Latent Time (Quiescence) Properties of Human Colonic Crypt Cells : Mechanistic Relationships to Colon Cancer Development

Olaf A Runquist¹*, Rachel Mazac¹, John Roerig¹ and Bruce M Boman²

Received: September 12, 2017;   Published: September 22, 2017

DOI: 10.26717/BJSTR.2017.01.000386

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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.

Keywords : Latent time; Quiescence; Latenzzeit; Colon cancer; Familial adenomatous polyposis; Cell Cycle

Abbreviations : “i” = crypt cell position expressed as fraction along crypt axis (relative to total crypt length); ADA = adenomatous crypts; APC = adenomatous polyposis gene; AUC = area under the curve; CRC = colorectal cancer; FAP = familial adenomatous polyposis; FP = fraction of proliferative cells; F_Pⁱ = fraction of proliferative cells at each “i”; F_PR ⁱ ADA = fraction of proliferative cells at each “i” for ADA crypts; FF_PR ⁱ FAP =fraction of proliferative cells at each “i” for FAP crypts; FF_PR ⁱ NOR = fraction of proliferative cells at each “i” for NOR crypts; F_s = fraction of cells being in S-phase; F_s i = fraction of S cells at each “i”; L(z-a)ⁱ FAP = set of values for Lzⁱ FAP minus “a-line” values – designated “b” line FAP; L(z-a) ⁱ NOR = set of values for Lzⁱ NOR minus “a-line” values – designated “b” line NOR; L(z-a-b)ⁱ NOR = set of values for Lzⁱ FAP minus “a+b-line” values – designated “c” line FAP; L(z-a-b)ⁱ NOR = set of values for Lzⁱ NOR minus “a+b-line” values – designated “c” line NOR; LI = labeling index; LImax = LI maxima; ln[Lzi ADA] = logarithmic plot of Lzi for adenomatous crypt data; ln[Lzi FAP] = logarithmic plot of Lzi for FAP crypt data; ln[Lzⁱ NOR] = logarithmic plot of Lzⁱ for normal crypt data; ln[Lzⁱ] = logarithmic plot of Lzⁱ; Lz = latenzzeit (latent time or quiescence); Lzⁱ = Lz at a given crypt position “i”; Lzⁱ ADA = Lzⁱ for adenomatous crypts; Lzⁱ FAP = Lzⁱ for FAP crypts; Lzi NOR = Lzi for normal crypts; NOR = normal; PS = probability of cells being in S-phase; P_S ⁱ = probability of S cells at each “i”; Psi ADA = probability of ADA cells at crypt position “i” being in S phase (F_S ⁱ ADA/F_PR ⁱ ADA) T_c ⁱ ADA = T_c ⁱ for adenomatous crypts (TS/P_sⁱ ADA); Tc = total cell cycle time; T_c ⁱ = Tc at a given crypt position “i”; T_c ⁱ NOR = T_c ⁱ for normal crypts or T_c ⁱ minus T_c ^lim; T_c ^lim = limiting cell cycle time at the crypt top (“i” = 1.0); T_c ^lim FAP = T_c ^lim for FAP crypts; T_c ^lim NOR = limiting T^{c i} at top of normal crypts; T_c ^lim NOR = T_c ^lim for normal crypts; TG₁ = time of G₁ phase; TG₂ = time of G₂ phase; TM = time of M phase; TS = time of S phase

Foot note :

¹In this report, the term latenzzeit (Lz), (German translation for latent time) will be used instead of the older term “quiescence.” Quiescence implies sleeping/resting inactivity, waiting for the next event. The term “latenzzeit or latent time” as used in the chemical and physical sciences describes systems to which energy is supplied without visible change in energy of system, e.g. latent heat of fusion and latent heat of vaporization. Latent is used in biological literature to imply undeveloped but capable of normal growth under proper conditions. Since there is evidence that cells between mitosis and beginning of G1 undergo biochemical and physical changes, “latenzzeit” which implies active but unseen movement toward a new condition is an appropriate term, which can be described quantitatively, and is consistent with usage in other scientific fields.

Abstract| Introduction| Methods| Results And Discussion| Significance| Conclusion| Acknowledgement| References|