ScienceWeek

DEVELOPMENTAL BIOLOGY: ON ANGIOGENESIS

The following points are made by Peter Carmeliet (Nature 2005 438:932):

1) Blood vessels arose during evolution to carry oxygen to distant organs. Not surprisingly, these vessels are crucial for organ growth in the embryo and repair of wounded tissue in the adult. But an imbalance in the growth of blood vessels contributes to the pathogenesis of numerous disorders. In less than 15 years, an explosion of interest in angiogenesis research has generated the necessary insights to develop the first clinically approved anti-angiogenic agents.

2) In primitive animals, such as the worm Caenorhabditis elegans and the fruitfly Drosophila melanogaster, oxygen is capable of diffusing throughout their small bodies to all cells. In other species, which developed later in evolution and grew to larger sizes, a vascular network distributes oxygen in the blood to distant cells. The Ancient Greek physician Galen (c. 130-200) originally proposed that the blood does not circulate but is locally regenerated by the body when its supplies are consumed. Only in 1628 did William Harvey (1578-1657) discover that the heart pumps the blood around the body through arteries and that veins return the blood to the heart. A few decades later in 1661, Marcello Malphighi (1628-1694) identified the capillaries as the smallest vessels that close the circulatory loop between arteries and veins. Around the same time, Caspar Aselius (1581-1626) discovered another type of vessel, the lymphatic vessel. Because of the blood pressure, blood plasma continuously leaks from the capillaries, and lymph vessels return this fluid back to the blood circulation. Although blood vessels arose earlier in evolution, lymph vessels are only present in amphibians onwards[1]

3) In the embryo, blood vessels provide the growing organs with the necessary oxygen to develop. Apart from their nutritive function, vessels also provide instructive trophic signals to promote organ morphogenesis. Blood vessels arise from endothelial precursors, which share an origin with haematopoietic progenitors. This close link between the blood and blood vascular systems remains important for angiogenesis throughout life, even in disease. These progenitors assemble into a primitive vascular labyrinth of small capillaries -- a process known as vasculogenesis. Already at this stage, capillaries have acquired an arterial and venous cell fate, indicating that vascular-cell specification is genetically programmed and not only determined by haemodynamic force.

4) During the angiogenesis phase, the vascular plexus progressively expands by means of vessel sprouting and remodels into a highly organized and stereotyped vascular network of larger vessels ramifying into smaller ones. Nascent endothelial-cell channels become covered by pericytes and smooth muscle cells, which provide strength and allow regulation of vessel perfusion, a process termed arteriogenesis. The lymphatic system develops differently, as most lymphatics transdifferentiate from veins. Over the past 15 years, genetic studies in mice, zebrafish and tadpoles have provided insights into the key mechanisms and molecular players that regulate the growth of blood vessels (angiogenesis) or lymph vessels (lymphangiogenesis) in the embryo.[2-5]

References (abridged):

1. Ny, A. et al. A genetic Xenopus laevis tadpole model to study lymphangiogenesis. Nature Med. 11, 998 1004 (2005)

2. Carmeliet, P. Angiogenesis in health and disease. Nature Med. 9, 653 660 (2003)

3. Carmeliet, P. & Tessier-Lavigne, M. Common mechanisms of nerve and blood vessel wiring. Nature 436, 193 200 (2005)

4. Lambrechts, D. , Storkebaum, E. & Carmeliet, P. VEGF: necessary to prevent motoneuron degeneration, sufficient to treat ALS? Trends Mol. Med. 10, 275 282 (2004)

5. Luttun, A. , Autiero, M. , Tjwa, M. & Carmeliet, P. Genetic dissection of tumor angiogenesis: are PlGF and VEGFR-1 novel anti-cancer targets? Biochim. Biophys. Acta 1654, 79 94 (2004)

Nature http://www.nature.com/nature

--------------------------------

Related Material:

MEDICAL BIOLOGY: ON MODULATING ANGIOGENESIS

The following points are made by B. Sivakumar et al (J. Am. Med. Assoc. 2004 292:972):

1) It is now more than 30 years since Folkman first proposed that formation of new blood vessels (angiogenesis) was critical to tumor growth and development.(1) What was then a novel concept has during the intervening years gained widespread acceptance and is the basis not only of groundbreaking research in many fields, ranging from cancer through rheumatoid arthritis (RA) and cardiovascular disease, but also of exciting therapeutic approaches. In the 1970s, as an indicator of the emerging importance of this area, there were approximately 100 references in the National Library of Medicine's database with the key words angiogenesis or angiogenic. This increased to more than 7000 in the 1990s, although since the advent of the new millennium, there have been (at the last count) more than 13 000. Indeed, it is significant that the first antiangiogenic agent, bevacizumab, an antibody that binds to vascular endothelial growth factor (VEGF), was recently approved by the US Food and Drug Administration (FDA) for the treatment of metastatic colorectal cancer.(2)

2) The requirement for blood vessels arises from the need to maintain oxygen homeostasis, as well as to deliver nutrients and to remove waste products in vivo. The earliest vessels provide nutrients and oxygen to the growing embryo, as a result of vasculogenesis, during which precursor cells commit to form endothelial cells rather than hematopoietic cells and fuse to form a primitive meshwork. Subsequently, angiogenesis extends and remodels these structures to form the primordial aorta and vein, as well as yolk sac arteries and veins. In contrast, endothelial cell turnover in adults can often be measured in years, because the body can normally cope with changes in oxygen delivery without compromising respiration.

