Oncologists tend to get excited about the wrong things. They think that they know more than ever before about the genetic faults driving different cancers and are happy that they are getting better at designing drugs that target them. They are stuck on a merry-go-round of their yellow brick road genetics finding as they do that the more they know the more complicated things become.
Using genetics to classify tumors is a blind alley that forces doctors to perceive and diagnose a growing number of cancer types. Only last year our scientists in Cambridge showed that breast cancer is actually at least ten different diseases.
The genetics trap is seen in the fact that different groups of cells within a tumor have different genetic faults – an issue known as ‘intra-tumor heterogeneity’. This suggests that doctors will need to figure out what’s going on in different parts of the tumor (sounds complicated doesn’t it?). This implies that not all cells within a cancer can be targeted by a single drug. So using combinations of targeted drugs – or using them in particular sequences – may be needed.
Gene faults within a tumor also tend to change over time, so some doctors suggest that doctors cannot just rely on initial biopsies when planning treatments – they’ll probably need to keep monitoring things over time to find out whether the genetic make-up has changed.
But some of the gene changes may make the cancer resistant to particular drugs, and treatments themselves can sometimes cause genetic changes. Oncologists are running down an ever deepening black hole of complications making it difficult for doctors to match their patient to the drug most likely to work for them. Actually none of them really work except in a temporary sense.
Dr. David Solit of the Memorial Sloan Kettering Cancer Centre, New York highlighted that secondary tumors can differ from each other as well as from the primary tumor – and that tumor heterogeneity can also exist in a secondary tumor, which helps us understand why some areas of metastasis may shrink in response to a particular treatment but other areas of metastasis may continue to grow.
Dr. Solit describes how cells from a secondary tumor can break away, circulate in the blood and reach the primary tumor – delivering cells with new genetic changes – a phenomenon he referred to as ‘self-seeding of the primary’.
The notion that genes cause disease is a many decades old myth that literally billions of dollars have gone into disproving, but why is the global media still reporting on the topic as if it were true?
Dr. Andrew Clark of Cornell University and Dr. Emmanouil Dermitzakis of the University of Geneva Medical School, Switzerland say in Science Magazine, "the magnitude of genetic effects is uniformly very small" and therefore "common variants provide little help in predicting risk." Consequently, the likelihood that personalized genomics will ever predict the occurrence of common diseases is "bleak". This aim, they believe, will have to be abandoned altogether.
Gene mutations are part of the process of cancer, but mutations alone are not enough to cause cancer to take hold and spread, thus threatening people’s lives through domination of precious life resources (nutrition) as well as precious real estate where other healthy cells live. Genes do become damaged and sustain mutations in some cells and not others during people’s lifetimes. An oncogene—a gene that causes tumors in animals and uncontrolled growth in cells in culture—cannot in and of itself change cells from normal to cancerous. It is the cells’ surroundings, known as its microenvironment, that contributes in some way to how cancer has occurred.
Cancer involves an interaction between rogue cells and surrounding tissue. This is the clear message of Dr. Mina Bissell, who is the director of life sciences at the Lawrence Berkeley National Lab in California (LBNL), and she is now sharing this with the world. The interactions between cancer cells and their micro and macroenvironment create a context that promotes tumor growth and protects them from immune attack or, on the other hand, prevent tumors from making any kind of beachhead so they cannot take hold or spread themselves around. Cancer cells routinely form in most people’s bodies but that does not mean they are going to succeed in capturing their host’s valuable resources so they can invade (inland so to speak) as they win their war and take our life.
What this means is that the surrounding cells and the surrounding extracellular matrix interact to shape cancer cell behaviors such as polarity, migration and proliferation. The microenvironment includes a complex scaffolding on which cells grow and develop, called the extracellular matrix. The microenvironment is what actually surrounds a cell. The extracellular matrix (microenvironment) has been shown to regulate gene expression so it has more to do with the state of cancer than the cancer cells themselves.
“If tissue architecture and context are part of the message, then tumor cells with abnormal genomes should be capable of becoming ‘normal” if grown in a healthy microenvironment. She and her students tested that hypothesis with some malignant cells, growing them on a healthy scaffolding. And yes, they were able to revert the malignant phenotype to a normal one. They could even inject the cells into mice where they didn’t cause tumors, unlike malignant cells, which would cause cancer. This, says Bissell, indicates that there is another way to look at cancer—that cancer genes are regulated by the environment around them.
Dr. Bissell’s basic idea is that cancer cells cannot turn into a lethal tumor without the cooperation of other cells nearby. It is not just the other surrounding cells but also the interstitial environment, which of course would include pH and nutrient levels being supplied by the blood. That may be why autopsies repeatedly find that most people who die of causes other than cancer have at least some tiny tumors in their bodies that had gone unnoticed. According to current thinking, the tumors were kept in check, causing no harm.
Medicine to Make One Well
Listening to Dr. Nick Gonzalez, who has had remarkable success treating patients with some of the most lethal forms of cancer, one hears him tell stories about how impossible it is, even for a president of Sloan-Kettering hospital to publish anything that suggests something different from the official party view of orthodox western oncology. You will also hear him talk about a patient who has survived 39 years after being diagnosed with the worst form of pancreatic cancer.