Angiogenesis & Cancer

As the cliche would have it, I have good news and bad news.  The good news is all about the most exciting new medical research area I have heard about in a long time.  But first, the bad news:

Just about everybody reading this sentence has cancer.

It had been known for years that autopsies of people who die in traffic accidents (optional in the U.S., required in a number of other countries) often showed the presence of small carcinomas.  These were dutifully reported in dozens of individual papers.  Finally, a paper came out in 1993, collating all of the different reports to date.  The results were startling:  most people, particularly those above 40 or 50 years of age, had numerous small cancers scattered throughout their bodies in virtually every organ.  39 % of the women over 40 had breast cancers, 46% of the men over 50 had prostate cancers, and a whopping 98% of all those over 40 had thyroid cancers.

You might be forgiven for doubting this.  It just seems too bizarre.  Is it really some strange misuse of the term cancer?  That is, are these actually benign little collections of harmlessly mutated cells, harboring no desire to grow massive in size and metastasize all over the place?

No.  Turns out that many of these little groups of cells, known as carcinomas in situ, have delusions of grandeur as great as the worst nightmares we can imagine.  Given the right circumstances, they will explode into activity, growing and spreading like mad.

What then, is it that keeps them quiescent?  And, more importantly, is there anything we can do to make sure they stay that way?

The answer to both questions is simple: blood.

To understand this, we have to go into a little detail.  Imagine we can look down at a single cell.  From whatever cause, it has acquired the genetic abnormality that will cause it to grow and divide without limit.  In short, it is cancerous.  At the moment, it is living in the midst of its healthier brethren, pretty well indistinguishable from them.  But whereas they are content to live out their cycle of getting a limited supply of oxygen and nutrients from the adjacent capillary, our cancerous friend is voraciously sucking up all it can, growing madly larger.  Pretty soon it will divide itself into two cells, each with the same gluttonous appetite.

Unfortunately (for the cell, anyway), one of those cells is located a bit further away from the capillary, no longer in direct contact, so it is dependent upon the slow rates of diffusion to supply its needs. Naturally, its growth rate is slower.  Still, it will grow and divide as best it can, producing progeny, each generation of which finds itself farther and farther from the source of oxygen and nutrients, and hence less able to proliferate.

Eventually, what you end up with is a self-limited little cluster of cancer cells, about a millimeter across, containing perhaps 500,000 cells.  The cells most remote from the blood supply are so starved for nutrients that they have stopped the growth of the entire colony.

This is a cancer (carcinoma) in situ.

The next question one might logically ask is whether that is the end of the story.  That is, are all of these carcinomas scattered in the body destined to simply grow up to the diffusion limit and then stop?  Is that previous statement that we all have cancer simply meaningless hyperbole?

The answer is yes…sort of.  That is, the vast majority of cancers will stop right there.  Looking back at those breast and prostate cancers, 99% will never progress beyond the in situ stage.  In the case of the thyroid cancers, the odds are even better.  Out of every 1,000 carcinomas, 999 will never progress beyond the self-limiting phase.

Ah, but how about the others I mentioned?  The 1% of the breast and prostate cancers and the .1% of the thyroid cancers?  What happens to them?  Do they have some special talent that allows them to beat the natural laws that limit their growth?

The answer is that they have, indeed, developed a way to beat the system.  Specifically, recognizing that what they really need to grow without limit is their own supply of oxygen and nutrients, they have figured out how to convince the body to supply them with the one essential they lack: blood vessels.

There is a natural process in the human body whereby new blood vessels are grown.  It is called angiogenesis (lit. vessel birth).  Obviously, in early life, when the body is growing, new blood vessels are needed, so angiogenesis is more or less constant.  However, once adulthood is reached, angiogenesis ceases in healthy people except in a few natural processes such as menstruation, pregnancy, etc.  One other vital exception to the no angiogenesis rule is when the body receives a wound that damages blood vessels.  Within about twelve hours angiogenesis is magically turned on and stays active for (normally) about two weeks, supplying new vessels to keep the cells affected by the wound alive.

For the rest of the time and for most of the body, angiogenesis simply doesn’t occur.  The vast blood supply system (someone has calculated that there is about 1 of capillaries for every pound of fat) is remarkably stable throughout our lives.  For that matter, the endothelial cells that line all those capillaries are themselves remarkably stable.  As a bit of trivia, the cells lining our intestines are replaced about every three days. The endothelial cells are replaced every three to five years.

Still, there are those occasions when angiogenesis is needed.  So the human body preserves the capability of growing new vessels, but it keeps the system in check by maintaining a careful (and complex) balance of chemicals that promote angiogenesis with other chemicals that inhibit angiogenesis.

It is this balance that provides the open door through which malignant cancers manage to slip and thereby achieve the unlimited growth they want.  By stimulating the production of angiogenic factors they command the body to supply them with a never-ending supply of new blood vessels.  This is the trick that those 1% of breast and prostate cancers and those .1% of thyroid cancers manage to achieve.  And that is what allows them to change from small, harmless, self-limiting carcinomas in situ into the raging monsters we all fear.  Just to really put icing on the cake, those new blood vessels that the cancer demands for growth will also serve as the pathways it uses for metastasis.

Lovely.

Our awareness of this process is quite new.  It was only in 1971 that Dr. Judah Folkman first suggested the possibility that tumor growth is dependent upon their stimulus of angiogenesis (and was roundly condemned as a heretic by all the leading experts in the field).  Since then, something like 20 angiogenesis growth factors and about 30 angiogenesis inhibitors have been identified in the body.  These are the endogenous varieties.  There are, in addition, lots of other external chemicals that can stimulate or inhibit angiogenesis.

