Angiogenesis (blood vessel growth), lymphangiogenesis (lymph system growth) are all intrinsically connected with lymphedema and share many of the same genes. We have several pages on both processes.
May 19, 2008
|Process of Angiogenesis
Physiological and pathological angiogenesis
tissues develop a vascular network that provides
cells with nutrients and oxygen and enables them to eliminate
metabolic wastes. Once formed, the vascular network is a stable system
that regenerates slowly.
In physiological conditions, angiogenesis occurs primarily in embryo development, during wound healing and in response to ovulation.
However, pathological angiogenesis, or the abnormal rapid proliferation of blood vessels, is implicated in over 20 diseases, including cancer, psoriasis and age-related macular degeneration.
| The angiogenic
|The normal regulation of
angiogenesis is governed by a fine balance between factors that induce
the formation of blood vessels and those that halt or inhibit the
process. When this balance is destroyed, it usually results in
pathological angiogenesis which causes increased blood-vessel formation
in diseases that depend on angiogenesis.
More than 20 endogenous positive regulators of angiogenesis have been described, including growth factors, matrix metalloproteinases, cytokines, and integrins. Growth factors, such as vascular endothelial growth factor (VEGF), transforming growth factors (TGF-beta), fibroblast growth factors (FGF), epidermal growth factor (EGF), angiogenin, can induce the division of cultured endothelial cells thus indicating a direct action on these cells.
However, other factors have virtually no effect on the division of cultured endothelial cells or, in the case of TGF-beta and TNF-alpha, paradoxically inhibit their growth indicating that their angiogenic action is indirect.
The Body's Control
Angiogenesis occurs in the healthy body for healing wounds and for restoring blood flow to tissues after trauma, injury or insult. In females, angiogenesis also occurs during the monthly reproductive cycle (to rebuild the uterus lining, to mature the egg during ovulation) and during pregnancy (to build the placenta, the circulation between mother and fetus).
The healthy body controls angiogenesis through a series of "on" and "off" switches:
When angiogenic growth factors are produced in excess of angiogenesis inhibitors, the balance is tipped in favor of blood vessel growth. When inhibitors are present in excess of stimulators, angiogenesis is stopped. The normal, healthy body maintains a perfect balance of angiogenesis modulators. In general, angiogenesis is "turned off" by the production of more inhibitors than stimulators.
Angiogenesis inhibitors are natural molecules present in tissues that halt the angiogenic process.
in Disease: The Big Picture
In many serious diseases states, the body loses control over angiogenesis. Angiogenesis-dependent diseases result when new blood vessels either grow excessively or insufficiently.
Angiogenesis is a
disease common denominator
In 1994, the Angiogenesis Foundation identified angiogenesis as a "common denominator" in society's most important diseases. Angiogenesis therapies - designed to "turn on" or "turn off" - are revolutionizing medicine by providing a unified approach for treating crippling and life-threatening conditions. Currently, more than 200 biotechnology, genomics, and medical device companies and every major pharmaceutical company are racing to develop new angiogenesis-based medicines.
The process of angiogenesis occurs as an orderly series of events:
1787 - British surgeon Dr. John Hunter first uses the term 'angiogenesis' (new blood vessel growth) to describe blood vessels growing in the reindeer antler
1935 - Boston pathologist Dr. Arthur Tremain Hertig describes angiogenesis in the placenta of pregnant monkeys.
1971 - Surgeon Dr. Judah Folkman hypothesizes that tumor growth is dependent upon angiogenesis. His theory, published in the New England Journal of Medicine, and is initially regarded as heresy by leading physician and scientists.
1975 - The first angiogenesis inhibitor is discovered in cartilage by Dr. Henry Brem and Dr. Judah Folkman.
1984 - The first angiogenic factor (basic fibroblast growth factor, bFGF) is purified by Yuen Shing and Michael Klagsbrun at Harvard Medical School.
1989 - One of the most important angiogenic factors, vascular endothelial growth factor (VEGF), is discovered Dr. Napoleone Ferrara by Dr. Jean Plouet. It turns out to be identical to a molecule called Vascular Permeability Factor (VPF) discovered in 1983 by Dr. Harold Dvorak.
1989 - The first successful treatment of an angiogenesis-dependent benign tumor (pulmonary hemangioma) using interferon alfa2a is reported by Dr. Carl White, a pediatric radiologist, in Denver.
1992 - The first clinical trial of an antiangiogenic drug (TNP-470) begins in cancer patients, sponsored by TAP Pharmaceuticals
1994 - The Angiogenesis Foundation is founded to improve global efforts by facilitating the development and application of angiogenesis-based medicines
1997 - First angiogenesis-stimulating drug (becaplermin, Regranex) is FDA-approved for treatment of diabetic foot ulcers
1997 - Dr. Michael O'Reilly publishes research finding in the journal Nature showing complete regression of cancerous tumors following repeated cycles of antiangiogenic therapy using angiostatin and endostatin
1998 - First angiogenesis-stimulating laser is FDA-approved for the treatment of severe, end-stage coronary disease.
