ANGIOGENESIS AND CANCER
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 23, 2008
|Author: David Olle|
|Published on: November 12, 2000|
Judah Folkman is a surgeon with the eye of a researcher. More than
thirty years ago, when he saw the bloody red appearance of malignant
tumors,he postulated that they were caused by the creation of new blood
vessels within the tumors. At the time, his ideas were greeted with
skepticism within the scientific community, since he did not have the
research data to back him up.
Angiogenesis as a normal process
Angiogenesis is a normal process in the body, and involves the formation of new blood vessels from existing ones. Angiogenesis is needed whenever there is growth of new tissues, such as during fetal development, wound healing, and the menstrual cycle. An extensive network of fine blood vessels (called capillaries) is needed to provide the cells with necessary nutrients and oxygen. Vessel growth is normally controlled by a finely tuned balance between angiogenic inhibitors and stimulators (activators). When new capillary growth is needed, the angiogenic stimulators send out signals to the endothelial cells that line blood vessels. The activated endothelial cells then make enzymes that break down the surrounding tissue (extracellular matrix). This allows the endothelial cells to advance beyhond the confines of the blood vessel. The endothelial cells continue to divide and differentiate, forming new capillary branches.2
Angiogenesis in the cancer process
If it weren't for the process of angiogenesis, cancer tumors would remain at microscopic size. In order to continue to grow, the tumor effects a shift in the equilibrium between stimulators and inhibitors. In particular,researchers have found out that vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF)are overexpressed in many tumors and seem to be the most important activators in sustaining cancer growth. In some cases, angiogenic inhibitors can become downregulated and even nonfunctional.
this has been shown to occur with mutation of the tumor suppressor gene, p53.With new capillary growth, the cancer cells now have nourishment to continue to grow, and with access to the circulatory system, can spread to other parts of the body. Tumor cells produce inhibitory as well as stimulatory factors. In many cases, the amount of inhibitory factors produced is sufficient to keep secondary tumors in check. This may account for those cases where the cancer spreads rapidly after the surgeon removes the primary tumor.
Dr. Folkman's breakthrough
After toiling for endless years in the lab, a breakthrough finally came in 1994. Dr. Folkman and his colleagues isolated the first natural angiogenesis inhibitor in mice, naming it angiostatin.The following year, another inhibitor even more potent was discovered,which was named endostatin. With guarded optimism, the first human clinical trials using endostatin began in 1999. This trial is a Phase 1 trial that is designed more to study safety of the drug rather than its effectiveness.This type of trial typically uses small numbers of patients;in this case the patients were in advanced stages of cancer. To learn more, please click on the following PBS link to access the PBS web page that is a companion piece to the excellent PBS program on television, "Cancer Warrior" broadcast on February 28. The program describes in dramatic detail how Dr. Folkman and his colleagues discovered angiogenesis inhibitors. While on the web page, click on "Designing Clinical Trials". The article explains why the public should not expect to see definitive cancer cures from these preliminary trials. Even so, endostatin has shown to be remarkably non-toxic compared to chemotherapy, and many patients have shown an arrest in tumor growth. The actual determination of effectiveness will take place during follow-up trials.
Current clinical trials
Now that Dr. Folkman's theory is widely accepted, angiogenesis inhibitors are being studied in over 100 laboratories, including around 40 biotechnology companies. Clinical trials of around 20 experimental drugs are currently in progress. They range from Phase 1 to large scale Phase 3 trials that directly lead to FDA approval for marketing of the drugs. The drugs are designed to block angiogenesis at various stages, including blocking the activators, blocking matrix breakdown, or inhibiting the endothelial cells directly. 3 They are being tested against a broad range of cancers, including breast, lung, kidney, melanoma, brain and multiple myeloma. Of particular interest is the testing of thalidomide, which achieved notoriety in the 1960's, when it caused the birth of thousands of babies with limb abnormalities. It now appears the the fetal abnormalities were caused by thalidomide's action as a angiogenesis inhibitor.
