Abstract 1429: Apc heterozygosity in the C57BL/6J-Min/+ mouse produces an abnormal exuberant proliferative response in excisional wound healing

Abstract

Abstract The Min mouse is a model for intestinal tumor formation. Previously, we showed that the ApcMin allele produces a dominant-negative effect on enterocyte migration and stromal interaction in vivo. Tumorigenesis is driven by features of epithelial-mesenchymal interaction that are observed in wound healing, therefore we hypothesized that the Min phenotype also involved abnormalities in the wounding response program. We performed excisional wound assays on female Min mice (10 or 20-week old), comparing response to that of female age-matched Apc+/+ (WT) mice. The healing kinetics of full thickness dorsum wounds were quantified by digital planimetry. Histological cross sections on post-operative day 7 were used to measure granulation tissue thickness, nascent blood vessel density, and cell proliferation. Western blotting was performed using granulation tissue lysates to compare the expression of adhesion and extracellular matrix proteins, as well as α-smooth muscle actin, a marker for the presence of contractile cells. Immunofluorescent histochemistry was performed to detect the co-expression and quantitation of αSMA+, vimentin+, SM22+, desmin− myofibroblasts at wound edges. Wound closure was faster in Min mice relative to WT mice, 88.85% versus 68.86% (P<0.01). Min mice also showed the strongest induction of granulation tissue formation; the relative granulation tissue thickness in the centre of wounds was 171.15±47.53 and 147.96±16 mm (P<0.01) in Min and WT, respectively. Blood vessel density, measured by counting the number of CD31+ cells/high power field, was increased (40.72 + 22.6) in Min mice when compared to WT (19.03 ± 17.6, P<0.01). The number of proliferating cells in granulation tissue (Ki67+ nuclei/all) in Min mice (63.72±16.83) was greater than in WT (41.58±23.46) (P<0.01). Masson's stain demonstrated that more collagen deposition was present in wounds of Min/+ relative to WT. In conclusion, this study showed that wound healing was accelerated in Min/+ mice relative to WT. Therefore, even before the loss of the WT allele, Apc heterozygosity likely promotes tumor formation because it affects wound-induced invasive, homing, and engraftment responses of the epithelial stroma. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1429. doi:10.1158/1538-7445.AM2011-1429