Tag: VEGF

Need an excuse to drink coffee?

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Thanks to Sherlock, who sent me the full study that I will be discussing today, and to a Grouppe Kurosawa mailing, I found out something that I had not previously known about coffee. As it did for yours truly, the following should put a smile on the faces of coffee drinkers. This was meant to be a simple brief discussion of a study on caffeine, but it turned into a huge time-consuming bit of research. One thing led to another…I did my best not to go overboard!
 
An Italian study (see abstract: http://tinyurl.com/3862f5) published in May 2007 in “Molecular Pharmacology” states that caffeine inhibits VEGF and IL-8 (interleukin-8) in human colon cancer cells. Specifically, it inhibits HIF-1 alpha, or “hypoxia-inducible factor alpha.” Let’s take a closer look at HIF-1 alpha before proceeding.

I read that solid tumours are unable to grow beyond a certain size because of hypoxia, which means "insufficient oxygen." What happens is that, as tumours grow, they need more and more nutrients and oxygen. At a certain point, though. the tumour microenvironment just can’t deal with this constant demand (if I got that right…) and becomes hypoxic. Under hypoxic conditions (less than 6% oxygen, I read), HIF-1 alpha, a transcription factor, becomes activated, and it in turn activates genes, dozens of them!, that keep tumours alive and well, via angiogenesis, glucose transport and whatnot. So tumour progression goes hand in hand with the increased activity of HIF-1 alpha.

Is this bothersome transcription factor present in myeloma, I wondered for just a split second? I really didn’t need to do a search to answer that question.  But I did do a search, and, quelle surprise!, it turns out that HIF-1 alpha is involved in myeloma angiogenesis as well. See this Italian study: http://tinyurl.com/36eywf. And see also this very colourful PDF presentation prepared by an Italian team for the 10th International Myeloma Workshop (Sydney, 2005): http://tinyurl.com/ytwej8 It also shows the involvement of HIF-1 alpha in myeloma angiogenesis.

Back to the Italian study on caffeine (see abstract): “Pretreatment of cells with caffeine significantly reduces adenosine-induced VEGF promoter activity and VEGF and IL-8 expression.” (Wait…adenosine? Uffa, another thing to look up…) Here we go: simply put, adenosine is a natural chemical, a neurotransmitter, released by brain cells to make us sleepy. The more we stay awake, the more adenosine gets released. But I should point out that adenosine is present also in all cells of the body, and, aha!, has the function of protecting cells from damage under conditions of hypoxia.  And it protects solid tumours from the attacks of NK cells and T-lymphocytes, as can be seen in this abstract (“International Journal of Oncology,” March 2008): http://tinyurl.com/yu7o72. It seems to be involved in a lot of mischief! Well, ok, not all the time!, for instance it mediates the damage caused by strokes…

Enough. You can read more about the importance of adenosine on the Grouppe Kurosawa public blog (February 29 post): http://tinyurl.com/23fbgo. The main thing we need to know is that, when adenosine is released, HIF-1 alpha and VEGF, the very best friends of cancer cells, are activated.

I started going through the Italian caffeine study with my usual (exaggerated!) attention to detail, then I decided that that didn’t make any sense. Do we really care that much about how this all works? Naaah. The important thing is the study’s clear message (well, to me, a morning coffee drinker, at least!): DRINK COFFEE! (yes, yes, YES…!).
 
Okay, just a few points (can’t help it, sorry! ):
  1. Hypoxic tumour cells are resistant to chemotherapy and radiotherapy. Eh!
  2. Hypoxia stimulates IL-8, which is involved with cancer progression (including myeloma progression, as we know from a previous post).
  3. HIF-1 “contributes to tumor progression and metastasis.”
This, according to the authors, “is the first report examining the in vitro effect of caffeine on hypoxic cancer cells.” Their “data suggest three potential chemopreventive targets for caffeine: 1) HIF; 2) VEGF and IL-8; and 3) cell migration.” They add: “our results indicate that, in tumor colon hypoxic cells, adenosine increases VEGF promoter activity via the HIF-1 pathway and that caffeine is able to block this effect.”
 
Now, while the cancer cells studied here were not myeloma ones, there is quite a bit of common ground, as we have seen (VEGF, IL-8 etc.). So I will be interested to read future studies on this topic. In the meantime, I will enjoy my usual morning homemade cappuccino with much more gusto!
 
