Infection, Inflammation and Cancer

A few years ago a brilliant resident in medicine, a friend of mine, one day collapsed while seeing patients. He was in his late twenties. He immediately diagnosed himself, calling for the radiologist to do a chest X-Ray that revealed a left lung pleural effusion (Pleurisy). He then asked the resident pulmonologist to “tap” his lung so that he could breathe better. He conducted his own care in a very detached and practical manner in the Intensive Care unit until the fluid was subjected to analysis and it was determined that there were cancer cells in that fluid. It turned out that he had a long-standing “enchondroma” (a benign tumor) of the bone in his right knee. He had in the past year gone skiing and sustained an injury to that knee. The initial exaggerated limp had become barely perceptible over time, yet he revealed during questioning, that it still bothered him and from time to time and that he had seen the orthopedic surgeon to tap his knee for fluid buildup. Further tests and biopsies revealed that the cells from the pleural fluid in the lungs matched the cells obtained from the knee tumor. He had a diagnosis of chondrosarcoma of the knee cartilage with metastasis (spread) to the lung!

Tissue representation of inflammatory response

Infection, Inflammation and Cancer:

Does infection lead to cancer? This is a provocative question. If true it would send us all into some plastic bubble to live out our lives in seclusion from fear of acquiring infection. But true that this statement is, it is untrue for the majority of cases. A more apt question would be; does inflammation promote cancer? The answer to this statement is more apt to be a yes. Inflammation is a manifestation that occurs from injury and/or infection; it is the redness of the sore, the hurt from a wound, the throb from the injury and the fever/tissue warmth from an infection. Syllogisms aside, so if infections cause inflammations then by Giuseppe Peano’s logic, cancer must to some degree come from an infection.

Environment:

It is well known that 90% of all cancers are related to environmental stressors. 30% are directly attributable to smoking and other polluting agents like Asbestos, dust particles and radiation (Radon) amongst others. 20% of cancers are related to chronic inflammation resulting from various mechanisms.

Ulcerative Colitis and Colon Cancer:

Barium X-Ray of Colon Cancer

Let us look at the mechanisms of some known chronic infections that can cause cancer. The most well known is the disease Ulcerative Colitis. In this disease there is generalized inflammation of the colon and the constant inflammation leads to intestinal crypt deformation and a 43% chance of colon cancer within 25-35 years. The obvious question would be how does that happen. To solve that dilemma, we may have to delve deeper into the mode of action. So bear with me on this.

Cell, nucleus and the organelles

Infection, Inflammation and the Cell Within:

Imagine a cell, a round-looking thing that has another smaller round-looking thing inside it.  In between the two lies the cytoplasm where there are a host of little stunted sausage looking things called mitochondria. Ok so now that we have the concept, lets see what really happens:

PMN response

It appears that as the cell undergoes trauma from the infecting organism both outside the cell and within the cell there are two mechanisms of action that take place. For those who wish to avoid reading the technical aspect, a short summary goes like this: Infection causes the white cells to be liberated. These cells produce chemicals that invoke changes within the immune cells to help destroy the infection.

1. Outside the cell, before the infection has invaded it, the infecting agent causes irritation and liberation of the white cells. These cells called neutrophils or PMNs produce enzymes/cytokines to evoke the inflammatory and immune response. The immune cells are provoked via a protein product liberated by the (TAM1) or T cell activated Macrophages. This product is called TNFa. TNFa promotes another agent called NFkB that sends signals to the immune system via IL6 (a cytokine) This signal essentially motivates the immune system with an “intruder alert” warning. The immune system based on the data obtained from the sampling of the offending infective agent delivers first a host of antibodies in the blood stream and then parades the T- cells as the final line of defense. In most cases the infection is controlled by inducing death of the infective agent and then by causing suicide in the activated cells of the immune system and other tissue cells that were infected.

Lets take a deep breath from that. I said earlier that cancer would form but here I am ending that paragraph by saying the infection was contained by the very action that was supposed to cause cancer. Yes there is a beneficial aspect of the NFkB within the immune cells and therein lies the treachery of the dual edged sword. In the immune system the NFkB is designed to eradicate the potential for injury but in the tissues the mischief it creates is a whole different ballgame.

2. So assuming the infection was not contained and allowed to fester for a time. This leads to the continuous inflammatory response and further production of the TNFa and by shared cross-talk the production of NFkB in the infected tissue cells. The immune response having been overwhelmed by the chronic infection leads to further the sea of these proteins and associated agents that initiate the mischief. The overabundance of the NFkB leads to signaling via the STAT3 and IL6. The latter agent induces COX2, which stimulates the Prostaglandin E or PGE. This final agent then provokes the inflammatory response. The continued inflammation leads to a constant provocation of the tissue cells and aself-sustained vicious cycle of cytokine production that induces the cells to grow or proliferate. Somewhere in that confluence of this potpourri of enzymes, a genetic mutation lives or occurs and a cancer is born.

