Molecular Regulation of Inflammation and Angiogenesis in the Tumor Microenvironment

Sammanfattning: 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 ?B-crystallin in the tumor microenvironment. ?B-crystallin was first identified in a screen of proteins specifically up-regulated in endothelial cells forming vessel-like structures. We found that ?B-crystallin is expressed in a subset of tumor vessels and promotes angiogenesis by inhibiting endothelial apoptosis, suggesting that targeting of ?B-crystallin might inhibit angiogenesis and thereby decrease tumor growth. However, we also discovered an important role of ?B-crystallin in regulation of inflammatory processes. We show that ?B-crystallin increases the surface levels of E-selectin, an important leukocyte-endothelial adhesion molecule. Thereby, ?B-crystallin may alter leukocyte recruitment to inflamed tissues such as the tumor stroma. In addition, we found that ?B-crystallin is expressed in immature myeloid cells that accumulate in the periphery and at the tumor site during tumor development. Importantly, lack of ?B-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.