From the beginning of this century, cancer research has been focussing on Biological Information for every single tumour, to know why some people with same genetic predisposition and living in the same environment, get cancer and others do not. The focus has also been to discover therapeutic interventions to treat cancer. Research has made a large data available for practically every cancer type and many histological subtypes. However, decades of Research has not reduced the cancer burden globally.
Genome project was started with great enthusiasm and passion, with the objective of sequencing and identifying 3 billion genes in the Human Genome, so that the genetic roots of the disease can be found and specific treatment options could be developed. Human Genome was decoded at the end of the century. The entire Genome of 1000 people from all over the world was studied. The findings revealed that 1% of the Genome of every individual is unique but balance 99% is identical. The scientists are still doing research on what are the differences in this 1%, which can prove to be highly critical. Almost 800 genetic variations have been identified in the individual Genome, which are responsible for major diseases including cancer. To evaluate these genetic variations, scientists are looking for biological markers associated with cancer. We need 8000 biomarkers, but as of today, only 2 are available. We are still not able to predict which pre-malignant oral lesions will become malignant.
Sequencing and analysis of the human Genome shows that there are more than 20,000 genes in tens of tumours. Mutations in these genes are responsible for initiating the cancer. Detected mutations do not include chromosomal rearrangement
Role of sequencing of genes is becoming harder to define. No. of mutations in each gene are much higher than expected. Out of these 20,000 genes, function of even 100 genes is not clear. These mutations are triggered by several environmental factors within our body. Research on oncogenes, tumour suppressor genes, genotyping of tumours has been carried out to find out different mutations. Impairment of DNA and mutation of 7p53 induces loss of DNA methylation and amplification of 7ROPI gene which leads to cancer, but we are still not able to predict, who will get cancer.
Inflammation and Immune Research
The other scientific development is the emergence of holistic nature of cancer, where the focus is on the role played by the body’s own physiological processes which convert normal cells into cancer cells and enable them to grow and spread to other parts of the body. Inflammation and Immune Research is going on to explore the role of the micro-environment around the tumour i.e. trillions of bacteria and fungi that live inside our body. There are the bacteria, fungi and viruses that live in our body, all the time and do not cause any damage. They are present on our skin, respiratory tract, gastrointestinal tract, urogenital tract. The vast colonies of these microorganisms have 1000-2000 species. They are highly responsive to changes in diet, environment and other lifestyles factors and play an important role in regulating numerous physiological functions, some of these functions specially inflammatory and innate adoptive immune response have a key role to determine whether or not a cancerous mutation will go on to grow, thrive and spread to other tissues.
Immune, inflammatory and angiogenic (building of new blood vessels to feed the tumour) responses are being studied along with a range of hormones that are related to nutrition. Researchers have already started to reveal the mechanisms linking cancer with diet, exercise and obesity. This will help in strengthening the evidence base for strategies to prevent, suppress or reverse the carcinogenic process.
The most surprising finding is that this regulatory role is not confined only to the areas where these microorganisms live. For example, if someone has a viral lung infection and inflammation, the immunity in the lung will not be effective unless one has got microbiota (bacteria, fungi and viruses). The role of microbiota in cancer has been demonstrated in various ways with the first oncogene. It has been shown that if you inject a virus into an adult bird, a tumour develops at the site of injection or other parts of the body, where it induces inflammation. If the same virus is injected into a germ-free embryo, tumour does not develop. Inspite of the fact that cells where virus was injected, show a transformed phenotype, they do not grow in the embryo without the right microenvironment.
The questions being asked are – “Is the microbiota acting exclusively or you need inflammatory damage by the virus to induce tumours”. If it is sterile environment nothing happens with inflammation alone.
Similar results are produced by injecting mutated KRAS cells to knock out p53 tumour suppressor gene into a germ-free mice. In other words, to turn into tumours, the mutated cells need the desired microenvironment, which has the potential for intervening in the processes that regulate numerous physiological functions.
It has been proved beyond doubt that tumours are formed due to genetic alteration of cells. A lot of research has been done to understand the oncogene (cancer-causing gene) cancer suppressing gene and genotyping of tumours to find different mutations. A mutated cell can never grow or spread. If the seed (mutated cell) does not find the right soil, the right tissue and right micro-environment, especially the desired level of inflammation and innate adoptive immune response in the microenvironment, (that will permit the mutated cells to grow) mutated cell will not become cancerous..
The role of microbiota throws light on our existing knowledge about the role on inflammation and the adaptive immune response plays, in carcinogenesis and development of tumour.
There are two types of inflammation, acute and chronic. Acute inflammation induces a strong and active immune response, which can be developed to fight cancer . On the other hand chronic inflammation induces a different response, which actually promotes growth of the tumour, by suppressing immune response and favouring spread of the tumour.
This explains the reason for reduction of many types of cancer in people who have been taking low-dose aspirin, which acts partially as an anti-inflammatory, over a period of many years. It also suggests a likely role of microbiota in regulating inflammatory and immune responses, in the mechanism of linking certain diets, environments and lifestyle with a higher risk of cancer. Therefore to prevent cancer, we can alter some of these factors i.e. diet and lifestyle changes.