1999 - First vascular targeting therapy is FDA-approved for treatment of age-related macular degeneration
1999 - Massive wave of antiangiogenic drugs in clinical trials: 46 antiangiogenic drugs for cancer patients; 5 drugs for macular degeneration; 1 drug for diabetic retinopathy; 4 drugs for psoriasis
1999 - Massive wave of angiogenesis-stimulating drugs in clinical trials: 5 drugs for coronary artery disease; 5 drugs for peripheral vascular disease; 1 drug for stroke; 10 drugs for wound healing.
1999 - Laboratory research, led by Dr. Robert Kerbel and Dr. Judah Folkman shows that some traditional cytotoxic chemotherapies may inhibit tumor angiogenesis when given at low-doses
1999 - Dr. Richard Klausner, Director of the U.S. National Cancer Institute designates the development of antiangiogenic therapies for cancer as a national priority.
2003 - The monoclonal antibody drug Avastin (Bevacizumab) becomes the first antiangiogenic drug shown in large-scale clinical trials inhibiting tumor blood vessel growth can prolong survival in cancer patients.
To find out more about angiogenesis and angiogenesis-based medicines, please return to our homepage.
by Chaya Venkat
article is intended to provide a little background on angiogenesis.
Angiogenesis (angio - blood vessel, genesis - creation) is the process by which new blood vessels, called capillaries are formed. Normal angiogenesis occurs under very tight physiological regulation when stimulators and inhibitors work in balance with each other. Normally the proliferation rate of endothelial cells (capillaries are lined with endothelial cells) is very slow, with duplication times for these cells exceeding 1,000 days. There are a few exceptions where angiogenesis proceeds much more rapidly, in a matter of just a few days: in wound healing, pregnancy, during menstruation, and also in cancer.
Tumor cells need a rich blood supply in order to grow and metastasize. The switch in tumors from the resting state to malignant growth is signaled by the commencement of the angiogenesis process. The NCI has declared research and clinical trials using anti-angiogenesis approaches its top priority. There is now clear evidence that anti-angiogenesis not only will be useful in the control of solid tumors, but also may be valuable as therapy for patients with leukemia and myeloma. Here is the URL for PubMed: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed. If you type the keywords "cll" "and" "angiogenesis", and search the site, a dozen articles pop up. Same thing with the Blood-Online website. Come on, try it. And read some of the abstracts. Just remember, buzzwords and jargon are not brain surgery, a lot of people use jargon to baffle you with their bull@#$% when they cannot dazzle you with their brilliance. Me, I do that only rarely!
There are more than 40 anti-angiogenesis compounds identified thus far, dealing with different aspects of the angiogenic pathway. Many clinical trials are underway, for just about every conceivable cancer under the sun. Unfortunately they have not yet percolated down to the CLL group, (why am I not surprised?) except for a couple of trials using thalidomide. It may take a while for some of the more potent anti- angiogenic compounds like Endostatin, angiostatin and Canstatin to reach us. So what can you do to limit your exposure to angiogenesis, while you are waiting patiently for the medical establishment to notice us? (I am assuming you are not pregnant or lactating. If you are, talk to your doctor before you do anything. Prevention of angiogenesis does truly horrid things to babies, remember the thalidomide babies back in the 50's and 60's?).
The five links below have a lot of information on angiogenesis and how to control it. The first two are particularly user friendly.
BIDMC/Harvard Medical School
dmoz open directory
Angiogenesis is the physiological process involving the formation of new blood vessels from pre-existing vessels. This is a normal process in growth and development, as well as in wound healing. However, this is also a fundamental step in the transition of tumors from a dormant state to a malignant state.
Cancer cells are cells that have lost control of their ability to divide in a controlled fashion. A tumor consists of a population of rapidly dividing and growing cancer cells. Mutations rapidly accrue within the population. These mutations (variation) allow the cancer cells (or sub-populations of cancer cells within a tumor) to develop drug resistant and escape therapy. Tumors cannot grow beyond a certain size, generally 1-2 mm3, due to a lack of oxygen and other essential nutrients.
Tumors induce blood vessel growth (angiogenesis) by secreting various growth factors (e.g. Vascular Endothelial Growth Factor or VEGF). Growth factors, such as bFGF and VEGF can induce capillary growth into the tumor, supplying required nutrients and allowing for tumor expansion. Thus angiogenesis is a necessary and required step for transition from a small harmless cluster of cells, to a large tumor. Angiogenesis is also required for the spread of a tumor, or metastasis. 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. Evidence now suggests that the blood vessel in a given solid tumor may be in fact be mosaic vessels, comprised of endothelial cells and tumor cells. This mosaicity allows for substantial shedding of tumor cells into the vasculature. The subsequent growth of such metastases will also require a supply of nutrients and oxygen.
Endothelial cells are much more genomically stable than cancer cells, and have a doubling time of approx 120 days. The genomic stability allied to their longevity (compared to the tumor cell), makes then an ideal target for therapies directed against them. They will not 'escape' therapy, as they will not undergo mitosis at such a rapid rate and carry any drug resistance variation through to the next generation within the lifespan of the therapy.
