Prevent cancer from hibernating
Cancer cells have shown the ability to go into "sleep mode"
Maria Azarova, Naked Science
Acute myeloid leukemia (AML), a malignant tumor of the myeloid blood germ, is considered the deadliest of all blood cancers, killing three out of four patients within five years. Although about 70-80% of patients with AML younger than 60 years achieve complete remission, many relapse occurs mostly in a "secretive way".
One of the popular ideas today is that, since not all tumor cells are the same at the genetic level (that is, it is heterogeneous), some of them may resist treatment, causing repeated growth. Another assumption is that relapse in leukemia occurs due to a drug-resistant immature subpopulation of stem cells that can reform the tumor. Thus, according to observations, it is in AML cells with an immature immunophenotype (CD34+, CD38-) that cancer is able to survive, despite chemotherapy – the use of toxic drugs that inhibit the reproduction of cancer cells or irreversibly damage them. However, other recent studies have shown that other factors are also responsible for relapse and immunity to chemotherapy.
Scientists from the University of Virginia, Wile Cornell Medical College, Fox Chase Cancer Center, Harvard Medical School (USA), the University of Pennsylvania and the Center for Cancer Biology at the University of South Australia tried to find out why AML returns after treatment. Their findings can be found in a publication for the journal Cancer Discovery (Duy et al., Chemotherapy induces senescence-like resilient cells capable of initiating AML recurrence).
"Acute myeloid leukemia can go into remission with chemotherapy, but it almost always returns. When this happens, the disease is incurable," said Dr. Ari M. Melnik, Professor of hematology and medical oncology. – A long-standing question in this area was: "Why can't we get rid of all cancer cells?" A similar question can be asked in the context of other types of aggressive cancer besides AML."
The study was carried out both on organoids and on laboratory mice that were injected with cancer cells. The results were also confirmed on samples taken from patients with acute myeloid leukemia during the course of treatment and during relapse. As scientists found out, when leukemia cells were subjected to chemotherapy, some of them passed into a state of aging with signs of "active hibernation": they looked damaged, in need of accelerated wound healing, turned off most of their functions and attracted immune cells to repair.
Genotoxic stress caused by chemotherapy, in addition to apoptosis, provokes aging – a cellular stress reaction characterized by aberrant metabolic activity in the absence of proliferation. The transition to "sleep mode" allowed the tumor cells to survive this: due to the phenotype of resistance to aging. According to scientists, the effect of aging was temporary and gave an excellent chance for the formation of colonies, and after recovery, AML cells caused a relapse with an increased potential of stem cells.
"This can often be observed in developing embryos that temporarily stop their growth due to lack of nutrition. This condition is also called embryonic diapause," Melnik added. "This is not a special process, but a normal biological activity that manifests itself in the context of tumors."
The authors of the study also found that the state of aging and diapause in tumor cells is caused by the ATR protein (serine/threonine protein kinase ATR, known as ataxia-telangiectasia and Rad3-related protein (ATR) or FRAP-related protein 1 (FRP1)). That is, it is logical to block ATR so that cancer cells do not fall into hibernation. After conducting experiments in the laboratory, scientists have confirmed that the introduction of an inhibitor of this protein – VE821 – 24 hours before chemotherapy helps to avoid starting sleep mode and aging, thereby allowing to kill all tumor cells.
Now scientists are working with manufacturers of ATR inhibitors. Of course, questions about when and how such treatment should be prescribed have yet to be answered. However, other parallel studies have already shown that the state of aging and "hibernation" is important not only in the context of acute leukemia, but also for patients with recurrent breast, prostate or stomach cancer.
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