Nanoparticles cause cancer cells to die and stop spreading

More than nine in ten cancer-related deaths occur because of metastasis, the spread of cancer cells from a primary tumour to other parts of the body. While primary tumours can often be treated with radiation or surgery, the spread of cancer throughout the body limits treatment options. This, however, can change if work done by Michael King and his colleagues at Cornell University, delivers on its promises, because he has developed a way of hunting and killing metastatic cancer cells.

When diagnosed with cancer, the best news can be that the tumour is small and restricted to one area. Many treatments, including non-selective ones such as radiation therapy, can be used to get rid of such tumours. But if a tumour remains untreated for too long, it starts to spread. It may do so by invading nearby, healthy tissue or by entering the bloodstream. At that point, a doctor’s job becomes much more difficult.

Cancer is the unrestricted growth of normal cells, which occurs because mutations in normal cell cause it to bypass a key mechanism called apoptosis (or programmed cell death) that the body uses to clear old cells. However, since the 1990s, researchers have been studying a protein called TRAIL, which on binding to the cell can reactivate apoptosis. But so far, using TRAIL as a treatment of metastatic cancer hasn’t worked, because cancer cells suppress TRAIL receptors.

When attempting to develop a treatment for metastases, King faced two problems: targeting moving cancer cells and ensuring cell death could be activated once they were located. To handle both issues, he built fat-based nanoparticles that were one thousand times smaller than a human hair and attached two proteins to them. One is E-selectin, which selectively binds to white blood cells, and the other is TRAIL.

He chose to stick the nanoparticles to white blood cells because it would keep the body from excreting them easily. This means the nanoparticles, made from fat molecules, remain in the blood longer, and thus have a greater chance of bumping into freely moving cancer cells.

There is an added advantage. Red blood cells tend to travel in the centre of a blood vessel and white blood cells stick to the edges. This is because red blood cells are lower density and can be easily deformed to slide around obstacles. Cancer cells Have a similar density to white blood cells and remain close to the walls, too. As a result, these nanoparticles are more likely to bump into cancer cells and bind their TRAIL receptors.

Leukocytes are WBCs and liposomes are nanoparticles. King/PNAS

King, with help from Chris Schaffer, also at Cornell University, tested these nanoparticles in mice. They first injected healthy mice with cancer cells, and then after a 30-minute delay injected the nanoparticles. These treated mice developed far fewer cancers, compared to a control group that did not receive the nanoparticles.

“Previous attempts have not succeeded, probably because they couldn’t get the response that was needed to reactivate apoptosis. With multiple TRAIL molecules attached on the nanoparticle, we are able to achieve this,” Schaffer said. The work has been published in the Proceedings of the National Academy of Sciences.

While these are exciting results, the research is at an early stage. Schaffer said that the next step would be to test mice that already have a primary tumour.

“While this is an exciting and novel strategy,” according to Sue Eccles, professor of experimental cancer therapeutics at London’s Institute of Cancer Research, “it would be important to show that cancer cells already resident in distant organs (the usual clinical reality) could be accessed and destroyed by this approach. Preventing cancer cells from getting out of the blood in the first place may only have limited clinical utility.”

But there is hope for cancers that spend a lot of time in blood circulation, such as blood, bone marrow and lymph nodes cancers. As Schaffer said, any attempt to control spreading of cancer is bound to help. It remains one of the most exciting areas of research and future cancer treatment.The Conversation

First published at The Conversation.

Image credit: Cornell University

Ageing cells reveal features of cancer

The older we get, the higher our risk of cancer. With age, we accumulate exposure to environments and chemicals that increase the risk of acquiring cancer-causing mutations. But the danger doesn’t increase in a linear manner, and we know little about why there is such a dramatic increase with ageing.

Accumulated damage isn’t the only thing going on as we age. The body’s cells also go through a process called senescence. Chief among the changes that come with senescence are alterations to the epigenome, the proteins and chemical modifications that are attached to our DNA. These epigenetic changes can influence which genes are active in different tissues.

During this phase of a human cell’s life, the changes are an attempt to shutdown the process of cell division. Cell division involves creating copies of chromosomes and distributing them into two identical copies of the parent cell. But cells that go senescent must stop multiplying.

Cancer cells manage to bypass the mechanisms that stop them multiplying, including those put in place during senescence.

In the new study, published in Nature Cell Biology, Peter Adams at the University of Glasgow followed the ageing process in fibroblasts, which are cells that form connective tissue.

Adams and his colleague found that ageing cells have less control over their epigenome leading to widespread changes in DNA. Many sections of the genome, which were supposed to be under the control of DNA methyltransferase (DNMT1), end up with fewer methyl groups than would be expected. While some sections, known as CpG islands, get more methyl groups. It was surprising that comparison of these epigenetic changes with those found in cancer cells showed many similarities.

