Protease Activity of Urokinase and Tumor Progression in a Syngeneic Mammary Cancer Model

Merchan, Jaime R.; Tang, Jian; Hu, Guang; Lin, Yanfeng; Mutter, Walter P.; Tong, Caili; Karumanchi, S. Ananth; Russell, Stephen J.; Sukhatme, Vikas P.

doi:10.1093/jnci/djj208

Cited by 12 publications

(21 citation statements)

References 41 publications

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“…Consequently, the tumor-promoting role of uPA in neoplastic cell invasion, growth, and metastasis has been extensively studied in many different types of cancer, including colon cancer [15], [16], [17], [18], [25], [26], [36]. Except for a few studies reporting on an antiangiogenic tumor-suppressor effect of uPA in human patients [37] and syngeneic orthotopic tumor cell transplant mouse models [37], [38], [39], the vast majority of scientific data suggests that uPA confers increased aggressiveness to tumors. For that, uPA is widely accepted as a protease of emerging importance in cancer research [15], [17], [18].…”

Section: Discussionmentioning

confidence: 99%

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

Karamanavi

Angelopoulou

Lavrentiadou

et al. 2014

Translational Oncology

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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.

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Section: Discussionmentioning

confidence: 99%

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

Karamanavi

Angelopoulou

Lavrentiadou

et al. 2014

Translational Oncology

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“…We also demonstrated that overexpression of uPA paradoxically delayed tumor growth, metastases, and improved survival in a syngeneic, immunocompetent mammary cancer model, (18). Urokinase’s tumor delaying effects were due to its protease activity, as tumors overexpressing proteolytically inactive uPA mutants were not associated with antitumor effects.…”

Section: Introductionmentioning

confidence: 75%

“…cDNA encoding murine uPA [obtained from (18)] and PAI-1 (gift from Foidart Jean-Michel, University of Liege) were subcloned into the BamH I- Not I site of the lentiviral vector pHR-SIN-CSGWd1NotI (a gift of Y. Ikeda, Mayo Clinic, Rochester, MN), from pcDNA3.1(+)- muPA and pBS-mPAI-1 respectively, and the cDNA sequence was verified. Lentiviral packaging was performed by cotransfection of the vector plasmid with pCMV-Gag-Pol vector and pCMV-VSVG-poly-A vector into 293T cells using CaCl 2 transfection kit (Promega, Madison, WI).…”

Section: Methodsmentioning

confidence: 99%

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Role of Plasminogen Activator Inhibitor-1 in Urokinase's Paradoxical In Vivo Tumor Suppressing or Promoting Effects

Jing

Kovacs

Kurisetty

et al. 2012

Molecular Cancer Research

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Tumor proteases and inhibitors have been associated with paradoxical effects on tumor progression in preclinical and clinical settings. We previously reported that urokinase (uPA) overexpression delays tumor progression in mammary cancer. This study aimed to determine the role of plasminogen activator inhibitor-1 (PAI-1) on uPA’s paradoxical in vivo effects. Using syngeneic murine models, we found that stable uPA overexpression promoted in vivo growth of colon tumors (MC-38) naturally expressing high PAI-1, while growth inhibition was observed in renal tumors (RENCA) expressing lower PAI-1 levels. In murine mammary carcinoma (4T1), uPA overexpression shifted the uPA/PAI-1 balance in favor of the protease, resulting in significantly reduced tumor growth and metastases in vivo. Conversely, increased tumor progression was observed in stable PAI-1 overexpressing 4T1 tumors, compared to uPA overexpressing and control tumors. These effects were associated with down regulation of metastases promoting genes in uPA overexpressing tumors, such as metalloproteinases, CXCL-1, c-Fos, integrin α-5, VEGF-A, PDGF-α and IL-1β. In PAI-1 overexpressing tumors, many of the above genes were upregulated. PAI-1 overexpressing tumors had increased total and new tumor microvessels, and increased tumor cell proliferation, while the opposite effects were found in uPA overexpressing tumors. Finally, PAI-1 down-regulation led to significant inhibition of 4T1 tumor growth and metastases in vivo. In conclusion, uPA’s dual effects on tumor progression occur in the context of its interactions with endogenous PAI-1 expression. Our studies uncover novel mechanisms of in vivo tumor control by modulation of the balance between tumor proteases and inhibitors, which may be exploited therapeutically.

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“…However, absence of host PAI-1 has been shown to reduce tumor burden in tumor transplant or transgenic tumor-induction models. 80,81 Furthermore, both uPA transgenic and uPA knockout mice show reduced metastasis in syngeneic or xenograft mammary tumor models [82][83][84] and this might be related to hyperactive protease activity or the normal growth promoting role of uPA activity, respectively. In an MMTV-PymT transgenic mouse model of metastasizing breast cancer, PAI-1 knockout in the host has been reported not to lead to metastasis, 81 although in other models it has been shown that in xenograft experiments the PAI-1 levels of the host do seem to be most important in invasion and vascularisation.…”

Section: Pai-1 Stroma and Breast Cancermentioning

confidence: 99%

Senescence, Wound Healing, and Cancer: the PAI-1 Connection

Kortlever¹,

Bernards²

2006

Cell Cycle

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Protease Activity of Urokinase and Tumor Progression in a Syngeneic Mammary Cancer Model

Cited by 12 publications

References 41 publications

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

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

Role of Plasminogen Activator Inhibitor-1 in Urokinase's Paradoxical In Vivo Tumor Suppressing or Promoting Effects

Senescence, Wound Healing, and Cancer: the PAI-1 Connection

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