Accumulation of lingering senescent cells is one of the causes of aging; these cells secrete a potent mix of molecules that produce inflammation, disrupt tissue structure and function, and alter the behavior of other cells for the worse. This signaling is useful during wound healing, where senescent cells are created and then destroyed once they have served their purpose, but like most such processes it becomes quite harmful when sustained over the long term. Researchers are presently hotly engaged in developing senolytic therapeutics to destroy senescent cells, and thereby achieve a narrow form of rejuvenation.
Prior to the present focus on senescent cells in aging, most work on cellular senescence was carried out in the context of cancer research. Senescent cells have quite the interesting relationship with cancer. While the state of senescence is an anti-cancer mechanism, shutting down replication in cells that are damaged and may become cancerous, the presence of too many senescent cells makes the tissue environment more hospitable to cancer, more amenable to cancer growth and survival. Along with the age-related decline of the immune system, this is one of the reasons why cancer is an age-related condition.
The work here demonstrates an addition complexity to the relationship between cancer and senescence. Since senescence is contagious to some degree, meaning that a senescent cell can drive nearby cells into senescence as well, why not a cancer that co-opts that mechanism in order to make the local environment more conducive to its growth? That is what researchers observe here in the case of acute myeloid leukemia (AML). This suggests that, for at least some cancers, senolytic treatments capable of destroying senescent cells might be a useful a way to weaken the cancer, make it more vulnerable to other therapies. Existing standard treatments such as chemotherapy and radiotherapy will create numerous further senescent cells, either forcing cancer cells into senescence, or damaging bystander cells that become senescent as a consequence. Senolytics will be useful after the fact as well, cleaning tissues of therapy-induced senescence to prevent the long-term harm to the patient that results from cancer treatments.
New findings show that healthy bone marrow cells were prematurely aged by cancer cells around them. It is well known that ageing promotes cancer development. But this is the first time that the reverse has been shown to be true. Importantly, the aged bone marrow cells accelerated the growth and development of the leukaemia - creating a vicious cycle that fuels the disease. The study also identified the mechanism by which this process of premature ageing occurs in the bone marrow of leukaemia patients and highlights the potential impact this could have on future treatments.
NOX2, an enzyme usually involved in the body's response to infection, was shown to be present in acute myeloid leukemia (AML) cells - and this was found to be responsible for creating the ageing conditions. The research team established that the NOX2 enzyme generates superoxide which drives the ageing process. By inhibiting NOX2, researchers showed the reduction in aged neighbouring non-malignant cells resulted in slower cancer growth.
Acute myeloid leukemia (AML) is an age-related disease that is highly dependent on the bone marrow microenvironment. With increasing age, tissues accumulate senescent cells, characterized by an irreversible arrest of cell proliferation and the secretion of a set of pro-inflammatory cytokines, chemokines, and growth factors, collectively known as the senescence-associated secretory phenotype (SASP). Here, we report that AML blasts induce a senescent phenotype in the stromal cells within the bone marrow microenvironment. We report that the bone marrow stromal cell senescence is driven by p16INK4a expression. The p16INK4a-expressing senescent stromal cells then feedback to promote AML blast survival and proliferation via the SASP.
Importantly, selective elimination of p16INK4a-positive senescent bone marrow stromal cells in vivo improved the survival of mice with leukemia. Next, we find that the leukemia-driven senescent tumor microenvironment is caused by AML induced NOX2-derived superoxide. Finally, using the p16-3MR mouse model we show that by targeting NOX2 we reduced bone marrow stromal cell senescence and consequently reduced AML proliferation. Together, these data identify leukemia generated NOX2 derived superoxide as a driver of pro-tumoral p16INK4a-dependent senescence in bone marrow stromal cells. Our findings reveal the importance of a senescent microenvironment for the pathophysiology of leukemia. These data now open the door to investigate drugs which specifically target the 'benign' senescent cells that surround and support AML.