Research

Introduction

The overall goals of our ongoing research are to identify and to characterize molecular targets controlling inflammatory and tumor angiogenesis and lymphangiogenesis, using genetic disease models together with genomics approaches and chemical library screens, and to characterize genetic polymorphisms to determine disease susceptibility and to develop individualized therapeutic strategies.

Tumor angiogenesis – a novel therapeutic target

Cancer research and therapy has predominantly focused on the genetic alterations and the abnormal growth of cancer cells. However, non-cancerous cells in the tumor stroma play an essential role in cancer progression. In particular, tumors need to induce the growth of new blood vessels (angiogenesis) in order to grow beyond minimal size and to metastasize. We have identified thrombospondin-2 (TSP-2) as a novel, potent inhibitor of cancer growth and tumor angiogenesis. We currently explore mechanisms of TSP-2 action in vitro and in vivo, using transcriptional profiling and functional studies in genetic mouse models. The overall aim is the development of new anti-cancer therapies.

Chemoprevention of carcinogenesis and ultraviolet-B-induced skin damage

We have identified the natural angiogenesis inhibitor thrombospondin-1 (TSP-1) as one of the most potently downregulated genes during the distinct steps of skin carcinogenesis and after ultraviolet B (UVB) irradiation. Based upon these findings, we developed a transgenic model for targeted overexpression of TSP-1 and demonstrated that TSP-1 inhibited multistep carcinogenesis and organ metastasis, and also completely prevented UVB-induced photodamage and aging of the skin. To identify defined small synthetic TSP-1-inducing molecules that might be used clinically for the chemoprevention and/or treatment of human cancers, we currently screen chemical libraries in high throughput assays. We are also interested whether specific polymorphisms of the TSP-1 gene might be detected in patients with high cancer incidence.

Tumor lymphangiogenesis and metastasis

Metastasis to regional lymph nodes represents the first step of tumor dissemination in most cancers and serves as a major prognostic indicator and parameter for the choice of adjuvant therapy. However, little is known about the mechanisms how tumor cells matastasize to lymph nodes. In 2001, we discovered the first direct evidence for active tumor lymphangiogenesis, demonstrating that overexpression of the growth factor VEGF-C by breast cancer cells resulted in enhanced lymphangiogenesis and lymph node metastasis. These findings led to a new model of cancer progression and suggested tumor lymphangiogenesis as a new prognostic parameter and therapeutic target. Our recent results reveal that tumor lymphangiogenesis indeed serves as a prognostic indicator for lymph node metastasis and survival in human malignant melanomas. We are particularly interested in identifying new therapeutic targets to block metastatic cancer spread and to inhibit the growth of existing lymph node metastases. To this end, we use laser capture microdissection of normal and malignant tissues, and co-culture systems for metastastic and non-metastatic cancer cells with lymphatic or blood vascular endothelial cells. These models allow us to screen – using genomics and proteomics approaches - for the distinct effects of metastatic cancer cells on lymphatic endothelium, and for the effects of lymphatic endothelium-derived factors on the activation of metastatic cancer cells, potentially leading to the identification of novel targets for advanced cancer therapy.

Transcriptional profiling for target identification

In contrast to the extensive molecular and functional characterization of tumor angiogenesis, little is known about the mechanisms how tumor cells gain entry into the lymphatic system, mainly due to the lack of specific markers and of identified mediators of lymphatic vessel formation. We have developed a new method for the selective isolation and culture of human blood vascular and lymphatic endothelial cells and have identified more than 300 lymphatic-specific and blood vessel-specific genes. We are investigating whether these genes are also involved in the pathogenesis of inflammatory diseases and of human lymphedema, and whether some of these gene products might serve as novel targets to inhibit tumor angiogenesis, lymphangiogenesis and metastasis. Interestingly, we recently found that cancer viruses can re-program the vascular transcriptome, potentially identifying new molecular targets for the treatment of AIDS-associated malignancies.

New approaches to treat inflammatory diseases

Psoriasis is a chronic inflammatory skin disease that affects approximately 2% of the population. In 1994, we identified VEGF-A as the major factor responsible for the vascular pathology of psoriasis. More recently, we found that VEGF-A overexpressing transgenic mice are unable to downregulate experimentally induced inflammation and that they develop a chronic inflammatory disease that almost completely resembles human psoriasis, therefore representing a new in vivo model for this disease. We also found that blockade of VEGF-A signaling potently inhibited inflammation. These findings have stimulated developments by the pharmaceutical industry to develop anti-VEGF therapies for human psoriasis and other inflammatory diseases, and our ongoing research aims to take advantage of this disease model for further elucidate the molecular mechanisms of chronic inflammation and to identify new anti-inflammatory drugs.

Genetic polymorphisms, disease susceptibility, and pharmacogenomics

Recent evidence indicates that genetic polymorphisms of distinct genes within the general population are responsible for the susceptibility to many of the major chronic diseases, and they they might also be responsible for an individual’s response towards drug therapy. Recent studies indicate that distinct single nucleotide polymorphisms (SNPs) of the VEGF gene are associated with reduced or increased levels of circulating VEGF in normal individuals, and that distinct polymorphisms are found significantly more often in patients with severe psoriasis, as compared with healthy control subjects. These findings indicate that the individual “angiogenetic constitution” determines disease susceptibility. Therapeutic blockade of the VEGF-A/VEGF-A receptor system might represent a novel, pharmacogenomic approach for the future treatment of psoriasis, and we aim to identify individuals that might be particularly sensitive to anti-VEGF-A therapies.

Research Perspectives

Angiogenesis and lymphangiogenesis are currently receiving tremendous scientific and clinical interest as novel targets for the treatment of cancer and of inflammatory diseases. The identification and characterization of new mediators of lymphatic and blood vessel growth and function will likely lead to the development of new therapies for a number of human diseases. Comprehensive research strategies include target identification by transcriptional profiling, validation by genetic models, and establishment of high-throughput screening assays. The identification of genetic polymorphisms that predispose to the development of clinical disease and to the positive response (or adverse effects) to specific drug therapies will likely lead to the future development of individualized, molecular pharmacogenomic therapies for cancer and many other human diseases, avoiding potentially life-theatening adverse effects and providing enhanced efficiency.