Biological processes occurring in any organism involve the interaction of multiple cell types, biologically relevant factors, and the organism's environment. Some of the fundamental questions remaining in biology are related to understanding how the different cells within organisms communicate and organize to form an individual. One frequently studied system in which multiple cell types function together and influence each other is angiogenesis.
Angiogenesis is a biological process of generating new blood vessels from pre-existing blood vessels into a tissue or organ. Angiogenesis has been intensively studied over the past several decades because of its fundamental importance in tissue development, vascular diseases, and cancer. Under normal physiological conditions, humans or animals undergo angiogenesis only in very specific restricted situations. For example, angiogenesis is normally observed in fetal and embryonal development and formation of the corpus luteum. Post-natal angiogenesis is an important physiological function in the ovary, endometrium, placenta, and in wound healing.
New vessel growth is tightly controlled by many angiogenic regulators (see for example Folkman, J., Nature Med., 1: 27-31, 1995a), and the switch of the angiogenesis phenotype depends on the net balance between up-regulation of angiogenic stimulators and down-regulation of angiogenic suppressors. Pathological deregulation of angiogenesis is a prominent feature of a number of human diseases, including atherogenesis, arthritis, psoriasis, corneal neovascularization, diabetic retinopathy, rheumatoid arthritis, and cancer, for example during malignant transformation that facilitates tumor growth and metastasis.
In cancer, tumors induce angiogenesis by secreting various growth factors, such as vascular endothelial growth factor (VEGF), and basic fibroblast growth factor (bFGF) among others. Growth factors, such as bFGF and VEGF, can induce capillary growth into the tumor, which is thought to drive tumor expansion by supplying the tumor with nutrients and/or removing the cellular waste.
Angiogenesis is also an element of metastasis of a tumor. Single cancer cells can break away from an established solid tumor, enter the blood vessel, and be carried to a distant site, where they can implant and begin the growth of a secondary tumor. It has even been suggested that the blood vessels in a solid tumor may in fact be mosaic vessels, comprised of both endothelial cells and tumor cells. Such mosaicity allows for substantial shedding of tumor cells into the vasculature.
Angiogenesis-based anti-tumor therapies typically use natural and synthetic angiogenesis inhibitors such as angiostatin, endostatin and tumstatin. Recently the Food and Drug Administration (FDA) approved an antibody therapy targeting angiogenesis in colorectal cancer. This therapy is based on a monoclonal antibody directed against an isoform of VEGF and is marketed under the trade name Avastin®. While established anti-angiogenesis therapies are promising, the need still exists for the development of additional modulators of angiogenesis.