Collagen clue reveals new drug target for untreatable form of lung cancer
Collagen, the stuff of ligaments and skin, and the most abundant protein in the human body, has an extraordinary role in triggering chemical signals that help protect the body from cancer, a new study reveals.
Scientists at The Institute of Cancer Research, London, have uncovered a series of chemical signals sent out by collagen that appear to protect against cancer’s growth.
Boosting those signals could act as an effective treatment for cancers that grow in the presence of collagen, including squamous cell lung cancer, for which no targeted treatments currently exist.
And the findings suggest that switching off these chemical signals, as some treatments for leukaemia do, is likely to be counter-productive in cancers where interaction with collagen plays an important role.
The study was funded by The Institute of Cancer Research (ICR), the Wellcome Trust and the Biotechnology and Biological Sciences Research Council (BBSRC).
The ICR team explored the role of signals triggered by collagen in human embryonic kidney cells, a type of cell often used in studies of this type. They analysed the role of a molecule called DDR2, which relays signals from collagen as a means of maintaining tissue structure and function, and is mutated in some forms of squamous cell lung cancer.
Lung cancer is the second most common cancer in the UK (2010), accounting for 13% of all new cases. It is the second most common cancer in both males (13% of the male total) and females (12%).
In 2010, there were 42,026 new cases of lung cancer in the UK: 23,175 (55%) in men and 18,851 (45%) in women, giving a male:female ratio of more than 12:10. The crude incidence rate shows that there are 76 new lung cancer cases for every 100,000 males in the UK, and 60 for every 100,000 females.
The European age-standardised incidence rates (AS rates) are significantly higher in Scotland compared with the other constituent countries of the UK, and significantly lower in England.
They treated cells with collagen, and found that DDR2 responded by activating a second protein called SHP-2, in a process that appears to be important in protecting against the growth of some cancers.
But a specific mutant form of DDR2 present in some squamous cell lung cancers seemed unable to signal through SHP-2, suggesting the loss of function had left the tissue vulnerable to cancer growth.
That finding offers an exciting opportunity to design the first targeted treatments for squamous cell lung cancer, perhaps by mimicking the action of SHP-2 to re-erect the normal controls against cancer’s growth in the presence of collagen.
Dr Paul Huang, Team Leader in Protein Networks at The Institute of Cancer Research, said: “We knew collagen was capable of slowing the growth of some cancer types, presumably by maintaining the structure of tissues, but our new study for the first time identifies how this effect occurs in lung cancer.
Lung cancer incidence statistics by age
Lung cancer incidence is strongly related to age, with the highest incidence rates being in older men and women. In the UK between 2008 and 2010, an average of three-quarters of cases were diagnosed in men and women aged 65 years and over.
Age-specific incidence rates rise steeply from around age 40 and peak in the 80-84 age group. Incidence rates are similar for men and women in their 40s, but thereafter male rates are higher than female rates, and this gap widens with increasing age. At age 50-54, the male:female incidence ratio of age-specific rates (to account for the different proportions of males to females in each age group) is around 11:10; by age 85+, it is around 22:10
“We sifted through data on 428 different proteins stimulated by collagen, and isolated just one we think can play a key role in protecting tissues from cancer. Identifying this molecular trigger opens up the prospect of targeted treatments for squamous cell lung cancer.
“Importantly, we also highlighted the duplicitous nature of this important signalling network. Although we know it directs a lot of cellular processes that can contribute to cancer - such as differentiation, proliferation and motility - in the presence of collagen, it actually seems to protect against cancer. That means we will need to treat cancers that develop in collagen-rich environments differently to blood cancers such as leukaemia.”
Professor Alan Ashworth, Chief Executive of The Institute of Cancer Research, said: “Survival rates for lung cancer remain extremely poor, and one of the ways to improve this is to discover new ways of targeting the disease with drugs. This new study is valuable for two reasons - it identifies an exciting new potential route for treating lung cancers, and it also shows us why some other approaches are unlikely to work.
Lung cancer is the leading cancer killer in both men and women in the United States. In 1987, it surpassed breast cancer to become the leading cause of cancer deaths in women.
Lung cancer causes more deaths than the next three most common cancers combined (colon, breast and prostate). An estimated 160,340 Americans were expected to die from lung cancer in 2012, accounting for approximately 28 percent of all cancer deaths.
“Scientifically, these results are very interesting as they demonstrate how one of the most common proteins in the human body plays a role not only in building the structure of tissues but also in cancer.”
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Notes to editors
Squamous cell cancer accounts for around 25 per cent of all lung cancer cases (Heist, R.S., et al., J Thorac Oncol, 2012. 7(5): p. 924-33).
Some cancer drugs developed to target a different signalling pathway in leukaemia - called BCR-ABL - actually block the action of DDR2, but this study shows these are unlikely to be effective against specific DDR2 mutations in squamous cell lung cancer.
The Institute of Cancer Research, London, is one of the world’s most influential cancer research institutes. Scientists and clinicians at The Institute of Cancer Research (ICR) are working every day to make a real impact on cancer patients’ lives.
Through its unique partnership with The Royal Marsden Hospital and ‘bench-to-bedside’ approach, the ICR is able to create and deliver results in a way that other institutions cannot. Together the two organisations are rated in the top four cancer centres globally.
The ICR has an outstanding record of achievement dating back more than 100 years. It provided the first convincing evidence that DNA damage is the basic cause of cancer, laying the foundation for the now universally accepted idea that cancer is a genetic disease. Today it leads the world at isolating cancer-related genes and discovering new targeted drugs for personalised cancer treatment.
As a college of the University of London, the ICR provides postgraduate higher education of international distinction. It has charitable status and relies on support from partner organisations, charities and the general public. The ICR’s mission is to make the discoveries that defeat cancer.
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Henry French
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Institute of Cancer Research