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Targeting the prostate tumor microenvironment and vasculature: the role of castration, tumor-associated macrophages and pigment epithelium-derived factor
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
2009 (English)Doctoral thesis, comprehensive summary (Other academic)Alternative title
Mikromiljö och angiogenes i prostatacancer : effekter av kastration, tumör associerade makrofager och Pigment epithelium-derived factor (Swedish)
Abstract [en]

BACKGROUND: Prostate cancer is the most common cancer among Swedish men. For patients with metastatic prostate cancer the standard therapy is castration, a treatment that initially provides symptomatic relief but unfortunately is not curative. New therapeutic targets for advanced prostate cancer are therefore needed.  Prostate cancers are composed of tumor epithelial cells as well as many non-epithelial cells such as cancer associated fibroblasts, blood vessels and inflammatory cells.  Many components of the tumor microenvironment such as tumor associated macrophages and angiogenesis have been shown to stimulate tumor progression. This thesis aims to explore mechanisms by which the local environment influences prostate tumor growth and how such mechanisms could be targeted for treatment.

MATERIALS AND METHODS: We have used animal models of prostate cancer, in vitro cell culture systems and clinical materials from untreated prostate cancer patients with long follow up. Experiments were evaluated with stereological techniques, immunohistochemistry, western blotting, quantitative real-time PCR, PCR arrays and laser micro dissection.

RESULTS: We found that the presence of a tumor induces adaptive changes in the surrounding non-malignant prostate tissue, and that androgen receptor negative prostate tumor cells respond to castration treatment with temporarily reduced growth when surrounded by normal castration-responsive prostate tissue. Further, we show that macrophages are important for prostate tumor growth and angiogenesis in the tumor and in the surrounding non-malignant tissue. In addition, the angiogenesis inhibitor Pigment epithelium-derived factor (PEDF) was found  to be down-regulated in metastatic rat and human prostate tumors. Over-expression of PEDF inhibited experimental prostate tumor growth, angiogenesis and metastatic growth and stimulated macrophage tumor infiltration and lymphangiogenesis. PEDF was found to be down-regulated by the prostate microenvironment and tumor necrosis factor (TNF) α.

CONCLUSIONS: Our studies indicate that not only the nearby tumor microenvironment but also the surrounding non-malignant prostate tissue are important for prostate tumor growth. Both the tumor and the surrounding non-malignant prostate were characterized by increased angiogenesis and inflammatory cell infiltration. Targeting the surrounding prostate tissue with castration, targeting tumor associated macrophages, or targeting the vasculature directly using inhibitors like PEDF were all shown to repress prostate tumor growth and could prove beneficial for patients with advanced prostate cancer.

Place, publisher, year, edition, pages
Umeå: Medicinsk biovetenskap , 2009. , 57 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1293
Keyword [en]
Prostate cancer, angiogenesis, castration therapy, microenvironment, stroma, tumor-associated macrophages, pigment epithelium-derived factor, PEDF, vasculature
National Category
Cell and Molecular Biology
Research subject
Pathology
Identifiers
URN: urn:nbn:se:umu:diva-30300ISBN: 978-91-7264-862-3 (print)OAI: oai:DiVA.org:umu-30300DiVA: diva2:281603
Public defence
2010-01-22, Hörsal Betula, 6M, Norrlands universitetssjukhus, Umeå, 10:00 (Swedish)
Opponent
Supervisors
Available from: 2009-12-22 Created: 2009-12-16 Last updated: 2010-04-20Bibliographically approved
List of papers
1. Androgen-insensitive prostate cancer cells transiently respond to castration treatment when growing in an androgen-dependent prostate environment.
Open this publication in new window or tab >>Androgen-insensitive prostate cancer cells transiently respond to castration treatment when growing in an androgen-dependent prostate environment.
2007 (English)In: The Prostate, ISSN 0270-4137, Vol. 67, no 4, 370-7 p.Article in journal (Refereed) Published
Keyword
Androgens/*metabolism, Animals, Anoxia/metabolism/pathology, Apoptosis, Cell Division, Epithelial Cells/cytology/metabolism, Male, Neoplasm Transplantation, Orchiectomy, Organ Size, Prostate/blood supply/cytology/metabolism, Prostatic Neoplasms/metabolism/*pathology/*surgery, Rats, Rats; Inbred Strains, Receptors; Androgen/metabolism
Identifiers
urn:nbn:se:umu:diva-6839 (URN)10.1002/pros.20473 (DOI)17192959 (PubMedID)
Available from: 2008-01-11 Created: 2008-01-11 Last updated: 2009-12-22Bibliographically approved
2. Extratumoral macrophages promote tumor and vascular growth in an orthotopic rat prostate tumor model.
Open this publication in new window or tab >>Extratumoral macrophages promote tumor and vascular growth in an orthotopic rat prostate tumor model.
2009 (English)In: Neoplasia, ISSN 1522-8002, Vol. 11, no 2, 177-186 p.Article in journal (Refereed) Published
Abstract [en]

