By Jerome Burne
Professor Mina Bissell presents a fascinating challenge to the cancer establishment. She is a highly respected academic and leading authority on breast cancer at the University of California, where she is Distinguished Scientist with Lawrence Berkeley National Laboratory’s Life Sciences Division next to UCB campus.
For the last 30 years she has been working on a radical theory about cancer that until recently put her right outside the mainstream. ‘The dominant cancer theory,’ she said in a TED talk a couple of years ago ‘stated that a single oncogene (a gene that can trigger cancer) in a single cell leading to tumours could make you a cancer victim.
‘This has never made sense to me. We have trillions of cells and if even a tiny fraction had a cancerous mutation you would rapidly become a lump of cancer.’ Her studies in the 1980s showed that if a potent oncogene for chickens, (the first such gene was reported in 1911 by Rous), was injected into chick embryos, the oncogene could be expressed and be activated, but the infected cell could form part of a healthy organ because no tumour developed. The implication is that something more than a gene mutation is needed to turn a cell cancerous.
This is not to say that genetic mutations aren’t important but Bissell believes that in focusing almost exclusively on cancer causing mutations we are in danger of missing the forest for the trees.
Need a healthy network
What counts, it turns out, is the health of the network of cells that surround any cells that have cancer causing potential. It’s known as the “extracellular matrix” (ECM) and it’s made up of a dense scaffolding of large, insoluble proteins surrounding almost all tissues, but the exact molecular composition of the ECM for different tissues is different. Blood vessels pipe in nutrients while lymph vessels handle the drainage.
When the ECM is healthy, the cells nestle tightly against each other like terraced houses and any hint of leakage from a cell or abnormal behaviour is quickly dealt with by the neighbours. In areas that are breaking down, cells lose touch with their neighbours, spew waste and grow uncontrollably.
Bissell and other researchers are now convinced that by properly managing a cancer’s local environment it can be contained. ‘We really should be able to control cancer as a chronic but dormant disease, like diabetes’ she says. There is now a whole field of microenvironment, based on work from her and a number of other laboratories such as the Tumour Microenvironment Network at the National Cancer Institute in Bethesda, Maryland.
The idea that what happens in a cell turning cancerous can be affected by its neighbours makes obvious sense, so how come it has been ignored until very recently?
A simplistic view of genes
‘The excitement in the late ‘70’s early 80’s when oncogenes (cancer causing) and the suppressor genes that turned them off were first discovered was so great that some senior scientist still believe the simplistic view that a single oncogene is enough to cause cancer,’ says Bissell. As a result identifying single genes and developing drugs to block them became the standard approach. In an article in Nature magazine many years ago, this approach was compared with trying to reduce the incidence of traffic jams by concentrating all your attention on individual cars.
Widening your angle of vision so you also investigate the conditions in the area surrounding the tumour – the ECM – and the health of the neighbouring cells opens up a whole new approach to the origins and treatment of the disease. It suggests that combining treatments aimed at boosting our immune and energy generating systems with less toxic drugs makes a lot of sense.
It also switches the spotlight to prevention. ‘If we took seriously at all the things that we know can help cancer prevention,’ says Bissell ‘such as tackling obesity, exercising, eating fewer carbohydrates especially sugar, we would have many fewer fully fledged tumours and a reduction in mortality.
‘But if we understood the importance of the microenvironment and the cancer context we could, in some cases, make cancer into a lower risk chronic disease.’
Starve cancer cells of sugar
An example of what she is talking about is cutting back on carbohydrates and especially sugar because cancer cells are well known to need much more glucose than healthy cells, so starving then makes sense. Bissell cautions that once a tumour has developed any such approach should be combined with regular drug treatment.
Early work supports the damaging role of sugar. A paper published by Onodera and Bissell just this past year in J. Clinical Investigation showed that overtly tumorigenic breast cancer cell lines could be “reverted to a quiescent and normal phenotype if glucose (sugar) was removed from the medium in which these were cultivated.”
Cancer cells’ high sugar demand is usually said to be a result of cells turning cancerous. However Bissell has found that a high level of blood sugar (glucose) can itself promotes cancer and what’s more that cutting back on sugar can reverse it.
“More research is needed but a dramatic increase in sugar intake could be a cause of oncogenesis,” she says on the Berkeley Lab website. The change involved a protein called GLUT3, involved in moving glucose into cells, which is found in very high levels in cancerous breast tissue.
Sugar can turn cells cancerous
With the aid of a revolutionary 3-dimensional system her laboratory has developed for analysing cancer cells, Bissell showed that healthy cells became disorganised when GLUT3 production was pushed up. Then damping down GLUT3 in the cancerous cells turned down the genes driving the cancer growth. The result was that the cells became healthy-looking again, even though the cancerous mutations were still there. In other words changes in the microenvironment of cancer cells can change the effect of cancer causing genes.
