HKU Bulletin August 2010 (Vol. 11 No. 3)

14 The University of Hong Kong Bulletin 15 August 2010 HKU researchers are the first to identify cancer stem cells that are responsible for metastasis – the spread of cancer to other parts of the body. Their work focuses on colorectal cancer, the second most common cancer in the world and in Hong Kong. More than 50 per cent of patients develop metastasis even after adequate surgical removal of the primary tumour, and aggressive treatment of the metastasis usually fails: fewer than 10 per cent of patients with metastasis of colorectal cancer survive for more than five years. Researchers from the Departments of Medicine and Surgery have shown that cancer cells endowed with stem cell properties are the likely cause. ‘Cancer stem cells’ are like all other stem cells in that they can produce further cells like themselves (self-renewal) and also differentiate to provide more mature cell types. They are largely dormant and divide infrequently within the tumour, while the mature cells usually divide rapidly and make up most of the tumour bulk. “What happens with current therapies such as chemotherapy and radiotherapy is that they target and kill all the rapidly dividing cells, leaving behind the cancer stem cells,” says Dr Roberta Pang, Research Assistant Professor of Medicine. “Moreover, these cancer stem cells cannot be killed because like other stem cells, they are equipped with an intrinsic detoxifying capacity. Cancer stem cells that have not been eradicated can lead to a recurrence of the cancer because they are able to replenish the tumour mass through self- renewal and differentiation. “The re-established tumours are more enriched by cancer stem cells and become more resistant to conventional therapies, which accounts for the more aggressive and resistant nature of recurrent tumours.” This pattern parallels what’s often seen in clinical settings. “When patients are treated with chemotherapy, you may observe tumour shrinkage initially and the disease will seem to resolve. However, in a substantial number of patients, recurrence or a distant metastasis will then develop and the recurrent tumour usually becomes much more aggressive and resistant to conventional chemotherapeutic agents. We believe the reason for this recurrence and metastasis is the failure to effectively target the cancer stem cells,” Dr Pang says. Alarming as that may sound to patients, the research offers hope of detecting the risk of metastasis at an early stage. A new marker was found that detects cancer stem cells in the blood even when the disease is at an early stage, which can accurately predict the likelihood of metastasis. (Current monitoring consists of a blood test that is not accurate in detecting cancer recurrence and cannot detect metastasis.) This will alert doctors to be extra vigilant in monitoring. “Patient compliance is also an issue. Some patients may attend follow-up for only one or two years and think the disease is cured. So it’s important to have a marker that can accurately predict their likelihood of metastasis,” Dr Pang says. The HKU team has begun testing different molecular targeting drugs that can specifically target these cancer stem cells, and is conducting similar studies of cancer stem cells in gastric and liver cancer. The findings on colorectal cancer were featured on the cover of the June issue of Cell Stem Cell , the leading publication on stem cell research. STEM CELLS in cancer A breakthrough study sheds light on the spread and recurrence of cancer. CHEMOTHERAPY LEADS TO REDUCTION IN TUMOUR SIZE, BUT ENRICHMENT OF CD26+ POPULATION Dr Roberta Pang SECRETS OF ageing Premature ageing may be linked to stem cell decline. One researcher has shown it can be halted. Stem cells are the origins of all the things that bring us to life – our organs, bones, skin, hair and other features. They may also hold clues to ageing. Zhou Zhongjun, Associate Professor of Biochemistry, has shown that stem cell numbers decline rapidly in mice with progeria, an accelerated ageing disease, unlike normal mice. Moreover, he identified oxidative stress as the cause for this and used that knowledge to extend the life spans of the mutant mice by rescuing their stem cells. “We can’t say for sure that stem cells are the reason for ageing, but they definitely have an important role to play in the process because when you rescue stem cells, you can rescue or extend the life span of the animals,” he says. Mutant and normal mice have almost the same number of stem cells at birth but this quickly declines in the mutant mice after a few weeks. Dr Zhou and his team found that left untreated, half of the mutant mice they tested died within 20 weeks. However, those treated with anti-oxidants such as resveratrol – a constituent of red wine, among other things – lived to 28 or 29 weeks. In addition, the bone density of the treated mice was much greater so they had less osteoporosis, which is related to ageing. The best results occurred when the mice were treated at one to two months old, but improvements were also achieved in older mice. Unfortunately, that result does not yet extend to somatic cells – the cells that have differentiated from stem cells into organs, tissues and other body parts. It may also be difficult to test the results in humans. “Our results give an impression of the relationship between stem cell decline and ageing. So far there is little evidence to show a direct link because technically this is difficult to achieve unless you could physically eliminate stem cells after building up tissues,” Dr Zhou says. “One could imagine, though, that because stem cells are an important resource for replenishment of all these somatic cells in our tissues, that there is some correlation between stem cells and ageing. Whether it’s a consequence or cause of ageing is hard to say. “This area of study could have practical applications in future to improve the health standards of ageing populations and find ways for them to live longer and healthier. If we could improve osteoporosis under normal circumstances, it would mean people suffer few fractures. So the results from the animal experiments should hopefully apply to human situations in future.” Cover Story