Updated: August 11, 2007
EPO May Increase Angiogenesis
by Chaya Venkat
The prepublication paper in the latest Blood journal caused me to revisit an issue that has been bugging me for a while, and it has to do with many of the hematopoietic drugs used in treating cancer patients today. In this article I will deal mainly with EPO, or erythropoietin, used to boost red cell production in seriously anemic patients.
EPO is a widely used drug, especially in cancer therapy. Most of us are familiar with the name, it is used frequently when our RBC levels drop below comfort levels, either due to bone marrow not working as well as it ought to, or as a side effect of chemotherapy, or any number of other causes such as auto-immune disease where the red blood cells are attacked and killed before their time by an immune system gone berserk.
It sounds like the old adage of there being no free lunch is proven once again. The Blood article cites increasing evidence linking use of EPO type of bone-marrow stimulants to increased neovascularization. Now that is just a long word for the formation of new blood vessels, and another word that says the same thing is "angiogenesis". For those of you who are unfamiliar with the term, below is a link to one of my previous articles on the subject, where we discussed it in detail: Angiogenesis in CLL.
In a nutshell, no cell or group of cells can live without the constant supply of nutrients flowing in from the blood stream. This is especially true of cancers, both because cancer cells are notoriously greedy and inefficient users of energy, and also because they are often in a growth mode and therefore need the extra helping of nutrients. Dr. Judah Folkman is a legendary figure in this field, he was the first one to prove the connection between the growth of cancer, and the ability of malignancies to force the formation of new blood vessels to feed themselves. This link between angiogenesis, formation of new blood vessels, and cancer was clearly demonstrated in solid cancers. In fact there are a number of clinical trials underway to halt the growth of cancer by starving them to death, by preventing angiogenesis. At one time, anti-angiogenic drugs were (prematurely) hailed as the magic bullets that would cure cancer in short order. Not quite that simple, but the science is nevertheless solid and a lot of work is being done in this field.
More recently, it has been shown that angiogenesis plays a part in "liquid" cancers as well, such as lymphoma and CLL. Patients with advanced or aggressive CLL were shown to have a much higher level of new blood vessel formation in their bone marrows, compared to normal people or patients with smoldering CLL. Makes sense, as the bone marrow gets progressively infiltrated and taken over by the cancer, more and more blood vessels must be created in order to bring in the nutrients required to build the army of clonal CLL cells.
The article in Blood, as well as the several PubMed citations below are quite clear, stimulating bone marrow function to increase the production of blood cells by drugs such as EPO carries with it the risk of increasing angiogenesis, and therefore assisting the cancer in its future growth. For me, this is a real note of caution: we are all rightly cautious of the double edged sword represented by chemotherapy, it can kill cancer cells but it sometimes has pretty heavy duty side effects. I think cytokine drugs such as EPO may also soon join the ranks of double edged swords, they may help boost critically needed levels of red blood cells and the like, but sounds like it is no free ride, you may pay for it by increased risk of angiogenesis.
For a further discussion of the side effects of EPO drugs and their negative implications for survival, please read the November 22, 2003 article, Anemia in CLL - Unwanted Side Effects of Epoetin Drugs.
Blood First Edition Paper; prepublished online April 17, 2003
Erythropoietin is a potent physiological stimulus for endothelial progenitor cell mobilization
Christopher Heeschen et al, University of Frankfurt, Frankfurt, Germany
Increasing evidence suggests that postnatal neovascularization involves the recruitment of circulating endothelial progenitor cells (EPC). Hematopoietic and endothelial cell lineages share common progenitors. Cytokines formerly thought to be specific for the hematopoietic system have only recently been shown to affect several functions in endothelial cells.
Accordingly, we investigated the stimulatory potential of erythropoietin (Epo) on EPC mobilization and neovascularization. The bone marrow of Epo-treated mice showed a significant increase in number and proliferation of stem and progenitor cells as well as in colony forming units. The number of isolated EPCs and CD34+/flk-1+ precursor cells was significantly increased in spleen and peripheral blood of Epo-treated mice compared to PBS-treated mice.
In in vivo models of postnatal neovascularization, Epo significantly increased inflammation- and ischemia-induced neovascularization.
The physiological relevance of these findings was investigated in patients with coronary heart disease. In a multivariate regression model, serum levels of Epo and vascular endothelial growth factor were significantly associated with the number of stem and progenitor cells in the bone marrow as well as with the number and function of circulating EPC.
In conclusion, the present study suggests that Epo stimulates postnatal neovascularization at least in part by enhancing EPC mobilization from the bone marrow. Epo appears to physiologically regulate EPC mobilization in patients with ischemic heart disease.
