All polyps (seven of seven) contained neoplastic gland foci staged as LGD and HGD. Four polyps also contained CIS lesions (four of seven). No polyp (zero of seven) contained early invasive adenocarcinoma lesions, such as neoplastic gland invasion into the polyp stalk or the underlying submucosa. Immunohistochemically,
the polyps showed abnormal β-catenin (Figures 1D and W1D) and E-cadherin ( Figure W1D) patterns, with loss of normal cell membrane localization and cytoplasmic stabilization. Neoplastic glands with CIS lesions also had epithelial cells with nuclear translocation of β-catenin. TGF-β1 expression within polyps had no specific pattern. Areas of normal, increased, Palbociclib and decreased expression co-existed ( Figure W1D). LGD and HGD lesions, however, most often were overexpressing TGF-β1, whereas occasional HGD and CIS lesions showed a decreased or a complete loss of positive immunolabeling. The proliferation and apoptosis was typical for polypoid adenomas with Ki-67– and caspase-3–positive neoplastic cells being more abundant in HGD and CIS lesions ( Figure 1D). To further characterize the uPA−/− + DSS mouse model of colorectal neoplasia, we next examined the topographic distribution of inflammatory
cells in the polyps. The major part of the tumor-associated inflammatory cell infiltrate located in the lamina propria overlying the muscularis mucosa and the submucosa layer at the base of the polyp (Figure W2A). Secondarily, LGK-974 supplier inflammatory cells accumulated in the lamina propria below the surface epithelium of the polyp and the non-neoplastic epithelium at the peripheral margins of the polyp. Less inflammatory cells were seen within the tumor stroma of the main body of the polyps. At the base of the polyp, the infiltrate consisted of lymphocytes, neutrophils, macrophages, mast cells, myeloid precursor cells, and plasmacytes ( Figure W2A). Subepithelially, there were mainly macrophages, neutrophils,
and fewer lymphocytes, whereas at the tumor margins there were macrophages, lymphocytes, PtdIns(3,4)P2 and less neutrophils and plasmacytes. Within the main body of the tumors, there were neutrophils, macrophages, and occasional lymphocytes. The immunohistochemical labeling of selected immune cells and cytokines confirmed the above-mentioned histologic observations (Figure W2, B–H). The main body of the polyp was infiltrated primarily by MPO + neutrophils ( Figure W2B) and, to a lesser extent, by F4/80 + macrophages. At the base of the polyp, there were numerous MPO +, F4/80 + ( Figure W2C), and CD3 + ( Figure W2D) cells. CD3 + T-lymphocytes and Foxp3 + Treg confined at the periphery of the polyp ( Figure W2E) and rarely located between neoplastic glands, whereas c-kit + mast cells were almost exclusively found at the base of the polyp and the underlying submucosa and muscle layers ( Figure W2F).