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.

Tumor cells are a mosaic of different cell types

For the last decade or so, progressive cancer treatments involved taking samples of tumors, testing the cells to determine the genetic makeup, and then prescribing medicines targeted to specific mutations. There are many benefits to this approach, but it doesn’t always work.

It turns out that tumors aren’t uniform; they are mosaics of cells that can be genetically very different. A recent paper in the New England Journal of Medicine showed that a cell in one area may not be the same as a call in another area (a phenomenon called “intratumor heterogeneity”). So a treatment based on a sample from one area may not work for the whole tumor. Some tumor cells may be resistant to the drug so the cancer persists, or even grows.

In this British pilot study, cells from 9 different locations within a primary kidney tumor, and several metastatic tumors, were analyzed using next generation DNA sequencing. Only 34% of the 118 mutations identified were present in all the samples, and several of the major cancer genes were mutated in different ways in different locations. This turned traditional ideas about cancer cells being “clones” of a single, mutated cell on its head.

Previously, it was thought that a tumor develops when a single cell accumulates sufficient mutations over time that eventually lead to it dividing uncontrollably. Therefore if you could find the original mutation, and target treatment to that, then every cell would react to the treatment. But if the tumor is made up of a mosaic of cells, then they could all react differently to the drug. The researchers then created a phylogenetic “tree,” identifying which cells were more persistent, being in the trunk of the tree. They proposed that if those cells were receptive to a targeted medicine, the treatment might be more effective; if not, less so.

Although this study only involved four patients, the results provide a new way of thinking for researchers and clinicians. If we remove the presumption that all tumor cells are identical, we open the way for more creative thinking about how to tackle the problem.

Recently three high school students took out top honors in science fairs for their projects involving cancer research:

• Angela Zhang from California developed nanotechnology to destroy cancer stem cells and win the 2011 Siemens Competition in Math, Science & Technology;
• Shree Bose from Texas discovered a protein that could help prevent resistance to chemotherapy to take out first prize in the first International Google Science Fair; and
• Michigan native Nithin Tumma won the 2012 Intel Science Talent Search with his investigation of molecular pathways to compare breast cancer treatments.

The budding researchers walked away with a combined $250,000 in prize money for their efforts!

Angela used nanotechnology in a three-pronged approach to eradicating cancer stem cells, similar to my recent post on using DNA nano-robots to deliver cancer drugs to tumor cells. Not only did Angela design a nanoparticle to find the stem cells, and deliver the drug straight to the cells, but she used gold and iron molecules in the nanoparticle to allow non-invasive imaging via MRI and photoacoustic methods. Any one of these discoveries was worthy of an advanced level science fair project, let alone combining all three. As she told ABC News, “I created a nanoparticle that’s kind of like the Swiss Army knife of cancer treatment in that it can detect cancer cells, eradicate the cancer cells and then monitor the treatment response. So the major aim of the project was to personalize cancer medicine.”

Shree investigated how cancer cells become resistant to chemotherapy. Using ovarian cancer cell cultures, she found that the protein adenosine monophosphate-activated protein kinase (AMPK) modulated resistance to the drug cisplatin at different times during treatment. If AMPK was combined with cisplatin early in treatment, it reduced the drug’s effectiveness, but if added later during treatment, it helped maintain effectiveness; in effect, reducing resistance. Shree realized the importance of her work, commenting, “That opens up a lot of new avenues for research.”

Nithin’s project looked at the protein cytokine TGF-A involved in cell signaling, one of the key concepts in the Pathways to Cancer. As I wrote in a past post, we can use the analogy of a car to think about cancer cell growth: tumor cell overgrowth is like pressing down on the accelerator; apoptosis is like applying the brakes. Nithin used computational biology techniques (bioinformatics) to research how to inhibit TGF-A to slow cancer cell growth and decrease malignancy.

Science fairs have been running almost as long as we’ve been teaching science, and giving aspiring scientists an opportunity to shine. Alumni of the Intel competition alone have gone on to win seven Nobel Prizes, two Fields Medals, three National Medals of Science and 11 MacArthur Foundation Fellowships!

So what’s your next science fair project going to be about?

You can find out more about cancer treatments and cell signalling pathways at www.insidecancer.org.

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 a brilliant example of multidisciplinary research, Harvard Medical School’s Shawn Douglas, Ido Bachelet, and George Church combined forces to build nanostructures that would mimic the body’s immune system to recognize cancer cells and trick them into self-destructing. Their research is published today in Science but the discovery didn’t just happen overnight. It’s the culmination of several key discoveries going back several years, by researchers around the globe.

In 2006, Paul Rothemund at the California Institute of Technology, discovered  “DNA origami,” where the Watson-Crick base-pairing rules are exploited to create molecules from viral DNA in specific 3-dimensional shapes. The molecules use small, “staple” strands to bind longer strands and hold them in place. In 2009, chemists and nano-technologists at the Danish National Research Foundation’s Center for DNA Nanotechnology then used DNA origami to create a nano-cube that self-assembled, using staple strands to open a lid.

The Harvard group wondered if there was a way to deliver a nano-cube “robot” to cancer cells and kill them. This is where the immunology expertise paid off: antibodies patrol the bloodstream, honing in on specific cells, binding to them, and signalling them to self-destruct. So how can a DNA nano-robot deliver antibodies to the surface of cancer cells? Remember the cube’s lid?

