In the 1930s, Nobel Laureate Otto Warburg suggested that cancer cells produce the bulk of their energy by breaking down glucose in the absence of oxygen, a process called glycolysis. The Warburg effect, as it is called, is now widely accepted in orthodox cancer research.
But it’s WRONG, according to Michael Lisanti at the Kimmel Cancer Center in Philadelphia, Pennsylvania. He has a completely different model, which puts a whole new light on how cancer cells feed and grow.
Cancer, as we all know, is made up of rogue cells, where the DNA has gone frighteningly wrong and lets cells off the leash of restraint. They multiply out of control and often cannot be stopped: the immune system works hard against them but with certain cancers, they grow too fast, even for a competent immune system.
The missing part of the mechanism says Dr. Lisanti, with good evidence to back up his new theory, is that cancer cells release a lot of hydrogen peroxide, which hammers nearby support cells in the tissues called fibroblasts. These decay and lose their vital mitochondria.
Without their mitochondria, fibroblasts cannot now metabolize properly using oxygen. They switch to glycolysis, which we thought was being used by cancer cells. Not so, says Lisanti. According to him, “It’s the Warburg effect, but in the wrong place.” Lisanti calls is the Reverse Warburg Effect. He believes the reason Warburg got it wrong is because he looked at cancer cells in isolation, rather than in co-culture with fibroblasts.
So Warburg wasn’t exactly wrong but this new idea takes things forwards several paces. It’s a revolution, if true. But is it?
Surprisingly, there is an astonishing amount of evidence to suggest that it is.
THE WOUND THAT DOESN’T HEAL
This form of “metabolic coupling” is already known to exist and mirrors the way in which the epithelial cells that make up the skin and the surface of the body’s organs produce hydrogen peroxide during wound healing. In doing so they rally immune cells to repair the damage – but in cancer the signal is never turned off. Cancer is “a wound that doesn’t heal”, because it keeps on producing hydrogen peroxide.
When Lisanti and his team cultured breast cancer cells alongside fibroblasts for five days, they spotted the cancer cells releasing hydrogen peroxide on day two. By day five, most free radicals generated by the hydrogen peroxide were found inside the fibroblasts (Cell Cycle, DOI: 10.4161/cc.9.16.12553).
Also, the team found a reduction in mitochondrial activity in fibroblasts, consistent with the cells self-destructing. There was also an increase in glucose uptake by the fibroblasts – a sign of glycolysis (Cell Cycle, DOI: 10.4161/cc.10.15.16585).
In a further experiment, they found that treating cancer cells with catalase, an enzyme that destroys hydrogen peroxide, triggered a five-fold increase in cancer cell death, possibly by preserving the fibroblasts and cutting off the cancer cells’ fuel supply.
The theory looks pretty solid.
WHY CHEMO IS A BAD OPTION
This new theory would explain why chemo often makes things worse.
Lisanti makes the point that his own father was saved from colon cancer by timely and effective chemo (yes, it does happen). But he admits it’s a fine line between success and damaging the body. If by chance the chemo is too much, it may be damaging fibroblasts.
That would HELP the cancer cells, by feeding them with more “victims”. In certain circumstances, chemo or radiation therapy could be adding to the problem (as well as hurting the patient).
It would also reinforce my frequently voiced objection, that at least 50% of a tumor consists of healthy cells (my book “Cancer Research Secrets”, page 15). So gauging the success of a treatment by tumor shrinkage is very foolish indeed; it might just be killing the good guys and not the bad guys. Yet that’s what orthodoxy does and is the “required” proof of effectiveness for a drug to be officially approved.
ANY OTHER EVIDENCE?
Can we look around and find any similar mechanisms? You bet!
For example, malaria is another disease in which local tissue cells get damaged, giving the malaria parasite a free banquet. Oxidative stress kills infected cells, which then auto-digest and release food for the malaria parasite.
Chloroquine, one of the principal antimalarials for decades, has the effect of blocking this self-digestion process and may turn out to be a key anti-cancer agent.