It is important to realize that the primary goal of angiogenesis inhibitors is to keep cancers in check, rather than to effect a complete cure. It would, therefore, most likely require lifetime treatment. Since angiogenesis inhibitors are directed toward normal epithelial cells, it is unlikely that drug resistance will be a problem, as is the case with chemotherapy drugs. Drug resistance develops because cancer cells are genetically unstable, and through mutations produce cells that are resistant to drugs.
Work is in progress to develop laboratory tests that could detect cancers based on the angiogenesis concept. The tests could have application in checking for secondary tumors after the surgeon has removed the primary tumors. 6
Finally, I should mention that many solid tumors have multiple defects in the expression of angiogenic regulators. These situations may rrequire treatment with several angiogenic inhibitors. 1
4. Gaiso, M. Antiangiogenesis: A New Anticancer Therapy? Medscape Oncology 2(1), 1999
5. Lush, R. et.al., Review of Three New Agents that Target Angiogenesis, Matrix Metalloproteinases, and Cyclin-Dependent Kinases Moffitt
Universitätsklinikum Charité, Berlin, Germany
To the Editor:Two stimulating reviews1,2 on angiogenesis in cancer were published in the February 15, 2001, issue of the Journal of Clinical Oncology, which we read with great interest. Miller et al1 pointed out that microvessel density returned to normal after remission in acute myeloid leukemia and myeloma. In multiple myeloma we reported for the first time that a significant decrease in the microvessel density occurred in patients who achieved a complete or partial remission after chemotherapy in comparison to their pretreatment values (P < .01).3,4 On the contrary, in patients who did not achieve a remission, no significant change in the bone marrow microvessel density could be detected. In the article cited by Miller et al, a significant difference in bone marrow angiogenesis was found in patients with active versus nonactive myeloma, but this was a comparison of two different patient groups.5
Poon et al2 concluded in the abstract of their review that circulating vascular endothelial growth factor (VEGF) levels were a "reliable surrogate marker of angiogenic activity" in cancer patients, but this conclusion seems premature before a correlation between tumor angiogenesis and circulating VEGF levels has been shown for a variety of malignant tumors. Although the number of publications on tumor angiogenesis or circulating VEGF levels is comparatively high, studies showing a correlation between circulating VEGF levels and tumor angiogenesis are extremely rare. Furthermore, in some of these studies a significant difference in dichotomized groups was shown but not a correlation on an individual level. The clinical value of microvessel density has been established, for example, in breast cancer.6,7 VEGF is known to be released by several types of blood cells. Circulating VEGF was shown not to be correlated with microvessel density or VEGF expression in breast cancer in recent studies.8,9 In another report, tumor vascularity was correlated directly with VEGF production by the tumor, but once again no correlation was found either between the number of vessels in the tumor or the production of VEGF by tumor cells and the level of serum VEGF.10 In the study11 that was cited by Poon et al as having shown a positive correlation between serum VEGF levels and tumor VEGF expression in breast cancer, only 19% of patients with VEGF expression in the tumor tissue had elevated VEGF serum levels, so that the sensitivity of the serum VEGF in this study seems to be too low for calling it a reliable marker. To give another example among malignant diseases, in multiple myeloma we were unable to find a correlation between serum VEGF levels12 and bone marrow microvessel density, which has been shown to be a prognostic factor for survival.13 Thus prognostic significance of circulating VEGF in cancer patients as reviewed by Poon et al does not necessarily mean that "circulating VEGF level is a good reflection of tumor angiogenic activity." This issue may be important in the context of future antiangiogenic treatment strategies that should be aimed against tumor angiogenesis rather than circulating VEGF levels.
