Cancer: When Cells Resist Programmed Cell Death and Promote Tumor Growth
Programmed cell death, or apoptosis, is a key process for proper cell function. Paradoxically, it is when this process goes awry—when certain cells exhibit “immortality”—that cancers can develop and become life-threatening.
Abdel Aouacheria (University of Montpellier) examines these tumor processes in a chapter of *Death, Architect of Life*, published by Belin. He also discusses the therapeutic strategies currently being used to prevent these cells from becoming “immortal.”
Abdel Aouacheria, University of Montpellier
While programmed cell death is essential to the proper functioning of living organisms, it can also become their enemy. Too little cell death, and cells accumulate uncontrollably: this is cancer. Too much cell death, and tissues atrophy, as in degenerative diseases.
Abnormal cell death can disrupt embryonic development, weaken the immune system, impair fertility, or harm cognitive functions. Cells no longer die to make way for new ones; instead, they die off en masse or, conversely, persist unabashedly when they should disappear, thereby compromising the essential functions of tissues and organs.
The same process, which in a physiological context aims to promote integration and harmony, can, in a different context, take on an entirely different, deadly form and lead to serious pathologies, or even cause the death of the entire organism.
Cancer: When Cell Death Malfunctions
According to data from Inserm’s CépiDe (Center for Epidemiology on Medical Causes of Death), cancer is the leading cause of death in France, accounting for about one-quarter of all deaths in 2023.
Among the deadliest are lung, colorectal, prostate, and pancreatic cancers.
But what exactly is the role of cell death in this biological catastrophe? What are the links between cancer and cell death?
Carcinogenesis is a progressive, multifactorial cellular process characterized by a series of stages. First comes initiation, in which an irreversible genetic mutation alters a key gene (an oncogene or a tumor suppressor gene), often as a result of a mutagenic agent, such as certain chemicals or radiation.
Next comes the promotion phase, during which the mutated cells proliferate excessively under the influence of environmental or hormonal signals, promoting the accumulation of aberrant clones.
Finally, progression refers to the accumulation of additional abnormalities that endow the transformed cells with new capabilities, such as invading tissues, evading the immune system, and colonizing other organs after forming metastases.
Cells that are unable to die when they should
In a remarkable review published in 2000 and updated ten years later, two California-based physicians, Douglas Hanahan and Robert Weinberg, formalized the fundamental characteristics of cancer cells. Among the “hallmarks of cancer,” it comes as no surprise that resistance to programmed cell death is included.
The conclusion reached by these authors is unequivocal:
“The ability of tumor cell populations to multiply is determined not only by the rate of cell proliferation but also by the rate of cell attrition. Programmed cell death—apoptosis—is a major source of this attrition. Evidence is accumulating—primarily from studies using mouse models and cultured cells, as well as from descriptive analyses of biopsies taken at various stages of human carcinogenesis—that acquired resistance to apoptosis is a characteristic of most, if not all, types of cancer.”
At the cellular level, resistance to cell death favors the survival of cells with major genetic alterations, thereby promoting genomic instability, which is a key driver of carcinogenesis. This failure to eliminate such cells fuels a spiral of mutations, promotes the selection of increasingly aggressive clones, and boosts the tumor’s invasive potential. Cancer is therefore characterized not only by the uncontrolled proliferation of cells, but also by their inability to die when they should.
The tumor resists death signals and shapes its environment
Resistance to apoptosis is also closely linked to cellular plasticity. Many cancer cells undergo a transformation (epithelial-mesenchymal transition, or EMT) that makes them more mobile and invasive, but also less sensitive to death signals. In particular, these cells develop a tolerance to oxidative stress, which allows them to survive in hostile tissue environments.
At the same time, the tumor shapes its microenvironment. It stimulates angiogenesis—that is, the formation of new blood vessels—to ensure a constant supply of oxygen and nutrients. It also secretes inflammatory cytokines that help create an environment conducive to its own growth. Resistance to cell death is part of a complex process involving cellular, metabolic, and immunological adaptations.
Metastasis is also promoted by the cessation of cell death
This inhibition of apoptosis (the cell death that shapes our tissues, ed.) also plays a central role in metastatic spread. To leave their site of origin and colonize other organs, tumor cells must withstand the mechanical forces of the tissues they pass through, as well as evade the immune system’s defenses. They achieve this in part by hijacking the action of cytotoxic T cells—the immune system cells responsible for tracking down and destroying abnormal cells.
To do this, tumors overexpress inhibitory molecules such as PD-L1 (programmed death ligand 1), which binds to the PD-1 (programmed death-1) receptor on the surface of T cells, deactivating them and thereby short-circuiting the immune response.
Treating Cancers by Reactivating Apoptosis
This evasion mechanism has paved the way for innovative therapies that use immune checkpoint inhibitors (such as anti-PD-1 antibodies), which restore the ability of lymphocytes to recognize and destroy tumor cells. These treatments have revolutionized the prognosis for certain cancers that were previously highly resistant, by restoring the immune system’s ability to do its job.
Generally speaking, most cancer treatments aim to reactivate cell death pathways in tumors, whether through chemotherapy, radiation therapy, or targeted therapies. But here again, the plasticity of cancer cells complicates the task. When the mechanisms of self-destruction are severely impaired, treatments become ineffective.
Survival pathways such as PIK/AKT (a signaling pathway that plays a role in cell growth, proliferation, and survival—Ed.) or NF-κB (a family of proteins involved in the immune response—Ed.), which are often hyperactivated in cancers, allow tumor cells to evade the cytotoxic effects of therapies. This example illustrates how tumor cells actively manipulate cell death pathways to ensure their own survival.
Cancer Cells: "Quasi-Immortal" Entities
Cancer not only evades lethal signals but also subverts survival pathways, as resistance to cell death confers a selective advantage on tumor cells. This resistance makes cancer cells “quasi-immortal,” capable of multiplying unchecked by evading normal control mechanisms, reshaping their environment, and surviving far from their original site.
It is this ability to persist against all odds that makes cancer not only a disease of uncontrolled cell proliferation, but also a disease of cellular “immortality” that, paradoxically, can ultimately lead to the death of the organism. Ultimately, every cancer is destined to saw off the branch on which it sits…
Abdel Aouacheria, biologist, research fellow at the CNRS, specialist in cell life and death, University of Montpellier
This article is republished from The Conversation under a Creative Commons license. Readthe original article.