This research suggests why the high blood sugar levels found in people who are obese or diabetic can increase the risk of cancer.This is the reason why other researchers have become very interested in the ketogenic diet – which involves a major reduction in carbohydrate consumption. More details.
Bissell’s ideas are being picked up by other researchers and more compounds in the ECM are showing up as affecting whether a cell turns cancerous. One of these is a protein known as CD36 which is involved in making both fat and connective tissue but also controls processes that promote healthy breast tissue. Researchers at the University of California, San Francisco found that when CD36 is missing it leaves an environment where cancer is more likely to grow.
But it is not just chemicals in the ECM that can restore cancerous cells to health. Daniel Fletcher, a professor of Bioengineering at Berkeley in collaboration with Bissell’s laboratory found that pressure exerted by cells in the ECM can also produce a reversal of cancer. This involved a new way of studying cells in the lab – the 3D system mentioned above. Rather than squashing them flat on a slide, cancerous cells were held in specially designed flexible silicone chambers.
Cancer cells lost in the big city
Fletcher and his collaborators found that the squeezing had a beneficial effect on a protein called E-cadherin that is involved in keeping cells closely bound together. Breast cancer patients with low levels of E-cadherin have poorer chances of recovery. This doesn’t mean that squeezing tumorous tissue is going to help but it shows the variety ways the micro-environment can affect cancer development. Other ways to increase E-cadhedrin production includes black tea. (Read more.)
“Cancer is not only a problem with growth,” Bissell argues “instead it is a matter of context, which when altered could lead to disorganized growth.’ She makes an analogy with human society. Just as kids from a small town can lose their bearings in in a big city, so cancer cells can find themselves disoriented when their surroundings change. Soon, they are running amok, behaving in ways they never would at home, where their neighbours help keep them grounded.
Other changes to a neighbourhood that can trigger cancer promotion, beside high levels of glucose and a loosening of the bonds between neighbouring cells, includes the oxidants that the body produces in response to stresses.
These in turn send out chemical signals that cause inflammation, which can trigger more changes in a cancerous direction. This is the thinking behind giving anti-inflammatory drugs such as aspirin to help cut cancer risk.
Combination treatments for cancer
Recently Professor Lisa Coussens of the Oregon Health and Sciences University in Portland has suggested that combining therapies such as vaccines, anti-inflammatories and fasting (calorie restriction) is an effective way to reduce the inflammation that’s linked with cancer.
‘But you can’t shut inflammation right down because it is part of the immune response which is crucial to controlling cancer,’ says Coussens. ‘The fact that we don’t all walk around with big tumours is proof that the immune system works most of the time.’
The complicated dance between tumours, inflammation and the immune system show how important the ECM is. For instance, Coussens has found that sometimes immune cells can help a tumour. ‘Macrophages are attracted to tumours under attack from chemotherapy,’ she says. ‘They can toughen it up, making it less vulnerable to the drugs.’
Bissell’s approach shows up the shortcoming of chemotherapy which damages cancerous and surrounding healthy cells alike. ‘It will still be needed,’ she says ‘but it should be combined with other approaches such as signalling inhibitors and antibodies. Also potentially useful would be lowering carbohydrate intake, losing weight if you are obese and exercise. ‘Exercise lowers your chance of recurrence better than most available drugs in a number of cancers,’ she says.
Who will pay for the new treatments?
But moving from the theory of the influence of the ECM to using it as a guide to new and experimental treatments will be challenging. “It’s already accepted by some oncologists, ’she says ‘especially for those working with leukaemia and lymphomas.
‘But it should also be applied to treating solid tumours. Problem is that almost none of this research showing how the microenvironment can affect gene regulation, which goes back four decades, is in the text books.’
The criticism that is always made of the non- standard therapies is that they don’t have trial data to support them. But as Bissell points out: ‘Someone has to pay for the clinical trials to get the data. The drug companies aren’t going to do it, which leaves the government and charities, but science budgets are being cut.
So what should patients do who want to try unconventional sort of approaches ‘For now the best way is combining a wise use of the standard therapies with the non-conventional ones, such as acupuncture, massage, osteopathy.’
Bissell is all too familiar with criticism for advocating non-standard therapies as a way of effecting beneficial changes in the ECS, but she believes it is grounded in solid research. ‘We have made amazing discoveries,’ she says ‘thanks to the support of some heroic individuals within the funding agencies, in my case, for example, the Department of Defense Breast Cancer program, Breast cancer Research Foundation, and we will continue to publish high quality science despite the people who have much narrower visions.’
‘There is so much more to be discovered. There is so much mystery still. I always say to my students – as I said in my TED talk: Don’t be arrogant because arrogance kills curiosity and passion.’
It would be great if her work generated more curiosity than arrogant resistance.