University of Hong Kong Medical Center, Hong Kong, China
In Reply:We thank Drs Sezer, Jakob, and Niemöller for their comments. We agree that circulating VEGF level may not reflect tumor microvessel density. However, there is quite compelling evidence that circulating VEGF level is of prognostic significance in cancer patients. In our review article, we included 32 studies published up to July 2000 that demonstrated a positive correlation between circulating VEGF level and tumor stage or prognosis.1 At least six additional studies published subsequent to our review have demonstrated the prognostic value of circulating VEGF level in cancer patients.2-7 Sezer et al have also reported that serum VEGF level increased with more advanced stage of multiple myeloma, and that tumor response to chemotherapy was associated with a decrease in the serum VEGF level.8 The most important biologic effect of VEGF known so far is its angiogenic effect, and it has been demonstrated to contribute to tumor angiogenesis in almost every type of cancer. Hence we conclude that "circulating VEGF seems to be a reliable surrogate marker of angiogenic activity and tumor progression in cancer patients." We have indicated in the text that the source and biologic significance of circulating VEGF remains uncertain, and it is not yet clear whether the circulating VEGF is derived mainly from tumor secretion of VEGF. We have been cautious in not being assertive in our conclusion.
We use the term angiogenic activity in a broader sense than do Sezer et al. Tumor microvessel density has been demonstrated to be of prognostic value in many cancers and thus has been widely used as an index of tumor angiogenesis. It is one but not the only one indicator of tumor angiogenic activity. The widespread clinical use of microvessel density has so far been hindered by the difficulty in obtaining objective measurement, which may partly explain why some studies failed to demonstrate its prognostic significance. For example, as opposed to the finding of Sezer et al, a recent study demonstrated no prognostic influence of bone marrow microvessel density in multiple myeloma patients.9 Tumor expression of angiogenic factors is another measure of angiogenic activity. In fact, some studies have demonstrated that tumor expression of VEGF was not correlated with tumor microvessel density, and the former but not the latter was prognostic of outcome in cancer patients.10,11 The main issue regarding circulating VEGF is not whether it is correlated with tumor microvessel density but whether it reflects tumor expression of VEGF. Thus far the evidence for this is limited and controversial. Some studies demonstrated a correlation between serum VEGF and tumor expression of VEGF,12,13 whereas other did not show a significant correlation.14,15 However, these studies used immunohistochemical staining for evaluating tumor expression of VEGF, which is a semiquantitative method. It is important to have a direct quantitative correlation between circulating VEGF and tumor expression of VEGF. We are currently conducting a study of quantitative evaluation of tumor expression of VEGF mRNA by quantitative polymerase chain reaction and serum VEGF level by enzyme-linked immunosorbent assay in hepatocellular carcinoma patients, and we hope that such a study will provide a better clue to the relationship between tumor VEGF expression and circulating VEGF.
The relationship between circulating VEGF level and tumor angiogenesis may be more complicated than a simple linear correlation. As pointed out in our article, tumor angiogenesis is the overall result of balanced activity of several angiogenic and antiangiogenic factors, and thus it may be necessary to evaluate multiple factors in the circulation to provide a true reflection of tumor angiogenic activity. Of course, it is possible that circulating VEGF may have other unknown biologic significance that explains its prognostic value. Rather than providing a definite conclusion, our review article summarized the current findings related to circulating angiogenic factors in cancer patients with the aim of providing insights into future directions of research in this area.
......................Angiogenesis in Cancer
It has been
more than 25 years since the initial insight put forth by Dr.
Judah Folkman that tumors require new blood vessel growth
(angiogenesis) to grow
beyond very small lesions (under 1/4 inch). The field of angiogenesis
itself with the study not only of tumor-associated vessels but with the
and remodeling of vessels during development, pregnancy, ovulation,
and processes that require tissue regeneration. Breast cancer provided
important early clinical insight into the workings of angiogenesis.
cancer clinicians have recognized that the ability of breast cancer to
even many years after the original diagnosis and surgery may be due to
of the angiogenic capabilities of "dormant" cancer cells. These
investigations have led to an increasingly detailed understanding of
molecules and structures involved in angiogenesis. The picture that has
is one of a balance between molecules that promote and molecules that
angiogenesis. As tumors grow and their nutritional needs increase, new
vessels arise as a consequence of an imbalance between stimulators and
inhibitors of angiogenesis. This work is leading to the rapid
development of new
cancer therapies that address ways to diminish the action of the
angiogenesis and promote the work of the inhibitors.
