Generations of scientists have been tirelessly looking for a cure, to what appears to be public enemy number one- cancer. Cancer, is not one “disease”, its causes are even more variable than the variety of organs and cells types within those organs it can affect. Accumulated “mutations” or errors in genes, to inherited genetic conditions or exposure to tobacco or asbestos can cause cancer, that can arise anywhere in the body from the skin, colon, stomach, lungs, oesophagus, pancreas to the lymph nodes and the brain. Neither is cancer a modern disease, the oldest documented case dates as far back as 2500 B.C, found in Egyptian inscriptions on papyrus ( the precursor to paper), where incidents of breast tumors are reported.
Aiding the journey towards cancer- when our defenses betray us
There is a well characterized route of cancer progression from when cells give rise to “benign” or non cancerous tumors to “malignant” or cancerous tumors that have the property of invading other tissues and spreading throughout the body. However, only some key points or stop-overs and the final destination in the route are constant, like going from Delhi to Chennai. The possibilities to actually make the trip are numerous, one can fly, take the train, go by car or on a Harley – Davidson. The routes a cell can take to become a cancerous tumor are even more diverse. Now, since the cell on its way to becoming a tumour, is acting against the body- it is more like a terrorist, and what does our body do to contain a stray cell? Same as what the international police would do to contain a terrorist and to capture him. There are curfews and checkpoints and the wanted person’s photographs or sketches are circulated at every port of entry to another country, with special surveillance in areas he was last seen. Similarly, our body has surveillance mechanisms that look for abnormally acting cells, that form a part of our immune system. As is imaginable, escaping the surveillance is possible either through conning or conniving with, the system. That is essentially what the cancer cell does.
Mammalian defense mechanisms have evolved to fight germs and heal wounds in a concerted way because both external and internal injuries increase the risk of infection to vital organs. Therefore, the initial reaction of our body to a pathogen, like bacteria or virus, is the same as after a broken bone or a bruise. Remember the burning, redness and swelling that came soon after the cut in your hand? That is the first stage of ‘inflam’-mation. This is the body’s normal response designed to heal afflicted tissue. The main types of cells involved are the white blood cells (WBCs) or leukocytes. Only recently has there been an increasing acceptance of the role of inflammation in cancer.
What makes the inflammatory response a mechanism for cancer progression? Coming back to wound healing, it is apparent that there is a need for increase in cell number to replenish the cells that were lost, additionally an open wound gives an invitation to external bacteria and other parasites, therefore some immunologically active WBCs called monocytes also enter the wounded region. So, inflammation creates an micro-environment, around the afflicted region, conducive to cell proliferation and increases access of WBCs normally floating around in the blood to enter the site of injury. The WBCs secrete proteins called cytokines that are responsible to accentuate cell proliferation. These are the most obvious parallels to cancer, cell proliferation and an increasing permeability of the tissue which can allow cells to enter or exit the boundaries of the tissue or metastasize and then spread throughout the body.
“ Over 2 million people in the world have inflammation associated cancer. That can be because of acquired infections like Hepatitis B or C viruses in the liver and bacterial infections of the stomach,” said Dr. Curtis C. Harris, chief of lab of human carcinogenesis at the National Institutes of Health, in a podcast from the 2010 Frontiers in cancer prevention research conference.