DNA damage

Ok, so inflammation is there, what about deeper intracellular (inside the cell) issues? There are inducements within the nucleus of the cells that are also ongoing. It appears that the NFkB causes about 500 different reversible and irreversible actions within the cellular DNA through epigenetics (Modulating the gene function by virtue of minor or major pressures from micro RNA, Histones etc. imposed on the genome) So not only is this cascade in flow, but other mechanisms are also being cumulated and promoted. In other words, “the hip bone is connected to the thigh bone…” The outside world is influencing the inside world through fluid connections.

Cancer cell with inflammatory cells

Proof:

Remember there was an answer to the question that was posed in the beginning? Does inflammation lead to cancer? And the answer was: Yes! Ok so if the forgoing is true, then an anti-inflammatory agent should reduce the incidence of cancer in patients with ulcerative colitis. And the answer is by using specific COX-2 inhibitors (Celexecob) including aspirin and other NSAIDs (Advil. Aleve etc.) the incidence of polyp formation and cancer is reduced many-fold in patients with ulcerative colitis, in Familial Polyposis Coli and Inflammatory Bowel Disease. So the proof IS indeed in the pudding.

Obtained from Oncology Journal

Mitochondrium (Cell's energy factory)

Mitochondria: 

3. There is another mechanism, a more sinister one that has yet to unfold its wings for us. This one is related to those stubby sausage-looking things called Mitochondria. The mitochondria in the cytoplasm of the cell are the energy-producing organelles for the cell function. Without them life would not survive.  Since no energy equates to no function. These little energy factories are at work from birth to death and it is believed that the aging process is the quiet, slow, unseen degeneration of the mitochondria. Interestingly the mitochondria undergo stresses via infection and inflammation by releasing Reactive Oxygen Species (ROS) and Reactive Nitrogen Species (RNS). 80% of all ROS is produced by the mitochondria. These reactive or nascent radical elements when released within the mitochondria lead to damage to the mitochondrial DNA (mtDNA), which leads to loss of energy needed for cell growth and function, cell senescence and finally cell death. In the aging process, mtDNA damage occurs over decades. While in infection-inflammation scenario the time is shorter. These ROS and RNS liberations are directly related to the TNFa and NFkB production. Suppressing these particular protein may lead to slowing of the aging process and also help in abrogating the malignant process someday, if we can only keep their benefits and rid the bad stuff.

Before we ascribe cancer to just infection and inflammation it is important to note that a genetic mutation must underlie or occur for cancer to form. Although there is direct reference to certain agents that do cause cancer and a list is appended below, the vast majority of cancer have a gene mutation that when provoked with inflammation will lead to the propagation of the malignancy. For instance, a woman has a small lump in her breast and she sustains a traumatic injury to the breast. Shortly thereafter the breast cancer reveals itself as a rapidly growing tumor. Although the inception of the malignancy lay hidden within the tissues the provocateur was the trauma that promoted the disease by the liberation of the various enzymes and cytokines (Cell signaling protein molecules) alluded to before. Hence the inflammation provoked an existent quiescent (dormant) malignancy into a full-bore hell.

Dividing cancer cell

There is also recent data, which shows that excess oxygen acts as a culprit in enhancing the malignant nature of a tumor. Studies done on p53 deficient mice and in APC rendered mice when exposed to oxygen lead to a rapid development and propagation of the cancer.

     How irksome is this music to my heart!
     When such strings jar, what hope of harmony?

2 Henry VI, II, i  ~ William Shakespeare

Certain infectious agents when allowed to reside within human tissue cells for a period of time will cause cancer:

HCV

HIV

1. The Human Papiloma Virus (HPV). 15 of the 40 HPV types cause 70% of he malignancies attributed to these viruses by directly inducing the ROS damage to the cervical cells and causes Cervical Cancer. In addition these viruses also cause cancer of the penis, vulva, vagina and some of the head and neck region.
2. Hepatitis B and C viruses can cause after a long-term inflammation of the liver cause hepatoma. A select mutation in the Hepatitis B virus on its X-gene at T-1898 region is thought to be the cause.
3. Helicobacter Pylori (specific strain) infection of the esophageal and gastric (stomach) region have been known to cause esophageal cancer, and MALT lymphoma. H.Pylori with a Cag-A component inserts the H. Pylori into the gastric (stomach) cell and allows it to create an inflammatory response leading to release of Interleukin1-a (Cytokine) that creates the inflammation. H.Pylori has also been epidemiologically related to pancreatic cancer.
4. Bacteroides Fragilis a bacterium has been found in a high percentage of patients with colon cancer. Is this bacterium merely a by-stander or the chief instigator?
5. EColi a common bacterial pathogen called EPEC (Enteropathogen E Coli) specifically of the EColi O157:H7 strain has been reported to have cross linkage with colon cancer.
6. HIV infected people have a higher predilection for Lymphomas, Hodgkin’s disease and Kaposi Sarcoma.
7. Breast Implants: Recent studies have shown a higher risk of Malignant Lymphoma arising in the breasts of patients with breast implants. Questions remain as to the inflammatory link as the probable causality.
8. Schistosoma Japonicum (a parasite) causes bladder cancer with associated chronic cystitis in the surrounding urinary bladder tissue.

