The Frequency of Various Types of Cancers Explained

For more than a century, the medical world has known that certain kinds of cancers are far more prevalent than others.   The question, of course, that comes to mind is why is this so?  There has been much speculation concerning the answer to this important question.

Drs. Cristian Tomasetti and Bert Vogelstein form the Division of Biostatistics and Bioinformatics at the Department of Oncology at the Sidney Kimmel Cancer Center at John Hopkins University School of Medicine and the Department of Biostatistics at the John Hopkins Bloomberg School of Public Health in Baltimore MD conducted an exhaustive statistical analysis of patient data.  The following represents a summary of their results.

 The table below shows the relative lifetime risk of a number of different types of cancers.

Cancer by Tissue Type	Percentage of Lifetime Risk of Cancer
Lung	6.9
Thyroid	1.08
Brain and Nervous System	.6
Pelvic Bone	.003
Laryngeal Cartilage	.00072

Although some of these differences can be associated with certain risk factors such a smoking and alcohol use, ultraviolet light exposure and human papilloma virus (HPV) infection, such etiology only applies to specific populations.  In addition, environmental factors cannot explain the wide differences found in lifetime risks involving cancers of the alimentary tract – esophagus .51%, large intestine 4 82%, small intestine .20% and stomach .86%.

    

Interestingly, cancers of small intestine are three times less common than brain cancers even though the epithelial cells of the small intestine are far more exposed to environmentally dangerous substances than brain cells that are protected by the so-called blood –brain barrier.

Another factor that is often cited to explain differences in risk of various cancers is inherited genetic variation.  The statistical data shows, however, that this risk factor accounts for only between 5 and 10 percent of the etiology of cancer.

Therefore, there must be another cause that accounts for the wide variability shown in the table above.  The investigators went on to demonstrate that a very close correlation (81%) exists between the lifetime risk for a given cancer and the, “total number of divisions of the normal self-renewing cells (stem cells) maintaining the tissue’s homeostasis.”   From this perspective, it is the probability of sustaining deleterious random genetic mutations that transform a cell into a cancerous state that increases with the number of cell divisions of tissue-specific stem cells.

 

This may prove to be a very important finding in regards to understanding the etiology of cancer. 

A Promising New Class of Antibiotics

As mentioned in an earlier report, the current classes of antibiotics (See table below) being utilized to fight infection are no longer effective in regards to certain diseases, especially since many pathogenic organisms have developed an effective immunity against them. 

Classes of Antibiotics Currently in Use -

Class	Mode of Action	Example
Β-lactam	Inhibits bacterial cell wall biosynthesis	Penicillin
Aminoglycoside	Inhibits protein synthesis in Gram-negative bacteria  such as Streptomyces griseus	Neomycin
Macrolide	Inhibits protein synthesis in Gram-positive bacteria such as Streptococcus pneumoniae by preferentially binding to the  50S component of the bacterial ribosome	Erythromycin
Tetracycline	Inhbits protein synthesis by preferentially binding to the  30S component of the bacterial ribosome	Tetracycline
Fluoroquinolone	Irreversibly binds to and inactivates key enzymes that maintain bacterial DNA	Norfloxacin

Note: Antibiotics are of no use in treating viral infections since the biology of the virus is markedly different than that of bacterial agents.

There is, however, some basis for renewed optimism in regard to this global public health concern.  Most antibiotics currently being utilized are natural products produced by cultured soil micro-organisms.  For varied reasons, some economic in nature, the synthetic production of antibiotics has been unable to adequately supply new and effective classes of antibiotics.  Uncultured bacteria, on the other hand, although large in number, have been an untapped resource for new antibiotics.

Dr  Losee Ling and his colleagues at the Novobiotic Team,  NovoBiotic Pharmaceuticals, LLC.  767C Concord Ave, Cambridge, MA have developed specific methodologies to grow uncultured organisms thereby opening up a vast new resource.  As a result of an exhausted screening of uncultured bacteria,  they discovered a new antibiotic that they have called teixobactin (see the structure below).

Teixobactin acts by inhibiting cell wall synthesis.  It  accomplishes this by binding to highly conserved constituents of the bacterial cell wall and, in this way, effectively interfering with cell wall synthesis resulting in bacterial cell death.  The investigators were able to demonstrate that no resistant strains were produced when teixobactin was used to undermine the growth of both Staphylococcus aureus and Mycobacterium tuberculosis- pathogens responsible for Staphylococcus infections and Tuberculosis, respectively .   According to Dr. Ling, “The properties of this compound suggest a path towards developing antibiotics that are likely to avoid development of resistance.”

This is a very exciting development in regards to global public health.

