Academic Journal
Activation of Pro-uPA Is Critical for Initial Escape from the Primary Tumor and Hematogenous Dissemination of Human Carcinoma Cells
| العنوان: | Activation of Pro-uPA Is Critical for Initial Escape from the Primary Tumor and Hematogenous Dissemination of Human Carcinoma Cells |
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| المؤلفون: | Erin M. Bekes, Elena I. Deryugina, Tatyana A. Kupriyanova, Ewa Zajac, Kenneth A. Botkjaer, Peter A. Andreasen, James P. Quigley |
| المصدر: | Neoplasia: An International Journal for Oncology Research, Vol 13, Iss 9, Pp 806-821 (2011) |
| بيانات النشر: | Elsevier, 2011. |
| سنة النشر: | 2011 |
| المجموعة: | LCC:Neoplasms. Tumors. Oncology. Including cancer and carcinogens |
| مصطلحات موضوعية: | Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282 |
| الوصف: | Urokinase-type plasminogen activator (uPA) and plasmin have long been implicated in cancer progression. However, the precise contributions of the uPA/plasmin system to specific steps involved in cancer cell dissemination have not been fully established. Herein, we have used a highly disseminating variant of the human PC-3 prostate carcinoma cell line, PC-hi/diss, as a prototype of aggressive carcinomas to investigate the mechanisms whereby pro-uPA activation and uPA-generated plasmin functionally contribute to specific stages of metastasis. The PC-hi/diss cells secrete and activate significant amounts of pro-uPA, leading to efficient generation of plasmin in solution and at the cell surface. In a mouse orthotopic xenograft model, treatment with the specific pro-uPA activation-blocking antibody mAb-112 significantly inhibited local invasion and distant metastasis of the PC-hi/diss cells. To mechanistically examine the uPA/plasmin-mediated aspects of tumor cell dissemination, the anti-pro-uPA mAb-112 and the potent serine protease inhibitor, aprotinin, were used in parallel in a number of in vivo assays modeling various rate-limiting steps in early metastatic spread. Our findings demonstrate that, by generating plasmin, activated tumor-derived uPA facilitates early stages of PC-hi/diss dissemination, specifically the escape from the primary tumor and tumor cell intravasation. Moreover, through a series of in vitro and in vivo analyses, we suggest that PC-hi/diss-invasive escape and dissemination may be enhanced by cleavage of stromal fibronectin by uPA-generated plasmin. Together, our findings point to inhibition of pro-uPA activation at the apex of the uPA/plasmin cascade as a therapy-valid approach to control onset of tumor escape and ensuing metastatic spread. |
| نوع الوثيقة: | article |
| وصف الملف: | electronic resource |
| اللغة: | English |
| تدمد: | 1476-5586 1522-8002 |
| Relation: | http://www.sciencedirect.com/science/article/pii/S1476558611800333; https://doaj.org/toc/1476-5586; https://doaj.org/toc/1522-8002 |
| DOI: | 10.1593/neo.11704 |
| URL الوصول: | https://doaj.org/article/44f007cd4147400588faa5b808ec26b6 |
| رقم الانضمام: | edsdoj.44f007cd4147400588faa5b808ec26b6 |
| قاعدة البيانات: | Directory of Open Access Journals |
Full Text Finder | تدمد: | 14765586 15228002 |
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| DOI: | 10.1593/neo.11704 |