Urokinase-Type Plasminogen Activator Deficiency Promotes Neoplasmatogenesis in the Colon of Mice

Abstract

Urokinase-type plasminogen activator (uPA) participates in cancer-related biologic processes, such as wound healing and inflammation. The present study aimed to investigate the effect of uPA deficiency on the long-term outcome of early life episodes of dextran sodium sulfate (DSS)–induced colitis in mice. Wild-type (WT) and uPA-deficient (uPA−/−) BALB/c mice were treated with DSS or remained untreated. Mice were necropsied either 1 week or 7 months after DSS treatment. Colon samples were analyzed by histopathology, immunohistochemistry, ELISA, and real-time polymerase chain reaction. At 7 months, with no colitis evident, half of the uPA−/− mice had large colonic polypoid adenomas, whereas WT mice did not. One week after DSS treatment, there were typical DSS-induced colitis lesions in both WT and uPA−/− mice. The affected colon of uPA−/− mice, however, had features of delayed ulcer re-epithelialization and dysplastic lesions of higher grade developing on the basis of a significantly altered mucosal inflammatory milieu. The later was characterized by more neutrophils and macrophages, less regulatory T cells (Treg), significantly upregulated cytokines, including interleukin-6 (IL-6), IL-17, tumor necrosis factor-α, and IL-10, and lower levels of active transforming growth factor–β1 (TGF-β1) compared to WT mice. Dysfunctional Treg, more robust protumorigenic inflammatory events, and an inherited inability to produce adequate amounts of extracellular active TGF-β1 due to uPA deficiency are interlinked as probable explanations for the inflammatory-induced neoplasmatogenesis in the colon of uPA−/− mice.

Fibrinolysis and the control of blood coagulation

“…Murine knockout models have demonstrated increased intravascular deposition of fibrin in adult mice that are deficient in tPA or uPA [125]. Deficiencies of uPA may also promote cancer progression in experimental models of inflammatory colon cancer [126]. In murine models, deficiency of TAFI has been linked with increased fibrin deposition and inflammation leading to liver damage [127].…”

‘Hygienic’ Lymphocytes Convey Increased Cancer Risk

“…The classification of small intestinal polyps according to the most advanced lesion they contained showed that “hygienic” T cell recipient mice had significantly more polyps bearing CIS compared to control mice [Fig 3b and 3c]. Lymphocytes, macrophages, neutrophils, plasmacytes and mast cells in the intestinal adenomas of both groups of Apc Min/+ mice followed the typical polyp-associated inflammatory cell topographical distribution pattern(23, 44). However, the inflammatory cell accumulation was more pronounced in the polyps of “hygienic” cell recipients.…”

“…Based on previously described histomorphological criteria (21, 43, 44) focal lesions of dysplasia/adenoma within polyps were identified as low-grade dysplasia (LGD) or high-grade dysplasia (HGD) and carcinoma in situ (CIS, intraepithelial neoplasia) [Fig 3a]. The classification of small intestinal polyps according to the most advanced lesion they contained showed that “hygienic” T cell recipient mice had significantly more polyps bearing CIS compared to control mice [Fig 3b and 3c].…”

“…However, the inflammatory cell accumulation was more pronounced in the polyps of “hygienic” cell recipients. We have previously shown that neutrophils enhance intestinal tumorigenesis and that their accumulation in cancer-prone epithelia is influenced by CD4 + cell subsets(23, 44, 45). We next quantitatively assessed MPO+ granulocytes (neutrophils) in the polyps of Apc Min/+ mice.…”

“…Polypoid adenomas were classified according to the worst preneoplastic lesion they contained. Preneoplastic lesions were classified as low (LGD) and high grade dysplasia (HGD) or Carcinoma in situ (CIS) using histomorphological criteria that have been earlier described (21, 44). MPO-specific immunohistochemistry and quantitative histomorphometry of MPO-positive cells were performed as previously described(44).…”