Unravelling the MADness of cancer
Posted on: 03 October 2020
MAD2 is an intriguing protein, which has been associated with poor survival in cancer. Depending on the organ-specific cancer, either high expression or low expression levels of the protein have been correlated with low survival rates in patients. MAD2 is also a marker of contradiction.
The protein regulates chromosomal segregation during cell division. In this process, cells split in two and MAD2 makes sure that each new daughter cell receives the correct number of chromosomes. It forms part of a checkpoint complex that puts the brakes on cell division if there is any issue with the chromosome segregation machinery.
But in cancer MAD2 creates some contradictory MADness. Both low levels and high levels of this protein correlate with poor outcome in cancer patients, depending on the specific type of cancer.
Cancers with high levels of MAD2 often exhibit ‘aneuploidy’ or abnormal chromosome numbers which is almost counter-intuitive since the job of MAD2 is to prevent this happening in the first place. In this instance either mutations in some of the other checkpoint proteins or due to other abnormal processes as a result of cancer transformation, MAD2 is essentially unable to do its job despite its high levels and the cells divide even with the defects in the chromosome segregation machinery.
Cancer with low levels of MAD2 conversely undergo a process known as cellular senescence which means they essentially stop dead in their tracks and stop dividing. Similarly, this is counter intuitive as low levels of MAD2 would signal to a cell that it is safe to divide so why then have they stopped dividing?
The answer lies in the conventional trigger for cellular senescence which is telomere shortening on chromosomes. Normal healthy cells divide around 60 times and each time they do telomeres (the caps at the end of chromosomes which protect our DNA) are gradually eroded, eventually triggering senescence. In the cancer context, low levels of MAD2 signal to the cell that it is safe to divide even if the chromosome segregation machinery hasn’t properly separated chromosomes for cell division, resulting in a chromosomal mis-segregation event which mirrors normal telomere shortening thus triggering cellular senescence.
Dr Mark Bates, Research Fellow, Histopathology, Trinity College and his research group at the Trinity St James Cancer Institute have examined MAD2 in ovarian cancer; both in patient samples and cell models. In ovarian cancer patients’ low levels of MAD2 correlated with poor outcome in patients. In cell model’s suppression of MAD2 leads to senescence and resistance to paclitaxel one of two main drugs used to treat ovarian cancer patients.
Normally senescent cells would be cleared by our immune system but in cancer patients, immune cells are impaired preventing their clearance. Senescent cells although not dividing are still very metabolically active and produce a lot of growth factors, along with inflammatory mediators which would normally signal the immune system. However, in the case of the cancer impaired clearance, they are essentially sitting there promoting inflammation and as a result promoting the growth of the cancer.
Ovarian cancer is the 4th most common cause of cancer death in women worldwide and the most lethal gynaecological malignancy. Worldwide, 239,000 new cases of ovarian cancer are diagnosed annually with 152,000 deaths reported each year. Most patients present with advanced-stage disease, due to the difficulty in detecting the disease at the early stages, where prognosis rates are much improved. The 5-year survival rate for this disease is less than 40% and mortality rates have remained largely unchanged for the last number of decades. Furthermore, a major cause of the poor prognosis associated with the high rate of recurrent disease and chemoresistance. Despite initial response rates to standard paclitaxel/carboplatin-based chemotherapy, of over 80%, most patients will develop recurrent chemo-resistant disease and yet, no reliable method of treating recurrent chemo-resistant disease exists.
The research aims
The aim of this research at TSJCI is to develop new diagnostic and prognostic biomarker tests for ovarian cancer. A cancer biomarker refers to a substance or process that is indicative of the presence of cancer in the body
The development of new molecular diagnostics will pave the way forward for precision medicine-based approaches and tailor-made therapies for ovarian cancer patients. Dr Bates and his team hope that their work on paclitaxel resistance biomarkers will ultimately lead to more selective treatments for ovarian cancer patients and ultimately improved outcomes.
The group also works in the area of breast, cervical and prostate cancer.
Joining the global research efforts against cancer
The team’s work on ovarian cancer biomarkers has been part of a long-standing collaboration with University College Dublin (UCD) as well as other researchers in Queen’s University Belfast (QUB) and now also with researchers in Royal College of Surgeons in Ireland (RCSI), the university of Middlesex, and two universities in Australia; RMIT and UniSA. We are dedicated to global efforts to increase survival rates for ovarian cancer patients.
Dr Bates said:
Identifying the right patient for the right therapy is crucial to improve the incredibly poor survival rates for ovarian cancer patients which have remained unchanged for over three decades. It is therefore hugely important that we do something to improve the lives of patients with this devastating disease.
Research funding is vital for the development of new and improved molecular diagnostics and therapies for ovarian cancer and to fundamentally understand cancer and how we may one day eradicate it for good.
You can read the full research paper here:
Too MAD or not MAD enough: The duplicitous role of the spindle assembly checkpoint protein MAD2 in cancer. Cancer Lett. 2020 Jan 28;469:11–21. (Review) PMID: 31593803
https://www.sciencedirect.com/science/article/abs/pii/S0304383519304963
Trinity St James’s Cancer Institute (TSJCI)
The mission of Trinity St James’s Cancer Institute is to integrate innovative and ground-breaking cancer science with compassionate, multi-disciplinary , patient-focussed care through translation of key research findings into incremental advances in the prevention, diagnosis and treatment of cancer.