The team led by Manel Esteller, director of the Cancer Epigenetics and Biology Program at the Bellvitge Biomedical Research Institute (IDIBELL), professor of Genetics at the University of Barcelona and ICREA researcher, has identified a mechanism that explains this change. Tumours “shed their skin” because molecular switches called microRNAs — responsible for maintaining epithelial appearance of cells — turn off. The finding has been published this week in the online version of the international scientific journal Oncogene, Nature group.
"We have discovered that some microRNAs, a group called microRNA-200S, undergoes a chemical inactivation and inhibit their expression. When these cellular appearance drivers are not present, tumour cells change, stretch, stop their inhibition and thus the tumour progresses," explains Dr. Esteller, adding that "the results from research show that this is a very dynamic process."
Change involves from the appearance of the tumour to the onset of metastasis, but if we change the environmental circumstances that influence these cells, the process reverses. Dr Esteller compares the process “with a small planet in Darwinian evolution but in an expedited manner.”“
The changes a cell goes through to become cancer, are in many ways, fundamental changes. They change their metabolic patterns, going from an aerobic (demanding oxygen) to an anaerobic ( more based on sugar, not needing lots of oxygen) metabolic pattern. They lose contact inhibition so that they can invade other cells, they lose their “stickiness” which allows them to break lose and metastasize to distant body regions, they become primitive immortal warriors, and make those changes they need to make, in order to hide from Natural Killer Cells.
In an odd way, it is as if the new behavioral pattern, i.e. becoming killer wanderers, invaders with no allegiance to their host, are like the Mongols galloping across the steppes, and in an odd fashion, it is as if they know their deadly task and make those changes in their morphology and physiology, to enable them to do those horrible things.
As I said, cancer cells act to ensure their own demise, unless, as in the case of the HeLa strain, they are extracted from the host and grown in vivo or in vitro. And, as noted, it is not just humans that are struck with cancer. Tasmanian devils were also hit by cancer, and this phenomenon helps to demonstrate the ability of cancer cells to evade detection.
Here is a limited quote from that article:
" The immune system should catch these tumor cells, but the cancerous invasion causes no immune response in devils, said Hannah Siddle, a University of Cambridge immunology researcher. Siddle and her colleagues have now discovered why: The tumor cells lack surface molecules called major histocompatibility complex molecules. These MHC molecules allow the immune system to detect the invading cells. Without them, the cancer is essentially invisible.
"That explains why the immune system of the devils doesn’t recognize those DFTD (devil facial tumor disease) cells as foreign, as it should, or as cancerous, for that matter," Siddle told LiveScience.
But there is good news. Typically, cancer cells that ditch their surface coating of MHCs do so via a permanent genetic mutation. That’s not the case for DFTD cells, said study researcher Jim Kaufman, also of Cambridge.
"What we stumbled on was the fact that the MHC molecules disappeared by regulation," Kaufman told LiveScience.
In other words, the genes that hold the instructions for making the MHC molecules still exist in the cancer cells’ genome. Those instructions simply aren’t transcribed, and the molecules never form. What that means, Kaufman said, is that the cancer cells’ invisibility is reversible.
The researchers proved the concept by using a communication protein called gamma interferon to “switch on” the MHC-coding genes in a culture of devil tumor cells in a Petri dish. The once-MHC-free cells started making MHC molecules again.
In addition, the researchers examined tumor biopsies from wild Tasmanian devils and found that in some rare portions of tumor, immune cells were invading. In these areas, the cancer cells were making MHC molecules, suggesting that the genes can sometimes be spontaneously switched back on. It’s not enough to save Tasmanian devils from death, but it does suggest hope for a vaccine, Kaufman and Siddle said. [See Photos of the Infected Tasmanian Devils]
"What we hope to do is to figure out a way to tip the balance so that the immune system does a better job of recognizing and can get rid of the tumor," Kaufman said. The researchers published the findings today (March 11) in the journal Proceedings of the National Academy of Sciences. "
So, let’s think of it like this. Imagine that you have immortal psychotic serial killers that exist in society. They look similar to other, law abiding citizens, except they wear a red bandanna. Well, it wouldn’t take long for cops to catch and imprison them….but, now imagine they became smart enough to take the red bandanna off. Now, they blend in with the normal people and essentially, are not invisible. The shedding of the MHC (major histocompatibility complex ) enables cancer cells to survive, to reproduce, and ultimately, they can grow into giant tumors and spread to other parts of the body.
The scary thing about this Tasmanian devil cancer, is that it is contagious insofar as one infected animal can transmit it to another via biting or nipping each other in fights or play. We can think of it as an organic hypodermic…the needle being the infected animal’s teeth.
Since we have talked about cancer cells often starting out as normal cells which transform, a natural question is WHY do these normal cells transform. There are many elements which science has identified as causes of cancer cells forming. There are so-called "oncogenes" which can cause cancer. This shows a genetic component to cancer which can explain why some people in families have a predisposition toward developing certain cancers.
