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new way to get breast cancer stem cells to become sensitive to treatment discovered
Cancer stem cell discovery
[Cardiff University]
A Cardiff team has identified a weakness in breast cancer stem cells which could help prevent the disease from spreading.
The team has found a laboratory method to switch off breast cancer stem cells' resistance to a particular drug. The breakthrough offers the long-term possibility of blocking the cells from creating new tumours in patients.
The finding also highlights Cardiff's strength in the increasingly important field of cancer stem cell research, having created the European Cancer Stem Cell Research Institute. This new discovery underlines just how critical cancer stem cells are in the spread and re-appearance of the disease.
Cancer stem cells make up only a small proportion of the cells in a tumour but many scientists now believe they are responsible for cancer growth, spread and relapse. They are also known to be highly drug-resistant. However, the Cardiff team, based at the School of Biosciences, has now managed to make breast cancer stem cells sensitive to the anti-cancer agent TRAIL.
TRAIL had not previously been seen as a breast cancer treatment, as it is blocked by a protein in the cells called c-FLIP. The Cardiff scientists have suppressed the effect of c-FLIP, making the cancer stem cells sensitive to TRAIL. With this method, the scientists achieved a 98 per cent reduction in secondary tumours. Importantly, they also showed that repeat treatment is equally effective in eliminating cancer stem cells if they re-appear. The Cardiff team's long-term goal is now to trial the method on breast cancer in the body.
The paper on the findings has just been published in the journal Breast Cancer Research, with PhD student Luke Piggott the lead author. Luke is also familiar to ice hockey fans and has just signed a new contract with the Cardiff Devils Elite League team.
Luke's supervisor, Dr Richard Clarkson of the School of Biosciences, said: "We believe we have found a crucial 'Achilles heel' in breast cancer stem cells. We can almost completely shut down their ability to spread the disease through the body through secondary tumours. Our success with repeat treatments is also important, offering hope that we can reduce relapse rates of the disease.
"These are very promising results but so far we have only seen this method work on cells in the laboratory. We need a lot more work to establish how best to suppress C-FLIP in patients and whether this can eliminate cancer stem cells in tumours in the breast."
Professor Alan Clarke, Director of the European Cancer Stem Cell Research Institute, added: "Luke's results highlight the key role played by cancer stem cells in the spread and relapse of breast cancer. His study is further evidence for the Institute's belief that it is vital to eliminate cancer stem cells if we are to be completely successful in treating all types of cancer."
Luke's PhD studentship is funded by the cancer charity Tenovus through a support programme for early career cancer researchers. Research Grants Officer, Dr Anita Howman said: "Tenovus funded research is continuing to further our knowledge of how cancers form and create new drugs for some of the hardest to treat cancers. We are delighted to support Luke's PhD studentship which has made an innovative discovery that will potentially benefit many people affected by breast cancer.
"One of Tenovus' proudest achievements is the early career research scientists we have helped to support and train through our PhD studentship funding programme which have benefitted close to 200 students. We now have nine active PhD studentships throughout Wales, with a further ten due to start in September. These projects not only aim to find new ways to detect and treat cancer, they also help to nurture the next generation of world class cancer researchers. "
The research was also funded by Breast Cancer Campaign. Dr Lisa Wilde, Director of Research at the charity said: "Over 12,000 people still die each year from breast cancer in the UK, mainly as a result of the disease spreading to other parts of the body. This research is an important early step in understanding the role cancer stem cells play in this process and could help us develop desperately needed new treatments to halt breast cancer spread in its tracks."
OPEN ACCESS: Suppression of apoptosis inhibitor c-FLIP selectively eliminates breast cancer stem cell activity in response to the anti-cancer agent, TRAIL
[Breast Cancer Research]
Introduction: It is postulated that breast cancer stem cells (bCSCs) mediate disease recurrence and drive formation of distant metastases - the principal cause of mortality in breast cancer patients. Therapeutic targeting of bCSCs however, is hampered by their heterogeneity and resistance to existing therapeutics. In order to identify strategies to selectively remove bCSCs from breast cancers, irrespective of their clinical subtype, we sought an apoptosis mechanism that would target bCSCs yet would not kill normal cells. Suppression of the apoptosis inhibitor cellular FLICE-Like Inhibitory Protein (c-FLIP) partially sensitizes breast cancer cells to the anti-cancer agent Tumour Necrosis Factor-Related Apoptosis Inducing Ligand (TRAIL). Here we demonstrate in breast cancer cell lines that bCSCs are exquisitely sensitive to the de-repression of this pro-apoptotic pathway, resulting in a dramatic reduction in experimental metastases and the loss of bCSC self-renewal.
Methods: Suppression c-FLIP was performed by siRNA (FLIPi) in four breast cancer cell lines and by conditional gene-knockout in murine mammary glands. Sensitivity of these cells to TRAIL was determined by complementary cell apoptosis assays, including a novel heterotypic cell assay, while tumour-initiating potential of cancer stem cell subpopulations was determined by mammosphere cultures, aldefluor assay and in vivo transplantation.
Results: Genetic suppression of c-FLIP resulted in the partial sensitization of TRAIL-resistant cancer lines to the pro-apoptotic effects of TRAIL, irrespective of their cellular phenotype, yet normal mammary epithelial cells remained refractory to killing. While 10%-30% of the cancer cell populations remained viable after TRAIL/FLIPi treatment, subsequent mammosphere and aldefluor assays demonstrated that this pro-apoptotic stimulus selectively targeted the functional bCSC pool, eliminating stem cell renewal. This culminated in an 80% reduction in primary tumours and a 98% reduction in metastases following transplantation. The recurrence of residual tumour initiating capacity was consistent with the observation that post-treated adherent cultures re-acquired bCSC-like properties in vitro. Importantly however this recurrent bCSC activity was attenuated following repeated TRAIL/FLIPi treatment.
Conclusions: We describe an apoptotic mechanism that selectively and repeatedly removes bCSC activity from breast cancer cell lines and suggest that a combined TRAIL/FLIPi therapy could prevent metastatic disease progression in a broad range of breast cancer subtypes.
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