Thus, Epo serum levels may help identifying patients with impaired EPC recruitment capacity.
Carcinogenesis 2002 Nov;23(11):1797-805
Erythropoietin is involved in growth and angiogenesis in malignant tumours of female reproductive organs.
Yasuda Y, Fujita Y, Masuda S, Musha T, Ueda K, Tanaka H, Fujita H, Matsuo T, Nagao M, Sasaki R, Nakamura Y.
Department of Anatomy, Kinki University School of Medicine, Osaka-Sayama, Japan.
The accumulating evidence that erythropoietin and erythropoietin receptor are expressed in various non-haematopoietic organs suggests that erythropoietin signalling might be involved in the growth of tumours, but this possibility has never been examined. We found that mRNAs for erythropoietin and erythropoietin receptor are expressed in malignant tumours of female reproductive organs, where erythropoietin levels are higher than in normal tissues. Furthermore, tumour cells and capillary endothelium showed erythropoietin receptor immunoreactivity. To investigate the role of the erythropoietin/erythropoietin receptor pathway in these tumours, we injected mouse monoclonal antibody against erythropoietin or the soluble form of erythropoietin receptor into blocks of tumour specimens and cultured the blocks. After 12 h of injections, these blocks were examined and compared with control blocks injected with mouse monoclonal antibody, heat denatured soluble form of erythropoietin receptor, mouse serum or saline. Tumour cells and capillaries were markedly decreased in a dose-dependent manner after either injection. A marked increase of the cells containing fragmented DNA and the histopathological characteristics of these cells suggest that the decrease in tumour cells and capillary endothelial cells was due to apoptotic cell death. The co-existence of JAK2 and phosphorylated-JAK2, and STAT5 and phosphorylated STAT5, all of which are involved in the mitogenic signalling of erythropoietin, was found frequently in tumour cells and capillary endothelial cells in the untreated blocks. In contrast, most of the phosphorylated-JAK2- or phosphorylated-STAT5-positive cells had disappeared in the experimental blocks. Moreover, reduced tyrosine phosphorylation of STAT5 in the experimental blocks was confirmed by western blotting analysis. The results strongly indicate that erythropoietin signalling contributes to the growth and/or survival of both transformed cells and capillary endothelial cells in these tumours. Thus, deprivation of erythropoietin signalling may be a useful therapy for erythropoietin-producing malignant tumours.
Leukemia 1994 Mar;8(3):523-9
Angiogenic factors are hematopoietic growth factors and vice versa.
Bikfalvi A, Han ZC.
INSERM U 118, Paris, France.
Angiogenic factors are potent growth factors promoting proliferation and differentiation of vascular endothelial cells. Recent evidence suggest that these factors also promote hematopoietic cell growth. The major group of angiogenic growth factors is the fibroblast growth factor (FGF) family. Two prototypes, acidic FGF and basic FGF, have been demonstrated to interact with granulopoiesis and megakaryocytopoiesis. Basic FGF stimulates granulopoiesis in long term bone marrow cultures while acidic and basic FGF promote megakaryocytopoiesis. These effects are presumably mediated via specific FGF receptors, that have been identified in bone marrow and leukemia cell lines. Besides the FGF family, angiogenic inhibitors such as platelet factor-4 (PF-4) have been found to exhibit an inhibitory effect on megakaryocytopoiesis. In contrast, it has been demonstrated that hematopoietic growth factors including granulocyte-macrophage colony-stimulating factor (GM-CSF), or erythropoietin promote angiogenesis in vivo and in vitro. In light of these recent observations and the common origin of endothelial cells and hematopoietic cells, it is suggested that angiogenic factors are hematopoietic growth factors and vice versa. However, these data must be interpreted with caution and a careful in vivo evaluation should be done before these observed in vivo effects are proven to be significant to the physiopathology of hematopoiesis or angiogenesis.
Blood 2002 Nov 1;100(9):3344-51
Prognostic value of enhanced bone marrow angiogenesis in early B-cell chronic lymphocytic leukemia.
Molica S, Vacca A, Ribatti D, Cuneo A, Cavazzini F, Levato D, Vitelli G, Tucci L, Roccaro AM, Dammacco F.
Department of Hematology/Oncology, Azienda Ospedaliera Pugliese-Ciaccio, Viale Pio X, I-88100 Catanzaro, Italy.
