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Entries in cancer (6)

Friday
Nov102017

Will pancreatic cancer be the next target for immunotherapy?

Pancreatic cancer is one of the scariest diagnoses a patient can receive. Even though it is a rare disease, with only 1 in 100 people developing it, it is a rapid killer - even with the best medical attention the median survival rate is less than 6 months.

In a study just published this week in Oncotarget, our laboratory looked at the relationship between autoimmunity of the pancreas and pancreatic cancer. We found that mice prone to pancreatic autoimmunity develop greater levels of immune infiltration around tumours in the pancreas, and this substantially slowed the growth of the tumour.

The reason why this result is so important is that it means our immune system can actually combat pancreatic cancer, if we can just drive an autoimmune reaction against the tumour. Here we used genetics to create an autoimmune-prone mouse, but immune checkpoint blockade therapies can create exactly the same pro-autoimmune response in patients. Our results therefore suggest that there is an effective latent response against pancreatic cancer that is waiting to be unleashed by immune checkpoint inhibitors. 

Original article: Dooley et al, "NOD mice, susceptible to pancreatic autoimmunity, demonstrate delayed growth of pancreatic cancer". Oncotarget, 8(46):80167

 

Monday
Feb272017

The perils of food science

The intersection of science and the public is always a delicate balance. Medicial research is explicitly performed for the public benefit, and good communication of the results to the public aids in further investment. Difficulties arise due to the discrepancy between scientific publication (with all the caveats, nuance and steady progress) and a brand of journalism that tends to be excessively focused on sensationalism. 

One of the areas where this balance is most difficult to achieve is in any medical research related to food. People are interested in food, and a story that one of our favourite foods is either going to kill us or save us always makes headlines. The area abounds with popular myths that go so far beyond the supported science that they have lost all connection with reality.

Take the issue of artifical sweetners and pancreatic cancer. Aspartame is often the boogeyman of the artifical sweetner world. Aspartame is one of the most studied food additives and to date there is no robust link to cancer, and yet aspartame is oft campaigned against in the public sphere. Indeed, the public pressure against aspartame is such that major food companies have started to phase it out, replacing it with much less studied compounds, such as stevia. By contrast, stevia is the darling child of food advocates in the public sphere. It is touted for a myriad of benefits, including as a potential inhibitor of pancreatic cancer. So what is this based on? Next to nothing, actually. There are a handful of studies using pancreatic cancer cell lines, and adding stevia to them while they grow in a dish inhibits them a bit. As for data on stevia being anti-cancer in an actual organism, the only experiment is one where stevia paste was applied to the skin, which was then treated with a carcinogen. The mice were protected from developing skin cancer, but that is likely because the stevia paste acts as a barrier, like sunscreen. In other words, there is zero evidence that stevia in the diet is actually anti-cancer in function.

In a recent study we directly tested whether aspartame or stevia had any influence, either positive or negative, over pancreatic cancer development, growth or lethality. We used mice, rather than just cells grown in a dish, and we gave the artificial sweetners in the drinking water in doses that are similar to popular beverages. We found.... nothing. No effect, either positive or negative. Aspartame won't kill you, stevia won't protect you. Sorry Daily Mail.

Read more: Dooley, Lagou, Dresselaers, van Dongen, Himmelreich and Liston. "No effect of dietary aspartame or stevia on pancreatic acinar carcinoma development, growth or induced mortality in a murine model". 2017, Frontiers in Oncology. 

Wednesday
Nov162016

World Pancreatic Cancer day

Tomorrow is World Pancreatic Cancer day 

Pancreatic cancer is a relatively rare form of cancer, with a lifetime risk of developing pancreatic cancer of 1 in 76. However due to the deadly nature of the disease it is the fourth biggest killer in terms of the absolute numbers of fatalities. The main reason for the high mortality is the late detection of pancreatic cancer, with only 15-20% of cases being diagnosed at a point when are operable, leading to a median survival of less than six months and a five year survival rate of under 8%. At a time when the mortality rates of most cancers are dropping, the death rate from pancreatic cancer is still rising.

It is critical for us to understand the causes of pancreatic cancer, both so that we can develop effective treatments and also so that we can better design screening strategies for earlier detection. The known risk factors for pancreatic cancer include age, smoking, obesity, lack of physical activity, diet, type 2 diabetes, chronic pancreatitis, cirrhosis and genetic background. The big problem is that many of these risk factors are inter-connected, and it is difficult to dissect out the effect of obesity, diet and diabetes. In the Translational Immunology Laboratory we have just completed a multi-year study of more than 300 mice with pancreatic cancer. We used longitudinal MRI tracking to determine the factors that drive the development, growth and lethality of pancreatic cancer - stay tuned for our forthcoming papers that give the result!

 

Thursday
Jun232016

Journal club: Transmissible cancer may not be so rare

Cancer is a disease of our own cells gone wrong. Normally our cells work in harmony with each other, taking cues from each other as to when to proliferate, when to differentiate and when to die. In cancer, mutation takes away this level of regulation, leaving a "selfish cell" that ignores all of these signals and proliferates uncontrollably, even to the point of killing the host.

There have been a handful of rare cases where cancers can actually physically cross-over from one individual to another, such that the second individual is actually growing cancer cells that are not self, but are fully derived from the original host. This has been seen in a few human cases as well as well-described transmissible cancers in Tasmanian Devils and dogs. There was even a recent case study that suggests a tapeworm cancer crossed over into the host. In general, however, it is thought that this type of event is going to be exceptionally rare. Even ignoring the protective effect of our immune system killing foreign cells, it is not like cells from one individual can just float through the air to colonise another. Except, of course, under the water.