How Cells Overcome Oxidative Stress

At some point in the evolutionary past, living organisms began to use molecular oxygen in cellular respiratory metabolic pathways and therefore gained access to increased amounts of energy to support life.  This was especially important in the evolution of complex multi-cellular organisms.    Along with this new capability came the issue of dealing with the harmful by-products of oxidative respiration.  The most detrimental of these are reactive oxygen species (ROS) that are produced in the mitochondria – those organelles that generate most of the energy required for cellular processes within eukaryotic cells.

ROS can produce oxidative damage and have been shown to be involved in a number of serious human pathologies including Alzheimer’s, cancer, diabetes and Parkinson’s.  These reactive molecular species are also involved in cellular senescence and cell death.

In response to this threat - referred to as oxidative stress - cells have developed mechanisms designed to minimize the damage.   the ROS defense system localized in the mitochondria transforms highly reactive and potentially destructive superoxide anions (O₂^--)  to hydrogen peroxide (H₂O₂) that is subsequently broken down to water by ubiquitous peroxidase enzymes that use reduced glutathione (GSH) as their substrate.  Given the essential role that GSH plays in this mechanism, it is crucial that appropriate levels of this substance are maintained.   A key enzyme that is employed in providing high levels of GSH is the nicotinamide nucleotide transhydrogenase (TH) enzyme.

Dr. Leung and his colleagues at the Department of Integrative Structure and Computational Biology at the Scripps Research Institute in La Jolla CA studied the three dimensional structure of TH and elucidated its mechanism of action.  This kind of information is important in so far as it increases the overall understanding of how cells cope with oxidative stress.    

The Role of Endogenous Retroviruses in B Cell Immune Response to Foreign Antigens

Over the course of evolution, retroviral infections have left remnants of their genetic footprint imprinted within the human genome.  This is believed to play such an important role in human biology that the collective genomes from viruses that innocuously inhabit the human body is referred to as the virome.

The virome is a part of the larger community of microbiota that shares a commensal or symbiotic relationship with the human body.   Important participants in this community are the gut microorganisms that collectively breakdown food, produce important nutrients, inhibit the growth of deleterious organisms and stimulate immune responses.

The immune reaction to an invasive organism typically results in the production of specific antibodies by circulating B cells in response to antigens presented by the offending organism.  There are two arms to B cell involvement – one involving T cell dependent (TD) processes and the other a T cell–independent (TI) response.   This latter response is elicited through the innate immune sensing pathways in antibody production through specific B cell receptor (BCR) cross-linking

.

Dr. Ming Zeng and his colleagues at the Center for the Genetics of Host Defense at the University of Texas Southwestern Medical Center in Dallas, Texas studied the involvement of endogenous retroviruses (ERV) in innate immune pathways.

In the course of their investigation, they exposed mice to protein molecules ordinarily found on the outer membranes of invasive bacteria and viruses.  These proteins are known to invoke the TI-mediated B cell response.   What they discovered was that immunization with these antigens resulted in the enhanced production of endogenous retrovirus (ERV) RNAs in the responding B cells.  Furthermore, this response apparently triggered a sustained reaction against the specific antigens through enhanced immunoglobulin M production.

These findings are of particular interest, for they offer further validation for the role of endogenous retroviruses in the immune response to invasive and deleterious microorganisms.  A well-functioning immune system is absolutely essential for the individual life of the organism and has been perfected during the evolution of life on the planet.

Prevention and Cure of Rotavirus Infection

Rotavirus (RV) is an RNA virus that causes diarrhea leading to severe dehydration in children and moderate intestinal discomfort in adults.  Mice have proven to be a useful animal model in studying infection of RV – the findings in mice are consistent with what is found in regards to human infection as well.  In this model, it has been shown that the level of infection of this virus can be ascertained by the appearance of the appropriate viral antigens in feces.    It has also been shown that the typical target for RV is the epithelial cells that line the small intestine.  

Furthermore, it seems that the predominant antigen that activates host cell gene expression as a defense against infection in intestinal epithelial cells (IECs) is the protein flagellin – a major component of bacterial flagella.  Flagellin seems to be the dominant activator of the immune system in the intestine.   It has been shown that flagellin-activated responses protect mice against bacterial infection, chemical insult and radiation.  In addition, administration of flagellin to mice seems to reduce the likelihood of infection with a cultured and attenuated form of RV.

Benyue Zhang and his colleagues at the Center of Inflammation, Immunity and Infection at the Institute of Biomedical Sciences Georgia State University, Atlanta Georgia, sought to discover if the administration of flagellin could serve as a prophylactic to protect mice from a highly contagious and pathogenic mouse RV strain.

