Variability of cell proliferation in the proximal and distal colon of normal rats and rats with dimethylhydrazine induced carcinogenesis

Abstract

Aim: To investigate the patterns of cell proliferation in proximal and distal colons in normal rats and rats with 1,2-dimethylhydrazine (DMH) induced carcinogenesis using the thymidine analogue bromodeoxyuridine.

Methods: Colonic crypt cell proliferation was immunohistochemically detected using the anti-bromodeoxyuridine Bu20a monoclonal antibody.

Results: Marked regional differences were found in both groups. Total labelling index (LI) and proliferative zone size in both normal (8.65+/-0.34 vs 7.2+/-0.45, 27.74+/-1.07 vs 16.75+/-1.45) and DMH groups (13.13+/-0.46 vs 11.55+/-0.45, 39.60+/-1.32 vs 35.52+/-1.58) were significantly higher in distal than in proximal colon (P<0.05), although the number of cells per proximal crypt was greater (31.45+/-0.20 vs 34.45 +/-0.39, 42.68+/-0.53 vs 49.09+/-0.65, P<0.0001). Crypt length, total LI and proliferative zone size all increased in both proximal and distal regions of DMH rats compared to normal controls (P<0.0001). In DMH-treated rat colon a shift of labelled cells to higher crypt cell positions was demonstrated distally whilst a bi-directional shift was evident proximally (P<0.05).

Conclusion: Our results show that changes in cell proliferation patterns, as assessed by bromodeoxyuridine uptake, can act as a reliable intermediate marker of colonic cancer formation. Observed differences between proliferation patterns in distal and proximal colon may be associated with the higher incidence of tumors in the distal colon.

Figure 1

Labelling indices of compartment 1 and compartment 3 in proximal and distal colon of normal rats. ^aP < 0.0001 when distal is compared to proximal colon in the same compartment. Values are mean ± SEM.

Figure 2

The different patterns of cumulative labelling distributions in proximal (NP) and distal (ND) rat colon of normal controls. The curve is significantly shifted towards the right when the proximal colon is compared to distal colon.

Figure 3

Labelling indices of normal proximal colon (NP) and DMH proximal colon (DP) for the 5 compartments. ^aP < 0.0001 when labelling indices in the compartments of DMH proximal colons were compared to those found in normal proximal colons in the same compartments.

Figure 4

Labelling indices of normal distal colon (ND) and DMH distal colon (DD) for the 5 compartments. ^aP < 0.05, ^bP < 0.0001 when labelling indices in the compartments of DMH distal colons were compared to those found in normal distal colons in the same compartments.

Figure 5

Cumulative labelling distribution in normal (ND) and DMH distal (DD) rat colon. The curve is significantly shifted towards the right in DMH distal colon compared to normal distal colon.

Figure 6

Cumulative labelling distribution in normal (NP) and DMH proximal (DP) rat colon. The curve of DMH treated proximal rat colon is initially significantly shifted towards the left and then in the higher centiles shifted to the right.