If you have been patient enough to read to this point, you might be asking yourself, So what?  I mean this is academically interesting and suitably frightening, no doubt, and a curious footnote about how the human body operates, but of what use is it?

Ah, I’m glad you asked that question.  Because angiogenesis is the most exciting area in cancer treatment and the one with the most potential to make not merely incremental improvements in survivability but giant leaps.

Let me explain.

The essential insight of Dr. Folkman was that if he was correct, if cancer cells needed to turn on angiogenesis to turn malignant, then turning it off again would at least stop a tumor’s growth and might actually cause it to shrink.  In addition, inhibiting angiogenesis would also inevitably have the measureless fringe benefit of stopping metastasis in its tracks.  Finally, by addressing not the cancer cells themselves but a natural body function they have perverted, one had the chance of turning a totally natural process against cancer.

The key here, and the source of much of it power, lies in the fact that, while cancer cells are by definition abnormal cells in the body, endogenous angiogenic factors and inhibitors are natural chemicals, present in the body in either a stable balance or in a predictable rise-and-fall cycle.  When a tumor begins to grow, it upsets that balance by releasing one or two angiogenic factors.  What this implies is that the cancer, an inherently unnatural growth, is dependent upon a totally natural bodily process.

For Folkman, this pointed the way to a cascade of implications, all beneficial.  First, that abnormal presence of growth factors must be detectable in the blood.  That these can serve as unambiguous bio-markers of pathological conditions (tumors and other angio-dependent conditions), allowing early and certain diagnoses.  That identifying which angiogenesis factors are being abnormally stimulated automatically identifies the corresponding inhibitors that can control the process.  And, as many of these inhibitors are natural, endogenous chemicals, already present in the body and hence completely safe, that a whole new set of benign therapies are foreshadowed.  Instead of some harsh, alien poisons like those used in chemotherapy treatment, we begin to see (potentially at least) a natural chemical treatment that has already been tested as safe in the human body for of  years or so.

The results are already visible.  You can see them in some of the chemical trials being conducted today.  Anti-angiogenic treatments involving endogenous factors are in trial pretty much right alongside the latest chemotherapy treatments.  However, whereas those on chemotherapy drag their debilitated, balding bodies into the clinic clutching their barf catchers, those in anti-angiogenic trials stroll in, carrying books to read.

But the benefits don’t stop there.  A secondary benefit lies in the targets of the new therapies.  Cancer cells are, by their very nature, highly mutagenic.  Any therapy targeting them has to deal with the fact that the cells will change and adapt in response to the treatment.  Hence  chemotherapy must aim for 100% success in the first treatment regimen.  Any regimen that fails to achieve a cure in the first round of treatment is liable to be ineffective in a second round: the cancer has become resistant.

But the target of anti-angiogenesis is those endothelial cells that line the blood vessels.  They are the cells that were either stimulated or retarded by the growth factors and inhibitors.  And remember that those are extremely stable, long-lived cells.  Unlike the cancer cells, they are the very reverse of mutagenic, faithfully reproducing exact copies of themselves.  An anti-angiogenic treatment plan that produces a 10% shrinkage in a tumor this year is likely to produce 10% next year, too.

The indirect consequences of angiogenesis are opening up whole new worlds as well.  When the angiogenic process is turned on, the new blood vessels in effect tunnel their way through existing tissues to create a pathway.  They do this by means of special enzymes called MMPs, Matrix Metalloproteases, that are secreted at the end of the new vessel.  Using the same logic as that underlying angiogenic research itself, Dr. Marsha Cross at Boston Children’s Hospital has recently demonstrated that the production of enzymes precedes detectable tumor growth.  She detected an angiogenic enzyme in the urine of women 3 to 4 years before the resultant tumors were detectable.

This suggests a potential one-two punch: first, detect the beginnings of the growth process by a (relatively) simple test for enzymes in the urine.  Second, determine the actual angiogenic factors that stimulated the enzyme production.  Third, treat the still undetectable tumor with endogenous angiogenic inhibitors targeted at the specific type of angiogenic factor(s) detected.

The potential is here for a complete revolution in the way we detect and treat cancers.

I told you it was exciting.

And there is still more.

There are 62 other diseases that have been identified as involving out-of-control angiogenesis.  For instance, the age-related macular degeneration that leads to blindness includes the production of new blood vessels under the macula within the eye.  In rheumatoid arthritis, dense masses of blood vessels are essential to the the destruction of the joint tissues.  Endometriosis, where endometrial cells back up into a woman’s abdomen and grow there, is obviously dependent upon providing a blood supply to the mislocated cells.  The list goes on and on, from the familiar to such gems as pulmonary hemangiomatosis and angioblastoma.  But rare or common, they are all angiogenic dependent and hence subject to angiogenic inhibition.

These discoveries, too, go on and on, involving more and more conditions and more and more angiogenic factors.  The story of the revival of that much-maligned drug, Thalidomide, as an angiogenic inhibitor alone is worth a lengthy article.  So is the fact that Down’s Syndrome children do not get cancers because they have a extra gene that makes an abnormal amount of endostatin, one of those endogenous inhibitors.  Then, too, the discovery that the plaque buildup that plugs arteries is full of little capillaries and that angiogenesis inhibitors reduce the amount of plaque has a lot of vascular investigators climbing on the angiogenesis bandwagon.

There is no natural stopping point to this story, so I’ll just have to end it here.  But I’d like to emphasize that all of this is directly due to one man’s brilliance and uncommon stubbornness in pursuing a single insight.  I don’t know if Judah Folkman has yet made it to the short list for the Nobel Prize in Medicine, but he’s already got one civilian’s vote.

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