Certain non-infectious agents of ill repute:

Radiograph of Lung Cancer

Normal and Diseased Lung

1. Smoking is the scourge of a civilized society. Tobacco smoke contains 500 Reactive chemicals.1,000,000,000,000,000 radicals in gas phase and 1,000,000,000,000,000,000 radicals in the free radical phase per gram of tar phase. That includes hydrogen peroxide (H2O2) and  hydroxyl group (OH) radicals. Smokers with Emphysema or Chronic Obstructive Pulmonary Disease (COPD) have a 1.5-6-fold increase in lung cancer. Tobacco causes persistent inflammation by virtue of the radicals inhaled through smoking. This chronic inflammation is the net cause and effect of lung cancer and other organ cancers including bladder, oral and esophageal. Need any further reason to quit?

2. Asbestos in the Amphibole form with its straight sharp-edged fibers leads to chronic inflammation through low-level continuous production of the mitochondrial ROS. Smokers with exposure to Asbestos have a much higher risk of developing Lung Cancer. Again that is compounding the degree of inflammation.

Removing Asbestos from ceilings 

There are two genetic mutations amongst many that cause an enhanced signaling between the inflammatory agents/cytokines and the proliferative (growth) potential of the cells. These are the c-Myc and K-Ras genes. Mutation of the c-Myc and the K-Ras genes lead to the production of TNFa and NFkB, both within the tissue cells and the mitochondria spontaneously thus liberating the ROS and RNS (Oxidative Stressors) that force the cell to commit suicide or resisting, which then convert to the wayward cancer cells. Here a mutated gene has shown direct evidence of propagating the curse by inducing inflammation. Hence to some degree if not totally, inflammation is a part and parcel of cancer initiation and progression.

Cancer Cell

P53 The Guardian of the Genome:

Another very important mechanism, which acts as a guardian against genetically mutated cells by forcing them into committing suicide, is the p53 gene (aka the guardian of the genome, this is a tumor suppressor gene and it relegates any cell that shows up for doubling (growth) with an abnormal gene make-up into committing suicide (apoptosis)). If too many cells show up with gene mutations and a single one strays through this protective mechanism that cell will become the progenitor of cancer. On the other hand a defective p53 gene may be handicapped for its own function allowing the escape of bad cells. Circumventing the immune system and the p53 mechanism through this barrage of bad news leads to the conscripting of bad cells into the proliferative (growth) pool of cancer cells.

It therefore becomes obvious that although there are several protective layers representing multiple lines of defense against cancer, the vulnerability remains. The slow methodical process via infection and inflammation can inundate and subjugate the defense mechanisms of the body.

The issue of the chicken or the egg of cancer and inflammation is as yet little understood and under scrutiny of debate of whether the c-Myc and K-Ras genes get provoked by the constant and continuous release of NFkB as in chronic inflammation, or are they the initiators, preceding the inflammatory event? The promotional aspect is well detailed and there are rumblings about inflammation working as both the initiator and promoter. The data for the initiator effect is lacking but ever so step-by-detailed-step mounting.

From Pharma to Farmers:

Cooking Spices

Our bodies are our gardens to which our wills are gardeners. ~William Shakespeare

We then come to what can we do to prevent these ongoing inflammatory problems?

1. Aspirin. A large meta-analysis of eight studies done by Rothwell et al revealed that those individuals talking daily aspirin had a60% lower risk of colo-rectal cancer and a 30% lowered risk of other solid malignancies.
2. Natural agents: Fruits, vegetables, legumes and spices are notable in their ability to reduce inflammatory response.
3. Curcumin used in curry has been shown to decrease the levels of Y+TNFa and NFkB in the blood of individuals consuming curcumin when exposed to inflammatory provocations. In addition there was a reduction by 40% of abnormal crypt formation in the intestines of patients with inflammatory bowel disease (IBD), which also is proof positive.
4. Green Tea, Red wine, grape juice and other bioflavonoid also reduce the ROS liberation and the inflammatory response.