Hepatocellular carcinoma (HCC), or cancer of the liver cells can arise due to several causes and is the third most common cause of cancer associated death. Epidemiological studies to look at environmental causes of HCC led to a very unique finding. It was already known that the Hepatitis B virus causes chronic inflammation in liver, that as explained above, preordains cancerous growth. “Looking at the incidence of HCC in regions prone of Hepatitis B viral infections, an immediate disconnect was detected. While regions with high HCC also had a incidence of Hepatitis B infections, the corollary was not true. This indicated that an additional factor might increase the progression to cancer, post viral infection”, said Dr. John D. Groopman, Chair, department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, at the 2010 conference for Frontiers in Cancer Prevention Research. “ This led to a multi-institutional and multi- disciplinary study in Eastern China. The study established that a Hepatitis B infection in addition to exposure to aflatoxin, synergistically increases the likelihood of HCC,” he added. Dr. Groopman was awarded the 2010 American Association for Cancer Research Award for Excellence in Cancer Prevention Research. His lab has been intensively involved in the studying the affects and mechanism of action of aflatoxin- a toxin produced by a mould called Aspergillus flavus, a common contaminant found in wheat, corn and other food crops and is a potent carcinogen ( an agent that can cause cancer). His research has previously shown that aflatoxin, binds DNA and causes a mutation in one of the most important tumor suppressor genes- the p53 gene, this makes a liver cell capable of crossing an intra- cellular check- point, that would normally restrict its proliferative capacity.
The recent endeavours by NGOs in India to ban the use of asbestos is definitely warranted. Inhalation of asbestos causes mesothelioma, which is inflammation of the lining of the lung and is a causal factor for lung cancer. The apparent paradox between the cytotoxic effects of asbestos and its involvement in lung cancer was solved when inflammatory cells, called monocytes were brought into the picture. As they get activated following exposure to asbestos, they release cytokines in an attempt to heal the tissue injury. But chronic exposure leads to mesothelioma and cancer.
Being your own enemy- addicted to cancer?
Another inflammatory response that increases the chances of liver cancer is cirrhosis a chronic inflammatory disease, that is known to be caused by alcoholism. The International Agency for research on cancer (IARC) is a part of World Health Organization (WHO) and recruits international expert working groups to evaluate the scientific evidence, from epidemiological and experimental studies, of carcinogenicity of specific exposures. Their 2010 monograph on Alcohol consumption evaluated scientific evidence from the past couple of decades from all over the world and grades alcoholic beverages as carcinogenic to humans ( Group 1- scientific evidence confirms carcinogenicity). Alcohol consumption was found to causally relate to malignant tumors (cancers) of the mouth, neck, oesophagus, colorectum and the female breast, in addition to liver cancer. The monograph states that the primary component in alchoholic beverages- ethanol is carcinogenic because of its metabolism produces acetaldehyde, which is genotoxic or causes DNA damage. Additionally, other components of the beverages may also be carcinogenic.
The most common and widely known environmental carcinogen associated with increasing the risk for lung and oral cavity cancers by about 20 times, is tobacco smoke. Additionally, it increases the risk for pancreatic, stomach, liver, cervical and colorectal cancer. It is also a Group 1 carcinogen identified as far back as 1986. Between one-fifth and two thirds of men in most populations still smoke one or the another form of tobacco. Lung cancer is the most common cause of death from cancer in the world. Many components of tobacco smoke are carcinogenic, including benzene, polycyclic aromatic hydrocarbons, nitrosamines etc. These organic compounds can cause DNA damage by binding to DNA ( forming DNA- adducts) and causing errors during DNA replication. Exposure to these foreign agents also activates the immune system and lung cancer is often predated by chronic inflammatory diseases like emphysema and asthma (yes, asthma is an inflammatory disorder).
Dr. Avrum E. Spira, Director of translational bioinformatics program, at Boston University school of medicine, calls the oral cavity, wind pipe, nasal passage and the lungs a “ molecular field of injury” prone to accumulated genomic alterations because of increased exposure to toxins from tobacco smoke. In 2008, his lab published a very interesting way to identify people with a high risk of developing lung cancer. Smoking changes the pattern of gene expression in all smokers' and profiling these biomarkers from cells in the lining of the nose, mouth and airways from people diagnosed with lung cancer could be used to test if a patient with a history of smoking, showing abnormalities in CT scans are on the way to develop cancer or not. As with all forms of cancer, the earlier the detection the better the prognosis.
