Apoptosis and Colorectal Cancer

Colorectal cancer, like many other cancers, is characterized by the uncontrolled cell growth, mainly in the colon’s epithelial (inner) lining. Normally, cells naturally go through growth and death in order to maintain a steady number of cells within a tissue, known as tissue homeostasis. Cancer, therefore, happens when cells either grow uncontrollably, or do not die when they are supposed to.

A cell may die for many reasons, such as when exposed to chemical or physical stressors. These factors may cause a cell to die accidentally, and these accidental, passive deaths are referred to as necrosis. Necrosis is a known cause of inflammation, and as such plays a critical role in many diseases.

However, compared to cell necrosis, cells may also intentionally “die”, or undergo apoptosis.

Apoptosis can also be referred to as programmed cell death. Unlike necrosis, where a cell dies when they are unable to withstand different stressors, apoptosis is an intended cell death. One could liken apoptosis to a planned or scheduled removal of a cell.

Apoptosis may be induced by external or internal causes. Extrinsic apoptosis is triggered by external signals binding to death receptors on the cell surface. Intrinsic apoptosis, on the other hand, originates from within the cell due to internal signals, involving mitochondrial proteins and the Bcl-2 family. Both pathways converge at the activation of caspases, a family of proteases that cleave proteins in the cell to initiate programmed cell death.

When a cell’s DNA is damaged, the cell will normally attempt to repair the DNA through different repair systems according to the type of damage sustained. While the DNA is being repaired, the cell cycle — the series of events through which a cell grows and divides — is also arrested to prevent the defects and mutations in the DNA from being passed down to newly divided cells.

However, if the damage is too severe and the cell is unable to repair the DNA, the cell then undergoes apoptosis and dies, thereby preventing the mutated DNA from being inherited through cell division and proliferation.

The role of apoptosis in eliminating unwanted cells is crucial in preventing cancerous growth. Unfortunately, apoptosis is often dysregulated in many cancers, including colorectal cancer, and the evasion of apoptosis by cancer cells also has implications on treatment.

Many genetic mutations can result in cancerous growth in the colon, but not all of the mutations linked with colorectal cancer are specifically linked with apoptosis dysregulation. Typically, tumor suppressor genes can regulate the cell cycle by inhibiting its progression or by inducing apoptosis. Mutations in such genes would mean that the cell can continue growing and dividing, unhindered and unregulated.

Adenomatous polyposis coli (APC)

Mutations in the APC (adenomatous polyposis coli) gene is famously linked with the hereditary, genetic condition familial adenomatous polyposis (FAP) that carries a 100% lifetime risk of developing colorectal cancer if left untreated. APC is a tumor suppressor and also plays an important role in the alignment of chromosomes during metaphase (a stage during cell division) and regulating programmed cell death.

In the absence of functioning APC, apoptosis is prevented, and results in the uncontrolled growth of cells. This uncontrolled growth is responsible for the formation of hundreds to thousands of polyps and adenomas in the colon — the key characteristic of FAP.

p53

Another tumor suppressor gene that is commonly mutated in colorectal cancer — so common that 70% of colorectal cancer cases are found with this mutation — is p53. Unlike APC, the mutations in p53 are often acquired rather than inherited.

When activated, p53 proteins are able to promote cell cycle arrest to allow DNA repair. p53 also has a direct influence on the apoptotic process; it binds to specific DNA sequences and regulates the expression of pro-apoptotic genes — genes that lead to cell death when activated. Mutations in the p53 gene results in the loss of function and allows cell division to proceed unchecked.

The dysregulation of apoptosis in cancer tissue not only means that cell growth proceeds uncontrolled, but also impacts the effectiveness of certain cancer treatments, particularly those that are hinged on activating the apoptotic pathway to kill cancer cells.

Radiation therapy and chemotherapy are two such treatment methods. Radiation therapy involves exposing cancer cells to doses of radiation, which causes damage to the cell’s DNA. Similarly, many chemotherapy drugs have cytotoxic effects that damage the cell’s DNA. In doing so, both radiation therapy and chemotherapy rely on the induction of programmed cell death to kill the cancer cells.

However, in instances where the genes related to the activation of apoptosis, such as p53, are mutated, the cells are not programmed for elimination. In fact, mutated p53 genes have also been found to confer cancer cells with an additional survival advantage by promoting oncogenesis and chemoresistance. This makes p53 a possible drug target, as restoring p53 function means that the cells can become re-sensitized to chemotherapy and enable more effective treatment. While there are several such drugs currently undergoing clinical trials, at the moment, none of them are applicable to colorectal cancer.

Apoptosis stands as a fundamental process that, when inactivated, leads to uncontrolled growth of abnormal cells and cancer development. While apoptosis has been well researched in the last two decades, more research is yet required to pave the way for innovative treatments that restore the delicate balance between cell survival and programmed cell death.