Angiotensin-(1-7)

It’s that time of year.  The time of year when you can’t get anything DONE in the lab because you’re forever going to people’s dissertation defenses.  Not that this is a bad thing.  Sometimes it gives me a little bit of hope that MAYBE I’ll get out of here.  Usually it just makes me feel hopeless at all the work I still need to get done. 

But yesterday I got to see one of the girls in my department do a truly fantastic defense.  She is now officially Dr. Menon, and she has definitely earned it.  I watched her seminar with slack-jawed admiration.  She’s one of those people who you wish with all your heart you could be like, and yet she’s so nice and humble about it that you never get truly envious.  Her thesis is the kind of work that makes me proud to call myself a scientist, knowing that I am associated in some way with her amazing dedication.  And what she’s done is going to be BIG.

Dr. Menon, did her thesis work on a peptide called Angiotensin-(1-7) (Ang – (1-7)).  This is a 7 amino acid (very small) peptide hormone that is part of something called the renin-angiotensin system.  This is a system that regulates long-term blood pressure control and fluid volume in the body.  The chemical precursors of Ang-(1-7) are angiotensin I (which is mostly a precursor) and angiotensin II, which is a potent vasoconstrictor in the body (which means it causes constriction of your blood vessels and a net increase in blood pressure).  Angiotensin II receptor blockers, such as Atacand, are drugs that are often prescribed to decrease high blood pressure. 

Ang-(1-7), which is only one amino acid away from angiotensin II, is a vasodilator, which decreases blood pressure.  Ang – (1-7) has roles other than vasodilation.  It regulates the growth of cardiovascular muscle cells (Tallant et al, 1999) (the muscles that make up your arteries), and appears to protect blood vessels following injury by decreasing the growth of injured cells.  So Ang-(1-7) is also an anti-proliferative hormone, which can stops rapidly dividing cells from going about their business (Tallant et al, 2005).  

All of this by itself is pretty cool, but a few years ago, Dr. Menon started to investigate the role of Ang – (1-7) in lung cancer.  I’m sure you all know that lung cancer is one of the leading causes of death in the US (Jemal et al, 2008, Cancer Statistics).  More than 160,000 people will die of lung cancer this year, which is more than deaths from breast cancer, colon cancer, prostate cancer, and leukemia COMBINED.   Even though treatments for many cancers have improved, lung cancer lags behind, and only 14% of lung cancer patients will survive five years after they are diagnosed (Miller, 2005) .  The reason that lung cancer has such a high mortality rate is because lung cancer is notoriously hard to catch, and usually someone only finds out they have it when there are several tumors in late stage metastasis, and by then the prognosis isn’t very good.

How do lung cancer and Ang-(1-7) go together?  A few years ago, scientists conducted a study in Scotland, and found that the incidence and fatality of cancer decreased significantly in patients being treated with ACE inhibitors.  Patients being treated with these drugs had a reduced incidence of cancer.  The difference was the most impressive with lung cancer and sex specific cancers like lung and prostate cancer. 

So what are these ACE inhibitors?  ACE, or angiotensin-converting enzyme, is the enzyme that converts angiotensin I to angiotensin II, and ACE inhibitors are often prescribed to treat high blood pressure.  Additionally, inhibiting ACE results in higher levels of Ang-(1-7), because without ACE around, angiotensin I can’t turn into angiotensin II, and turns into Ang-(1-7) as a second choice.  So these patients have higher levels of Ang-(1-7) around.  And Ang-(1-7) is a hormone that is known to be a vasodilator and also known to have anti-proliferative properties.  Could this be connected with the reduced rates of cancer?

To test this, Dr. Menon took human lung cancer cells and inoculated them into athymic mice, which are a kind of mice that have no thymus, and so are immune compromised (this is a process known as xenografting).  This means that their bodies won’t reject tissues from other mice or other animals, such as humans.  So you can put human cells in athymic mice, and they will grow.  (Athymic mice are also called nude mice, and below you can see why.)

 

So now these mice have human lung tumors.  Then Dr. Menon started treating the mice with Ang – (1-7).  While the tumors in saline treated mice kept on growing (up to 2cm in size, which is awfully big for a tumor in a mouse), the tumors in mice treated with Ang-(1-7) stopped growing.  In fact, they SHRANK!  Ang-(1-7) stopped the growth of the tumors and even caused some apoptosis (which is when cells are programmed to die).  This is a fantastic discovery.  But Dr. Menon also wanted to know HOW this was occurring.

So the next thing she looked at was something called COX-2.  Lung cancers and cancerous cells in general, have specific properties which make them different from other cells.  One difference is in the massive production of an inflammatory agent called mitogen-inducible cyclooxygenase-2 (or COX-2).  COX-2 promotes inflammation, produces pro-carcinogenic agents, and also recruits new blood vessels to come and feed a tumor while it is growing.  COX-2 also promotes inflammation in general, and several drugs have tried to inhibit production of COX-2, so far with limited success (remember Vioxx?). 

Dr. Menon already knew that Ang-(1-7) was anti-proliferative, stopping the reproduction of rapidly dividing cells.  So she looked in the tumors of the mice inoculated, and looked at their levels of COX-2.  In the saline treated animals, COX-2 levels were very high, as you would expect in cells that were proliferating rapidly and recruiting lots of new blood vessels.  But in the Ang-(1-7) treated animals, COX-2 levels were cut in half, meaning that the tumors weren’t receiving new blood vessels and were not able to replicate as fast.  So not only did Dr. Menon figure out that Ang-(1-7) reduced lung tumor growth, she showed HOW it was happening. 

So what does this mean?  It means that Dr. Menon could have discovered the next big thing in cancer.  Even better, her work has now progressed to a first stage clinical trial!  That’s a very rare event, only about 1 in every 1,000 test drugs will make it to a clinical trial.  I can’t wait to see how it turns out.  It’s so great to see someone do work that is both so effective and so incredibly important.  Keep an eye out for Ang-(1-7) in the news!

5 Responses

  1. oh my gosh, so freaking cool!

    also, love the naked mouse.

  2. […] Neurotic Physiology Let’s Talk Physio-Pharma-Philosophy « Posts of the Day Tangled Bank Is Up! June 11, 2008 I got a post into the 107th edition of Tangled Bank, which is up at Syaffolee!  Check it out!  Lots of cool science, including studies on how big raindrops are, historical contigency in evolution (a new REALLY big finding in E. coli), and my own post on Angiotensin-(1-7)!  […]

  3. this was very interssting for me. thanks alot.

  4. I’m doing research using Ang 1-7 right now, looking at it’s effects on norepinephrine release. But this is so cool! I’d love to see some of her papers, I could pass them on to people in our lab.

  5. The steps with the short step height and deep
    step depth are constructed for short little legs and are probably best
    for your cat. If he or she doesn’t immediately accept it, don’t be discouraged.
    Scratching is a natural behaviour for cats, although you’ve probably figured this out
    by now given the state of your furniture and curtains.

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s

%d bloggers like this: