The Role of Apoptosis in Normal Cells
One must not forget the many functions apoptosis has beyond the context of cancer. In general, apoptosis serves as a clean way to remove dying cells while circumventing damaging inflammatory responses, but it also plays very specific and important roles during development and throughout life (1). Apoptosis helps correct for genetic errors, compensating for mispatterning and overgrowth, since misplaced cells don’t receive their microenvironment’s specific trophic factors required for survival (1, 2). It plays major roles in neural synaptogenesis, immune system development and regulation, removing unregulated cancer-like or compromised cells, and keeping a homeostatic balance to cell numbers (1, 2, 3).
Compromised cells can take many forms in the human body, but one thing they have in common is that they are apoptotic targets. Researchers often suggest that apoptotic and proliferative pathways are tightly coupled, and strong associations between increased proliferation and high levels of apoptosis are frequently seen (8). Precancerous cells losing regulation of their proliferative pathways are typically sensitized to apoptosis by three independent mechanisms (1). First, when a cell leaves its specific trophic environment, oncogenes like Myc, or transcription factors that promote cell cycle progression past G1, induce cytochrome c release from the mitochondria. This subsequently activates the intrinsic pathway of apoptosis (1). Second, growth promoting oncogenes encourage the expression of p53, sensitizing the cell to apoptosis after DNA damage or cell stress (1). Lastly, oncogenes often result in the down regulation of Cadherins, which are important for cell adhesion (1). Their loss, and the subsequent inappropriate cell matrix interactions, trigger anoikis – apoptosis induced by a loss of anchorage (1). Anoikis ensures the correct number of cells in high turnover tissues, and therefore is key in preventing over-proliferation and cancer (11). Precancerous cells lacking the ability to circumvent these processes are removed, but this also strongly selects for cells with the ability to avoid apoptosis - cancer cells (1).
Cells can become compromised in other ways as well, through physical injury or viral infection (9). When the cell membrane endures damage it produces a secondary messenger, ceramide, from membrane lipids, sensitizing the cell to apoptosis (9). Mitochondrial injury causes its membrane’s depolarization, and the release of pro-apoptotic factors like cytochrome c (9). Viral infection can induce apoptosis through a multitude of mechanisms (9,10). Binding of many viral protein coat antigens to cell surface receptors triggers apoptosis, as many of the cell’s receptors are in the TNF superfamily (10). Cytokines are also released to signal apoptosis for nearby cells to prevent their viral infection (10). Some viruses posses double stranded RNA (dsRNA); cells wield dsRNA dependant protein kinases, which upon activation trigger an apoptotic cascade (10). Immune responses to viruses can also utilize apoptosis – cytotoxic T-cells can induce apoptosis by either binding the cells FasL receptor with its surface Fas ligand, or by injecting granules, like granzyme B, which activate caspase cascades (9). Viral gene expression can also activate p53 for apoptotic induction (10). The vast range of apoptotic defenses against viral infection has forced the evolution of several subversive mechanisms in viruses, which are frequently associated with cancer formation (10). For example, viruses can manufacture products that block apoptosis – like the papillomavirus E7 protein, which acts by sequestering Rb (10). Such viral proteins often help immortalize cells, contributing to the progression of a cancerous state (10). By eliminating virally infected cells, viruses, and therefore their viral oncogenes, apoptosis serves an additional indirect important role in cancer prevention. For an in depth look at viral oncogenes, and viral causes of cancer see Chapter 2.
Another key function of apoptosis is the regulation of cell turnover within an organism. As multicellular organisms are composed of many different cells each with their own unique role and life cycle, apoptotic regulation as a whole is extremely complicated (2,8). This function is key to maintaining homeostasis and allowing new cells to develop without the need for continued growth while recycling the building blocks for future production (3,8). This function is somewhat related to carcinogenesis, since circumventing the mechanisms that decrease apoptotic turn over also contribute to immortalization (3,8).
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