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Gene transfer of matrix metalloproteinase-9 induces tumor regression of breast cancer in vivo
Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences.
Department of Pathology and Molecular Medicine, Centre for Gene Therapeutics McMaster University, Hamilton, Ontario, Canada.
Department of Pathology and Molecular Medicine, Centre for Gene Therapeutics McMaster University, Hamilton, Ontario, Canada.
Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Oncology . Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
2008 (English)In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 68, no 9, 3405-3412 p.Article in journal (Refereed) Published
Abstract [en]

Matrix metalloproteinases (MMP) are important regulators of angiogenesis and tumor progression by degradation of extracellular matrix. Clinical trials using MMP inhibitors have failed and recent studies suggest that MMPs may in contrast suppress tumor growth. It is not known, however, if MMPs or their inhibitors, tissue inhibitor of metalloproteinases (TIMP), can be used as therapy of established cancer. Here, adenovirus vectors carrying the human genes for MMP-9, TIMP-1, or empty controls were injected intratumorally in breast cancers established in mice supplemented with estradiol and treated with tamoxifen. Microdialysis was used to quantify MMP activity and sampling of endostatin and vascular endothelial growth factor (VEGF) in situ. We show that AdMMP-9 increased MMP activity in vivo, decreased tumor growth rate, and decreased microvessel area significantly. AdMMP-9 therapy resulted in significantly increased levels of endostatin in vivo, whereas VEGF levels were unaffected. As previously shown, tamoxifen exposure by itself increased MMP activity in all treatment groups. Moreover, the combined therapy with AdMMP-9 and tamoxifen further reduced tumor growth and increased the endostatin levels compared with either treatment alone. Gene transfer of TIMP-1 had no effects on tumor progression and counteracted the therapeutic effect of tamoxifen in our breast cancer model. This is the first report showing that overexpression of MMP-9 results in increased generation of antiangiogenic fragments, decreased angiogenesis, and therapeutic effects of established breast cancer.

Place, publisher, year, edition, pages
2008. Vol. 68, no 9, 3405-3412 p.
Keyword [en]
Adenocarcinoma/*genetics/metabolism/pathology/*therapy Adenoviridae/genetics Animals Breast Neoplasms/*genetics/metabolism/pathology/*therapy Disease Progression Endostatins/metabolism Female Gene Therapy Gene Transfer Techniques Humans Matrix Metalloprot
National Category
Medical and Health Sciences
URN: urn:nbn:se:liu:diva-43152DOI: 10.1158/0008-5472.CAN-08-0295Local ID: 72099OAI: diva2:264010
Available from: 2009-10-10 Created: 2009-10-10 Last updated: 2011-01-03
In thesis
1. Angiogenesis regulation in hormone dependent breast- and ovarian cancer
Open this publication in new window or tab >>Angiogenesis regulation in hormone dependent breast- and ovarian cancer
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Angiogenesis is a key event in tumor progression and a rate-limiting step in the establishment of a clinical cancer disease. The net balance of pro- and anti-angiogenesis mediators in the tissue dictates the angiogenic phenotype of a tumor. Matrix metalloproteinases (MMPs) are major regulators of extracellular matrix turnover and have for long been associated with pro-tumorigenic activities due to their tissue degradation capacities. However, broad-spectra MMP inhibitors as anti-tumor therapy in clinical trials have failed, and it has now become evident that several MMPs may induce biological activities beneficial to the host, such as suppressed angiogenesis. In this thesis the protective role of specific MMPs in breast and ovarian tumor tissues was further demonstrated.

The process of angiogenesis is essential for physiological functions in the female reproductive tract, where sex steroids regulate new blood vessel formation and regression in each cycle. Despite progress made during the past years, our knowledge in sex steroid regulation of angiogenesis in hormone-dependent tumor tissues remains limited. Tamoxifen is a cornerstone in the treatment of estrogen receptor (ER)-positive breast cancer. The therapeutic value of tamoxifen in the treatment of ER-positive ovarian cancer is to date less investigated. The results presented in this thesis suggest that tamoxifen may induce anti-tumorigenic responses in ER-positive ovarian cancer by means of both anti-proliferative and anti-angiogenic mechanisms. In experimental models of human ovarian cancer in vitro and in vivo, tamoxifen treatment increased extracellular levels of MMP-9 and enhanced generation of the angiogenesis inhibitor endostatin which resulted in significantly decreased angiogenesis and tumor growth. Low levels of MMP-9 and endostatin in ascites collected from ovarian cancer patients suggest a possibility to therapeutically enhance MMP-9 by administration of tamoxifen, and thereby counteract angiogenesis in ovarian tumors by increased generation of anti-angiogenesis fragments, such as endostatin.

The significance of enhanced MMP activities in tumor tissues was further investigated by experimental models of intratumoral MMP gene transfer to human breast tumor xenografts, which were assessed by using microdialysis. Treatment of tumors with MMP-9 or MMP-3 resulted in dose-dependent inhibition of tumor growth. Low dose of either MMP induced tumor stasis whereas a higher dose induced significant tumor regression. MMP-9 and tamoxifen exerted synergistic therapeutic effects on breast tumor angiogenesis and growth whereas gene transfer of the MMP-inhibitor TIMP-1 counteracted the beneficial effects induced by tamoxifen.

Further on, we confirm the pro-angiogenic potential of estradiol by demonstrating a significant correlation between local levels of estradiol and the pro-angiogenic cytokine IL-8 in normal human breast tissues and in ER/PgR-positive breast cancers of women. Estradiol-induced IL-8 secretion was additionally confirmed in normal human whole breast biopsies in culture and in experimental human breast cancer in vitro and in vivo.

In conclusion, the results of this thesis may hopefully increase the overall understanding of several mechanisms involved in angiogenesis regulation and may additionally be useful in the development of novel approaches for targeted therapy in the treatment of hormone-sensitive breast- and ovarian cancer.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2011. 96 p.
Linköping University Medical Dissertations, ISSN 0345-0082
National Category
Medical and Health Sciences
urn:nbn:se:liu:diva-63745 (URN)978-91-7393-280-6 (ISBN)
Public defence
2011-02-04, Berzeliussalen, Hälsouniversitetet, Campus US, Linköpings universitet, Linköping, 13:00 (Swedish)
Available from: 2011-01-03 Created: 2011-01-03 Last updated: 2011-01-03Bibliographically approved

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Bendrik, ChristinaDabrosin, Charlotta
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Oncology Faculty of Health SciencesDepartment of Oncology UHL
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