A paper just published in Nature looks for transmissible cancers in mussels and clams and finds three examples of cancer cells from one individual clam or mussels infecting and growing in other indiviudals of the same, or even different, species. With high population densities and water flow acting to directly transfer cancer cells, it is probably that transmissible cancers are actually a common feature in many marine environments.

Nature 2016, in press. Widespread transmission of independent cancer lineages within multiple bivalve species. Metzger, Villalba, Carballal, Iglesias, Sherry, Reinisch, Muttray, Baldwin, Goff.

Saturday
Jan162016

Journal club: Patient diagnosed with non-human cancer

In a fascinating case report in the New England Journal of Medicine, Muehlenbachs et al identified a patient with disseminated cancer through the lungs and lymph nodes. The major oddity of the cancer was the small size of the cells, far smaller than human cells, indicating that the cancer cells were non-human. Extensive analysis identified the cancer cells as coming from Hymenolepis nana, the dwarf tapeworm. The patient was infected with tapeworms, one of which developed cancer (as can happen to any organism). These tapeworm cancer cells then metasized from the tapeworm into the host, adapted to the host and spread throughout the body as a foreign cancer. While the immune system is normally highly effective at clearing foreign organisms from the body, the tapeworm cancer cells were able to survive and disseminate throughout the body, possible for a combination of three reasons: i) tapeworms induce immune tolerance against their antigens, ii) the tumour cells were selected to be of low immunogenicity, and iii) the patient was HIV+ and immunodeficient. While this may be a one-off case, since parasite infections are so common perhaps we will find non-human cancers in other patients?

Muehlenbachs et al. 'Malignant Transformation of Hymenolepis nana in a Human Host'. New England Journal of Medicine. 2015. 373:1845

Monday
Oct192009

Infectious cancer

It has long been known that the several causes of cancer are infectious. Typically a virus contains a number of oncogenes to enhance its own proliferation, and in an infection gone wrong (for both virus and host) a viral oncogene is incorporated into the host DNA, creating an uncontrollable tumour cell. One of the best examples of this is human papillomavirus (HPV), a virus which infects most sexually active adults and is responsible for nearly every case of cervical cancer worldwide (which is why all girls should be vaccinated before they become sexually active).

However these cases are not "infectious cancers", they are infectious diseases which are capable of causing cancer. True infectious cancers, where a cancer cell from one individual takes up residency in a second individual and grows into a new cancer, were unknown until recently. With the publication of a new study in PNAS we now have three examples of truly infectious cancers.

1. In the most recent study, researchers in Japan documented the tragic case of a 28 year old Japanese woman who gave birth to a healthy baby but within two months had been diagnosed with acute lymphoblastic leukemia and died. At 11 months of age the child also become ill and was diagnosed with acute lymphoblastic leukemia. Genetic analysis of the tumour cells in the baby demonstrated that the tumour cells were not from the child herself, but rather maternal leukemia cells that had crossed the placenta during pregnancy or childbirth and had taken up residency in their new host. With this information, retrospective analysis indicates that this is probably not a one-off event, and at least 17 other cases of mother-to-child transmission of cancer have probably occurred.

2. In addition to mother-to-child transmission of cancer, cancer can spread from one identical twin to another. Identical (mono-zygotic) twins have identical immune systems, preventing rejection of "transplanted" cells, unlike non-identical (di-zygotic) twins. Thus a tumour which develops before birth in one identical twin can be transferred in utero to the other identical twin, where it can grow without being rejected. In one improbable but highly informative case, a set of triplets were born where two babies were identical and the third was non-identical. A tumour had arisen in one of the identical twins in utero and had passed to both other foetuses, but had been rejected by the non-identical foetus and accepted by the identical foetus. Of course, with the advent of medical transplantation, transmission of infectious cancers is now no longer limited to the uterus. Transplantation of an organ containing a cancer into a new host can allow the original cancer to grow and spread, as transplantation patients are immunosuppressed to prevent rejection. There is also a single case of a cancer being transmitted from a surgeon who cut his hand during surgery to a patient who was not immunosuppressed.

3. In a medical mystery well known to Australians, the population of Tasmanian Devils has been crashing as a fatal facial tumour has been spreading across the population. The way the fatal tumours have spread steadily across Tasmania and sparing Devils on smaller islands first suggested a new infectious disease that causes cancer, similar to HPV in humans. However a suprising study demonstrated that the cancer was directly spreading from one Devil to the next after having spontaneously developed in a single individual. These scrappy little monsters attack each other on first sight, biting each other's faces. The cancer resides in the salivary glands and gets transmitted by facial bites to the new Devil. Unfortunately for Tasmanian Devils, a genetic bottleneck left all Devils so genetically similar that they are, for immunological purposes, all identical twins. This means that the cancer cells transmitted from one Devil to another through biting are able to grow and kill Devil after Devil. The cancer from a single individual has already killed 50% of all Devils, and it is possible that we will have to wait until the cancer burns out by killing all potential hosts before reintroducing the Devil from the protected island populations. As unlikely as this seems, another similar spread occurs in dogs, where a cancer that arose in a single individual wolf is being spread through sexual transmission from dog to dog around the world. This example also illustrates the point made about cancers being "immortal" - the original cancer event may have occured up to 2500 years ago, with the tumour moving from host to host for thousands of years without dying out.