Important substances that impair angiogenesis have been isolated from patients with cancer. Among several examples, angiostatin and endostatin appear to hold promise in anti-tumor therapy. However, these protein drugs are not yet in clinical trials. Their ultimate usefulness in controlling cancer growth still remains unproven, but expectations of success are cautiously high, based on encouraging animal and other laboratory data.
Other avenues of investigation concern the use of antibodies that prevent the action of angiogenesis stimulators by binding to molecules on the surface of blood vessel cells. In this way, these antibodies can block the binding of the stimulators of angiogenesis. One important example in this category is the antibody directed against the receptor for vascular endothelial growth factor (known as anti-VEGF), which is already in clinical trials. Anti-VEGF has been shown to slow down the growth of tumors in several patients, with tolerable side effects. Interestingly, anti-VEGF appears to also help the anti-tumor action of radiotherapy when both modalities are used together. This "cooperation" between treatment modalities is especially hopeful, since it is expected that anti-angiogenesis therapies will be, in general, well tolerated, and thus amenable to combinations with other treatments.
The Role of Copper in Angiogenesis
At the University of Michigan Cancer Center, we have been studying another approach to reducing new blood vessel growth by impairing the action of angiogenesis stimulators. Many studies in model systems have shown that key promoters of angiogenesis require binding to copper in order to function properly. This need for copper is fairly widespread among pro-angiogenic molecules and has been observed to be present in many different types of tumors.
Working together with Dr. George J. Brewer, an expert on the metabolism of trace elements such as copper, we have developed a clinical approach to exploiting the requirement of copper for angiogenesis. Drugs that lower copper levels exist in clinical practice primarily for the purpose of treating a rare hereditary disorder known as Wilson's disease. Patients with this condition do not have the ability to transport copper normally, and thus it accumulates in great quantities in organs such as liver and brain, causing severe malfunction often leading to death. However, with appropriate copper-lowering therapy, Dr. Brewer and others have developed well-tolerated therapies to control the level of copper in patients with Wilson's disease with excellent results. A particularly potent drug to lower copper in the body is the small molecule tetrathiomolybdate (TM) which is safely administered to patients with Wilson's disease.
U-M Clinical Trial with Tetrathiomolybdate (TM)
After completing an animal study that showed that TM was extremely effective in preventing the development of overt mammary tumors in cancer-prone mice, we embarked on a Phase I trial of TM in humans with metastatic cancer. After a year, this trial has now completed accrual. The patients in the trial have tolerated TM extremely well, with nearly no side effects.
It is important to remember that copper is required for many cellular processes, and in fact, absence of copper or very low copper levels would be very harmful to patients. The key observation of our trial is that it is possible to inhibit angiogenesis in many tumor types by lowering the copper to levels that still allow most other cellular processes to proceed relatively undisturbed. In this way, if patients can remain within a well-defined but apparently not too narrow "window" of mild copper deficiency, angiogenesis is brought to a halt without any other major side effects. It is important to point out that copper levels can be easily restored to normal in a matter of hours to days, by simply ceasing administration of TM.
Whereas new blood vessels appear to have a very strong dependence on copper for growth, low copper levels are unlikely to affect existing vessels; however, as tissue turnover eventually occurs, "old" vessels will not be replaced by new vessels, in the setting of copper deficiency. Therefore we postulated that in patients with established tumors, the achievement of chronic disease, and perhaps a very slow decrease in the number of viable tumor cells would be observed in cases in which TM is successful.
