human Colon Cancer Stem Cells: A New Paradigm in Gastrointestinal Oncology J. Clin. Oncol., June 10, 2008; 26(17): 2828 - 2838. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. M. Boman, J. Z. Fields, K. L. Cavanaugh, A. Guetter, and O. A. Runquist How Dysregulated Colonic Crypt Dynamics Cause Stem Cell Overpopulation and Initiate Colon Cancer Cancer Res., May 1, 2008; 68(9): 3304 - 3313. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W W J de Leng, M Jansen, J J Keller, M de Gijsel, A N A Milne, F H M Morsink, M A J Weterman, C A Iacobuzio-Donahue, H C Clevers, F M Giardiello, et al. Peutz Jeghers syndrome polyps are polyclonal with expanded progenitor cell compartment Gut, October 1, 2007; 56(10): 1475 - 1476. [Full Text] [PDF]
|
|
|
|
 |
|
 F. F. Costa, K. Le Blanc, and B. Brodin Concise Review: Cancer/Testis Antigens, Stem Cells, and Cancer Stem Cells, March 1, 2007; 25(3): 707 - 711. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. A. Woodward, M. S. Chen, F. Behbod, M. P. Alfaro, T. A. Buchholz, and J. M. Rosen WNT/beta-catenin mediates radiation resistance of mouse mammary progenitor cells PNAS, January 9, 2007; 104(2): 618 - 623. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. M. McCartney, M. H. Price, R. L. Webb, M. A. Hayden, L. M. Holot, M. Zhou, A. Bejsovec, and M. Peifer Testing hypotheses for the functions of APC family proteins using null and truncation alleles in Drosophila Development, June 15, 2006; 133(12): 2407 - 2418. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. K. Roy, Y. L. Kim, Y. Liu, R. K. Wali, M. J. Goldberg, V. Turzhitsky, J. Horwitz, and V. Backman Risk Stratification of Colon Carcinogenesis through Enhanced Backscattering Spectroscopy Analysis of the Uninvolved Colonic Mucosa Clin. Cancer Res., February 1, 2006; 12(3): 961 - 968. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Zhu, X. Zhong, S. Zheng, Z. Ge, Q. Du, and S. Zhang Transformation of immortalized colorectal crypt cells by microcystin involving constitutive activation of Akt and MAPK cascade Carcinogenesis, July 1, 2005; 26(7): 1207 - 1214. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Calabrese, S. Tavare, and D. Shibata Pretumor Progression: Clonal Evolution of Human Stem Cell Populations Am. J. Pathol., April 1, 2004; 164(4): 1337 - 1346. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Calabrese, J.-L. Tsao, Y. Yatabe, R. Salovaara, J.-P. Mecklin, H. J. Jarvinen, L. A. Aaltonen, S. Tavare, and D. Shibata Colorectal Pretumor Progression Before and After Loss of DNA Mismatch Repair Am. J. Pathol., April 1, 2004; 164(4): 1447 - 1453. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
