EXPLORATION AND VALIDATION OF ANGIOGENESIS MARKERS IN HUMAN CANCERS

Activated angiogenesis and tumor-vascular interactions are essential for tumor growth and spread, and tumors may be treated by attacking their blood supply, as suggested by Folkman in 1971. Recently, anti-angiogenesis drugs have been approved for clinical use, but predictive factors to select patients for optimal treatment are lacking. The aim of this study was to explore and validate tissue-based angiogenesis biomarkers, that can assist clinicians in patient stratification for targeted treatment and response evaluation. A second aim was to explore novel mechanisms of tumor associated angiogenesis. In several clinical studies, we have shown that markers of active angiogenesis, especially microvessel proliferation (MVP) and glomeruloid microvascular phenotype (GMP) can predict aggressive tumors and poor prognosis. Both increased angiogenesis, and vascular invasion by tumor cells, are associated with specific gene expression patterns, and microvessel proliferation was inversely associated with MRI-estimated blood flow and poor prognosis. In terms of treatment, anti-angiogenesis therapy (VEGF-blocking) was found to be associated with 30% clinical response in metastatic melanoma. In locally advanced breast cancer, presence of the GMP phenotype was associated with tumor hypoxia and predicted lack of chemotherapy response. In experimental breast cancer studies, we showed that HSP27 and other factors are important for angiogenesis regulation, tumor dormancy, and tumor prognosis. In ongoing studies, we have identified alternative angiogenic drivers and potential treatment targets within the group of aggressive basal-like breast cancers (in prep.).

Activated angiogenesis and tumor-vascular interactions are essential for tumor growth and spread, and tumors may be treated by attacking their blood supply, as suggested by Folkman in 1971. Recently, anti-angiogenesis drugs have been approved for clinical use, but predictive factors to select patients for optimal treatment are lacking. The aim of this study is to explore and validate novel angiogenesis markers, both tissue-based (tumor tissue) and systemic that can assist clinicians in patient stratificat ion for targeted treatment and response evaluation. A second aim is to explore mechanisms of tumor associated angiogenesis. The project has two arms. First, angiogenesis markers will be studied in various human tumors, to examine their ability to predict aggressive tumor subgroups, prognosis, and treatment response. We will focus on our novel angiogenesis indicators (vascular proliferation, glomeruloid microvascular proliferation, nestin/Ki-67), and we will use our collections of over 2000 human cancers, as well as ongoing prospective studies. Preliminary and novel data indicate that vascular proliferation is a strong angiogenesis marker in 3 independent series of breast cancer, and nestin/Ki-67 is markedly associated with clinical progress of prostate ca ncer. Second, in experimental studies, novel markers of activated endothelium will be explored by microarray screen after a) stimulation of endothelial cells with tumor cell conditioned medium, and b) hypoxia exposure of endothelial and tumor cells. Preli minary data indicate that multiple novel candidate genes are up-regulated in endothelium under these conditions. Selected markers are being validated in studies of different human cancers with clinical information and follow-up data.