According to co-author of the study Richard Meehan, a researcher at the University of Edinburgh’s Human Genetics Unit, the study shows that ageing cells have some of the same features as cancer. “But we must be careful about interpreting the results,” he said. The study involved looking at human cells in Petri dishes, so the experiments must be repeated in animals and then humans before we can draw firm conclusions.

If the study stands that test, however, then we will have a strong hint of why ageing increases our risk of cancer and better understanding of the ageing process. “I don’t know if the results will help us fight cancer, but if I am able to delay the ageing of my fibroblasts, one thing’s for sure: I’ll look a hell of a lot better when I’m older,” Meehan said.

Avi Roy, a researcher at the University of Buckingham, has also worked on the senescence of cells. He said, “What they have done is not completely new, but it is a big piece of work. And they have a lot of evidence to back up their claim.” Roy agrees with Meehan and warns that any conclusions about revealing how cancer works based on this work would be premature.

A 2011 study points to the difficulty of drawing wider conclusions. In the study researchers removed a particular kind of senescent cell from ageing mice. They found that in these mice many of the age-related diseases, such as cataracts, were delayed. “But the mice didn’t have their life extended. They died of either cardiac arrests or cancer,” Roy said. Much remains to be understood about how ageing causes cancer, and with the latest study from Adams and Meehan we take a few steps closer.The Conversation

First published on The Conversation.

Image credit:lnmurrey

Cancer immunity of strange underground rat revealed

Researchers have discovered how one of the world’s oddest mammals developed resistance to cancer, and there is hope that their work could help fight the disease in humans.

Naked mole rats live underground, where environmental conditions are harsh but predators are few. They can live for more than 30 years, almost seven times longer than its close cousin the house mouse, which is particularly susceptible to cancer. They breathe slowly due to the limited supply of oxygen, survive on very little food, have poor sight and are largely indifferent to pain.

They are also the only mammals that do not regulate their body temperature. Because they live in colonies where the queen rat does the job of producing progeny and only a few males father the litters, their sperms become lazy.

For cancer researchers, mice and naked mole rats fall on two extremes of the disease spectrum. Mice are used as animal models of disease because of their short lives and high incidence of cancer. These help researchers study the mechanism of cancer occurrence and test drugs that fight the disease.

Naked mole rats, on the other hand, have never developed cancer in the years that they have been studied. In labs, researchers often don’t wait for their animal models to develop cancer. Instead they induce cancer by blasting the animals with gamma radiation, transplanting tumours or injecting cancer-causing agents. Do that to a naked mole rat, though, and nothing happens.

Now, Vera Gorbunova and Andrei Seluanov at the University of Rochester think that they may have found one mechanism by which naked mole rats defend themselves against cancer. Their results, reported today in the journal Nature, make for a strange tale.

While studying cells taken from the armpits and lungs of naked mole rats, they found an unusually thick chemical surrounding the cells. This turned out to be hyaluronan, a substance that is present in all animals, where its main job is to hold cells together. Beyond providing mechanical strength, it is also involved in controlling when cells grow in number.

Cancer relies on the unregulated growth of cells, so hyaluronan was thought to be involved in the progression of malignant tumours. According to Gorbunova, there are aspects of hyaluronan may regulate cell growth: as well as its amount and thickness. As a polymer, the greater the number of hyaluronan molecules in a single chain the thicker it becomes.

When the molecular mass is high, cells are “told” to stop increasing in number. When the molecular mass is low, they are “asked” to proliferate. In the case of the naked mole rat, Gorbunova found that the molecular mass was unusually high, as much as five times that of mice or humans.

To understand whether this unusual hyaluronan was responsible for cancer resistance in naked mole rats, Gorbunova increased the amount of enzyme that degrades the chemical, reducing its molecular weight. Soon after, she observed that the rat’s cells readily started growing in thick clusters, like cancerous mouse cells do.

In a separate experiment, she also tested this hypothesis by reducing the amount of hyaluronan by knocking out the genes that encode for its production. Then on injecting cancer-causing virus, instead of resisting, the naked mole rat’s cells became cancerous.

Gorbunova thinks that having thick hyaluronan might have helped increase the elasticity of the rat’s skin, allowing it to live in small tunnels underground. This trait might then have accidentally developed a new role of preventing cancer.

Rochelle Buffenstein, a physiologist at the University of Texas Health Science Center, who has studied naked mole rats for years was pleased to see that some light has been shed on this creature’s remarkable resistance to cancer. “As we learn more about these cancer-resistant mechanisms that are effective and can be directly pertinent to humans, we may find new cancer prevention strategies,” she said.The Conversation

First published at The Conversation.

Image credit: Smithsonian National Zoo