Spinning Out In Control

In Signs of Resistance and Seeing the Invisible we emphasized two things well known to the interested, namely that most cancer deaths occur because cells spread from the original (primary) to secondary sites (metastases) where they are very difficult to treat, and that this places massive importance on early detection. Many will also be familiar with the currently used methods for tumor detection – X-ray based imaging (as in mammography and CT scans) and PET that detects injected radioactive tracers. The problem is that these are not sensitive enough to detect growths smaller than about 1 cm in diameter – and by that point there are several hundred million cells in the tumor and some may already have metastasized.

Tumor cells spread around the body by detaching from the primary and getting into the circulatory system and it’s beginning to look as though quite literally tapping into the circulation may revolutionize cancer detection. Seeing the Invisible showed how silicon chip technology can be used to retrieve circulating tumor cells (CTCs) by getting them to stick to targets anchored in a flow cell. Although this is hugely promising, another very recent advance may be even more effective. This uses centrifugal force to separate cells in blood on the basis of their size – that’s the one that pushes outwards on objects rotating about an axis. Because force is proportional to mass and tumor cells are larger than red blood cells and most white cells, this effect can be used to extract CTCs from fluid being pumped around a spiral microchannel. The spirals are made from a silicon-based polymer (the same stuff that’s used for contact lenses) stuck on glass slides and they have two outlet channels. Their shape creates two-counter rotating vortices in the fluid that exert a drag force on the cells so that bigger (heavier) tumor cells can be selectively directed to one of the outlets. Typically red blood cells are about 6 microns (one-millionth of a metre), white cells 8-14 microns and CTCs 16-25 microns in diameter.

The vortices are named after a Cambridge chappie, William Dean, who worked on flow patterns in curved pipes and channels and you can look up Dean vortices on the internet for images of these in action.

MCF7s right, rest left

In this picture of the two exits from a spiral microchannel breast cancer cells are carried to the right (yellow arrows) whilst all the other types of blood cell funnel left.

This method appears to be remarkably efficient in that over 90% of tumor cells (10-100 cells per ml of blood) can be separated from 99.99% of red cells (5,000,000 per ml) and 99.6% of white cells (10,000 per ml).

References

Hou, H.W., Warkiani, M. E., Khoo, B.L., Li, Z.R., Soo, R.A., Tan, D.S.-W., Lim, W.-T., Bhagat, A.A.S., and Lim, C.T. (2013). Isolation and retrieval of circulating tumor cells using centrifugal forces. Scientific Reports 3, Article Number: 1259. DOI: 10.1038/srep01259.

Bhagat, A.A.S. et al., 15th International Conference on Miniaturized Systems for Chemistry and Life Sciences October 2-6, 2011, Seattle, Washington, USA

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Three cancers for the price of one?

Damaging the DNA Double-helix

A colleague of mine works on double-stranded DNA repair, as it’s called in the trade. This is something that goes on in all of us as our cells patch up DNA that’s being continuously assaulted by things that cause mutations. One source of damage is radiation that can snip the double helix, leaving separate bits of chromosomes floating around in the nucleus. Anything involving ‘snipping’ suggests a pretty potent type of mutation and it does indeed present a real problem because the cell has to find ways of tagging the floating ends, bringing them together and stitching them up. Amazingly, Nature has come up with not one but several ways of doing this and, by and large, they work pretty well. In ferreting around to define the proteins involved, my friend and his team also tried out drugs that might block repair. Having found a very effective one they set up a company to develop it – duly taken over by AstraZeneca, with the result that I now know one person in science who is very rich. The hope is that the drug might work against ovarian, prostate and breast cancers – which would be very good news for AstraZeneca!

But, you may already be asking, what’s the use of a repair blocker? Surely that’s the last thing you want in staving off cancer? Well, yes – and no. All things being equal, you do want to keep repair systems working but, if one of them becomes defective as part of cancer development, knocking out another may push the cell over the brink so that it can’t deal with the DNA chaos and commits suicide.

Bear in mind that our picture of cancer is one of widespread damage to DNA. But the genetic anarchy of cancer has parallels with the political variety in that both have limits. If the Molotov cocktail fraternity so disrupt society that the binmen stop collecting rubbish, everyone dies of cholera – not exactly a great social reform. Cancer too walks a tightrope between the disruption needed to overcome normal cell control and an extreme level of chaos that would simply kill the cell.

Two of the most familiar ‘cancer genes’ are BRCA1 and BRCA2, mutated forms of which can be inherited to give rise to several types of cancer. It turns out that both BRCAs play roles in DNA repair. The drug that has improved my friend’s bank balance is olaparib and it targets another DNA repair pathway – involving an enzyme called PARP (for poly (ADP-ribose) polymerase). So that’s why it’s useful: if the BRCA route is already blocked by mutation, inhibiting a second repair pathway (PARP) may scupper the cancer cell.

