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Translating angiogenesis research into the clinic: the challenges ahead

Department of Vascular Biology and Angiogenesis Research, Tumor Biology Center, D-79106 Freiburg, Germany

View larger version (16K): [in a new window]   Figure 1. Number of angiogenesis-related articles published in Medline. The annual number of angiogenesis-related publications has increased by more than a factor 10 in the last 10 years (squares: number of articles with the term "angiogenesis" in the title; circles: number of articles with the term "angiogenesis" in any Medline heading).

View larger version (27K): [in a new window]   Figure 2. Clinically pursued avenues to therapeutically interfere with vascular endothelial growth factor (VEGF)/VEGFR signalling. Production of VEGF in VEGF-producing cells can be blocked with VEGF ribozymes or VEGF siRNAs. VEGF protein can be neutralized with neutralizing antibodies (Avastin), soluble receptors (VEGF trap) or VEGF aptamers. Activation of the VEGF receptors can be effectively inhibited with specific small molecular weight tyrosine kinase inhibitors. Lastly, the synthesis of VEGF receptors can be blocked with VEGFR ribozymes or siRNAs.

View larger version (141K): [in a new window]   Figure 3. Morphology-based histological techniques to functionally assess the vasculature of tumours. (A) Fluorescent-micrographic image of the dense vascular network of an experimental tumour using CD31 immunohistochemistry. Pan-endothelial cell markers such as vWF, CD31, or CD34 can be used to determine the overall microvessel density (MVD), which is a global angioarchitectural readout of the average intercapillary distance. (B) Double labelling of blood vessels (CD31, brown staining) and proliferating cells (Ki67, dark nuclei) in a human glioblastoma. Co-localization of CD31 and Ki67 staining allows the detection of the few proliferating endothelial cells (arrows) among the many proliferating tumour cells. (C) Fluorescent microscopic triple staining of tumour cell nuclei (Hoechst stain, blue), blood vessels (CD31, red), and proliferating endothelial cells (Ki67, green) in an experimental human tumour growing in an immunocompromised mouse. The anti-murine Ki67 stains only proliferating mouse cells and not the xenografted human tumour cells allowing the specific detection of the proliferatin, angiogenic mouse blood vessel compartment. (D) Three-dimensional co-localization of an endothelial cell marker (CD31, green) and a mural cell marker (desmin, red) demonstrating the intense mural coverage in the quiescent subcutaneous vasculature of the mouse. Correspondingly, the degree of maturation of the tumour vasculature can be traced by employing appropriate mural cell markers (-smooth muscle actin, desmin, NG2, RGS5).

View larger version (51K): [in a new window]   Figure 4. Research hierarchy from basic research-driven target identification and validation to clinical exploitation. The arrow denotes the relative knowledge gradient of the discipline. Much has been learnt about the basic mechanisms of angiogenesis within the last 20 years and solid proof-of-principle and proof-of-concept experiments have been performed in laboratory animals to demonstrate that anti-angiogenic intervention can not just halt tumour progression but actually induce active tumour regression. More than 50 compounds with anti-angiogenic activity are presently in various phases of clinical development. Yet, the inclusion and exclusion criteria of these clinical trials are largely not angiogenesis-based. Likewise, monitoring techniques to trace the efficacy of an anti-angiogenic intervention are urgently required. The necessary intermediate step, a better knowledge of the functional properties of the vasculature in human tumours, is emerging as the rate-limiting step in translating basic angiogenesis knowledge rationally into the clinic. Work aimed at better analysing the human tumour vasculature will also lead to the development of useful techniques for individualized functional angiodiagnostic procedures.