Because tumor progression is angiogenesis-dependent, angiogenesis density was investigated by immunohistochemistry and computed image analysis in bone marrow (BM) biopsies of 45 newly diagnosed patients with Binet stage A B-cell chronic lymphocytic leukemia (BCLL) and correlated to upstaging and progression-free survival during a 40-month follow-up period. Their microvessel areas and counts were significantly higher than those of patients with anemia due to iron or vitamin B(12) deficiencies. A cutoff value of 0.90 mm(2) x 10(-2) or greater of the microvessel area identified patients with earlier upstaging and shorter progression-free survival. When the cutoff was applied to the Rai subclassification, both Rai 0 and Rai I-II patients who upstaged and shortened the progression-free survival were classified correctly. Information of this type was not given by the microvessel counts. The cutoff did not correlate with other predictors representative of tumor mass or disease progression. The microvessel area correlated with the expression of angiogenic vascular endothelial growth factor (VEGF) by tumor tissue, and serum levels of VEGF were found to be of prognostic value. A causal relationship between risk of progression and BM angiogenesis in BCLL is suggested. A risk stratification inside Rai is proposed. The prognostic usefulness of BM angiogenesis in patients with BCLL is envisaged.
Low Dose Chemotherapy and Angiogenesis
Kerbel on Carcinogenesis
by Chaya Venkat
In view of the recent buzz about Dr. Kerbel's work on low dose chemotherapy and angiogenesis, here is a link that I published below. This is probably the best written and most informative article you will ever find on this subject. I will warn you ahead of time, while it is written clearly, it is quite long and takes determination to read it all the way through. Worth the effort, in my opinion ( but then, I liked War & Peace too!)
What has changed in the past couple of years is the understanding that angiogenesis is very much a part of hematological malignancies as well as solid tumors. So, the same logic that works for using anti-angiogenesis approaches to controlling blood vasculature for solid tumors works for diseases like CLL as well. Increased density of blood vessels is clearly documented in CLL patients, and the higher the density of these cancer feeding blood vessels, the poorer the prognosis.
On the other side of the coin, since the initial euphoria surrounding the breakthrough research of Dr. Judah Folkman, when it was trumpeted from the front page of the New York times that all cancers will be cured within the next couple of years using anti-angiogenesis approaches, reality has set in. The human body is a very complex system. You block one pathway for angiogenesis, it soon finds several new ones. Little bit like squeezing a tube of toothpaste. You squeeze one end and it just moves over to another spot. Nothing is simple in life or cancer therapy.
The other disheartening news is that a number of the best hope anti-angiogenesis drugs in clinical trials are in jeopardy. Lack of immediate and block-buster results, combined with venture firms that want to see quick returns on their investments has meant a number of companies working on this approach are going belly-up. Dr. Kerbel's approach is promising since he uses existing chemotherapy drugs, and Cox-2 inhibitors such as Celebrex. You may want to look up a bunch of articles we had on this subject, around the time we started CLL Topics. Also some articles on blocking NF-kb pathway, and thereby controlling inflammation.
Link: Kerbel on Carcinogenesis.
Angiogenesis in CLL
by Chaya Venkat
There has been a great deal of interest in angiogenesis and its role in facilitating cancer growth. However, much of the work had been done with solid tumors, and it was not always clear whether angiogenesis had a role to play in "liquid" tumors such as CLL. More and more research is now pointing to the pivotal role of angiogenesis in the case of CLL too. As pointed out in the ASCO 20002 abstract (Abstract no. 3031) below, compared to all of the other cancers studied, CLL had the highest amount of B-FGF, (basic fibroblast growth factor), a key material involved in angiogenesis.
There are several implications of this study, both in terms of less damaging therapy protocols, as well as lifestyle changes one could consider to try and control/reduce angiogenesis. There is also the whole subject of chemoprevention, making your body less hospitable to new malignancies, while one is recovering from chemotherapy. There seems to be general agreement that while one is immune compromised, either due to CLL itself, or due to the treatments one has had, other cancers have a much higher chance of taking hold. For example, skin cancer is much more common in CLL patients than in a "normal" population.
I know a lot of you follow angiogenesis research. I do too. Over the next weeks I will try and cover several aspects of this subject. It is a very large field, and I would appreciate help from those of you who have done your reading.
ASCO abstract number 3031
Circulating basic fibroblast growth factor (B-FGF) and vascular endothelial growth factor (VEGF) levels in cancer patients: implications for anti-angiogenic therapy
Ronald S Go, Andrew L Horstman, Gundersen Lutheran Medical Center, La Crosse, WI.
BACKGROUND: Over-expression of angiogenic factors, most importantly VEGF and B-FGF, are implicated in the growth and metastasis of cancers. Several indirect angiogenic inhibitors are now available. These agents inhibit the production (interferon-alfa), neutralize (bevacizumab), or block the receptor (SU5416) of angiogenic factors. Elevated circulating angiogenic factors have been shown to predict treatment response and prognosis in some malignancies.
