Scientists at Trinity College Dublin have made an important breakthrough in understanding how cancer cells can evade the cell-killing effects of chemotherapy and enter a “zombie-like state”, called premature senescence, that can attract the wound healing properties of the immune system.
Although our immune system protects us from infection it also plays a critical role in coordinating repair and replacement of damaged tissue, which is a process called wound healing. The wound healing capabilities of the immune system stimulates cell division within damaged tissue to replace cells that have been lost through injury and brings extra nutrients and oxygen into the injured tissue by triggering the growth of new blood vessels. This is a complex and highly coordinated process, which ensures that new cells are only produced where and when they are needed.
However, cancers can exploit these wound healing capabilities for their own ends by masquerading as damaged tissue and tricking the immune system into helping malignant cells to divide and acquire extra oxygen and nutrients rather than killing them. For these reasons, cancers have been described as “wounds that do not heal”, but how they switch on the wound healing capabilities of the immune system is still poorly understood.
But here, in a just-published piece of research in leading international journal Science Advances , scientists from the Smurfit Institute of Genetics at Trinity College Dublin have found that molecules called Inhibitor of Apoptosis Proteins (IAPs) can enable tumours to escape the cell killing effects of commonly used chemotherapeutic drugs.
The Trinity team, led by Prof. Seamus Martin, Smurfit Professor of Medical Genetics, and Dr Gokhan Gunay, Post-doctoral Research Fellow, found that IAPs functioned in this setting by neutralising the cell-killing effects of molecules called ‘Death Receptors’ that were switched on in response to DNA damage provoked by chemotherapy.
Furthermore, rather than simply allowing tumours to escape the cell-killing effects of chemotherapeutic drugs, IAPs enabled surviving tumour cells to enter a highly unusual zombie-like state called “premature senescence” that converts cells into coordinators of wound healing that can orchestrate a beneficial immune response and help tumours bounce back from chemotherapy.
Senescent cells are non-dividing zombie-like cells that undergo dramatic changes within a few days of exposure to chemotherapy, including becoming almost ten times bigger than a normal cell and ramping up genes associated with wound healing. These changes endow them with a greatly increased ability to secrete inflammatory mediators, which attracts cells of the immune system. The accumulation of senescent cells in tissues as we age is also thought to contribute to the inflammatory processes associated with aging, as well as a decline in the normal function of many tissues.
The Trinity scientists also found that senescent cells formed in response to chemotherapy are highly dependent on IAPs for their continued survival. Accordingly, compounds which neutralised IAPs (called IAP antagonists) selectively eliminated senescent cells by reactivating the Death Receptor self-destruct programme within these cells.
What is the potential impact of this research?
Tumours that evade chemotherapy remain a major challenge for clinicians attempting to treat patients living with cancer. Improved treatment options that neutralise more of these tumours promise to improve quality of life and survival rates, but to deliver these scientists need to understand how tumours function and where their weaknesses may lie. This research isolates a new mechanism that explains how some tumours evade death and use the body’s immune system to aid their recovery, as well as pinpointing promising new drug treatments (IAP antagonists) that killed them.
Commenting on the findings, Professor Martin said: “Discovering how tumours can evade the cell-killing effects of chemotherapy and enter senescence is an important and challenging problem.
“These new findings suggest ways in which we may be able to lower the defenses of tumours by neutralising IAPs after the delivery of chemotherapeutic drugs, which should block their entry to senescence and kill more cells of the tumour.”
Science Advances