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MMP-3 and MMP-9 Gene Transfer Decrease Growth and Angiogenesis in Breast Cancer Xenografts In Vivo
Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
2009 (English)Manuscript (preprint) (Other academic)
Abstract [en]

Matrix metalloproteinases (MMPs) are largely implicated in tumor behaviour due to their extracellular matrix (ECM) remodelling capacities. Although MMP activity generally is discussed in terms of facilitating tumor invasion, MMP inhibition in clinical trials has failed. Increasing amounts of data show that MMPs may inhibit tumor progression by generating anti-angiogenic factors such as endostatin from the tumoral stroma. We have previously shown that intratumoral gene transfer of MMP-9 induced tumor regression and reduced angiogenesis of breast cancer in vivo. Whether MMP activities induce tumor progression or regression may depend on type of MMP and the expression level in the tumor tissue. In this study we treated established breast cancers in nude mice with adenovirus vectors carrying the human genes of MMP-3 or MMP-9 in low or high dose. Microdialysis was used to sample endostatin in situ and tumor growth was monitored for 35 days. Tumors in mice treated with low-dose of either MMP-3 or MMP-9 vectors exhibited tumor stasis throughout the experiment whereas high-dose gene transfer of either MMP-3 or MMP-9 induced significant tumor regression compared to controls treated with empty vectors. The extracellular in vivo levels of endostatin were increased in tumors that received either high or low MMP-3 or MMP-9 gene transfer and these tumors exhibited decreased microvessel area compared to controls. Our results propose that increased expression of MMP-3 and MMP-9 have therapeutic effects of established breast cancer in a dose dependent manner where a slight increase of MMP expression results in tumor stasis and a high expression of either MMP-3 or MMP-9 by gene transfer results in a potent tumor regression.

Place, publisher, year, edition, pages
2009. Vol. 69, no 24, 761S-761S p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-63743OAI: oai:DiVA.org:liu-63743DiVA: diva2:382697
Available from: 2011-01-03 Created: 2011-01-03 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.
Series
Linköping University Medical Dissertations, ISSN 0345-0082
National Category
Medical and Health Sciences
Identifiers
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)
Opponent
Supervisors
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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