In a Chinese based population study, which looked at the impact of a range of vitamin and mineral supplements on rates of cancer of the oesophagus (food pipe). Epidemiologist You-Lin-Qiao, at china’s National Cancer Centre, presented some of the key findings, which included a 23% reversal rate of atypical oesophageal dysphasia and reduction in oesophageal and gastric cancers by 13% and 21% respectively. However many findings in one country are not directly transferrable to other parts of the world. Evidence from several populations, consuming full range of fresh food, suggests that it is healthy balanced diet, rather than dietary supplements that make the difference.
The epidemiological research that revealed the scientific rational or the Nutritional Intervention Trial started in 1959, when China was the poorest country in the world. This low-tech approach, which drew on traditional Chinese medicine and focussed on changing behaviours is held up as a template for cancer control- by WHO, even today.
European Prospective Investigation into Cancer (EPIC) and the nutrition study over the past decade has generated enough data to indicate that fibre and fish in the diet are protective against cancer risk, while red and processed meat, significantly raise- the risk for developing cancer.
International Agency for Research on Cancer has also evaluated that processed red meat is definitely carcinogenic to Humans and unprocessed red meat is probably carcinogenic. Paolo Viners, Chair of Epidemiology at Imperial College London, is trying to pinpoint mechanisms, which could give biological plausibility to epidemiological findings and provide biological markers that could be used in prevention trials. They are looking for biological biomarkers that are associated with both disease and dietary exposure.
A small study using metabolomics in EPIC, Italy, revealed eight metabolomics signals or features associated with colon cancer. Out of these eight, four were associated with dietary fibres. One of these four, indicates a possible link with gut microbial fermentation of plant phenolic in the colon, confirming some biological plausibility. Looking at the composition of the colonic microbiota, it shows that two families of bacteria commonly found in the colon – Bacteroides and clostridium, increase the incidence and growth rate of colonic tumours, induced in animals.This study opens possibilities for preventive strategies that intervene directly rather than through diet, to modify the microbiota.
Role of Nutritionally related Hormones
Obesity and its rising rates are considered to increase the incidence of cancer Michael Pollak, Director of the division of Cancer Prevention at McGill University, in Montreal is taken the challenge to find out the link between cancer and nutritionally related hormones i.e. insulin, insulin-like growth factors and many more, as the link.
The dietary energy supply influences some tumours by influencing the hormonal environment rather than the energy made available to the tumour. The link between Breast cancer and ovaries is one such example. The effect of macronutrients intake on cancer biology is just another context of hormonal dependency of neoplastic cells. This leads to other important implications for prevention. Although it is essential to eat moderately and exercise regularly, this may not always be enough and there may be other means to intervene directly on this group of hormones, using diabetes as a model. Experiments on mice show that prostate cancer grows faster, if they are fed junk food. If you induce type I diabetes in these mice, the growth rate of prostate slows down. The Glucose is very high but insulin is low, therefore it is not the glucose they need, It is insulin. Ant diabetic drug metformin is being used as a potential preventive agent for people at high risk of insulin related cancer. Metformin acts as mitochondria to inhibit energy production. It reaches liver and liver cells feel energy stressed and keep the glucose for themselves. This leads to fall of glucose and therefore fall of insulin level. Insulin dependent cancer can then be hit.
The principle of preventive therapies is now widely accepted and approved by FDA, specifically for Hormonal therapies in people at high risk of breast cancer. Similarly the role of aspirin in reducing the risk of colon cancer through its anti-inflammatory effect is undeniable. Therefore researchers are now looking at the strategy of denying the environment, required for converting precancerous lesions to become cancerous.
Latest discoveries in cancer:-
To summarise cancer awareness campaigns and Cancer Research does not yield immediate results. It takes decades to test, validate and implement the validated knowledge technologies. Sometimes, even after making stunning discoveries and translating knowledge into action, Research Scientists are disappointed, when the new molecules and technologies discovered by them, fail to yield the desired results.
Prime example of the above stated fact is that each molecular discovery which was made in the last decade with expectations and promise of a potential therapeutic target could not be translated into meaningful understanding of the malignant process. New discoveries have not resulted in substantial therapeutic gain, as reported by the Clinical Trials to achieve cancer-free survival for more than few weeks to months A 2-3% improvement in overall survival, could not satisfy scientists, clinicians and patients Technological advances in cancer diagnosis and therapeutic are growing at a rapid pace (robotic surgery and Proton therapy). However these technologies need a scientific rigour and correct data of their advantages , when a cost-benefit ratio is analysed. This situation is highly challenging for us in India, where human resources and funding for research are extremely limited.
The scientists are faced with dilemma of whether to follow Genomic driven Cancer Research or Pursue novel, hypothesis-driven and cost effective innovative Research.
The focus on curing advanced cancers might have been reasonable, 50 years ago, when molecular pathogenesis of cancer was mysterious and when chemo therapeutics against advanced cancers were showing promise. But this mindset is no longer acceptable.
All we need today is resources to promote the development and implementation of new evidence based strategies focussed at cancer prevention, risk assessment / early detection and early interventions, tailored to specific communities, cancers and populations.
There is a urgent need, worldwide for an honest introspection, whether current research and therapeutic strategies are appropriate and whether available resources are being used in a meaningful manner.
However before the Genomic era, several path breaking discoveries and inventions were developed, which are still applicable and are being used successfully.
Dr. S. Khanna, President, Dharamshila Cancer Foundation and Research Centre