From hamburgers and hotdogs to broccoli and cereals.

1. Moderating a diet from animal fat to vegetable, grain and fruit diet is heart and body healthy.
2. Adding colored vegetables and spices adds to the protective effects against wayward cells.
3. Stop smoking.
4. Stop Consuming alcohol.
5. Limiting exposure to sugar and salt.
6. Limit daily calorie intake to 2000 or less except in the case of athletes. A 30% reduction in caloric intake leads to a 25% increase in the life span.

What we have learned from gaining this knowledge is the old adage from Hippocrates: “Let food be thy medicine and medicine be thy food.”

In the days when trends are fashions may be we can lure the young with “Lets be cool and don’t play the fad food fool.” Or something like that. Inherent in all this is personal responsibility based on understanding. If the schools can teach the young about sex way before it is their time to know what the word itself means, then maybe we can educate them how to enjoy the colorful products of the farmers and their health benefits.

"...understanding
Begins to swell and the approaching tide
Will shortly fill the reasonable shores
That now lie foul and muddy." ~ Hamlet by William Shakespeare

References:

Rothwell PM, Fowkes FG, Belch JF, et al. Effect fo daily aspirin on long term risk of death due to cancer: analysis of individual patient data from randomized trials. Lancet 2011;377:31-41.

Weinberg F, Hamanaka R, Wheaton WW, et al. Mitochondrial metabolism and ROS generation are essential for K-ras-mediated tumorogenicity. Proc Natnl Acad Sci USA 2010;107:8788-93

Prasad S, Ravindran J, Aggarwal BB,  NFkB and cancer: how intimate is this relationship? Mol Cell Biochem. 2010;336:25-37.

Kamp Dw, Shacter E, Weitzman SA. Chronic inflammation and cancer: the role of the mitochondria. Oncology 2011;25:400-13.

Aggarwal BB. Nuclear factor kappaB: the enemy within. Cancer Cell 2004;6:203-8

Goldkorn t, Filosto S. Lung injury and cancer. Am J Resp Cell Mol Biol. 2010;43:259-68.

Grivennikov SI, Greten FR, Karin M. Immunity, inflammation and cancer. Cell 2919;140:883-99.

Montavani A, Garland C, Allavavena P. Molecular pathways and targets in cancer related inflammation. Ann Med 2010;42:161-70.

Ekbom A. Risk of cancer in ulcerative colitis. J Gasterointest Surg. 1998:2:132-13.

Weinberg F, Chandel NS. Reactoive oxygen specieces dependent signaling regulates cancer. Cell Mol Life Sci. 2009;66:663-73.

Balkwill F. Tumor Neoosis Factor and cancer. Nat Rev Cancer. 2009;’9:361-71.

Rachek Li, Grishko LI, et al. Role of nitric oxide induced mtDNA damage in mitochondrial dysfunction and apoptosis. Free Rad Biol Med 2009;47:750-9.

Prasad S, Phromnoi K, Yadav VR, et al. Targeting inflammatory pathways by flavonoids for prevention and treatment of cancer. Planta Med. 2010;76:1044-63

Gullett NP, Ruhul Amin AR, Bayraktar S, et al. Cancer prevention with natural compounds. Semin Oncol. 2010;37:258-81

Aggarwal BB, Kumar A, Bharti AC. Anticancer potential of curcumin: preclinical and clinical studies. Anticancer Res. 2003;23:363-98

Carroll RE, Benya RV, Turgeon DK, et al. Phase IIa clinical trial of curcumin for the prevention of colorectal neoplasia. Cancer Prev Res (Phila). 2011;4:354-64.

Popivanova BK, Kitamura K, Wu Y, et al. Blocking TNF-alpha in mice reduces colorectal carcinogenesis associated with chronic colitis. J Clin Invest. 2008;118:560-70

Nelson HH, Kelsey KT. The molecular epidemiology of asbestos and tobacco in lung cancer. Oncogene. 2002;21:7284-8.

Karin M. NF-kappaB as a critical link between inflammation and cancer. Cold Spring Harb Perspect Biol. 2009;1:a000141

      Sung HJ, Ma W, Starost MF, Lago CU, Lim PK, et al. (2011) Ambient

      Oxygen Promotes Tumorigenesis. PLoS ONE 6(5): e19785.

doi:10.1371/journal.pone.0019785

Ulger Toprak, N., Yagci, A., Gulluoglu, B. M., Akin, M. L., Demirkalem, P., Celenk, T. and Soyletir, G. (2006), A possible role of Bacteroides fragilis enterotoxin in the aetiology of colorectal cancer. Clinical Microbiology and Infection, 12: 782–786. doi: 10.1111/j.1469-0691.2006.01494.