Dr. Spira advocates non invasive techniques like bronchoscopy to remove cells that are used for looking for biomarkers. A thought echoed by Dr. Mary Reid, Associate Professor at Roswell Park Cancer Institute, Buffalo. Dr. Reid's laboratory is trying to establish new autofluorescence techniques to detect premalignant tumors in the lung, head and neck regions. Autofluorescence is an inherent property of biological tissue that makes them glow, and can be used to observe tissue architecture without the use of any dyes, if the right wavelength of light is used on them. Abnormal tissue architecture indicates the presence of premalignant tumors in many cases. “ This technique can complement CT scans and even detect lesions not seen on CT in the central airway and oral cavity,” she said.
The role of lifestyle and behavior reaches beyond tobacco smoking and drinking, to eating. Obesity has also been recognized as a chronic inflammatory disorder that also predisposes to many types of cancer. IARC recognized being overweight ( BMI of 25-30 kg/m^2) and obese ( BMI of 30kg/m^2 or higher) as conditions increasing risks for several types of cancer, like colon and breast. Chronic inflammation results in the presence of sustained levels of cytokines in the blood. A recent study published in American Society of Neurochemistry (ASN) Neuro, July 2010, conducted in the laboratory of Dr. Thomas N. Seyfried, at Boston College, Massachussets, in mice, which had glioblastoma (the most aggressive type of human brain cancer) showed that reducing calorie intake could reduce malignant brain tumour growth and metastasis. American cancer society estimates that 14% of all cancer deaths in men and 20% in women are attributable to excess body weight. A possible mechanism by which fat tissue can cause cancer progression was investigated in Dr. Charles Vinson's laboratory at Center for Cancer research in the National Cancer Insitute, Bethesda. They used fat less mice to study the mechanism linking obesity and cancer. The initial hypothesis had been that the white fat tissue (adipose tissue) secretes adipokines , that increase formation of tumours. However, the fat less mouse does not have any white adipose tissue or adipokines and still was found to have enhanced tumor development in some tumour types, except breast tumours. These mice are diabetic and have high circulating levels of insulin and insulin like growth factors, and proinflammatory cytokines, characteristics they share with obese people. The group concluded that these mice demonstrate the dissociation of the role of adipokines and chronic inflammation in obese people that makes them prone to cancer.
Preventing cancer progression, natural and chemical agents
Now that one of the aides of cancer has been recognized, what do we do about it? The old Indian home remedy for a fever or sore throat come to mind, turmeric in hot milk. Curcumin, the active ingredient derived from turmeric has been shown in a series of study conducted in the laboratory of Dr. Marc Diederich, Professor at the laboratoire de Biologie Moleculaire et Cellulaire du Cancer, Luxembourg to be anti-inflammatory and recently to be an effective chemopreventive agent for prostrate cancer. However, because of low bioavailability ( remember that turmeric is not water soluble) requires curcumin intake to be in several grams (8-16g) a day in tablets, for it to show any preventive effects.
“ Characteristically, epithelial cancers, like prostate and pancreatic cancer, have a long incubation period and are more amenable to chemopreventive intervention. Our lab is pioneering studies that would lead to the use of antibodies against epidermal growth factor receptor (EGFR) as a chemopreventive agent for cancer. EGFR levels are known to be upregulated in many types of cancer including lung, colorectal and pancreatic cancers. A sub- clinical dose is being tried at an ongoing clinical trial to see the efficacy of the antibodies in preventing invasive cancer development,” said, Dr. C. V. Rao, professor of medicine at the Oklahoma cancer center, Oklahoma city. EGFR antibodies have been used for a long time in treating last stage cancers of the lung, colon, breast etc. “ More than 70% of epithelial cancers are preventable using vaccines, prophylactic chemoprevention and life style changes.” he added. Vaccines for hepatitis B, human papilloma virus that causes cervical cancer in females, have been available for decades and the WHO widely recommends systematic increase in their distribution and use.
Note: Cancer was called a “wound that never heals” by a renowned pathologist, Rudolf Virchow, in 1863.
