Latent Time (Quiescence) Properties of Human Colonic Crypt Cells : Mechanistic Relationships to Colon Cancer Development by Olaf A Runquist in BJSTR
Abstract
Objectives : To determine latent time (quiescence) properties of human colonic crypt cells and explores relationships between these
properties and Colorectal Cancer (CRC) development.
Methods : Quantitative methods were developed to calculate
latent time1 (latenzzeit) of colonic cells at each position along the
crypt
axis and to evaluate available data on total cell cycle times for human
normal, familial adenomatous polyposis (FAP), and adenomatous crypts.
Results : Our analysis of normal colonic data revealed that
latenzzeit decreases from crypt base to top. Moreover, alogarithmic plot
of
latenzzeit versus crypt position was non-linear, but was equal to sum of
three lines showing that latenzzeit has three components (slow,
medium fast). A similar plot of FAP data was on linear and equal to sum
of three lines, but slopes and intercepts were not equal to results for
normal crypts. A logarithmic plot of adenomatous crypt data was linear
showing loss of two latenzzeit components (slow & fast) and
retention
of one (medium) component.
Conclusions : Our data indicate that, in normal crypts,
latenzzeit is regulated by three sequential, first order kinetic
processes. Quantifying
latenzzeit in neo-plastic crypts provides a measure of the effects of
APC mutations in CRC development. In FAP crypts, heterozygous APC
mutation modifies latenzzeit by affecting all three kinetic processes.
In adenomatous crypts, homozygous mutant APC modifies latenzzeit
through loss of two and modification of the third process.
Latenzzeit also explains control of total cell cycle time. In normal
crypts, the decrease in total cell cycle time along the crypt axis can
be
attributed to decrease in latenzzeit from crypt base to top. In
neo-plastic crypts, changes in latenzzeit explain progressive
lengthening of
the total cell cycle time along the axes of FAP and adenomatous crypts.
Thus, latenzzeit regulatory mechanisms appear essential for crypt
maintenance and, when altered, contribute to development of CRC.
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