Inhibition of tumor growth and metastasis by ATF-Fc, an engineered antibody targeting urokinase receptor

Hu, Xianwen; Duan, Haifeng; Shuyuan, Pan; Li, Yongmei; Yang, Xi; Zhao, Shijun; Yin, Liang; Li, Jinfeng; Chen, Huipeng; Wu, Cheng-Feng; Gao, Lihua

doi:10.4161/cbt.7.5.5643

Cited by 22 publications

(17 citation statements)

References 34 publications

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“…These findings are consistent with the fact that plasminogen, uPA, and PAI-1 deficiencies also fail to significantly influence tumorigenesis or tumor growth in PyMT-transgenic mice [41,42,45,47]. In contrast, tumor graft studies have generated conflicting results, with reduced expression of uPAR [27,29] or interruption of the uPA:uPAR interaction leading to reduced tumor size [32,33,36,37]; however, this reduction was attributed to longer tumor latency rather than decreased tumor growth in the studies that addressed these stages separately [27,33]. This effect on latency in the transplanted models cannot be compared directly to tumorigenesis in a transgenic model.…”

Section: Discussionsupporting

confidence: 89%

“…Finally, there is an abundance of experimental evidence from rodent cancer models, in which uPAR expression is manipulated in transplanted cells [27][28][29] or in which the uPA:uPAR interaction is blocked [30][31][32][33][34][35][36][37], that directly implicates uPAR in tumor growth or metastasis. In contrast, results from uPAR-deficient mice are mixed, with no observable effect on the growth or invasion of transplanted keratinocyte or fibrosarcoma tumors [38,39] but growth arrest of a transplanted prostate tumor [40].…”

Section: Introductionmentioning

confidence: 99%

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Spontaneous lung and lymph node metastasis in transgenic breast cancer is independent of the urokinase receptor uPAR

Almholt

Lærum

Nielsen

et al. 2015

Clin Exp Metastasis

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Urokinase-type plasminogen activator (uPA) is an extracellular protease that plays a pivotal role in tumor progression. uPA activity is spatially restricted by its anchorage to high-affinity uPA receptors (uPAR) at the cell surface. High tumor tissue expression of uPA and uPAR is associated with poor prognosis in lung, breast, and colon cancer patients in clinical studies. Genetic deficiency of uPA leads to a significant reduction in metastases in the murine transgenic MMTV-PyMT breast cancer model, demonstrating a causal role for uPA in cancer dissemination. To investigate the role of uPAR in cancer progression, we analyze the effect of uPAR deficiency in the same cancer model. uPAR is predominantly expressed in stromal cells in the mouse primary tumors, similar to human breast cancer. In a cohort of MMTV-PyMT mice [uPAR-deficient (n = 31) or wild type controls (n = 33)], tumorigenesis, tumor growth, and tumor histopathology were not significantly affected by uPAR deficiency. Lung and lymph node metastases were also not significantly affected by uPAR deficiency, in contrast to the significant reduction seen in uPA-deficient mice. Taken together, our data show that the genetic absence of uPAR does not influence the outcome of the MMTV-PyMT cancer model.

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Section: Discussionsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Spontaneous lung and lymph node metastasis in transgenic breast cancer is independent of the urokinase receptor uPAR

Almholt

Lærum

Nielsen

et al. 2015

Clin Exp Metastasis

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“…Moreover, the relatively restricted expression in advanced tumor tissues adds another advantage for uPAR-targeted therapy as such therapy can be expected to be more specific to tumor tissues and thus less toxic to the non-cancerous tissues. Early works have mostly focused on inhibiting the proteolytic activity of uPA with specific inhibitors 107-109 or blocking uPA-uPAR binding with peptides 110, 111. Several recent studies have also generated anti-uPAR antibodies that can block uPAR-mediated downstream signaling and/or activation pathways.…”