BRCA mutations cause about 5% of breast cancers and 10% of ovarian cancers and they can also give rise to prostate cancer. Small-scale clinical trials of olaparib and several related PARP inhibitors have shown anti-tumour effects against all three of these cancers. However, the most recent trial showed no significant effect on survival of breast cancer patients. Whilst this is a set-back for the PARP inhibitor field, another trial has shown significant effects on ovarian cancer.

As so often in the history of cancer treatment, great expectations have taken a bit of a knock but the PARP story is far from over and it still holds the promise than one class of drugs may be effective against several different types of cancer. If it were to turn out that way it would be great news for some cancer patients – and not bad for one or two bank balances.

Sitting on a problem

Spouses around the world whose hubbies spend all their time with their butts parked on the sofa watching wretched football on the t.v. might try informing them that they are significantly increasing their risk of prostate cancer. Breast, lung and bowel cancers get much media coverage, rightly so as the three biggest cancer killers in the western world. But prostate is not far behind (it’s too serious for jokes) – it’s the fifth most common cancer overall – and world-wide it kills 258,000 men a year. Prostate cancer can be treated by surgery, radiation therapy or drugs, including ‘chemical castration’, a phrase guaranteed to send a frisson through any male – though it simply means administering oestrogen to oppose testosterone production. This is effective in many cases but advanced forms of the disease are resistant to chemotherapy and for these there is no real treatment. Thus the news that a new drug, (abiraterone, trade name Zytiga), will come into use next year has to be hailed as a step forward. Abiraterone has just negotiated a phase 3 clinical trial in which (administered with prednisone, the pro-drug of prednisolone) it extended the average survival time for men with advanced prostate cancer from 11 to 15 months and it was approved by the U.S. Food and Drug Administration in April 2011.

Four months doesn’t sound a lot but it is a 36% increase. What’s more, abiraterone works in a different way to chemical castration: instead of stopping testosterone activating its target cells it prevents its synthesis altogether by blocking the action of an enzyme. So this is a totally new targeting strategy.

It isn’t a cure for prostate cancer, so ladies you can still use the stats to get him to do the washing up rather than watching the degrading pantomine that is professional football. But it is a small step in the cancer war and may be the precursor to affecting a major cut in the number of men who die every day from prostate cancer in the UK (28) and in the 28,600 that it kills every year in the USA.

Surviving cancer in the UK and other places

Over the years a number of surveys have concluded that, despite progressive improvements, the UK five-year survival rates for common cancers are worse than the European average by 5 to 15%. The most recent of these has just emerged, comparing survival from four of the most important cancers – breast, bowel, lung and ovarian – at one and five years following diagnosis between 1995 and 2007 in the UK, Denmark, Norway, Sweden, Australia and Canada. Their conclusion was that, despite improvements in survival rates, the disparities remain and that the life expectancy of cancer patients in the UK is shorter than in other countries.

Before we get too downcast by these facts we should note that the UK five-year survival rate for breast cancer, for example, has now reached 82% whereas 40 years ago it was 40%. However, the UK clearly has a problem for which there might be three broad causes: (1) later diagnosis, (2) more aggressive forms of the disease, (3) variable standard of treatment.  It seems probable that all three play a part.

Where you live in the UK bears significantly on your cancer risk.  The National Cancer Intelligence Centre has produced a Cancer Atlas that compares incidence and death rate from the 21 most common cancers in different counties of the UK.  The differences reflect levels of smoking, drinking, poor diet and social deprivation and show that regions of northern England and Scotland are cancer ‘hot spots’.  Their estimate is that if the worst areas could be converted to the best there would be 25,000 fewer new cases and 17,000 fewer deaths a year: with about 156,000 cancer deaths per year that would represent an 11% decrease.

One sensible plan might be to concentrate cancer care into a smaller number of centres of expertise, along the lines of what has been proposed for heart disease.

World, USA and UK cancer deaths 2008.

Reference

Coleman, M.P., Forman, D., Bryant, H., Butler, J., Rachet, B., Maringe, C., Nur, U., Tracey, E., Coory, M., Hatcher, J., McGahan, C.E., Turner, D., Marrett, L., Gjerstorff, M.L., Johannesen, T.B., Adolfsson, J., Lambe, M., Lawrence, G., Meechan, D., Morris, E.J., Middleton, R., Steward, J., Richards, M.A. and the ICBP Module 1 Working Group. (2011). Cancer survival in Australia, Canada, Denmark, Norway, Sweden, and the UK, 1995—2007 (the International Cancer Benchmarking Partnership): an analysis of population-based cancer registry data. The Lancet, 377, 127–138.