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Cell Cycle 101: Cell Cycle Deregulation as a Hallmark of Cancer


Have you ever questioned how a wound heals? How does an embryo become a baby? How does a cancerous tumor grow? At the heart of these questions lies cell replication and division. The remarkable ability of a cell to grow and divide into two identical daughter cells underpins the success of life. This is, however, only conceivable because eukaryotic cells (that is, with nuclei) go through the cell cycle, a set of well-defined and tightly synchronized events. This process is divided in two main stages: the interphase, whereby a cell grows; and the mitotic phase, by which cells replicate (mitosis) and divide (cytokinesis). During this process deoxyribonucleic acid (DNA), also recognized as the "molecule of life," is accurately replicated and faithfully distributed to newly generated daughter cells. DNA is the molecule that carries and conveys hereditary material or genetic information from parents to offspring, thus holding all the information needed to construct and sustain an organism. The cell cycle thus functions as the master regulator of tissue growth, development and proliferation. It also ensures that old cells are removed in a timely manner as we age and replaced by new cells that proliferate in a tightly controlled fashion. This keeps the total number of viable cells constant, which is essential for life as we know it.

The Cell Cycle 101 series attempts to elucidate the most important aspects of the cell cycle: from its history and discovery to the underlying mechanisms that control cell division. This series aims to explore the intricacies of cell cycle control in development and the consequences of its failure in disease.

Therefore, this series is divided into the following chapters:

7. Cell Cycle 101: Cell Cycle Deregulation as a Hallmark of Cancer

Cell Cycle 101: Cell Cycle Deregulation as a Hallmark of Cancer

Normal cells rely on tightly regulated control mechanisms to proliferate and maintain tissue homeostasis, yet in cancer cells, this regulation is severely compromised. This is because normal cells can pause the cell cycle following DNA damage, a function fulfilled by cell cycle checkpoints, which is critical for preserving genomic integrity and avoiding mutations (permanent changes in DNA sequence). Cancer cells are defined as abnormal cells that have developed resistance to many of the signals governing cell growth and death through the accumulation of genetic mutations. Cancer-related mutations that disrupt cell cycle regulation enable ongoing cell division, primarily by affecting the cells' capacity to exit the cell cycle (Matthews et al., 2022). Defective checkpoint function is a great example of how mutations induced by DNA damage can lead to cancer, with the vast majority of human cancers containing abnormalities in cell cycle machinery and inactivation of checkpoint signalling (Molinari, 2000). Such genetic alterations often culminate in the activation of oncogenes (which drive cell proliferation) or the malfunctioning of certain tumor suppressor genes (which block tumor growth), allowing cancer cells to replicate at incredibly high rates (Stewart et al., 2003). As they grow and divide, cancer cells increasingly deviate from what would be regular cellular function (Cooper, 2000). A major challenge in the fight against cancer stems from the fact that this disease is typically caused by multiple mutations accumulating in several key genes, rather than a single mutation in an individual gene. In addition, there are over 200 identified forms of cancer, and multiple tumor subtypes can be detected inside specific tissues (K. R. Loeb & Loeb, 2000; Types of Cancer, n.d.). The concept of “Hallmarks of Cancer” has emerged to provide a framework for clarifying and unifying the intricacies of cancer disease.

The Genetics of Cancer

Cancer is a genetic disease, meaning it is caused by changes in genes, which are fragments of DNA that govern protein production in the human body. Genes, therefore, serve as instruction manuals that control how cells function, specifically how they grow and divide. While most genetic mutations are harmless, an accumulation of deleterious mutations can alter protein function to such an extent that benign cells transform into malignant ones (L. A. Loeb, 1991). Cancer-causing genetic mutations can develop as a result of random errors that occur during cell division, DNA damage caused by hazardous chemicals in the environment (e.g., carcinogens present in tobacco smoking or UV rays from the sun), or by inheritance from our ancestors (Laiho & Latonen, 2003; The Genetics of Cancer, 2022).

Figure 1 - Tumorigenesis comprises multiple steps of mutations in cancer driver genes that provide the cell clone with a selective growth advantage over its neighboring cells (Li et al., 2020).

While many mutations occur in the human body on a daily basis, cells have evolved an array of unique mechanisms known as cell cycle checkpoints, as well as processes for DNA damage repair, to restrict the growth of such abnormal cells. For this reason, cancer is assumed to develop through a multi-step process involving the failure of multiple mechanisms before a malfunctioning cell becomes malignant (Vogelstein et al., 1988). Loss of proper growth regulatory instructions owing to mutations in cell cycle control genes allows cells to expand uncontrollably, move to other parts of the body, or not to die when they should. All of these constitute the defining features of cancer cells (Vogelstein & Kinzler, 2004). It is noteworthy that the alterations underlying cancer development often affect three categories of genes: proto-oncogenes (genes that support or sustain cell growth and division), tumor suppressor genes (genes that, when activated, control cell proliferation and inhibit tumor growth), and DNA repair genes. Mutations in any of these genes can cause cells to start over-synthesizing proteins that trigger cell division, or stop synthesizing proteins involved in cell cycle arrest, or even producing abnormal and malfunctioning proteins (Lee & Muller, 2010).

In a hypothetical scenario, the function of a cell cycle inhibitor may initially be lost due to mutation, meaning the next generation of cells will divide at a faster pace. Although unlikely to be malignant, these mutations can lead to a benign tumor, which is a collection of cells that divide abnormally but lack the ability to invade (metastasize) other tissues. Furthermore, another mutation that increases the activity of a positive cell cycle regulator, that is, one that favors replication, may emerge in one of the progeny cells over time. A second mutation may again not be sufficient to drive cancer development, but the progeny of that cell divides even faster, resulting in a greater proportion of cells in which a third mutation is more likely to occur (Chow, 2010). A cell can eventually acquire a sufficient number of mutations to take on the characteristics of a cancer cell, resulting in a malignant tumor, or a collection of cells that reproduce uncontrollably and invade surrounding tissues (Matthews et al., 2022). As they accumulate mutations with additional cycles of division, cancer cells grow increasingly heterogeneous. Heterogeneity is associated with therapeutic resistance as the tumor may comprise a diverse group of cells with different molecular fingerprints. Cancer cell heterogeneity also renders cancer cells more resistant to the control mechanisms that maintain tissue homeostasis over time, resulting in considerably faster proliferation rates compared to their healthy counterparts (Dagogo-Jack & Shaw, 2018).

Figure 2 - Clonal evolution and development of tumor heterogeneity (El-Sayes et al., 2021).

The Hallmarks of Cancer

With the lightning-fast development of cancer research in recent decades, a plethora of evidence has emerged demonstrating cancer as a disease characterized by dynamic alterations in the genome. The finding that most cancers are caused by mutations that activate oncogenes or deactivate tumor suppressor genes established the groundwork for a better understanding of the disease's complex biology. The concept of "Hallmarks of Cancer," first coined in 2000 by Robert Weinberg and Douglas Hanahan, compiled the key concepts underpinning cancer as well as the mechanisms behind tumor development, thus serving as an organizing principle to rationalize the disease (Hanahan & Weinberg, 2000). The Hallmarks of Cancer therefore emerged as a set of functional abilities acquired by human cells as they depart from normality to neoplastic or tumor development, particularly those capabilities required for the emergence and establishment of malignant tumors (Hanahan, 2022).

Weinberg and Hanahan outlined what they considered to be the fundamental characteristics that all tumors share at the phenotypic level, based on the understanding that human tumors are the outcome of multistep processes (Hanahan, 2022). The hallmarks of cancer originally included six traits common to all cancer cells: the ability to self-sustain proliferative signals, avoid growth suppressor signals, resist programmed cell death (apoptosis), allow replicative immortality (unlimited replication potential), induce angiogenesis, and actively invade and metastasize (Fouad & Aanei, 2017; Hanahan & Weinberg, 2000). To better illustrate this, cancer cells can be thought of as those that have pressed the accelerator but whose brakes are not working; who are not eliminated despite being defective; who can divide indefinitely while promoting the growth of new blood vessels to ensure nutrients; and who can migrate and spread to other organs or tissues (Fouad & Aanei, 2017). These hallmarks are supported by genomic instability, which provides the genetic makeup to drive cancer development and inflammation underlying most cancer hallmark events. Conceptual breakthroughs during the next decade prompted Weinberg and Hanahan to include two more cancer hallmarks in their 2011 review “Hallmarks of Cancer: the Next Generation”: aberrant metabolic pathways and immune system evasion (Hanahan & Weinberg, 2011).

Figure 3 - The Hallmarks of Cancer. ('Integrative Oncology: Implementing Patient-Centred Care', 2020)

Cell Cycle Deregulation: A Key Cancer Motif

Cancer is fundamentally a disease of unregulated cell division. Protein kinase complexes, each consisting of a cyclin and a cyclin-dependent kinase (CDK), promote cell cycle progression (Sherr & Roberts, 1999). Eukaryotic cells have evolved control mechanisms that govern cell cycle transitions in response to stress, a role filled by well-known regulatory signaling pathways, cell cycle checkpoints (Paulovich et al., 1997). Should an y biological processes prove to be incomplete or damaged at these checkpoints, cyclin-CDK regulatory function is promptly blocked, preventing the cell from progressing through the cycle until such errors are corrected (Morris et al., 2013; Pines, 1995). Therefore, loss of checkpoint integrity can allow DNA lesions to spread and result in permanent genetic changes (Paulovich et al., 1997). It should come as no surprise that checkpoint pathways governing cell-cycle progression are often compromised in tumor cells, underscoring the importance of properly functioning checkpoint signaling for safeguarding the genome. Cancer cells often arise from altered activity of cell cycle regulators and may exhibit dysregulation of at least four cell cycle checkpoints, including the restriction point (G0/G1), the G1 checkpoint, the G2 checkpoint, and the mitosis-associated spindle assembly checkpoint (SAC) (Molinari, 2000). The G0/G1 restriction point is a no-return point in G1 where withdrawal of growth factors no longer triggers reversion to a quiescent state, and hence represents the point at which the cell commits to division (Li et al., 2020; Pennycook & Barr, 2020). Most aberrant cell cycle components involved in tumor growth exert an effect on G1 restriction point and the G1/S transition. Why abnormalities in the G1 cell cycle stage provide tumor cells such a growth advantage over the S, G2 or M phases is yet to be explored. However, speculative theories suggest that this may reflect the critical role of G1/S events in driving the division of differentiated adult cells. This is plausible considering that tumors most typically arise from adult tissues where the majority of cells are quiescent or dormant. The proliferative advantage of tumor cells derives from their ability to bypass dormancy and cross this biological threshold (Malumbres & Carnero, 2003). This could be related to enhanced mitogenic signaling (signals that act from outside the cell to induce mitosis and cell division) or alterations that reduce the threshold for cell cycle commitment.

Unlike healthy cells, cancer cells do not depend on growth hormones nor protein signals to proliferate in culture (outside the body, in an experimental laboratory setting). Their ability to multiply much more frequently than a normal cell, known as replicative immortality, is also a well-known cell cycle-related alteration of cancer cells (Bartlett, 2014; Fouad & Aanei, 2017; Hanahan, 2022). While loss of control over commitment to cell division is an important step in human cancer progression, it is possible that deregulation of other cell cycle events could also contribute to malignancy. In fact, chromosomal instability and aneuploidy (cells carrying missing or extra chromosomes), two prominent consequences of defective M-phase checkpoints, are also hallmark features of cancer cells. Proper distribution of chromosomes is controlled at the metaphase-to-anaphase transition by the spindle-assembly checkpoint, whose constituent molecules have also been implicated in human cancers. The possibility that mistakes at crucial M-phase checkpoints may result in chromosomal aberrations has been keeping cancer researchers alert, despite the paucity of proof that mitotic event disruption leads to human cancer (Malumbres & Carnero, 2003).