Section: Upar As a Therapeutic Targetmentioning

confidence: 99%

Role of Urokinase Receptor in Tumor Progression and Development

Noh

Hong

Huang³

2013

Theranostics

108

102

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Elevated level of urokinase receptor (uPAR) is detected in various aggressive cancer types and is closely associated with poor prognosis of cancers. Binding of uPA to uPAR triggers the conversion of plasminogen to plasmin and the subsequent activation of metalloproteinases. These events confer tumor cells with the capability to degrade the components of the surrounding extracellular matrix, thus contributing to tumor cell invasion and metastasis. uPA-uPAR interaction also elicits signals that stimulate cell proliferation/survival and the expression of tumor-promoting genes, thus assisting tumor development. In addition to its interaction with uPA, uPAR also interacts with vitronectin and this interaction promotes cancer metastasis by activating Rac and stimulating cell migration. Although underlying mechanisms are yet to be fully elucidated, uPAR has been shown to facilitate epithelial-mesenchymal transition (EMT) and induce cancer stem cell-like properties in breast cancer cells. The fact that uPAR lacks intracellular domain suggests that its signaling must be mediated through its co-receptors. Indeed, uPAR interacts with diverse transmembrane proteins including integrins, ENDO180, G protein-coupled receptors and growth factor receptors in cancer cells and these interactions are proven to be critical for the role of uPAR in tumorigenesis. Inhibitory peptide that prevents uPA-uPAR interaction has shown the promise to prolong patients' survival in the early stage of clinical trial. The importance of uPAR's co-receptor in uPAR's tumor-promoting effects implicate that anti-cancer therapeutic agents may also be developed by disrupting the interactions between uPAR and its functional partners.

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“…The latter was a more challenging drug discovery problem due to the much larger surface area, compared with an enzyme active site, which would need to be targeted to block a protein-protein interaction (e.g., uPA-uPAR). Several proof-of-principle studies aimed at disrupting uPA-mediated proteolysis using small-molecule inhibitors of uPA (33), peptide inhibitors of the uPA-uPAR interaction (34), and antibody-like inhibitors (35) have been published, but for the most part the results have been disappointing with modest effects observed on tumor growth and metastasis. One of the problems in evaluating many of these agents and especially the ones that attempt to interfere with uPA binding to uPAR is that the interaction of uPA with uPAR is highly species specific such that mouse uPA does not bind to human uPAR and vice versa.…”

Section: Introductionmentioning

confidence: 99%

Urokinase Plasminogen Activator Receptor Choreographs Multiple Ligand Interactions: Implications for Tumor Progression and Therapy

Mazar¹

2008

Clinical Cancer Research

113

101

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The urokinase plasminogen activator receptor (uPAR) has been implicated in the growth, metastasis, and angiogenesis of several solid and hemotologic malignancies. uPAR is part of a cell surface system that also consists of the serine protease uPA and several specific inhibitors (plasminogen activator inhibitors 1 and 2). This system has classically been thought to drive tumor progression by mediating directed extracellular proteolysis on the surface of migrating or invading cells, and intervening with this proteolysis by targeting uPAR has been proposed to represent a novel approach for inhibiting tumor progression. However, despite abundant evidence suggesting the utility of targeting uPAR for the treatment of cancer, there are currently no uPAR-targeted therapies being evaluated in clinical trials. Recent data have provided new insights into the role of uPAR in tumor progression. In addition to mediating proteolysis, this receptor appears to also mediate cell signaling, proliferation, and survival, and these observations have revealed novel ways to target uPAR. How these data have led to a paradigm shift in how the role of uPAR in tumor progression is perceived as well as past and present attempts to therapeutically target a molecule that is generating renewed interest as a cancer target will be discussed in this article.

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Inhibition of tumor growth and metastasis by ATF-Fc, an engineered antibody targeting urokinase receptor

Cited by 22 publications

References 34 publications

Spontaneous lung and lymph node metastasis in transgenic breast cancer is independent of the urokinase receptor uPAR

Spontaneous lung and lymph node metastasis in transgenic breast cancer is independent of the urokinase receptor uPAR

Role of Urokinase Receptor in Tumor Progression and Development

Urokinase Plasminogen Activator Receptor Choreographs Multiple Ligand Interactions: Implications for Tumor Progression and Therapy

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