Anna Dimberg's research projects in tumour vascular biology
VASCULAR REGULATIon OF THE TUMOR MICROENVIRONMENT IN GLIOBLASTOMA
Roberta Lugano, Alessandra Vaccaro, Kalyani Vemuri, Beatriz Pereira, Patricia Fuenzalida, Stefano Barbera and Anna Dimberg
Glioblastoma, the most aggressive type of glioma, is characterized by high mitotic activity, nuclear atypia, microvascular proliferation, hemorrhage and necrosis. Extensive angiogenesis and markedly abnormal vessels are hallmarks 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 and their consequence for tumour progression are largely unknown.
We have characterized vascular gene expression in human glioblastomas and low grade gliomas and identified a subset of genes that are differentially expressed in tumour endothelial cells as compared to normal brain endothelial cells. Among these genes, we have demonstrated that CD93 regulates the endothelial cytoskeleton and is important for formation of functional tumour vessels in glioblastoma. Further, we have found that CD93 is required for organization of fibronectin in the extracellular matrix by interacting with the extracellular matrix protein MMRN2 and promoting activation of integrin β1. 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.
B) High magnification images of samples shown in A.
Regulation of leukocyte infiltration in the tumor microenvironment AND ITS IMPACT ON IMMUNOTHERAPY
Mohanraj Ramachandran, Alessandra Vaccaro, Tiarne van de Walle, Ilkka Pietilä, Stefano Barbera and Anna Dimberg
Tumor growth is significantly affected by recruitment of immune 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.
Vascular targeting can be used to improve the response to cancer immunotherapy. 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 this, cancer immunotherapy can be improved by co-treatment with the VEGFR kinase inhibitor sunitinib. Tumour endothelial cells can also limit the efficacy of immunotherapy through inducing immunosuppressive proteins such as IDO1 in response to IFN-γ secreted by activated T-cells. Pharmacological inhibition of IDO1 can improve T-cell activation and therapy response.
We are currently investigating alternative strategies to improve leukocyte recruitment by altering tumour vessel phenotype. The goal is to find new combinatorial therapies that can be used to boost anti-tumour immune response and improve patient prognosis.