Drugs that inhibit the ability of mitochondria to burn lactate and other products of glycolysis may also serve to cut off the tumor’s food supply. One such drug is metformin, widely prescribed to treat diabetes.
And guess what? Several recent studies have suggested that people taking metformin have a reduced risk of developing cancer! (Gastroenterology, DOI: 10.1053/j.gastro.2009.04.013).
Lisanti is now gathering evidence to find out whether his ideas can be applied to many cancers or just a few. His theory gives us what may become a valuable new marker for cancer (most of the existing ones are pretty unreliable).
A special protein is secreted by healthy fibroblast cells and, as they stop producing it when killed or even damaged, a lowering would suggest that destructive auto-digestion going on. It’s called caveolin-1. Lisanti has recorded a drop in caveolin-1 levels in 40 to 50 per cent of patients with breast cancer, and loss of the protein correlates with early tumor recurrence, metastasis, and resistance to the drug, tamoxifen (Breast Cancer Research, DOI: 10.1186/bcr2892).
He also has evidence for caveolin-1 loss in prostate cancer. So with this particular marker, a drop is a negative finding but could still be valid.
What is happening, in this new model, is that cancer cells form a parasitic relationship with nearby fibroblasts.
This changes EVERYTHING! Orthodox medicine has been obsessed with killing cancer cells.
A whole new take on this would be to block cancer cells from killing local cells, such as fibroblasts.
Antioxidants are supposed to just that. Surprisingly, the effect of taking everyday antioxidants is disappointing. But there is a measurable effect, as shown by a number of studies, which would certainly be predicted by this new theory.
Most chemotherapies work by generating lethal doses of free radicals to kill the cancer cells and this would cancel out the effects of any antioxidant treatments. That may be why the studied effects don’t show too strongly. I agree with Lisanti, who believes we need trials of antioxidants alone, rather than in combination with chemotherapy.
A great new direction to go in treatment would be to block the signaling between cancer cells and fibroblasts, which will stymie the nutrition process and starve cancer cells into submission.
It’s great to see orthodoxy taking an interest in the micro-environment surrounding disease tissues. But, as I keep pointing out (to the annoyance of “holistic” bigots!), there are some great people out there, pushing in towards the truth, with far more resources than we alternative practitioners could muster.
There are always naysayers. But in this case there are sensible objections. They don’t prove Lisanti’s theory is wrong, merely that it needs serious working up.
For example, it has been suggested by Dr. Ian Hart of Barts Cancer Institute in London, that if fibroblasts are sacrificing themselves so that the cancer can eat, sooner or later they are going to be completely depleted. And that doesn’t happen.
I don’t quite agree with Hart. Cells can replace themselves, after all, either by dividing or maybe from pluripotent stem cells. Hart says more evidence is needed to confirm this is happening.
But also, it may be objected, many previous studies have found increased glycolysis actually in cancer cells. Maybe that could be explained by the strongly symbiotic relationship that clearly develops between cancer cells and fibroblasts.
WHAT ABOUT THE FUTURE OF TREATMENT?
If proven correct, this new theory would change everything about eradicating cancer. Instead of trying to kill cancer cells, which is tricky and dangerous, we should be trying to protect and support local fibroblasts.
So good nutrition would be predicted to help – and it does!
The use of oxygen therapies would be predicted to help – and they do.
Anti-oxidants are crucial (they block the effect of hydrogen peroxide) – and they are.
If Lisanti is correct, his ideas would explain why people become more susceptible to cancer as they age. As we age, our body produces more hydrogen peroxide and free radicals and becomes a fertile ground for cancer.
More than 100 years ago, Steven Paget proposed that cancer cells are seeds that need the correct micro-environment in which to grow. “What we’re now saying is that the hydrogen peroxide is the fertiliser,” says Lisanti.
[Lisanti presented the idea earlier this month at the Strategies for Engineered Negligible Senescence meeting in Cambridge, UK].