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Apoptosis is a programmed death for the cell in other words it is a cell suicide therefore, it is totally different from necrosis where the cell dies as a result of injury. In the apoptosis process, the cell’s components are packed by immune cells.
Apoptosis is very important because it maintains the balance of the body by eliminating cells during development and removing the possibly cancerous cells and cells infected by viruses. In a lot of cases, it’s a bad thing for cells to die such as dying from injury. However, it’s beneficial to us that some cells of our bodies die, of course in a controlled way.
Cancer can be seen as the consequence of a progression of genetic changes during which a typical cell is changed into a malignant cell while the absence of apoptosis is one of the fundamental changes that cause this malignant transformation. In the early 1970s, Kerr et al illustrated the connection between apoptosis and the removal of potentially malignant cells, tumor succession, and hyperplasia. Hence, the elimination of apoptosis has an important role in carcinogenesis. There are numerous ways a malignant cell can decrease apoptosis. In general, the mechanisms that eliminate apoptosis can be divided into:
Mechanisms that contribute to apoptosis evasion and carcinogenesis.
The ligands of the death receptors and the death receptors themselves are central participants in the apoptosis pathway. The death receptors have a death domain and there is a death signal that triggers it, then several molecules get attracted to the death domain which activates the signaling cascade. Many abnormalities in the death signaling process that can lead to the elimination of apoptosis have been identified. These abnormalities may occur to the receptors or to death signals. For example, a reduced expression of CD95 was proved to have an essential role in the resistant treatment of leukemia.
A change in some of the components of the apoptotic pathway may have an essential role in the creation of resistance to chemotherapy in several types of tumors. interference in the stability of anti-apoptotic and pro-apoptotic members of the Bcl-2 family affects in the apoptosis in the affected cells. This may be because of overexpression of anti-apoptotic proteins or reduction of pro-apoptotic proteins or a combination of both. Anti-apoptotic Bcl-2 over-expression was found in multiple human cancers, such as prostate cancer, melanoma, DLBCL, etc. Colorectal cancer has also been linked to Bcl-xL overexpression. Overexpression causes tumor cells to participate in the resistance of drugs and prevents them from having apoptosis. Antiapoptotic proteins Bcl-2 and Bcl-xL expression levels have been connected to cisplatin resistance and tumor recurrence in several types of cancer, including lung cancer (NSCLC), head and neck, breast, and ovarian.
Caspases are good candidates for putative tumor suppressors because they are needed for apoptosis. CASP8 has been reported to be silenced due to gene deletion or promoter methylation in several studies, especially in pediatric tumors. The expansion of the MYCN oncogene and high levels of the corresponding protein is often associated with the loss of caspase-8 expression. However, it is unclear if these two genetic changes functionally lead to tumor development. In the clinic, methylation-independent caspase-8 expression reduction has also been discovered. CASP8 mutations have also been found in several types of cancers like colorectal cancer and gastric cancer but in lower frequencies. In primary breast tumor samples taken from patients having breast surgery, researchers discovered that about 75% of the tumors and morphologically normal peritumoral tissue samples have no caspase-3 transcripts and protein expression. Two studies, on the other hand, show that caspase-3 is upregulated in clinical breast tumor samples.
Gaining control of or probably terminating the uncontrolled growth of cancer cells is one way to treat cancer. Using the cell’s own death mechanism is a very successful technique. Apoptosis-targeting is perhaps the most effective non-surgical procedure. Apoptosis avoidance is a characteristic of cancer and is nonspecific to the cause, so targeting it is appropriate for all forms of cancer.
Two of the common strategies for therapy are activating proapoptotic molecules and inhibiting antiapoptotic molecules. Patients with leukemia or lymphoma have the strongest connections between apoptosis and treatment sensitivity in human cancer. P53 mutations are linked to brief remissions and drug resistance after treatment in these cancers. Bcl-2 has been linked to drug resistance in patients in a few studies, and high Bcl-2 levels could be a strong prognostic predictor for breast cancer. Finally, in clonogenic assays, loss of Bcl- 2 and p53 slows therapy-induced apoptosis in some cases but does not improve long-term survival.
The studies described above show that apoptosis disruption promotes tumor initiation, progression, and treatment resistance. It’s remarkable that the same genetic changes that affect apoptosis during tumorigenesis also affect treatment sensitivity. For example, c-Myc promotes apoptosis in the presence of low levels of survival factors or oxygen, as well as after exposure to a variety of cytotoxic agents, on the other hand, loss of p53 and overexpression of Bcl-2 inhibit apoptosis caused by oncogenes, survival factor depletion, hypoxia, and cytotoxic drugs. As a result, anti-apoptotic mutations that arise during tumor progression will select for chemo-resistant cells at the same time.
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