The result of this study was very encouraging since the data demonstrated that not only did the administration of flagellin to mice prevent the onset of RV infection, but also cured infected mice who suffered from a chronic infection of the virus.  Interestingly, their findings have shown that this protective effect was not dependent upon adaptive immunological responses nor did the underlying mechanism require the participation of Interferon (IFN) – a substance known for its potent anti-viral properties.

 

The data did show, however, that the flagellin-initiated response required Toll-like receptor 5 (TLR5) and the involvement of Dendritic cells that produce interleukin-22 (IL-22).  Interleukins are members of a family of cytokines that play an essential role in immune responses.  The net result of these processes is the expression of a so-called “protective gene expression program” within intestinal epithelial cells.

These results may have public health implications in regards to rotavirus infections within the human population.   This is of particular importance since it is estimated that RV infections result in the deaths of approximately 600,000 children annually throughout the world.    

How the Influenza A Virus Enters the Host Cell

Influenza A Virus (IAV) has, of course, major implications in regards to public health.  Given the possibility of an influenza pandemic, it is vitally important to understand the mechanism of infection for this virus, since all viruses are unique in this regard. 

IAV is a single-stranded RNA virus that is subdivided into eight RNA molecules.  Each of these is precisely packaged into helical ribonucleoproteins (vRNPs).   These vRNPs carry a copy of a viral polymerase enzyme complex and the nucleoprotein (NP).   Within the structure of the virus, these vRNPs are arranged into a capsid-like complex that forms a shell around the vRNPs.   This is the state of the virus prior to its entry into the host cell.

As IAV gains entry into the host cell, it begins a process of uncoating initiated by the acidic conditions within the endosome – a membrane-bound structure providing transport within eukaryotic cells.  In the later stages of the process, the protein hemagglutunin (HA) – native to the virus – is activated and the IAV finally is transferred to the cell cytosol – cytoplasm .  Ultimately, the vRNPs gain access to the nucleus through the nuclear membrane.  It is at this final stage that the viral genome begins to co-opt the host cellular machinery to make more copies of the virus leading to the death of the host cell and the release of many more infectious agents into the surrounding tissue.

Dr. Indranil Banerjee and his colleagues at the Institute of Biochemistry, Eidgenossische Technische Hochschule in Zurich, Switzerland studied the process of capsid disassembly in detail, since it plays such a crucial role in IAV entry into the host cell.  They found that the virus exploits the host cell’s aggresome formation and disassembly mechanisms.  An aggresome is a cellular complex that is created in response to cell stress characterized by misfolded or unfolded proteins .

By helping to elucidate the underlying mechanisms responsible for host cell entry of IAV, this knowledge creates opportunities for the application of novel therapeutic approaches to combat infection.    

Ocean Acidification Disrupts Chemical Signaling In Marine Organisms

The relationship between the apparently inexorable increase in atmospheric carbon dioxide (CO2) as a direct result of human activity and the increasing acidity in the world’s oceans has been well documented. The current projected estimate is that at the current rate of atmospheric CO2 buildup, the pH in the oceans will drop from the current and historic range of 8.15 – 8.25 to ~ 7.8 or below by the end of the 21st century.

In addition to the disastrous impact of acidification upon the calcification that impedes coral and shell formation in the affected organisms, there is an additional side effect of this acidification that is worthy of attention. Many of the waterborne biologically-significant chemical signals, such as pheromones, that play essential roles in marine biology are disrupted by changes in the pH of the local marine environment. These signaling processes play a crucial role in important biological activities associated with mating, foraging, recruitment and alarm mechanisms.

The impact of this chemical disruption resides on two distinct levels. Increased acidity can affect the signaling compounds directly, and, secondly, impact their required interaction with specific receptor proteins designed to bind with the signaling molecule. This specific interaction between a signaling compound and its unique receptor represents the essential first step in producing the desired effect. This kind of interaction is found throughout metazoan biology.

The mechanism of this disruption caused by increased acidity within the marine environment can be attributed to changes in hydrogen bonding, electrostatic potential and hydrophilic and hydrophobic interactions that affect both ligands and their specific receptors. The types of organic compounds that are so affected include pheromones, nucleosides, thiols (sulfur-based compounds) organic acids and others.

The critical behavioral patterns that suffer from continued acidification of the oceans include sexual reproduction, recognition of the presence of predators, fertilization, larval settlement and many others. Unfortunately, the rate of acidification exceeds the ability of evolutionary mechanisms to respond to the kinds of changes described. This kind of impact of the increase of greenhouse gases within the natural environment needs further study, for the implications can prove to be devastating.