Mutations in numerous pathways need to accumulate for cancer to progress. Given the ability of transposons to cause mutation and the role of mutation in cancer, it seemed likely that transposons would play a role in cancer. A few years ago, Iskow and colleagues showed that transposons jump in some lung tumors, suggesting a link to cancer progression. They also showed that methylation levels are often lower in lung cancers. Methylation is important for transposons silencing, so they hypothesized that lowered methylation in cancer could lead to more transposon jumps. This would “destabilize” the genome, allowing more mutations to accumulate, and accelerating cancer progression.

However, very little evidence of this connection existed until recently. With the advent of high-throughput sequencing, it is becoming possible to examine changes in the genomes of cancer cells. Lee and colleagues report on one such study. They decided to look at the effect of retrotransposons by comparing the location of these jumping genes in normal and cancer cells. Retrotransposons copy their sequence from one location to another by going through an RNA intermediate that is read “backwards” from RNA to DNA.

In their study, they had to overcome a problem: because transposons are found throughout the genome and are mostly the same in different individuals, it is hard to figure out exactly where new transposons are located. To sort this out, they developed a bioinformatics tool that could align sequence to a reference genome and identify new transposon sequence associated with this sequence. They then used normal tissue and cancer tissue from the same individual to identify transposition events in cancer cells.

Interestingly, different cancer types had different numbers of transposon jumps. Brain and blood cancers did not have many transposon-induced mutations, while epithelial cancers had frequent insertions. These jumping-gene insertions are probably important for cancer, as many of the insertions occur within genes known to affect cancer biology.

If these jumping genes cause mutations and promote cancer, why are they there? It’s still an area of contention, but all that jumping around helps provide diversity in our genomes. Sometimes that will prove to be bad, but it also allows natural selection to act on the diversity, allowing new, helpful innovations in our DNA power evolution.

Iskow el al, 2010. Natural mutagenesis of human genomes by endogenous retrotransposons. Cell. 141(7):1253-61.

Lee et. al, 2012. Landscape of Somatic Retrotransposition in Human Cancers. Science. 337(6097): 967-971.

The method is more effective than just using light. When light passes through tissue, it is scattered, and the scattering blurs images from light reflected off tissue. The effect is dramatic, because sound waves pass through tissue with about 10,000 times less scattering, so the sound waves coming from tissues are much less blurry. This means that tissues can be imaged with good detail up to 10 centimeters deep -rather than a few millimeters using just light.
Photoacoustic tomography is very flexible, as almost all molecules absorb light at some wavelengths. By changing the wavelength of light used to excite the tissue, different molecules can be heated and detected. For instance, DNA and RNA absorb specific wavelengths of ultraviolet light, so by shining UV light on tissue, they can be imaged. This can be used to identify nuclei with abnormal chromosomes, a common defect seen in cancer cells. Hemoglobin is also easy to image, which can identify blood vessel formation around tumors. In fact, the flow of blood can be imaged. Likewise, the level of oxygen can be measured, which can indicate regions with hypoxia which are found at the center of tumors and regions with heightened metabolism, such a quickly growing tumors. Tissues that are hard to image can also be imaged by introducing a dye that changes the light absorption. For instance, nanoparticles designed to stick to cancer cells can increase the contrast of the cells and make them easier to detect.

The technique is now being used to image skin cancer, detect breast and prostate cancer, and to follow the response of tumors to treatments. As the technology gets better, hearing the “echoes” off of tumors may become one of the best ways to find and monitor them!

Reference:
Photoacoustic Tomography: In Vivo Imaging from Organelles to Organs. Lihong V. Wang and Song Hu Science 23 March 2012: 1458-1462