Oh, I just can’t resist adding this lovely titbit at the end.  Guess what other substance inhibits HIF-1 alpha? Any ideas? Yes! CURCUMIN! (I always check…). See this abstract, published in “Oncology Reports” in 2006: http://tinyurl.com/2aooud It suggests that “curcumin may play pivotal roles in tumor suppression via the inhibition of HIF-1 alpha-mediated angiogenesis.” And a “Molecular Pharmacology” 2006 study (full text: http://tinyurl.com/27q93o) also suggests that curcumin inhibits tumour growth by targeting this transcription factor.
 
HAH! Now I have TWO good reasons to be happy today!

Curcumin and Angiogenesis

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Again, happy holidays to everyone! I have been busy busy busy, not with research but with family and holiday-related engagements. But I did have time this morning to take a quick look at a study dealing with curcumin and angiogenesis, and will attempt to present some of its findings. Quickly, since I have some folks downstairs waiting for me to join them for a card game, hehe!

A blog reader (thank you!) recently sent me the link to an article (see: http://tinyurl.com/36aaem) about a study (see abstract: http://tinyurl.com/ysyq4y)  published in the October 24 2007 issue of the “Journal of Cellular Physiology.” The study is titled “Opposing effects of curcuminoids on serum stimulated and unstimulated angiogenic response.” In a nutshell, a group of researchers from the University of Kerala, India, discovered that curcumin promotes the formation of blood vessels in HEALTHY cells. This may not sound so amazing, but it really IS, when you think about it, because their finding confirms the fact that curcumin has the ability to distinguish between healthy and cancerous cells. Curcumin provides a supply of blood to normal cells whenever they need it but cuts off that same supply to nasty cancer cells. This may appear to be contradictory, but the Kerala researchers, as we will see, may have found an explanation. And their finding may be important not only for the treatment of cancer but also of ischemic conditions where there is a shortage in blood supply and, consequently, of oxygen.

The Kerala study (the full text was sent to me by another blog reader, thanks!) begins with an explanation of angiogenesis, which “is the formation of new blood vessels from preexisting vessels. […] Physiologically, it plays an important role in wound healing and ovulation. Nevertheless, uncontrolled angiogenesis results in many pathological conditions.” Indeed!

Curcumin applied to wounds caused by radiation has strong healing properties. An interesting aside: while I was doing research for this part of the post, I came upon a 2007 study (http://tinyurl.com/2ahqmg)  showing that curcumin has both radioprotective AND radiosensitizing properties. How about THAT? So curcumin will protect our healthy cells from the harmful effects of radiation while enhancing the murderous effects of radiation on cancer cells. At the exact same time! Extraordinary. That is why it might be very useful in the radiotherapy treatment of cancer, the study suggests. Well, I already knew about the radioprotective effects of curcumin, and now in fact I am not at all nervous about having my annual skeletal exam, but not the radiosensitizing effects. Curcumin never ceases to amaze me!

A 1999 study (see abstract: http://tinyurl.com/2fs5bw) showed that curcumin both when taken orally and applied topically improved wound healing in diabetic rats and mice.

The above-mentioned Kerala researchers point out that it seemed contradictory for curcumin to have wound healing properties when it is also has these anti-angiogenic properties. So they focused on the cellular microenvironment to see if it had “any effect on the angiogenic potential of curcuminoids.” Well, it does. This was a difficult, very technical study for me to read (the abstract will give you an idea…), but the following is more or less clear: curcuminoids stimulated the expression of proangiogenic factors when there was no extracellular stimulation (of an angiogenic response) by serum or proangiogenic growth factors, whereas, in the presence of those stimuli, curcuminoids appeared to be anti-angiogenic. Okay, perhaps this is not clear at all, now that I reread it! Well, basically, depending on the presence or absence of serum or certain growth factors, curcuminoids help normal cells live happily ever after, but they can also kill cancer cells by cutting off their blood supply.

This study gives us another example of the wonderful dual nature of curcumin, able to distinguish between the good and the bad guys. Yeah!

Stress Involved In Myeloma Progression: Very Evil Growth Factor

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Today I will be putting back a couple of posts, including this one, which I posted on December 7, 2007. The original posts were gobbled up by the server, apparently, comments included. I will put the comments back as best I can. Sorry if they look funny! Not funny haha, funny weird. 😉

Other myeloma bloggers have posted about a recent study (abstract: http://tinyurl.com/2w4ndb) showing the link between myeloma and stress. My friend Sherlock sent me the full study, so I will try to provide some additional information. Conducted by a team of researchers at the Ohio State University Medical Center, this study was published in November 2007 in “Brain, Behavior and Immunity,” which by the way looks like a very interesting publication. I must keep my eye on it.