Angiogenesis research is a cutting edge field in cancer research, and recent evidence also suggests that traditional therapies, such as radiation therapy, may actually work in part by targeting the genomically stable endothelial cell compartment, rather than the genomicaly unstable tumor cell compartment. In short, the therapy is the selection agent which is being used to kill a cell compartment. Tumor cells evolve resistance rapidly due to rapid generation time (days) and genomic instability (variation), whereas endothelial cells are a good target because of a long generation time (months) and genomic stability (low variation).
This is a prime example of evolution in action at the cellular level, using a selection pressure to target and differentiate between varying populations of cells. The end result is the extinction of one species or population of cells (endothelial cells), followed by the collapse of the ecosystem (the tumor).
Angiogenesis-based tumour therapy relies on the existence of natural angiogenesis inhibitors like angiostatin. endostatin, and tumstatin. These are proteins that mainly originate as specific fragments pre-existing structural proteins like collagen or plasminogen.
by Kate L Pugh
The process by which new blood capillaries grow into a wound space after injury is known as angiogenesis. Wound angiogenesis is an important part of the proliferative phase of healing; in fact the term `granulation tissue' was used by John Hunter in 1787  to describe the appearance of the prominent blood vessels of the initial connective tissue formed in the wound space.
Healing of any skin wound other than the most superficial cannot occur without angiogenesis. Not only does any damaged vasculature need to be repaired, but the increased local cell activity necessary for healing requires an increased supply of nutrients from the bloodstream. Moreover, the endothelial cells which form the lining of the blood vessels are important in themselves as organizers and regulators of healing.
It is interesting to note that angiogenesis also occurs in many other situations, including solid tumour growth and metastasis; rheumatoid arthritis; psoriasis; scleroderma; placental growth and embryo implantation; and three common causes of blindness - diabetic retinopathy, retrolental fibroplasia and neovascular glaucoma (in fact, diseases of the eye are almost always accompanied by vascularization ) , . The process of wound angiogenesis has many features in common with tumour angiogenesis .
Angiogenesis proceeds concurrently with the formation of new tissue (granulation tissue), which typically begins about 4 days post-wounding . It is stimulated by the chemicals (soluble factors) released by wounded tissue . The resulting processes are tightly regulated by cell-cell interactions, cell-ECM interactions and cell-soluble factor interactions .
A blood capillary consists of a hollow tube lined with endothelial cells. The outside of the tube is covered with a layer known as the basement membrane, a major component of which is collagen IV, and which also contains fibronectin and proteoglycans (compounds consisting mainly of polysaccharides but also containing protein) .
Angiogenesis begins with degradation of the basement membrane, followed by migration of endothelial cells out of the vessel. These cells then form into a tube which `sprouts' from the old capillary and is extended further into the wound space as the cells behind the leading tip begin to proliferate. The tips of such tubes can branch and eventually join up with other sprouts to form a closed loop through which blood can flow.
The sprouting process begins again from these new vessels, until the wound space is permeated by a network of new capillaries. The cells of the capillaries first synthesize themselves a provisional covering containing fibronectin and proteoglycans, and finally form a true basement membrane [6, pages 18-19].
As the granulation tissue matures, most of its vessels begin to disappear . The endothelial cells begin to undergo programmed cell death (apoptosis) and are removed from the tissue by scavenging macrophages .
Lymphedema People Angiogenesis Related Pages:
Angiogenesis and Cancer
Angiogenesis and Cancer Control
Angiogenesis Inhibitors and Cancer
Lymphedema People Lymphangiogenesis Related Pages:
The Formation of
Lymphatic Vessels and Its Importance in the Setting of Malignancy
Lymphangiogenesis Lymphedema and Cancer
Lymphangiogenesis and Gastric Cancer
Lymphangiogenesis in Head and Neck Cancer
Lymphangiogenesis and Kaposi's Sarcoma VEGF-C
Lymphangiogenesis in Wound Healing
A model for gene therapy of human hereditary lymphedema
VEGFR-3 Ligands and Lymphangiogenesis (1)
VEGFR-3 Ligands and Lymphangiogenesis (2)
VEGFR-3 Ligands and Lymphangiogenesis (3)
Vascular Endothelial Growth Factor; VEGF
VEGF-D is the strongest angiogenic and lymphangiogenic effector
Inhibition of Lymphatic Regeneration by VEGFR3
VEGFR3 and Metastasis in Prostate Cancer
Lymphedema People Genetics, Research, Lymphangiogenesis, Angiogenesis Forum
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Support group for parents, patients, children who suffer from all forms of lymphangiectasia. This condition is caused by dilation of the lymphatics. It can affect the intestinal tract, lungs and other critical body areas.
Disorders Support Group @ Yahoo Groups
While we have a number of support groups for lymphedema... there is nothing out there for other lymphatic disorders. Because we have one of the most comprehensive information sites on all lymphatic disorders, I thought perhaps, it is time that one be offered.
Information and support for rare and unusual disorders affecting the lymph system. Includes lymphangiomas, lymphatic malformations, telangiectasia, hennekam's syndrome, distichiasis, Figueroa
syndrome, ptosis syndrome, plus many more. Extensive database of information available through sister site Lymphedema People.
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Page Updated: Dec. 15, 2011