Anna Dimberg's research projects in tumour vascular biology

Molecular regulation of vascular abnormalization in glioblastoma

Lei Zhang, Roberta Lugano, Kalyani Vemuri, Hua Huang, Maria Georganaki, Minttu-Maria Martikainen and Anna Dimberg

Glioblastoma, the most aggressive type of glioma, are characterized by high mitotic activity, nuclear atypia, microvascular proliferation, hemorrhage and necrosis. The median survival of adult glioblastoma patients is only twelve months. Extensive angiogenesis and markedly abnormal vessels are a hallmark of glioblastoma, leading to enhanced permeability and brain oedema. However, the molecular mechanisms that underlie the extensive morphological and functional changes observed in glioblastoma vasculature are largely unknown.

We have previously identified 95 genes that are differentially expressed in glioblastoma vessels and found that many of these genes are induced in response to growth factors highly expressed in the tumour microenvironment. Among these genes, we have demonstrated that CD93 regulates the endothelial cytoskeleton and is important for formation of functional tumour vessels in glioblastoma. We are also investigating other proteins highly expressed in glioblastoma vessels to determine how these contribute to aberrant vascular function and tumour progression in glioblastoma.

The role of pleiotrophin

Pleiotrophin is a small heparin-binding growth factor that is frequently expressed in human glioblastoma and low-grade glioma, but not detectable in normal adult brain tissue. It is considered to be a pro-angiogenic growth factor, but its net effect appears to be context dependent as it can also oppose angiogenesis in some systems.

In glioma, pleiotrophin has been shown to affect migration and proliferation of tumour cells that express its receptors. Our results show that pleiotroiphin is a key inducer of vascular abnormalization in glioblastoma. We are currently exploring different possibilities to target pleiotrophin and thereby normalize tumour vessels in glioblastoma. 

A) Immunofluorescent staining of human samples from non-malignant brain (normal), oligoastrocytoma (stage II) and glioblastoma multiforme (stage IV). The vasculature in stage IV glioma is markedly abnormal. Samples have been stained with UEA-1 (green), collagen IV (red) and Hoechst (blue).
B) High magnification images of samples shown in A.

Cross-talk between pro-angiogenic and pro-inflammatory signalling pathways in the tumour microenvironment and its impact on immunotherapy

Hua Huang, Maria Georganaki, Luuk van Hooren, Alessandra Vaccaro, Alexandros Karampatzakis, Minttu-Maria Martikainen and Anna Dimberg

Tumor growth is significantly affected by recruitment of inflammatory cells. This process is regulated by endothelial activation, endothelial up-regulation of adhesion molecules that capture leukocytes and enable slow rolling, firm adhesion and transmigration into the tissue.

Pro-angiogenic signalling in the tumour microenvironment affects endothelial activation through negative crosstalk with pro-inflammatory signalling pathways. Also, the aberrant architecture and blood flow in combination with changes in endothelial gene expression may limit effector lymphocyte recruitment into the tumour.

The success of cancer immunotherapy relies on efficient recruitment of immune cells into the tumour mass. Despite recent breakthroughs, the tumour vasculature still presents a hurdle for infiltrating leukocytes that limits the efficacy of cancer immunotherapy in solid tumours.

We have shown that inhibition of VEGFR-signalling will lead to tumour vessel up-regulation of chemokines necessary recruitment of T-cells. In line with these data, we have shown that CD40-activating cancer immunotherapy can be improved by co-treatment with the VEGFR kinase inhibitor sunitinib. Future efforts include investigating new strategies for vascular targeting to improve the efficacy of immunotherapeutic drugs. The goal is to find new combinatorial therapies for cancer.