By Robert Verkerk PhD, founder and scientific director

Chasing down cancer hallmarks

An important paper published in the peer-reviewed journal Cell Metabolism asks us to change the way we think about cancer. Understanding the difference between normal and tumorigenic cells has long been upheld as key to finding better ways of both treating and preventing cancer, one of the leading killer diseases, especially in the Western world.

The paper is authored by Craig Thompson MD, President and CEO of Memorial Sloan Kettering Cancer Center (MSKCC), and postdoctoral researcher at MSKCC, Natalya Pavlova. For some years now, there has been an assumed consensus that cancer is a process that develops because of defects in the cell cycle that lead to uncontrolled cell proliferation. For the last 50 years, this notion has been referred to as the somatic mutation theory (SMT), originating from the work of German biologist, Theodor Boveri, in the early 20th century. Boveri argued that cancers are formed when the make-up of chromosomes becomes scrambled so causing cells to divide uncontrollably. Boveri’s monograph was published in 1914, a year before his death. But the ideas he presented weren’t given a proper international airing until 1929 when his monograph, Concerning the Origin of Malignant Tumours, was translated posthumously into English by his American wife. As with most out-of-the-box thinkers, it took decades for cancer researchers to embrace Boveri’s prophetic ideas.

As the age of molecular biology developed at pace in the late 20th century, malignant cancers were increasingly seen either as the expression of scrambled genes or as the presence of specific cancer genes (oncogenes) that might be triggered in specific circumstances or life stages. This is essentially the basis of the dominant theory of oncogenesis today.

Other theories suggest that these changes in cellular behaviour that lead to the formation of malignant tumours don’t occur from individual cells. They occur at the tissue level, and disturbed cell cycle processes occur because of abnormal interactions of cells within whole tissues. This notion was put forward by Soto and Sonnenchein in 2011 and was referred to as the tissue organization field theory (TOFT) of cancer and it was seen as a replacement of the somatic mutation theory.

Now we’re being asked to think again – never a bad idea when there is still so much to learn about our interaction with our genes and environment. Thompson and Pavlova are saying that the evidence really points to cancers being formed when there are changes in cell metabolism and, in particular, changes, in cells’ uptake of nutrients in the microenvironment of the tumour.

Recognising the importance of the microenvironment isn’t of course a new idea. The big question is, what comes first, the chicken or the egg? Does the abnormal behaviour of cancer cells result from abnormalities in the cancer tissue or in the microenvironment surrounding it? Here there is no consensus and we find it surprising that so few biomedical researchers seem happy to suggest it might be both.

The importance of the microenvironment isn’t of course a new concept. Mina Bissell PhD of the Lawrence Berkeley National Laboratory has long upheld the view that cancer is about context and tissue architecture. While the search has been on for specific cancer genes (oncogenes) that trigger cancer in specific types of cells (e.g. breast, bowel, brain, pancreas, lung, etc.), Bissell argues that it’s the microenvironment that controls the expression of multiple genes within specific cells that may make them tumorigenic.

Mina Bissell: TED talk: “Experiments that point to a new understanding of cancer” (2012)

The six hallmarks

Thompson and Pavlova look at cancer not so much from the microenvironment of the cancer cell or tissue, but from the nature of the metabolism of the cancer cell itself. They point to a reprogramming of cellular metabolism. They highlight six hallmarks of malignant cancers, stressing that not all cancers exhibit all of these features, but all exhibit at least some of them. The identified hallmarks are as follows:

1. Deregulated uptake of glucose and amino acids (e.g. glutamine)

2. Use of opportunistic modes of nutrient acquisition

3. Use of Krebs cycle and electron transport intermediates for biosynthesis and NADPH production

4. Increased demand for nitrogen (e.g. from protein, amino acids)

5. Alterations in metabolite-driven gene regulation, and

6. Metabolic interactions with the microenvironment

These are, of course, effects, rather than causes. It’s interesting that these processes all suggest a powerful relationship between nutrition and cancer. As claimed by the authors, a better understanding of these processes opens new doors for cancer treatment and prevention. Thompson and Pavlova, we shouldn’t forget, are still coming from the point of view that oncogenes play a key role in cancer development. They uphold that cancer develops because of oncogene reprogramming of cellular metabolism. In other words, a pro-cancer genotype defined by particular combinations of oncogenes (and/or tumour suppression genes) needs to be present in one who develops cancer; and in specific circumstances the interactions between these genes and their microenvironment cause them to express a carcinogenic phenotype.