Another cause is chronic inflammation, chronic exposure to carcinogenic chemicals. Benzene, a hydrocarbon based on a ring structure, is a particularly nasty one. In the field of diseases in workers, one of the earliest proven links between types of work and development of cancer occurred in chimney sweeps who were men who cleaned out chimneys. They developed testicular cancer at a higher rate than men who did not do that job. What was discovered was they were constantly getting coal dust down their pants and dusting their testicles. The coal soot had a carcinogenic component, and it was causing scrotal cancer, also called “Soot wart”, a squamous cell carcinoma, and the first established occupational cause of cancer. See http://en.wikipedia.org/wiki/Chimney_sweeps’_carcinoma
Chronic, long term exposure to certain irritants, certain damaging factors which attack cells, which attack DNA, such as sunlight exposure, radiation, tobacco, are known to cause cancers, especially in people who have genetic or other qualities which make them more susceptible.
Here is an article on the topic of carcinogenesis
I see the many carcinogenic agents acting in the same way, i.e. by inducing many tiny damages, irritations, to a cell over time, until finally, the cell transforms itself in response to it.
Now, if we delve back into anthropomorphism about cancer again…one might see this change not just as a biochemical response to constant irritants, but also, a self defense response of a cell which has “decided” that it must survive at all costs. By becoming more primitive, more immature, it is responding to what it perceives as an agent which is threatening to kill it, by weaponizing itself. It no longer dies, and by ditching its “stickiness”, the cell can actually break lose and move away from the area of irritation. For example, if an area of the skin is being irritated by something, physical or chemical, day after day, normal cells are stuck there and have to endure the damage, which may destroy them. Cancer cells, by changing what they are, actually perhaps, are ensuring their ability to escape the local area of irritation. Now, of course, people can laugh at this because it seems to attribute sentience to “dumb cells”, however, these dumb cells adapt and overcome efforts to get rid of them. Somehow, that seems like a well conceived survival mechanism.
Not only are cancer cells able, through their own actions, able to become invisible to the specialized cells that could kill them, but they are able to become resistant to drugs purposed to kill them. Here is an interesting article about that ability ===> http://www.medicine.wisc.edu/~williams/drugresistance.pdf
An interesting point is made in this article, in that, normal cells tend to respond the same or similarly to drugs, but cancer cells respond in “their own way”…uniquely.
Here is another good article ===> http://www.slu.edu/x86540.xml
Tumors Elude Anti-Cancer Drugs Through “Fork Reversal” Repair, SLU Scientists Discover. Quoting from this article we see :
" In his recent findings, however, Vindigni and his team found that the cells are much “smarter” than they originally appeared.
Living up to their crafty reputation, cancer cells have a strategy to deal with this scenario. When TOP1 inhibition causes “replication stress” in the form of a nick on the DNA, the replication machinery pauses and reverses its course instead of colliding with the TOP1 induced DNA lesion. This mechanism of “replication fork reversal” gives time for the lesion to be repaired, so that replication can continue on again, preventing the hoped-for double strand break.
Representative electron micrograph showing the image of a reversed replication fork. D, daughter strand; P, parental strand; R, reversed arm.
In fact, not only does the strand halt when it reaches the nick, but it senses the problem ahead of time, coming down the line. The replication structure does not operate blindly, but has advance notice of the injury, which gives it time to halt and repair the lesion before it reverses course and move into forward gear again.
“This is important because it is the first evidence that says that cancer cells’ DNA replication machinery can react to drug treatment through fork reversal. Now we also uncovered the mechanism to restart the replication forks.”
Vindigni’s team also found that two important cellular proteins, PARP and RECQ1, control the fork reversal mechanism.
In particular, RECQ1, which is an enzyme that plays a key role in the maintenance of genome stability, appears to be responsible for restarting the reversed replication forks once the TOP1 induced lesion has been repaired. The reversed forks cannot restart without the help of RECQ1, suggesting it may be a promising target for a drug therapy.
Once they undercut the replication fork reversal process, researchers can return to the approach of encouraging a “fatal” double strand break for cancer cells by combing TOP1 inhibitors with novel inhibitors of the proteins that control the process of replication fork reversal and restart. In addition, inducing replication fork reversal by TOP1 inhibitor treatment and impeding reversed replication fork restart by RECQ1 inhibition should also stop DNA replication, thus allowing doctors to use lower TOP1 inhibitor doses, which, in turn, would mean fewer side effects.”
This is quite an elegant and novel means by which cancer cells can survive through the fork reversal.
IF we allow ourselves to engage in looking at cancer from a teleological perspective ( http://en.wikipedia.org/wiki/Teleology ), it is like cancer cells are Ninjas on a suicide mission, and that mission is to kill the host from which they sprang. Engaging in a teleologcal look at cancer, and believing that killing the host is actually the new goal of the cells which have been transformed, make many, if not most of the physiological, morphological, and behavioral changes of the cancer cells, make sense. In other words, they make the changes that enable them to survive for a protracted battle with their host, they in essence camouflage themselves, and develop high level, workable strategies to defeat the high tech weapons used against them.