PURPOSE: To review the expression of circulating VEGF and B-FGF in various cancers and describe its potential implications when using indirect anti-angiogenic therapy.
METHODS: We searched the MEDLINE database from 1996-2001 for studies reporting plasma or serum VEGF and B-FGF levels in hematologic and solid malignancies. VEGF or B-FGF level is defined as high when the reported mean or median level is greater than or equal to twice the level of that in the healthy control group. It is considered indeterminate when results are conflicting. Only malignancies in which there are at least 2 reported studies are included.
RESULTS: A total of 35 studies were reviewed. VEGF level is high in soft tissue sarcoma, colorectal, non-small cell lung and ovarian carcinomas. It is low in breast, prostate, renal, and small cell lung carcinomas and indeterminate in melanoma and head/neck carcinoma. B-FGF level is high in chronic lymphocytic leukemia (CLL), multiple myeloma and renal carcinoma. It is low in non-Hodgkin's lymphoma, colorectal and prostate carcinomas, and indeterminate in small cell and non-small cell lung carcinomas. VEGF and B-FGF are highest in ovarian carcinoma and CLL, respectively.
CONCLUSION: The expression of VEGF and B-FGF varies in patients with different types of cancers and within patients with similar cancers. In cancers in which either VEGF or B-FGF are grossly over-expressed, Indirect anti-angiogenic therapy maybe useful as a group. In cancers in which VEGF or B-FGF are low or indeterminate, screening patients for over-expression of these angiogenic factors maybe useful to identify patients more likely to respond to therapy.
Role of Copper in Angiogenesis
Possible Therapy Target
by Chaya Venkat
I do take copper's role in angiogenesis seriously. And we did get our water supply tested, after all Arizona is called "The Copper State"! But folks, please do take the caution below very seriously.
Caution! Copper is essential for many critical body functions, and reducing its level below safe limits, without medical supervision and monitoring can be extremely dangerous.
Copper is believed to be the switch that turns on the angiogenesis process in tumor cells. It has been observed that abnormally high serum copper levels are found in patients with many types of progressive tumors. According to the University of Michigan Oncology Journal, studies have shown copper to be an essential cofactor in the process of angiogenesis. Growth factors in angiogenesis require binding to copper in order to function properly. Copper-binding molecules [such as ceruloplasmin, heparin] are non-angiogenic when free of copper, but they become angiogenic when bound to copper.
Having established that copper is intimately involved in tumor growth via the angiogenic pathway, it is feasible to propose a method of treatment, which will decrease the body's concentration of copper. Drs. Brewer and Merajver from the University of Michigan have used TM (tetrathiomolybdate) to reduce copper levels in patients. On January 21, 2000, the University of Michigan reported that researchers had "successfully stopped the growth and spread of cancer by depriving the tumors of the copper supply they need to form new blood vessels." A larger 100 patient Phase II trial of TM is currently underway. "This is not a cure for cancer, but a disease stabilizer." Dr. Brewer said of the anti-copper drug.
TM has been shown to be essentially nontoxic, fast acting, and copper specific. TM binds to the copper (in the food) and keeps it from being absorbed. When taken on an empty stomach (2 hours away from any food) TM is absorbed into the blood stream where it forms complexes with copper and serum albumin. These newly formed copper complexes are gradually excreted through bile and urine.
The four links below have a lot of information on how to control angiogenesis through copper reduction therapy, and a bunch of other ways of controlling angiogenesis. Action items that may perhaps be considered to reduce daily intake of copper: (1) check your vitamin and other nutrition supplements labels to see if they has copper; (2) stay away form liver, lobster and shell fish, foods that are supposed to be rich in copper; (3) check the level of copper in your drinking supply.
I was unable to locate a trial using the drug tetrathiomolybdate (TM) for CLL. It is a little surprising how little fanfare there is about this potentially effective therapy, using a drug that is basically an industrial chemical, and dirt cheap. May be that is the reason, there is little hope of any big pharmaceutical company getting patent rights or corner the market in TM.
While I did not find any formal CLL clinical trials using TM, I understood quite a few "off label" clinical trials are underway for various NHL cancers, using TM. Apparently, Dr. Brewer does work with local oncologists who wish to prescribe TM to their patients. This is hearsay, and you need to check this out yourself, if you are interested. Once again for the record, while TM therapy may sound intriguing, it is not for the non-medically qualified do-it-yourselfer, it must be carefully done under well supervised and monitored conditions, or it can be very dangerous.
Read more about this subject at the sites below. The first one is especially user friendly.
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