VEGF and the quest for tumour angiogenesis factors

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Abstract

The ability of tumours to induce new blood-vessel formation has been a major focus of cancer research over the past few decades, and vascular endothelial growth factor (VEGF) is now known to be central to this process. The quest for VEGF and other factors that promote tumour angiogenesis was initiated many decades ago, and a long and complicated path has led to the development of inhibitors of these molecules as anticancer agents. How did this field begin, and how have we arrived at our present understanding of the role of VEGF in tumour progression.

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Figure 1: The earliest in vivo images of tumour angiogenesis.
Figure 2: Effects of an anti-VEGF monoclonal antibody on angiogenesis induced by the A673 rhabdomyosarcoma cell line, as seen in the dorsal skinfold transparent chamber model in the mouse.

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I thank E. Filvaroff and N. van Bruggen for critically reading this manuscript.

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melanoma

renal-cell carcinoma

rhabdomyosarcoma

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aFgf

aFGF

angiogenin

bFgf

bFGF

EGF

EG-VEGF

Flk1

FLK1

Flt1

FLT1

FMS

HIF-1α

IL-8

KIT

PDGF

RAS

TGF-α

TGF-β

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VEGF

VEGFB

VEGFC

VEGFD

Glossary

FOLLICULAR OR FOLLICULO-STELLATE CELLS

A population of non-hormone-secreting cells in the anterior pituitary. These cells are believed to have several functions, including ion transport, phagocytosis and production of several growth factors.

NH2-TERMINAL AMINO-ACID SEQUENCING

A technique that is used to determine a portion of the amino-acid sequence of a purified protein, starting at the amino terminus. Traditionally, this is a crucial step in protein discovery as it allows verification of the identity (or novelty) of the protein and enables the design of an oligonucleotide probe that is suitable for cDNA cloning.

SECRETORY SIGNAL SEQUENCE

An amino-terminal amino-acid sequence with a hydrophobic core that directs a protein to cross the membrane of the endoplasmic reticulum, where it is removed. It is a typical structural requirement for secreted proteins.

GRANULOSA CELLS

The cells around the oocyte in the ovarian follicle, which are devoid of blood vessels. After ovulation, granulosa cells differentiate into the progesterone-producing luteal cells and this process is accompanied by extensive angiogenesis.

HUMANIZATION

A technique that is used to overcome the immunogenicity of mouse antibodies for human clinical trials. In the simplest case, the complementarity-determining regions of a mouse monoclonal antibody with the desired antigen specificity are transferred into a human antibody that therefore acquires the binding characteristics of the mouse antibody. The amino-acid sequence of the final humanized antibody is 93–95% human.

INSULINOMA

A tumour that arises from the insulin-producing β-cells in the pancreatic islets.

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