Tumor-associated macrophages are involved in angiogenesis and tumor progression, but their role and specific site of action in prostate cancer remain unknown. To explore this, Dunning R-3327 AT-1 rat prostate tumor cells were injected into the prostate of syngenic and immunocompetent Copenhagen rats and analyzed at different time points for vascular proliferation and macrophage density. Endothelial proliferation increased with tumor size both in the tumor and importantly also in the extratumoral normal prostate tissue. Macrophages accumulated in the tumor and in the extratumoral normal prostate tissue and were most abundant in the invasive zone. Moreover, only extratumoral macrophages showed strong positive associations with tumor size and extratumoral vascular proliferation. Treatment with clodronate-encapsulated liposomes reduced the monocyte/macrophage infiltration and resulted in a significant inhibition of tumor growth. This was accompanied by a suppressed proliferation in microvessels and in the extratumoral prostate tissue also in arterioles and venules. The AT-1 tumors produced, as examined by RT(2) Profiler PCR arrays, numerous factors promoting monocyte recruitment, angiogenesis, and tissue remodeling. Several, namely, chemokine (C-C) ligand 2, fibroblast growth factor 2, matrix metalloproteinase 9, interleukin 1beta, interferon gamma, and transforming growth factor beta, were highly upregulated by the tumor in vivo compared with tumor cells in vitro, suggesting macrophages as a plausible source. In conclusion, we here show the importance of extratumoral monocytes/macrophages for prostate tumor growth, angiogenesis, and extratumoral arteriogenesis. Our findings identify tumor-associated macrophages and several chemotactic and angiogenic factors as potential targets for prostate cancer therapy.

Keyword
Animals, Biological Markers/analysis, Carbonic Anhydrases/analysis, Cell Hypoxia, Epithelial Cells/chemistry, Gene Expression/drug effects, Hypoxia-Inducible Factor 1; alpha Subunit/genetics/*metabolism, Male, Neovascularization; Physiologic, Nitroimidazoles/analysis, Orchiectomy, Prostate/blood supply/*growth & development/metabolism, RNA; Messenger/analysis, Rats, Rats; Sprague-Dawley, Receptor; Epidermal Growth Factor/drug effects/physiology, Signal Transduction/drug effects, Testosterone/*pharmacology, Vascular Endothelial Growth Factor A/analysis/genetics
Identifiers
urn:nbn:se:umu:diva-26492 (URN)19177202 (PubMedID)
Available from: 2009-10-12 Created: 2009-10-12 Last updated: 2009-12-22Bibliographically approved
3. Decreased pigment epithelium-derived factor is associated with metastatic phenotype in human and rat prostate tumors.
Open this publication in new window or tab >>Decreased pigment epithelium-derived factor is associated with metastatic phenotype in human and rat prostate tumors.
Show others...
2004 (English)In: Cancer Research, ISSN 0008-5472, Vol. 64, no 16, 5664-71 p.Article in journal (Refereed) Published
Keyword
Adenocarcinoma/*metabolism/*pathology, Animals, Cell Differentiation/physiology, Cell Line; Tumor, Disease Progression, Eye Proteins, Humans, Male, Neoplasm Metastasis, Nerve Growth Factors, Prostatic Neoplasms/*metabolism/*pathology, Protein Biosynthesis, Rats, Serpins/*biosynthesis
Identifiers
urn:nbn:se:umu:diva-14330 (URN)15313905 (PubMedID)
Available from: 2008-01-15 Created: 2008-01-15 Last updated: 2009-12-22Bibliographically approved
4. Pigment epithelium-derived factor stimulates tumor macrophage recruitment and is downregulated by the prostate tumor microenvironment
Open this publication in new window or tab >>Pigment epithelium-derived factor stimulates tumor macrophage recruitment and is downregulated by the prostate tumor microenvironment
Show others...
2010 (English)In: Neoplasia, ISSN 1522-8002, E-ISSN 1476-5586, Vol. 12, no 4, 336-345 p.Article in journal (Refereed) Published
Abstract [en]

Pigment epithelium-derived factor (PEDF) is a potent inhibitor of angiogenesis but whether it has additional effects on the tumor microenvironment is largely unexplored. We show that overexpression of PEDF in orthotopic MatLyLu rat prostate tumors increased tumor macrophage recruitment. The fraction of macrophages expressing inducible nitric oxide synthase, a marker of cytotoxic M1 macrophages, was increased, suggesting that PEDF could enhance antitumor immunity. In addition, PEDF overexpression reduced vascular growth both in the tumor and in the surrounding normal tissue, slowed tumor growth, and decreased lymph node metastasis. Contrary, extratumoral lymphangiogenesis was increased. PEDF expression is, for reasons unknown, often decreased or lost during prostate tumor progression. When AT-1 rat prostate tumor cells, expressing high levels of PEDF messenger RNA (mRNA) and protein, were injected into the prostate, PEDF is markedly downregulated, suggesting that factors in the microenvironment suppressed its expression. One such factor could be macrophage-derived tumor necrosis factor alpha (TNFα). A fraction of the accumulating macrophages expressed TNFα, and TNFα treatment downregulated the expression of PEDF protein and mRNA in prostate AT-1 tumor cells in vitro and in the rat ventral prostate in vivo. PEDF apparently has multiple effects in prostate tumors: it suppresses angiogenesis and metastasis, but it also causes macrophage accumulation. Accumulating macrophages may inhibit tumor growth, but they may also suppress PEDF and enhance lymph angiogenesis and, in this way, eventually enhance tumor growth.

Place, publisher, year, edition, pages
Neoplasia press, 2010
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-33268 (URN)10.1593/neo.92046 (DOI)000277646000005 ()20360944 (PubMedID)
Available from: 2010-04-20 Created: 2010-04-20 Last updated: 2015-10-02Bibliographically approved

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