I have often wondered what impact the diesel fumes from yellow school buses might have on students. I know that I don’t like driving behind those buses because the fumes don’t smell good, so it seemed to me that there might be some health consequences. Others have wondered, too, and there is evidence that exhaust levels in buses can have health effects. However, it is hard to study this sort of thing, because finding people that are exposed to high levels of diesel in a controlled environment over long enough periods to measure the effects is challenging. Now, a study from the National Cancer Institute in Maryland looking at people working with another type of big yellow vehicle- the diesel trucks used in mines- has shown that heavy exposure to their fumes can increase the risk of death from lung cancer.
In the study, underground mines with no high levels of other known cancer causing agents were used. The study looked at the rate of lung cancer in workers and measured the levels of exposure to diesel fumes. As would be expected, the higher the level of exposure, the higher the increase in risk of getting cancer. In mines with the highest levels of exhaust the risk of lung cancer was three times the risk in mines with little exhaust, and even in these mines, the risk of lung cancer was increased over levels seen in the population.
Clearly, this suggests that miners should be aware of the levels of exhaust, and that increasing air quality in mines would be to their benefit. However, the results also suggest that people working in other places with high levels of diesel fumes may also be at risk, and this includes millions of workers at warehouses and bus depots. Likewise, people living in cities are exposed to diesel fumes.
Luckily, there is a solution to this problem: reduce emissions from diesel vehicles. In fact, modern diesel engines produce much lower levels emissions than older models, with some diesel cars producing nearly no emissions.
I can’t help thinking back to the kids in the buses. It is hard to tell what the effect might be, but sitting in a bus every day that has diesel fumes coming out the tailpipe might not be very good for all those schoolchildren, and if a child grows up taking buses every day, the exposure will add up. Hopefully, the effects are minimal. Then again, it may be worth investing in buses and other diesels that are cleaner!
Reference: The Diesel Exhaust in Miners Study: A Nested Case–Control Study of Lung Cancer and Diesel Exhaust
J Natl Cancer Inst 2012;104:1–14

In the case of these relatively benign cancers, the treatment can be worse than the disease: surgery or radiation therapy can lead to loss of urinary control or diminished sexual function. The question is what to do? The answer, it seems, is to watch and wait. Luckily, there is a way to predict the outcome of prostate cancer. By monitoring the level of prostate-specific antigen and by examining tumor cells with a microscope, low-risk cancers can be identified.
Once identified, patients with these cancers can be monitored to ensure the cancer doesn’t progress, avoiding or delaying the possible side effects of treatment. This may let up to 100,000 men a year that have treatment for prostate cancer rest more easily, by opting for surveillance rather than treatment. The details of how best to monitor the patients still need to be figured out, but many will never need treatment. In fact, these types of cancer are so unlikely to be threatening that the NIH panel suggested not calling them cancer at all, if only to avoid anxiety on the part of patients.

This isn’t the only case when relatively harmless growths found during screening are treated aggressively when it may not be necessary. It is more complicated and scientists don’t always agree, but this may also be true for some breast cancers and certain forms of thyroid cancer. So, although being diagnosed with cancer is certainly a shock, it is important to discuss the costs and benefits of different approaches with your doctor to come up with the best plan.

Early approaches have used engineering to create bacteria that specifically invade tumor cells. In one approach, bacteria were engineered to invade cancer cells. First, E. coli was given the ability to bind to and enter cancer cells by genetically engineering them to express a surface protein called invasin from another species of bacteria. Invasin binds specifically to beta1 integrin, which is a protein that is often expressed on the surface of cancer cells. After binding, the cells engulf the bacteria. However, other cells also express beta1 integrin, so E. coli that express invasion at all times can invade multiple cell types. To avoid targeting non-cancer cells, the expression of invasion was engineered so that it is only on when the bacteria are in areas with low oxygen, which was accomplished by hooking up the DNA coding for invasion to DNA that turns on gene expression only in apoxic e

nvironments. These low oxygen areas are often found within tumors, where the number of blood vessels is lower than in normal tissue. So, by combining two functions- one that allows invasion of a cell and one that targets tissue with the right characteristics, tumor cells can be selectively infected.

A new study takes advantage of recent advances in our understanding of the relationship of small RNAs, called microRNAs (miRNAs), and cancer cells. It turns out that different tumors express distinct levels of miRNAs, which are small RNAS that are important gene regulators.  In fact, measuring the level of expression of different miRNAs can be used to diagnose certain cancers. This provides an opportunity: if a biological system could sense the levels of miRNAs and determ

ine if they matched a cancer profile, this could be used to target those cells.

Adapted from Xie, et al.

