Basic-alimentary tractProgastrin stimulates murine colonic epithelial mitosis after DNA damage☆
Section snippets
Animals
The following mouse strains were used: INS-GAS, hGAS, GAS-KO, FVB/N (wild-type counterparts of INS-GAS and hGAS), and C57BL/6 (wild-type counterparts of GAS-KO). hGAS mice are transgenic for 1.3 kb of the human gastrin promoter and the coding sequence of human preprogastrin, resulting in overexpression of the transgene in hepatocytes and elevated (1–100 nmol/L) serum levels of human progastrin.13 INS-GAS mice contain a gastrin transgene consisting of 0.4 kb of the insulin promoter upstream of
In hGAS mice, colonic mitosis persists after γ-irradiation
Mitotic figures were present in the colonic crypts of unirradiated FVB/N and hGAS mice (Figure 1A and C), and apoptotic bodies were seen at the base of colonic crypts from both strains after 8 Gy γ-irradiation (Figure 1B and D). However, hGAS mice additionally showed persistent mitotic figures in colonic crypts after 8Gy γ-irradiation (Figure 1D).
These findings have been confirmed by quantitative analysis of apoptotic and mitotic indices in the small intestinal and colonic crypts of hGAS and
Discussion
We have investigated the effects of expression of gastrin and its precursor peptides on spontaneous and γ-radiation–induced apoptosis and mitosis in murine intestinal epithelia. The most important observation was of higher levels of mitosis (P < 0.01) in the colonic crypts of hGAS mice compared with INS-GAS, wild-type (FVB/N), and GAS-KO animals at various times after 8 Gy γ-radiation.
There has been considerable recent interest in the role of gastrin and its precursors in colon cancer. Because
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Cited by (29)
Progastrin production transitions from Bmi1<sup>+</sup>/Prox1<sup>+</sup> to Lgr5<sup>high</sup> cells during early intestinal tumorigenesis
2021, Translational OncologyCitation Excerpt :In contrast, we show that progastrin expression becomes a feature of Lgr5- high cells from the early stage of colonic neoplasia, similar to the emerging co-expression between Prox1 and Lgr5 in developing colorectal tumors [43]. Considering the previously reported role for increased endogenous [33] and experimentally-induced progastrin production [13,15] in the resistance of colorectal tumors to radiation damage, and since us and others have shown that progastrin promotes the maintenance and expansion of stem/cancer stem cells in the colon [40], this data suggests that progastrin expression may contribute to the radio-resistance of LGR5- high cells in colorectal tumors. Our data also indicate that progastrin is produced by colonic cells located towards the lower third of colonic crypts in close proximity to epithelial progenitor cells, which were recently characterized as expressing GPR56, a receptor for this peptide [40].
Progastrin-induced secretion of insulin-like growth factor 2 from colonic myofibroblasts stimulates colonic epithelial proliferation in mice
2013, GastroenterologyCitation Excerpt :We therefore administered the IGF-1R antagonist AG1024 to hGAS and C57BL/6 mice and assessed distal colonic crypt length (Figure 6A), mitotic figures per hemi-crypt (Figure 6C), Ki67-positive cells per hemi-crypt (Figure 6D), DCAMKL-1–positive cells per hemi-crypt (Figure 6B), and relative expression of Lgr5 transcripts (Figure 7) 52 hours after drug administration.27 As previously described,13,15,23 cell number per hemi-crypt, mitotic figures per hemi-crypt, number of DCAMKL-1–positive cells per hemi-crypt, and Lgr5 expression were significantly increased in the colons of DMSO-treated hGAS mice compared with C57BL/6 mice (Figures 5–7 and Supplementary Figure 2). Administration of AG1024 to hGAS mice, however, resulted in significant reductions in the number of total cells, mitotic cells, DCAMKL-1–positive cells, and Lgr5 messenger RNA (mRNA) transcripts in the colon compared with DMSO-treated hGAS mice.
Flow cytometric detection of progastrin interaction with gastrointestinal cells
2008, Regulatory PeptidesHypergastrinemia increases gastric epithelial susceptibility to apoptosis
2008, Regulatory PeptidesColorectal neoplasia in veterans is associated with Barrett's esophagus but not with proton-pump inhibitor or aspirin/NSAID use
2006, Gastrointestinal Endoscopy
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Supported by the North West Cancer Research Fund. Dr. Pritchard holds an Advanced Fellowship for Clinicians from the Wellcome Trust.
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The authors thank Prof. R. Dimaline for useful discussions.