In addition, we have observed encouraging hints of cooperativity between TM and Herceptin(r) (anti-HER2 antibody) in breast cancer; TM and radiotherapy in kidney cancer; and TM and interferon in angiosarcoma. We are planning new trials to specifically study the efficacy of TM alone and in combination with other approaches in controlling metastatic sarcoma, breast and kidney cancer, and earlier stages of cancer. Although the results are promising, the exact clinical uses of this approach are yet to be rigorously defined in clinical trials.
Angiogenesis holds significant promise to help render cancer into a chronic or controllable disease or to contribute to its eradication, most likely in combination with other therapeutic modalities. The work in this field constitutes one more example of the concept that knowledge of the molecular and cellular events involved in cancer will lead to new therapies.
Irani JL, van Golen K, Lovelace JR, Brewer GJ, Merajver SD. Copper deletion as an anti-angiogenic strategy in HER2-neu transgenic mice. Abstract presented at the AACR's Special Conference, "Angiogenesis and Cancer." 1998.
Hanahan D, Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell. 86:353-364, 1996.
Folkman J. The influence of angiogenesis research on management of patients with breast cancer. Breast Cancer Res Treat. 36:109-118, 1995.
Folkman J. Angiogenesis inhibitors generated by tumors. Mol Med. 1:120-122, 1995
......................Angiogenesis in cancer
performs a critical role in the development of cancer. Solid tumors
smaller than 1 to 2 cubic millimeters are not vascularized. To spread,
they need to be supplied by blood vessels that bring oxygen and
nutrients and remove metabolic wastes.
Shortcomings of standard therapies
therapies to combat cancer are usually aimed at interfering with the
cellular replication process which is accelerated in tumors. Despite
the efforts made since 1971 to fight cancer -- the year the United
States declared war on the disease -- new cases of most cancers have
increased significantly. Ninety percent of all cancers are solid tumors
and thus depend on angiogenesis to support their growth.
Resistance to treatment is a major issue in oncology. In hormone-dependent cancer for instance, after standard anti-hormonal therapy, it is common to see a recurrence of cancer. This occurs when a malignant cell is transformed a second time, thus making its replication independent of hormones. The same phenomenon takes place with cancers treated with chemotherapy. Often a transformed cell exposed to a powerful chemical agent goes through a mutation, giving it a selective advantage for growth, such as the production of a growth factor or resistance to chemotherapeutic agents.
It has also been shown that the resection of a primary tumor is often accompanied by metastases caused by a systemic disturbance of the angiogenic balance of the body. All these standard therapies could profit from a concomitant treatment that would restrict latent tumors in a prevascular phase.
Antiangiogenesis as a strategy against cancer
early as the 1970s, Dr. Judah Folkman of the Harvard Medical School
suggested inhibiting new blood vessel formation as a way to fight
The malignant tissue would be deprived of its oxygen and nutrient supply, as well as be unable to eliminate metabolic wastes. This in turn would inhibit tumor progression and metastatic progression that accompanies most advanced cancers. These are the main steps of the angiogenic process that can be interrupted:
the challenge is to develop an antiangiogenic factor that does not
affect the existing vasculature.
Neovastat is an inhibitor of angiogenesis
number of studies have shown Neovastat to have antiangiogenic
properties. The mechanisms of action include:
As well, clinical and pre-clinical studies show Neovastat can be used alone or in combination with other therapies. Clinical experience with 540 patients, some of whom have been administered the drug for almost four years, have confirmed Neovastat’s excellent safety and tolerability profile in monotherapy and in concomitant chemotherapy and radiotherapy.
Angiogenesis Inhibitors for Cancer
Lymphedema People Angiogenesis Related Pages:
Angiogenesis and Cancer
Angiogenesis and Cancer Control
Angiogenesis Inhibitors and Cancer
Lymphedema People Lymphangiogenesis Related Pages:
The Formation of
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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
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VEGF-D is the strongest angiogenic and lymphangiogenic effector
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