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Dividing cells (credit: LRI EM Unit)

Cancer: a complex problem (credit: LRI EM Unit)

Cancer is a challenging yet fascinating problem for researchers all over the world. And a new paper from US researchers, looking at a way to treat cancer that has spread, shows just how surprising cancer research can be.

The research, published in the Proceedings of the National Academy of Sciences (PNAS), shows that an antibody treatment can slow the final stages of cancer by targeting healthy cells. This turns the idea of ‘targeted treatments’ on its head – usually targeted drugs are designed to seek out and destroy cancer cells, leaving healthy cells unharmed.

So how does this counter-intuitive new approach work?The right environment

Tumours don’t exist in isolation – they’re a bit like ‘rogue organs’ made up of faulty cells mixed with ‘hijacked’ healthy cells, and they need help from the rest of the body to survive. So in the same way that plants need soil and water, tumours also need the right conditions – oxygen and nutrients, as well as a constant supply of the many signalling molecules that cells produce to communicate with each other.

 

This local environment – known to scientists as the ‘tumour microenvironment’ – plays an important role in the early stages of cancer spread, providing the right conditions for  cells to break away from the ‘primary’ tumour and form ‘secondary’ cancers elsewhere in the body.  Many cancers aren’t diagnosed until they’re already advanced, and sadly most deaths from cancer are caused by the disease spreading.

But although researchers are starting to understand how this process starts, it’s still not clear how the later stages of cancer growth are controlled. Unravelling how late-stage cancer progresses could give clues for new treatments, helping to save many more lives. And this is what the US researchers set out to investigate.

PECAM-1 – a key molecular player?

The team, led by Robert Debs of the California Pacific Medical Center Research Institute in San Francisco, focused their attention on a molecule called PECAM-1. This is a ‘receptor’ protein found on the surface of the cells that line our blood vessels – but not cancer cells.

Like a miniature satellite dish, PECAM-1’s main role is to receive signals from around the body that tell new blood vessels to grow – a process known to help cancers grow and survive.

So the scientists wanted to find out whether PECAM-1 was involved in the later stages of cancer, once the disease has already spread through the body.

To do this, they created an antibody that sticks to the PECAM-1 receptor on healthy cells, stopping them from receiving signals. This allowed the researchers to effectively ‘switch off’ the satellite dish, and find out what subsequently happened to the cells.

When this antibody was given to mice with cancer that had spread, the scientists found that it reduced the growth of late-stage tumours. Intriguingly, the treatment didn’t affect early-stage cancers.

These results are the opposite of what we might expect, suggesting that PECAM-1 is important in the later stages of cancer, but not so crucial earlier on. So could the antibody treatment be effective against final-stage cancer too?

Tests showed that not only did the antibody help to shrink secondary tumours in terminally ill mice, it also increased the animals’ bodyweight. This is an encouraging result. Patients with advanced cancer often lose significant amounts of weight because of the way the disease affects the body, and this can make treatment more difficult.

Treating cancer by targeting healthy cells?

Good results are one thing, but the researchers wanted to know exactly how the antibody was slowing cancer down. Further studies showed that antibody treatment slowed the growth of new cancer cells inside secondary tumours. The researchers also found that the antibody was blocking PECAM-1 on the healthy cells lining blood vessels.

But how does an antibody affecting healthy cells slow down tumour growth? The researchers suspected that the tumour microenvironment was behind this mystery, and their next experiment proved them right.

Treating cancer cells directly with the antibody didn’t slow their growth in the lab – this was no surprise, as cancer cells don’t have PECAM-1 receptors.  Clearly something more complex was going on. The researchers decided to re-create conditions inside the body – the tumour microenvironment – with the help of some blood vessel cells.

These cells were grown in the lab and then treated either with the PECAM-1 antibody or with a control antibody that had no effect on the receptor. Next, cancer cells were added to both experiments.

The researchers discovered that the cancer cells that had been mixed with blood vessel cells treated with the PECAM-1 antibody showed much slower growth than the experiment with the control antibody. Something in the antibody-treated environment was having an important effect.

Exploiting the cancer microenvironment

So what was going on? Overall, the study suggests that PECAM-1 helps to control late-stage cancer growth. Blocking the PECAM-1 receptor with an antibody seems to dampen down some of the growth signals and slow the disease’s progression.

But, as so often happens in cancer research, these interesting results raise more questions than they answer.

As the researchers point out, it’s intriguing that the antibody is more effective against late-stage cancers. This illustrates how much cancer changes as it progresses, and suggests the exciting possibility that new drugs could be designed specifically to target late-stage cancer. And this study also shows how our increasing knowledge of the tumour microenvironment is giving clues for ingenious new ways to tackle the disease, even after it has spread.

The next step is to understand exactly how the antibody blocks cancer growth signals, with the aim of eventually testing this new approach in patients. This idea is still in its early stages, but the researchers are hopeful that it could give good results.

As Professor Margaret Frame, Cancer Research UK’s expert on cancer spread, commented, ‘this would be an exciting possibility… further testing and refinement is needed to establish the value of this as a potential treatment, but it is very encouraging.’

Nell Barrie, Science Information officer

Reference:
DeLisser, H.,et al (2010). Vascular endothelial platelet endothelial cell adhesion molecule 1 (PECAM-1) regulates advanced metastatic progression Proceedings of the National Academy of Sciences, 107 (43), 18616-18621 DOI: 10.1073/pnas.1004654107

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