“We could actually make an open-ended container and then all it would need to do is just turn itself inside out,” Douglas said.

A visual rendering of the DNA "nano-robot." Image courtesy of the Wyss Institute.

They created a “nano-clam” with antibodies waiting inside, ready to launch their attack. The nano-clam springs open when one of the staple strands is broken, just like turning a key in a lock.

And the really clever thing? The lock can be designed so that the key is in the shape of certain cancer cells. So when the cube encounters a cancer cell, such as lymphoma or leukemia cells, it springs open, exposing antibody fragments to the surface of the cell in a “surgical strike.” Unlike chemotherapy, which doesn’t discriminate between cell types, these DNA nano-robots only strike down cancer cells, leaving good cells alone.

The beauty of this discovery is that the underlying mechanism can be adapted for different diseases, by using different combinations of locks and antibodies. As the Danish chemist Kurt Gothelf commented, “People have been talking a lot about robots that enter your body, and go to a place where something is wrong and fix it. This is the first example that this might come true one day.”

The next step is to work out scalability. The current research was in Petri dishes in the lab, with 100 billion copies of the robot, but trillions are required for animals and humans. And the robot needs to become more robust to travel through the bloodstream, rather than through a pipette. Our body is very adept at getting rid of foreign bodies so they have to figure out a way for the nano-clams to swim “under the radar.”

Watch this space…

Well what do I mean by lasting changes? Research has shown that depending on what your mother eats may influence your genes and health in the long run. The gene agouti is found in humans and mice. The agouti/melanocortin system is an important regulator of body weight homeostasis. Mouse studies have shown that when the agouti gene is not methylated the result is obese yellow coated mice which may be at risk for cancer and diabetes. When the gene is methylated mice are brown, of normal weight and size. The only difference between the two types of mice is the methylation control on the agouti gene. In parallel experiments were carried out where yellow female mice were fed a methyl enriched diet; the offspring grew to be normal weight, size and were brown in color and remained so for the rest of their adulthood. This study identified that an individual’s wellbeing is not only determined by what they eat but also what their parents ate.

References
Nutrition and the epigenome. Retrieved February 8, 2012, from http://learn.genetics.utah.edu/content/epigenetics/nutrition/

This may help to answer many questions.  How can we have so many different types of cells and they all carry the same genetic information?  How is it possible for one identical twin to develop cancer while the other does not?  Can we use this control of the gene expression to help cells that may have lost their way?

It is amazing to think that just about all of the cells of the human body has the same DNA.  The full genetic profile with all of the instructions on how to make a human is in almost every cell.  When most students come through the DNA Learning Center, many of them think that there is different DNA inside of these cells.  That red blood cells have different DNA than bone cells and nerve cells.  One way this is done is through the interaction of small methyl groups (-CH₃) that get added to the DNA molecule, which can help to silence a gene that is not needed in some type of cell or at some point of development.  This is a epigenetic “tag” because there is no change to the sequence of DNA, it is just whether or not there is access to the DNA.  The methyl groups that get added make the cell unable to activate that gene.

This addition of methyl groups, called methylation, also can change throughout the course of our life.  So as we get older the interaction of these groups with our DNA can change.  So even with identical twins, who are born with the same DNA, their epigenetic “tags” can vary and occur independent of one another.  And even more, certain lifestyle choices and experiences throughout the life of a person can change the epigenetic profile of an individual.  And then this gets passed on to our children.  So even what a mother eats while pregnant can affect the tags that get passed to their child.  This ultimately will affect the expression of genes in the child.

And now we are using this information to help treat disease, such as cancer.  So if a gene is turned on that shouldn’t be, could we add methyl groups to that section of the DNA to turn it off?  This has started being used as a new therapy for the treatment for certain cancers.

Researchers have known for a while that not only are glioblastoma multiforme cells highly resistant to chemotherapy, but they can also deftly migrate away from sites of radiation or surgery, setting up camp and regrowing in other parts of the brain. This means that brain cancer is notoriously difficult to treat and the prognosis is almost always grim.

Last year the New York Times described Hanahan and Weinberg’s Hallmarks of Cancer as follows:

“Through a series of random mutations, genes that encourage cellular division are pushed into overdrive, while genes that normally send growth-restraining signals are taken offline. With the accelerator floored and the brake lines cut, the cell and its progeny are free to rapidly multiply. More mutations accumulate, allowing the cancer cells to elude other safeguards and to invade neighboring tissue and metastasize.”

This is a nice analogy, relating overgrowth of cells paired with lack of cell death (apoptosis) as the accelerator and brakes of a car.

However Amy Keating and colleagues at the University of Colorado Cancer Center focused on the car’s GPS system. They published data in Nature: Oncogene showing that when a receptor tyrosine kinase involved in cancer cell growth, Mer, is switched off, significantly less cancer cells migrate to neighboring tissue in cultured laboratory cells. Keating found that not only does Mer interfere with the molecular signaling pathway, but also the cytoskeletal organization (the structure of the cell).

In other words, the Mer switch interferes with the electrics of the GPS system as well as the steering wheel of the car.

This added to their previous finding that Mer could increase some brain cancer cells’ sensitivity to chemotherapy.

So Mer inhibition could be a “double whammy” approach to treating brain cancer: kill as many cancer cells as possible and stop those remaining from migrating.