But, if we accept that cancer cells are obligate parasites, they act in ways that most successful parasites do not act. Most successful parasites may weaken, and eventually kill the host, but they let the host live long enough to either transmit it on to a new host, or they exploit a hosts behavior to enable it to survive. In a bizarre example of this, let’s look at how a parasitic fungus, Ophiocordyceps unilateralis, changes the host’s behavior to enable its spreading and survival. See the article at http://www.sciencedaily.com/releases/2009/08/090811161345.htm . I quote from the article :
" When a carpenter ant is infected by a fungus known as Ophiocordyceps unilateralis, the victim remains alive for a short time. The fungus, however, is firmly in the driver’s seat. It compels the ant to climb from its nest high in the forest canopy down into small plants and saplings in the understory vegetation. The ant then climbs out onto the underside of a low-hanging leaf where it clamps down with its mandibles just before it dies. There it remains, stuck fast for weeks.
After the ant dies, the fungus continues to grow inside the body. After a few days, a stroma—the fungus’s fruiting body—sprouts from the back of the ant’s head. After a week or two, the stroma starts raining down spores to the forest floor below. Each spore has the potential to infect another unfortunate passerby.
Scientists have known for over one hundred years about this parasite’s ghastly ability to turn unsuspecting ants into zombies. But Hughes and his colleagues chronicle the amazingly precise control the fungus has over its victim.
At a field site in a Thai forest, Hughes’s team found that the infected carpenter ants are almost invariably found clamped onto the undersides of leaves that are 25 centimeters (about 10 inches) from the ground below. What’s more, most of the dead ants were found on leaves sprouting from the northwest side of the plant. Interestingly, the researchers found that temperature, humidity and sunlight in these spots are apparently optimal for the fungus to grow and reproduce. When the researchers placed leaves with infected ants at higher locations, or on the forest floor, the parasite failed to develop properly.
"The fungus accurately manipulates the infected ants into dying where the parasite prefers to be, by making the ants travel a long way during the last hours of their lives," Hughes said.
But getting the ant to die in the right spot is only half the battle, as the researchers found when they dissected a few victims.
"The fungus has evolved a suite of novel strategies to retain possession of its precious resource," said Hughes.
As the fungus spreads within a dead ant’s body, it converts the ant’s innards into sugars which are used to help the fungus grow. But it leaves the muscles controlling the mandibles intact to make sure the ant keeps its death grip on the leaf. The fungus also preserves the ant’s outer shell, growing into cracks and crevices to reinforce weak spots. In doing this, the fungus fashions a protective coating that keeps microbes and other fungi out. At that point, it can safely get down to the business of claiming new victims.
Carpenter ants apparently have few defenses against the fungus. The most important way they avoid infection seems to be staying as far away from victims as possible. That may be part of the reason why these ants make their nests in the forest canopy, high above fungal breeding zones. Carpenter ants also seem to avoid blazing their foraging trails under infected areas. This too might be an adaptive strategy to avoid infection, but more study is needed to confirm it, Hughes says.
The mechanisms and cues the fungus uses to control an ant’s behavior remain unknown. “That is another research area we are actively pursuing right now,” Hughes says. Whatever the mechanisms, this much is clear: O. unilateralis has evolved highly specialized abilities to get unsuspecting ants to do its bidding.”
Arguably, one might believe (again, from a teleological perspective) that cancer cells should be at least as “intelligent” as a fungus. But, the fungus, again, through some mechanism we have not clearly figured out, is able to treat the host like a puppet, shaping its behavior to benefit the parasite. If the ultimate goal of the cancer parasite is to kill the host, it does seem odd indeed….as if the cancer itself is suicidal, and using a very indirect method of killing itself.
Some might say, “No, cancer is merely an opportunistic disease that can arise for various causes, but flourishes in individuals with compromised or weakened immune systems…and has over the centuries, by trial and error, developed strategies both to evade detection by the body’s immune cells, and later, as scientists began using chemotherapy, to evade being killed”. Even writing that, one starts to slip into presenting cancer as if it has formulated these defenses intentionally.
So, except for those few “contagious” cancers, like the Tasmanian devil face cancers, they cannot “escape” the host, and end up killing themselves in order to kill the host.
Why do some people get cancer and some don’t ? Of course, the tendency to develop certain cancers can be, as we have discussed, be “hidden in your genes”. Some can be the result of continual or chronic exposure to a carcinogen. But, sometimes, it may be because of a weakened immune system. I believe that psychological negative stress can cause release of cortisol, and we know that cortisol tends to depress immune function. If one has more than one of these conditions…working in a high stress occupation in which one is exposed to carcinogenic agents, smokes tobacco and drink alcohol, and eats a lot of sugary, fat laden foods, the possibility that some sort of cancer may develop, I suggest, is enhanced and heightened.
And, we know that some folks who have surgery to resect a tumor, combined with chemotherapy and/or radiation therapy, may become cancer free, ONLY to see it reappear again. Thus, we can add “history” as another element which makes it more likely that an individual may contract cancer. (to be continued )