3) Only under certain situations, physiological and pathological, does active angiogenesis occur. In general, the common denominators are an increase in tissue mass, a reduction in oxygen levels, or both. These may occur simultaneously (eg, during tumor growth or atherosclerotic plaque development) and frequently are associated with expression of cytokines, such as tumor necrosis factor alpha (TNF-alpha) or transforming growth factor beta (TGF-beta), as well as angiogenic factors, such as VEGF. In certain conditions, hypoxia and inflammatory molecules seem to be the predominant driving force, as is the case when the vasculature is disrupted during bone fractures.(3-5)

4) In summary: The concept of manipulation of the vascular bed to either increase or decrease the number of blood vessels has attracted considerable interest. The authors focus on angiogenesis as a therapeutic target, particularly in the context of cancer and arthritis, as well as on promoting angiogenesis in cardiovascular disease and the healing of bone fractures. Although once touted almost as a panacea for treatment of tumors, as well as other diseases associated with angiogenesis, such as diabetic retinopathy or rheumatoid arthritis, it is now clear that enthusiasm for angiogenesis therapy was somewhat premature. Similarly, some clinical trials of therapeutic angiogenesis for the management of cardiovascular disease have been disappointing. Nevertheless, this field of research holds promise for more targeted therapies.

References (abridged):

1. Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med. 1971;285:1182-1186

2. Genetech Inc. FDA approves avastin, a targeted therapy for first-line metastatic colorectal cancer patients. Available at: http://www.gene.com/gene/news/press-releases/display.do?method=detail&id=7167. Accessibility verified July 19, 2004

3. Harry LE, Paleolog EM. From the cradle to the clinic: VEGF in developmental, physiological, and pathological angiogenesis. Birth Defects Res Part C Embryo Today. 2003;69:363-374

4. Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med. 2003;9:669-676

5. Lip PL, Blann AD, Hope-Ross M, et al. Age-related macular degeneration is associated with increased vascular endothelial growth factor, hemorheology and endothelial dysfunction. Ophthalmology. 2001;108:705-710

J. Am. Med. Assoc. http://www.jama.com

--------------------------------

Related Material:

MEDICAL BIOLOGY: TUMORS AND ANGIOGENESIS

The following points are made by J. Folkman and R. Kalluri (Nature 2004 427:787):

1) Many of us may have tiny tumors without knowing it. In fact, autopsies of individuals who died of trauma often reveal microscopic colonies of cancer cells, also known as "in situ tumors". It has been estimated that more than one-third of women aged 40 to 50, who did not have cancer-related disease in their life-time, were found at autopsy with in situ tumors in their breast. But breast cancer is diagnosed in only 1% of women in this age range. Similar observations are also reported for prostate cancer in men. Virtually all autopsied individuals aged 50 to 70 have in situ carcinomas in their thyroid gland, whereas only 0.1% of individuals in this age group are diagnosed with thyroid cancer during this period of their life.

2) Therefore, it has long puzzled physicians and scientists why cancer develops and progresses to be lethal only in a very small percentage of people. The realization that a lot of us carry in situ tumors, but do not develop the disease, suggests that these microscopic tumors are mostly dormant and need additional signals to grow and become lethal tumors. So, what are these additional signals, and why are most of us protected from them? The most likely answer is our body's inherent capacity to prevent the majority of these in situ tumors from recruiting their own new blood supply, thus preventing further growth owing to a lack of oxygen and nutrients. In the absence of a new supply of blood vessels by a process known as angiogenesis, an in situ tumour can remain dormant indefinitely.

3) Paradoxically, it is proposed that angiogenesis itself is under the control of many genes in our body known to promote cancer (oncogenes) or suppress growth of tumors (tumour suppressors) -- the same genes that are also involved in creating cancer cells, as encountered in the harmless in situ tumors. If the genes involved are the same, then why are most of us protected from the disease of cancer? To understand this better, we may have to define cancer as having two critical phases. In the first, acquisition of mutations, possibly due to genetic instability, leads to the transformation of normal cells in our body into cancer cells. This phase is not inherently lethal, and generally results in a microscopic tumour where the high rate of tumour cell division is balanced by cell death. The second phase involves a switch to the angiogenic phenotype, due to constant recruitment of new blood vessels, which converts the non-lethal in situ tumors into the expanding mass of tumour cells that is potentially lethal to an individual. Therefore, it is likely that there are critical governing factors that distinguish an individual's capacity to launch angiogenesis and enter a lethal phase of cancer.

4) This progression depends crucially on the balance between the in situ tumour's total angiogenic output and an individual's total angiogenic defence. The angiogenic output is contributed by growth factors such as basic FGF, VEGF, IL-8 and PDGF. An individual's defence is facilitated by endogenous angiogenesis inhibitors that are either associated with specific tissues or circulating in the blood. These inhibitors include thrombospondin, tumstatin, canstatin, endostatin, angiostatin, and interferon alpha/beta. Angiogenesis within the in situ tumour is probably initiated when the angiogenic stimulators overwhelm the host angiogenic defence. It is conceivable that such disruption in the angiogenesis balance is under the control of both the genetic make-up of any individual cancer cell and its microenvironment within the tumour. This would then explain why cancer in different individuals progresses at different rates, and also why some individuals enter the lethal phase of cancer and others do not, in spite of carrying cancer cells within their organs.(1-5)

References:

1. Black, W. C. & Welch, H. G. N. Engl. J. Med. 328, 1237-1243 (1993)

2. Hanahan, D. & Folkman, J. Cell 86, 353-364 (1996)

3. Hamano, Y. et al. Cancer Cell 3, 589-601 (2003)

4. Kalluri, R. Nature Rev. Cancer 3, 422-433 (2003)

5. Udagawa,T. et al. FASEB J. 16,1361-1370 (2002)

Nature http://www.nature.com/nature

ScienceWeek http://scienceweek.com