The biology of miRNAs makes this possible: miRNAs bind to target RNAs and affect gene expression. So, for any given miRNA, it is possible to engineer a target RNA that should be affected by it. To this end, Zhen Xie and colleagues developed a system that can sense whether the right combination of microRNAs is turned on or off in a cell and, if so, program the cell to commit suicide.  In essence, Xie designed a biological logic circuit that senses HeLa cells, a cervical cancer cell line. HeLa cells have a microRNA signature where two microRNAs are over-abundant and three are under-abundant. Xie made his circuit so that it will only be turned on when the complete signature is present: if just one of the microRNAs that is over-abundant is missing or even one of the under-abundant microRNAs is present, the circuit doesn’t turn on- because the cell isn’t a HeLa cells. The circuit controls the expression of hBAX protein, which kills the cell. So, if and only if the cell has the right signature to be a HeLa cell, it will be killed.

The beauty of the system is that it could be adapted to work for many cancer cell types, and for other diseases, too. As long as a diagnostic profile of miRNAs can be identified, a logic circuit reading that profile should be possible.

Perhaps, in the future, these two approaches can be combined, using engineered bacteria to introduce a biological computer into certain cells, and then using that computer to monitor whether those cells have dangerous characteristics which need to be altered.

For more information, see Xie, et al. Multi-Input RNAi-Based Logic Circuit for Identification of Specific Cancer Cells. Science 333:1307-1311 and Anderson, et al. Environmentally Controlled Invasion of Cancer Cells by Engineered Bacteria. Journal of Molecular Biology 355:619-627.

http://www.rockefeller.edu/research/faculty/labheads/RalphSteinman/

http://www.nobelprize.org/

Check this paper out here:

http://www.nature.com/onc/journal/vaop/ncurrent/full/onc201191a.html

To find these driver mutations, scientists look for the ones that occur frequently. Until recently, this was very difficult to do. However, new sequencing technologies now let scientists look for mutations in genes at an incredible rate. The cost of sequencing is dropping dramatically; to the point where in the near future sequencing the DNA from a cancer may be sequenced as a diagnostic. Soon, it may be the cost of computing that limits our sequencing efforts.

Improvements in technology allow scientists to look at the genomes of many tumors, and there is an international effort to look at 25000 cancer genomes. This will provide the data that will let them find the mutations that lead to cancer, even if they occur in a small proportion of tumors of a particular kind. Already, hundreds of tumors have been studied in detail, which is giving scientists a good feel for the patterns of mutations that happen in cancer cells. So far, over 400 genes directly linked to cancer have been identified in this and other studies. Figuring out how these many genes contribute to cancer is likely to lead to huge advances in diagnosis and treatment, although the task remains gargantuan.

In a turn-around of sorts, it may be comforting to know that cancers can become addicted, too. Cancer cells have many different genetic changes, as well as changes in the expression of genes that are not due to mutations called epigenetic changes. Although cancer cells do have many differences from normal cells, they are still very similar to normal cells, making it very difficult to find treatments for cancers that don’t have serious side-effects.

Scientists, however, are beginning to identify genes that appear to be “Achilles heels” for cancers. It turns out that in many cases, reversing a defect in just one gene can have a profound effect on the growth of a cancer. Genes that promote cancer when mutated are called oncogenes, so this dependence on a particular genetic change in a cancer is called “oncogene addiction.” Often, treating these changes can be accomplished with little effect on normal cells, because the biology of cancer cells and normal cells has different wiring. So, a cancer cell may need to express a particular protein to keep dividing, while a normal cell might have other ways to keep going.

For instance, HER-2 is a receptor that is expressed on the surface of many breast cancers. HER-2 expressing cancers are often dependant on HER-2 to keep growing. This dependence is exploited in breast cancer treatments by an antibody drug, called Herceptin, which binds and inhibits HER-2.

Just as you can bring a cigarette smoker to their knees by taking away nicotine, so some cancers are tamed by taking away their favorite oncogene. Unfortunately, just like cigarette smokers who turn to other ways to cope, like caffeine or (more healthily) exercise, cancer cells can also escape their addictions, but that is another story…