Nutritional environment

The authors are not shy to discuss the importance of the role of micronutrients in tumour formation and prevention. The role of particular vitamins and trace minerals, cofactors like choline and betaine, and amino acids like glutamine and serine, are referred to as a “promising area of research”. But the authors also allude to the delicate interplay between these nutrients, revealing evidence both of their role in triggering and preventing cancer development. None of this is surprising considering the key role of micronutrients in one-carbon metabolism required to produce new cells, as well as their role in energy production pathways (i.e. Krebs and associated electron transport) and in the modulation of the immune system.

For us, one the most exciting developments in the field of cancer biology relates to understanding how the aberrant behaviour of cancer cells and tissues can be restored. Viewed from this standpoint, poisoning tumours with chemicals or radiation, or removing affected tissues and organs from the body through surgery, appear especially primitive methods. British Lord and advertising guru Maurice Saatchi referred to these ‘conventional’ methods of cancer treatment when applied to his beloved late wife, novelist Josephine Hart, as medieval and barbaric.

Following in Mina Bissell’s footsteps, Italian researchers D’Anselmi and colleagues, writing in PLoS One in 2013, show how a changed microenvironment (in this case in a chicken egg white media) can cause cancer-susceptible human breast cells to revert to a non-carcinogenic phenotype. These changes are the result of alterations between the microenvironment and the genes in specific tissues that in turn affect cell behaviour and metabolism. Other researchers suggest that a small number of hits, assaults or traumas on the system may trigger reprogramming of cells, turning them into tumourigenic ones.

All of this and related research reminds us how important it is to manage the environment of the cancer patient. Feeding cancer patients with ice cream is simply not okay.

Oncologists: don’t turn your back on remissions

The rapidly expanding work on cellular metabolism, the microenvironment of cancer tissues and on the tissue organization field theory of cancer should spawn a new way of thinking about cancer and so-called remissions. In the world of functional medicine, clinical nutrition, nutritional therapy and a host of non-conventional healthcare modalities, observing people shifting to a normal, healthy state from stage IV ‘terminal’ cancer is not uncommon. These cases are rarely documented in the scientific literature because on presentation to oncologists, we hear time and time again, oncologists simply turn their backs. The more open-minded oncologists are typically reported as saying words to the effect “keep doing what you’re doing, as something is working”, although, curiously, they seem disinterested (threatened?) by what methods may have been used. Other oncologists simply don’t want to know anything. They simply turn their back and walk away, presumably recognising that they have no further role to play.

As a society, and as a community of researchers, we have spent too long looking at cancer in the manner of an infectious disease which then requires treatment through use of chemical or radioactive poisons, or excision. Conversely, we spend far too little time looking at cancer survivors, trying to understand why it is a malignant tumour might have reverted to a state commonly referred to as a ‘spontaneous remission’. Where they exist, medical records show that such reversion is often associated with a profound change in diet and lifestyle of the patient, which in turn changes the microenvironment within the individual. But of course these medical records are rarely collated or published.

Call to action

Our science unit at ANH International has long held a strong interest in clinical outcomes. As part of the Jon Lord Fellowship, we are presently co-supervising a project in the field of pancreatic cancer that is researching the effects of epigenetic interactions among cancer survivors.

We ask that any of our readers who have experienced cancer remission that is not related to chemotherapy, radiotherapy or surgery, email us at [email protected]. We will send you a questionnaire to help us collate relevant data, and you can opt to ensure that your data is anonymous. As is so often the case, it will be years, even decades, before there is any kind of consensus on the causes of cancer.

From what we already know, the environmental signals along with their interaction with the genome and epigenome, are so complex that the discovery of a ‘cure’ to cancer (in its many guises) will remain elusive, despite it appearing like an attractive proposition to those moved to donate to cancer research charities.

In the meantime, let’s help each other to build a repository of cases that could provide researchers with better insights on what makes some people more resistant to cancer or better cancer survivors.

Let’s also help oncologists to recognise that to turn their backs on those who have experienced ‘spontaneous remission’ is nothing short of professional or medical negligence. Simply by being reminded of this, we may be able to set precedents that encourage oncologists to record data about changes in a patient’s diet, lifestyle or other factors since the observed reversal of tumour development.

Note: Download full paper in Cell Metabolism

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