The study is titled “VEGF is differentially regulated in multiple myeloma-derived cell lines by norepinephrine.” A couple of notes before proceeding. Noradrenaline, also known as norepinephrine (NE), is a hormone and neurotransmitter involved in alertness and concentration, among other things. It is involved in heart rate, blood pressure and blood sugar level increases. VEGF stands for “vascular endothelial growth factor,” and is an evil signalling protein that is linked to tumour progression, feeding cancer cells, etc. Read this excerpt from an IMF article written in 2001 (http://tinyurl.com/2yh49k): “Dr. Kenneth Anderson of the Dana-Farber Cancer Center mentioned that VEGF might not only be important for the formation of new blood vessels in MM but also has the potential to stimulate directly the proliferation and migration of myeloma cells. His group demonstrated that production of VEGF by myeloma cells can be stimulated by activation of the CD40 molecule on the surface of the tumor cells.” CD40, we meet again!…remember my CD40 post? I am not done yet with natural ways we can use to inhibit CD40, I just need to find the time to read the studies that Sherlock sent to me.

But let’s get back to VEGF. The Ohio stress study tells us that “VEGF is a crucial cytokine that directs and promotes tumorogenesis and potentiation in the marrow. VEGF levels correlate with overall prognosis and associated bone destruction, which contributes substantially to clinical morbidity.” I told you VEGF was evil! In fact, I suggest that from now on it be known, perhaps more appropriately!, as “Very Evil Growth Factor.”

The introduction begins: “There is evidence that psychological factors can affect the incidence and progression of some cancers.” And, in fact, there is definitely a connection between our IL-6 levels and chronic stress, which is actually a topic on my infinitely long to-be-researched list. That is one reason why I was most interested in the finding, reported in the Ohio study, that NE has been found to stimulate IL-6 and IL-8 in human melanoma cells. But these two cytokines are also actively involved in myeloma. We know all about evil IL-6, but IL-8 has also been connected to progression in myeloma. No comment necessary, methinks.

Discussing a previous study, the Ohio researchers report that stress can inhibit T cells from responding “to tumor-associated antigens on tumor cells of immunogenic tumors.” T cells, hmmm, that sounds familiar.. And the effects caused by stress may “may contribute to tumor progression independent of its effects on the immune system.” Well, we knew that stress is bad for us, but this goes a bit beyond “bad.”The researchers tested three myeloma cell lines in different stages of development. All three had “the potential to respond to NE,” but one in particular “exhibited the greatest NE-dependent response.” Interestingly, this cell line came from someone whose myeloma was aggressive but ”in the earliest (and comparatively longest) clinical phase—i.e., where disease is confined to the bone marrow.” This could mean that in early stages perhaps the blood supply to the malignant cells could be diminished simply by inhibiting NE, which would not kill the malignant cells, of course, but should theoretically slow down tumour growth and disease progression.

Toward the end of the study, we find the following: “Whether the stress-associated activation of the sympathetic nervous system results in the upregulation of NE levels in the bone marrow is unknown. However, observations described here suggest the potential for a stress-associated stimulation of proangiogenic properties of MM cells through the upregulation of NE levels.” The Ohio team adds that “the mechanism involved in the NE-dependent increase in VEGF release by MM cells is not known.”So let’s have more studies like these instead of inanities of the following sort (I glanced at this article this morning and could hardly believe my eyes): “new research suggests that the presence of other people may enhance our movie-watching experiences. Over the course of the film, movie-watchers influence one another and gradually synchronize their emotional responses” (http://tinyurl.com/299s5x). Ehhhh??? You’ve got to be kidding. Isn’t it common knowledge that if you go see a fantastic movie with someone you don’t like, most likely you will hate it, but if you go to see the same movie on your own or with a good friend, you will probably love it, blablabla? Do we really need actual STUDIES to look into this sort of twaddle? Come on!

I would like to finish by saying that I hope to have time at some point to look at the other NE-cancer studies. The one I read today deals specifically with myeloma, but the other NE studies examine other types of cancer. And then there is the whole related issue of beta-blockers, which the Ohio team suggests might be beneficial for myeloma patients (but more info is needed, they add). Anyway, that topic too complicated to get into today. Interesting, though. Okay, have a fun laughing weekend, everyone!