Cell Death Pathways in Cancer
It is well known that cancer is a disease which proliferates indefinitely. So, there must be some way through which these notorious cells get an advantage to escape the tightly regulated signalling pathways of cell death and proliferation and also the stringent surveillance of the immune system.
Below are a few cell death pathways when dysregulated contribute towards cancer progression.
Cell Death Pathways
- Apoptosis
Apoptosis is a tightly controlled process of programmed cell death which is activated upon intrinsic signals such as DNA damage, stress, developmental cues or withdrawal of survival factors or extrinsic signals such as detection of extracellular death ligands from other cells. This process is controlled by the careful balance between the Bcl-2 family’s pro and anti-apoptotic factors.
Apoptosis is triggered when pro-apoptotic members such as BID, BAD, and BIM are activated in response to stress or damage cues, on the other hand, anti-apoptotic members such as Bcl-2, Bcl-xl, Mcl-1 bind and suppress pro-apoptotic proteins to suppress apoptosis.
Activation of pro-apoptotic proteins alters the permeability of the mitochondrial membrane (MOMP) causing the release of cytochrome c which forms a complex with an apoptosome called as apaf-1 that activates caspase 9 and triggers the apoptotic event. There is no cell rupture in apoptosis. In apoptosis, caspases are important mediators of the pathway divided into initiator and executioner caspases. The initiator or upstream caspases such as caspase 2, 8, 9, 10, and 12 are coupled to upstream pro-apoptotic signals and act by cleaving and activating the downstream/ executioner caspases such as caspase 3, 6, and 7 which alter the proteins responsible for the disassembly of the cell. In apoptosis, phagocytes rapidly recognize and engulf the dying cells preventing the intracellular components to be released and also maintaining the membrane integrity thus avoiding exposure to immunogenic substances and subsequent inflammatory responses.
This process is active under physiological conditions, but cancer cells find a way to dysregulate the signalling pathway causing a dominance of anti-apoptotic factors which prevent the cell death of tumour cells.
2. Necrosis
Necrosis has been classified as unprogrammed cell death which is not really intended but occurs in response to physical or chemical insults such as extreme physical temperature, pressure, chemical stress or osmotic shock. It is always pathological accompanied by cell rupture and inflammation which is a characteristic feature of necrosis. Upon an encounter with the pathogen, the cell is enlarged causing a loss of membrane integrity followed by leakage of cellular contents in the extracellular space called damage-associated molecular patterns (DAMPs) which ultimately activate the immune system and trigger an immune response causing nuclear degeneration.
There are different types of necrosis described below.
A. Necroptosis
It is a process of cell self-destruction activated in response to extracellular signals such as extracellular death receptor-ligand binding or intracellular cues such as microbial nucleic acids. Necroptosis is highly immunogenic and activated mainly in response to pathogens, neurodegeneration, cancer or inflammatory diseases serving as useful to the host defence mechanism.
This entire process is independent of caspases and is activated upon TNF binding on the extracellular space causing conversion of RIPK1 to RIPK3 which phosphorylates MLKL (this is described as necroptosome activation), p53 and cyclophilin D together alter the permeability of the mitochondrial membrane and cathepsin Q causes ROS production causing DNA damage. All these pathways ultimately cause necroptosis leading to cell death. Necroptosis-deficient cancer cells are poorly immunogenic and hence escape natural and therapy-elicited immunosurveillance.
B. Ferroptosis
Ferroptosis is a recently described form of programmed cell death with distinct morphological and biochemical characteristics. It is an iron-dependent cell death pathway involving lipid peroxidation. Iron homeostasis is controlled by a large protein complex called ferratin responsible for the transport of iron in its non-toxic form. Ferrtinophagy a selective autophagy process targeting ferratin regulates the level of ferratin in the body by the selective cargo-mediated receptor for ferratin called nuclear receptor coactivator 4 (NCOA4). A small lipophilic molecule such as ferrostatin-1 or liproxstatin-1 can inhibit ferroptosis. A central regulator of this is the glutathione peroxidase pathway which converts GSH to oxidized glutathione GSSG, thus protecting cells against ferroptosis and limiting cytosolic lipid peroxidation. GPX4 gene is controlled by the transcription factor Nrf2. Recent studies reported that the regulation of ferroptosis by p53 contributes to the tumour suppressive function of p53 and moreover, mutant p53 accumulation in the cancer cells sensitizes these cells for ferroptosis.
C. Pyroptosis
It is a type of cell death which is activated in response to intracellular infections from bacteria, viruses, fungi or protozoa in response to pathogen-associated molecular patterns (PAMPs) or cell-derived DAMPs. This is typically induced in the cells of the innate immune system such as monocytes, macrophages and dendritic cells.
Pyroptosis is characterized by the N-terminal cleavage of gasdermin D (GSDMD) resulting in oligomerization to form a lytic pore which is facilitated by inflammatory caspases such as 1, 4, 5, 11. The first pathway is the activation of the nuclear factor kappa beta which induces the expression of several proteins that become part of the inflammasome complex consisting of NLRP3 and PPR. The second pathway is the activation of procaspase 1 forming an inflammasome complex activating the GDSMD causing cleavage and the formation of the pore, also active caspase 1 activates cytokines IL-1 beta or IL-18. All these subsequently activated pathways lead to membrane pore formation, an influx of water and ultimately cell rupture causing cell death.
D. Efferocytosis
Efferocytosis is a physiologic phagocytic clearance of apoptotic cells, which modulates inflammatory responses and the immune environment and subsequently facilitates the immune escape of cancer cells, thus promoting tumour development and progression. Efferocytosis is an equilibrium formed between the “find me”, “eat me” and “don’t eat me” signals. This includes complex and coordinated molecular signalling.
1. Find me: The first step in efferocytosis is the recognition of the targeted apoptotic cell through find me signals which can be lipids, proteins, peptides and complex structures from dying cells. These signals act as chemo-attractants which aid in the recruitment of the scavenger cells near the apoptotic site in the initial stages of efferocytosis.
2. Eat me: This step is focused on the engulfment of the apoptotic cells by the arrived phagocytes by detecting the signals such as phosphatidylserine (PS) or calreticulin. These signals are unique surface markers on apoptotic cells which have exposed PS, which help the phagocytic cells to identify such cells and their subsequent engulfment.
3. Don’t eat me: On the contrary, phagocytes are capable of identifying live and normal-healthy cells by don’t eat me signals such as CD47 and CD31.
Subsequently, efferocytosis facilitate cancer proliferation and progression. Find-me signals are not tumour specific and are not a regimen of antitumor therapy hence, studies have been focused on targeting and taking advantage of eat-me and don’t eat-me signals. Efferocytic signalling influences cancer development and progression by affecting their proliferation, invasion, and angiogenesis. Thus, targeting this pathway represent the potential therapeutic target for cancer treatment.
Schematic representation of signalling pathways in the efferocytosis-induced immune suppression for tumour progression.
E. Netosis
It is a unique form of cell death characterized by membrane rupture and extrusion of intracellular components such as histones, chromatin, granular and cytoplasmic components into web-like structure called neutrophil extracellular traps (NETs). There is still study going on the pathological significance and therapeutic potential of Netosis but it has been associated with the host defence against pathogens and diseases such as autoimmune and CVS diseases, thrombosis, and tumour progression.
These are some of the important cell death pathways which are naturally designed by the body to eliminate any dying or damaged cell in response to a range of stimuli. Tumor cells by different means dysregulate the tightly controlled mechanism of the body which favor their growth, survival, proliferation, invasion and metastasis.
