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Angiogenesis regulation in hormone dependent breast- and ovarian cancer
Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
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: urn:nbn:se:liu:diva-63745ISBN: 978-91-7393-280-6 (print)OAI: oai:DiVA.org:liu-63745DiVA: diva2:382707
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
List of papers
1. Increased endostatin generation and decreased angiogenesis via MMP-9 by tamoxifen in hormone dependent ovarian cancer
Open this publication in new window or tab >>Increased endostatin generation and decreased angiogenesis via MMP-9 by tamoxifen in hormone dependent ovarian cancer
2010 (English)In: CANCER LETTERS, ISSN 0304-3835, Vol. 292, no 1, 32-40 p.Article in journal (Refereed) Published
Abstract [en]

There are several similarities between breast and ovarian cancer but anti-estrogen treatment is rarely used in ovarian cancer. We have previously shown that the most widely used anti-estrogen tamoxifen increased MMP-9 activity and endostatin generation in breast cancer. Here, we show that tamoxifen exposure of highly hormone responsive ovarian cancer cells decreased proliferation, and increased MMP-9 activity leading to increased levels of endostatin both in cell culture in vitro and in solid tumors of nude mice. Tamoxifen exposed tumors also exhibited significantly decreased tumor growth and vascularisation. Moreover, in ascites from ovarian cancer patients, MMP-9 was undetectable in majority of cases but a significant correlation of MMP-2 and endostatin was found. The effects on MMPs and endostatin generation are previously unknown mechanisms of estradiol and tamoxifen in ovarian cancer, which may have therapeutic implications in future anti-cancer options of hormone dependent ovarian cancer.

Place, publisher, year, edition, pages
Elsevier Science B.V., Amsterdam., 2010
Keyword
Estradiol, Sex steroids, Collagen, Microenvironment, Ascites
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-56806 (URN)10.1016/j.canlet.2009.11.002 (DOI)000277744800005 ()
Note
Original Publication: Christina Bendrik, Lisa Karlsson and Charlotta Dabrosin, Increased endostatin generation and decreased angiogenesis via MMP-9 by tamoxifen in hormone dependent ovarian cancer, 2010, CANCER LETTERS, (292), 1, 32-40. http://dx.doi.org/10.1016/j.canlet.2009.11.002 Copyright: Elsevier Science B.V., Amsterdam. http://www.elsevier.com/ Available from: 2010-06-04 Created: 2010-06-04 Last updated: 2011-01-03
2. Gene transfer of matrix metalloproteinase-9 induces tumor regression of breast cancer in vivo
Open this publication in new window or tab >>Gene transfer of matrix metalloproteinase-9 induces tumor regression of breast cancer in vivo
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.

Keyword
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
Identifiers
urn:nbn:se:liu:diva-43152 (URN)10.1158/0008-5472.CAN-08-0295 (DOI)72099 (Local ID)72099 (Archive number)72099 (OAI)
Available from: 2009-10-10 Created: 2009-10-10 Last updated: 2017-12-13
3. MMP-3 and MMP-9 Gene Transfer Decrease Growth and Angiogenesis in Breast Cancer Xenografts In Vivo
Open this publication in new window or tab >>MMP-3 and MMP-9 Gene Transfer Decrease Growth and Angiogenesis in Breast Cancer Xenografts In Vivo
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.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-63743 (URN)
Available from: 2011-01-03 Created: 2011-01-03 Last updated: 2011-01-03
4. Estradiol Increases IL-8 Secretion of Normal Human Breast Tissue and Breast Cancer In Vivo
Open this publication in new window or tab >>Estradiol Increases IL-8 Secretion of Normal Human Breast Tissue and Breast Cancer In Vivo
2009 (English)In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 182, no 1, 371-378 p.Article in journal (Refereed) Published
Abstract [en]

IL-8 or CXCL8 has been associated with tumor angiogenesis, metastasis, and poor prognosis in breast cancer. Estrogen is crucial in breast carcinogenesis and tumor progression. Whether sex steroids affect IL-8 secretion of normal breast tissue or breast cancer is not known. Several cell types in a tissue secrete IL-8. Hence, regulatory mechanisms of IL-8 need to be investigated in whole tissue. We used microdialysis to sample IL-8 in normal human breast tissue in situ in pre- and postmenopausal women, preoperatively in breast cancers of women, and in experimental breast cancer in mice. We found a significant positive correlation between IL-8 and estradiol in normal breast tissue and hormone-dependent breast cancer in vivo. Ex vivo, estradiol exposure increased the IL-8 secretion of normal whole breast tissue in culture. In experimental breast cancer, estradiol increased IL-8 whereas the anti-estrogen tamoxifen inhibited the secretion of IL-8 both in vitro and extracellularly in vivo in tumors of nude mice. An anti-IL-8 Ab inhibited endothelial cell proliferation induced by cancer cell produced IL-8 and tumors with low IL-8 levels exhibited decreased angiogenesis. Our results strongly suggest that estradiol has a critical role in the regulation of IL-8 in normal human breast tissue and human breast cancer. IL-8 may present a novel therapeutic target for estrogen driven breast carcinogenesis and tumor progression.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-16349 (URN)
Available from: 2009-01-16 Created: 2009-01-16 Last updated: 2011-01-03

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