How does cancer resist cell death?
How does cancer resist cell death?
There are three principal mechanisms through which cell death occurs in healthy tissues.
Apoptosis is programmed cell death and is frequently found to occur at markedly reduced rates in tumours,
particularly those of high malignant grade or those resistant to treatment. The cellular apoptotic system is composed of upstream regulatory elements, which sense intrinsic and extrinsic proapoptotic signals, and downstream effector components, which are responsible for the execution of apoptosis.
In response to signalling from
regulatory elements, effectors initiate a cascade of proteolysis and cell disassembly, resulting in a sequence of programmed cell death. This produces nuclear fragmentation, chromosomal condensation, shrinking of the cell with loss of intercellular contact followed by blebbing of the cell membrane, cellular fragmentation
and the formation of apoptotic bodies that are subsequently phagocytosed by neighbouring cells.
Apoptosis can result from multiple stimuli or indeed from the removal of survival factors such as IL-3 or IGF-1.
Lack of survival factors is particularly important during development as this prevents cells migrating
to wrong areas or structures. Direct signals to produce cell death can result from interaction between cytokines and cell surface receptors. Furthermore, if there is an imbalance between factors required for normal proliferation, such as when cyclin E is activated without cyclin D, it can result in apoptosis. This may appear confusing, as the
same genes that are used for normal cell proliferation can also trigger apoptosis if they are inactivated inappropriately.
However, the most important regulator of apoptosis is the TP53 tumour suppressor gene. TP53 is often described as the ‘guardian of the genome’ because it is able to induce apoptosis in response to sufficient
levels of genomic damage. The largest initiator of apoptosis via TP53 is cellular injury, particularly due to DNA damage resulting from chemotherapy, oxidative damage and UV radiation. When TP53 tumour suppressor function is lost in cancerous cells, a central control element of apoptosis is disabled.
Cancer cells will most
commonly demonstrate loss of TP53 tumour suppressor function. Other triggers include increased expression of antiapoptotic regulators (Bcl-2, Bcl-xL) or survival signals, downregulation of proapoptotic factors (Bax, Bim, Puma) and short-circuiting of the extrinsic ligand-induced death pathway.
Autophagy is a
catabolic process during which cellular constituents are degraded by lysosomal machinery within the cell. It is an important physiological mechanism, which usually occurs at low levels in cells but can be induced in response to environmental stresses, particularly in circumstances of nutrient deficiency. The cellular metabolites produced are
recycled and used for biosynthetic and metabolic purposes by the cell, a mechanism that is particularly useful in the nutrient-poor environments encountered by expanding cancer cell populations.
Paradoxically, in addition to nutrient starvation, radiotherapy and cytotoxic chemotherapy induce
elevated levels of autophagy that are cytoprotective for malignant cells, thus impeding rather than perpetuating the killing actions of these stress situations. Severely stressed cancer cells have been shown to shrink via autophagy to a state of reversible dormancy. This survival response may enable the persistence and eventual
regrowth of some late- stage tumours following treatment with potent anticancer agents.
Necrosis is premature death of cells and is characterised by the release of cellular contents into the local tissue microenvironment. This stands in marked contrast to apoptosis, where cells are disassembled in a step- by-step fashion and the
fragments are phagocytosed. Necrotic cell death results in the recruitment of inflammatory immune cells to the site of tissue damage.
There is strong evidence to suggest that these cells have tumour- promoting properties in the context of carcinogenesis, as they have been shown to
promote angiogenesis, cellular proliferation and tissue invasion in experimental conditions. In addition, necrotic cells release stimulatory factors, which promote proliferation of neighbouring cells and potentially contribute to cancer development. As a consequence, necrotic cell death within cancer cell populations may promote rather than