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Molecular Regulation of Inflammation and Angiogenesis in the Tumor Microenvironment
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Tumor growth and progression not only depend on properties of the malignant cells but are strongly influenced by the tumor microenvironment. The tumor stroma consists of various cell types such as inflammatory cells, endothelial cells and fibroblasts, which can either inhibit or promote tumor growth. Consequently, therapeutic targeting of the tumor stroma is increasingly recognized as an important tool to fight cancer. Two particularly important processes that contribute to the pathology of most types of tumors are angiogenesis and inflammation. In order to target these processes specifically and efficiently, it is fundamental to identify and understand the factors and signaling pathways involved.

This thesis initially describes the multiple functions of the small heat shock protein αB-crystallin in the tumor microenvironment. αB-crystallin was first identified in a screen of proteins specifically up-regulated in endothelial cells forming vessel-like structures. We found that αB-crystallin is expressed in a subset of tumor vessels and promotes angiogenesis by inhibiting endothelial apoptosis, suggesting that targeting of αB-crystallin might inhibit angiogenesis and thereby decrease tumor growth. However, we also discovered an important role of αB-crystallin in regulation of inflammatory processes. We show that αB-crystallin increases the surface levels of E-selectin, an important leukocyte-endothelial adhesion molecule. Thereby, αB-crystallin may alter leukocyte recruitment to inflamed tissues such as the tumor stroma. In addition, we found that αB-crystallin is expressed in immature myeloid cells that accumulate in the periphery and at the tumor site during tumor development. Importantly, lack of αB-crystallin resulted in increased accumulation of immature myeloid cells, which might increase tumor associated inflammation.

Finally, through combining laser microdissection of vessels from human tissue and microarray analysis, we identified a gene expression signature specifically associated with vessels in high grade glioma. Blood vessels in malignant glioma are highly abnormal and contribute to the pathology of the disease. Thus, knowledge about the molecular set-up of these vessels might contribute to the development of future vascular normalizing treatments.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2011. , 72 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 677
Keyword [en]
stroma, glioma, alphaB-crystallin, HSPB5, cryab, myeloid cells
National Category
Cell and Molecular Biology Biochemistry and Molecular Biology
Research subject
Molecular Medicine
Identifiers
URN: urn:nbn:se:uu:diva-152257ISBN: 978-91-554-8096-7OAI: oai:DiVA.org:uu-152257DiVA: diva2:413426
Public defence
2011-06-09, Rudbeck Hall, Rudbeck Laboratory, Dag Hammarskjölds väg 20, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2011-05-18 Created: 2011-04-27 Last updated: 2011-07-01Bibliographically approved
List of papers
1. alphaB-crystallin promotes tumor angiogenesis by increasing vascular survival during tube morphogenesis
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2008 (English)In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 111, no 4, 2015-2023 p.Article in journal (Refereed) Published
Abstract [en]

Selective targeting of endothelial cells in tumor vessels requires delineation of key molecular events in formation and survival of blood vessels within the tumor microenvironment. To this end, proteins transiently up-regulated during vessel morphogenesis were screened for their potential as targets in antiangiogenic tumor therapy. The molecular chaperone alpha B-crystallin was identified as specifically induced with regard to expression level, modification by serine phosphorylation, and subcellular localization during tubular morphogenesis of endothelial cells. Small interfering RNA-mediated knockdown of alpha B-crystallin expression did not affect endothelial proliferation but led to attenuated tubular morphogenesis, early activation of proapoptotic caspase-3, and increased apoptosis. alpha B-crystallin was expressed in a subset of human tumor vessels but not in normal capillaries. Tumors grown in alpha B-crystallin(-/-) mice were significantly less vascularized than wild-type tumors and displayed increased areas of apoptosis/necrosis. Importantly, tumor vessels in alpha B-crystallin(-/-) mice were leaky and showed signs of caspase-3 activation and extensive apoptosis. Ultrastructural analyses showed defective vessels partially devoid of endothelial lining. These data strongly implicate alpha B-crystallin as an important regulator of tubular morphogenesis and survival of endothelial cell during tumor angiogenesis. Hereby we identify the small heat shock protein family as a novel class of anglogenic modulators.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-16117 (URN)10.1182/blood-2007-04-087841 (DOI)000253251100048 ()18063749 (PubMedID)
Available from: 2008-04-24 Created: 2008-04-24 Last updated: 2011-07-01Bibliographically approved
2. αB-crystallin regulates expansion of CD11b+Gr-1+ cells during tumor progression
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(English)Manuscript (preprint) (Other academic)
Identifiers
urn:nbn:se:uu:diva-152231 (URN)
Available from: 2011-04-27 Created: 2011-04-27 Last updated: 2011-07-01
3. αB-crystallin influences endothelial-leukocyte interactions by increasing surface E-selectin
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(English)Manuscript (preprint) (Other academic)
Identifiers
urn:nbn:se:uu:diva-152246 (URN)
Available from: 2011-04-27 Created: 2011-04-27 Last updated: 2012-12-15
4. Transcriptional profiling reveals a distinct gene expression signature of vessels in high grade human glioma
Open this publication in new window or tab >>Transcriptional profiling reveals a distinct gene expression signature of vessels in high grade human glioma
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(English)Manuscript (preprint) (Other academic)
Identifiers
urn:nbn:se:uu:diva-152248 (URN)
Available from: 2011-04-27 Created: 2011-04-27 Last updated: 2011-07-01

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