Figure 4 - A normal human cell (left) contains 23 standard chromosomes, but a tumor cell (right) has an uneven karyotype known as aneuploid, containing some missing or extra chromosomes with traded fragments (Duesberg, 2007)

Breaking the Cell Cycle Norm: Loss of Tumor Suppressor Genes and Oncogenes

The transition of a normal cell to a malignant phenotype is mainly driven by genetic abnormalities affecting proteins involved in cell cycle regulation that activate multiple oncogenic signalling pathways. Years of extensive research in model organisms have led to the discovery of the genes and proteins essential for cell cycle progression (Chen et al., 2016). Since then, the quest to identify and understand the functional role of cancer genes has continued unabated, with over 500 genes defined as bona fide cancer drivers based on multiple lines of evidence (Chen et al., 2016; Clark et al., 2019). Oncogenes and tumor suppressor genes are two classes of genes that connect cell cycle regulation to tumor genesis and development (Chial, 2008a; Chow, 2010; Studzinski, 1989). Oncogenes and tumor suppressor genes, for instance, play an important role in cell cycle control, particularly those featuring either mutational stimulation of the RAS (from "Rat sarcoma virus") oncogenic pathway and/or inactivation of the retinoblastoma (Rb) or p53 tumor suppressor pathways, which are involved in both restriction point and the G1/S transition checkpoints (Blagosklonny & Pardee, 2002; Weinberg, 1995; Williams & Schumacher, 2016).

While activated oncogenes favor an uncontrolled cell cycle, defective tumor suppressor genes fail to restrict it. Oncogenes develop as a result of gain-of-function mutations of proto-oncogenes, that is, genes which enhance their expression or activity. The collection of genes called proto-oncogenes are those involved in normal cell growth, but when mutated cause normal cells to develop into cancer (Adamson, 1987; Weinstein & Joe, 2006). To drive cell growth and cell division, proto-oncogenes often encode proteins that fuel the cell cycle and drive cells to transition from one of the G phases (gap) to either chromosomal replication (S phase) or chromosome separation (mitosis) (Choudhuri et al., 2018; Haschek et al., 2010). They often encode products such as growth factors and their receptors, transcription factors, cell cycle regulators, or proteins that work with DNA to initiate replication (DNA-binding proteins) (Studzinski, 1989). While these processes are paramount in normal human development, oncogenes often produce an excess of these proteins, resulting in accelerated cell proliferation, decreased cell differentiation, and suppression of cell death (Chial, 2008a). In addition, proteins that typically switch between active (ON) and inactive (OFF) states, such as RAS proteins, can occasionally be permanently activated by mutations. These proteins act as binary molecular switches that can be activated or deactivated based on the nucleotide form (di- or tri-phosphate) to which they are attached (Simanshu et al., 2017). When active, the by-products of this proto-oncogene mediate signals that promote proliferation. However, challenges arise when mutations turn the proto-oncogene into an oncogene, causing RAS to be persistently active regardless of the signals received from the cell (Chow, 2010; Simanshu et al., 2017).

Figure 5 - Genes act as both the gas and stop pedals in the development of cancer (Bayer AG, 2016).

Tumor suppressor genes, on the other hand, encode negative regulatory proteins that, when activated, can stop excessive cell growth. They frequently block aberrant cell growth and division while encouraging cell death to preserve our cells in optimal equilibrium (Chial, 2008b; Velez & Howard, 2015). Furthermore, some of these genes participate in DNA repair processes that help prevent a buildup of mutations in cancer-related genes. Tumor suppressor genes operate as brakes, preventing cells from progressing toward malignancy (Chial, 2008b). Against this background, the loss of function of the tumor suppressor gene can have devastating consequences and often sets previously healthy cells on the path to malignant tumors. Retinoblastoma protein (Rb), p53 and p21, three of the best-studied tumor suppressor gene proteins, work together to arrest cell cycle progression (Engeland, 2022). Mutations of such negative regulators can prevent a cell from halting the cell cycle in the event of an error. Indeed, p53 is the most frequently altered gene in human cancers (Vogelstein et al., 2010). This finding is not surprising given that the p53 protein serves multiple roles at the G1 checkpoint. When DNA is damaged, the p53 protein activates other genes, the products of which either arrest the cell cycle (allowing time for DNA repair) or, if the damage is irreparable, trigger cell death (Williams & Schumacher, 2016). Furthermore, the damaged p53 found in cancer cells is incapable of promoting cell death. As a result, cells can divide uncontrollably, passing their mutation to offspring and allowing new mutations to emerge.

The Odd Dichotomy of Having More Cells yet Less Cancer

From the massive Antarctic blue whale to the little bumblebee bat, animals come in all shapes and sizes. Although cancer can strike any species, some are more prone to it than others. Considering that each cell has an equal likelihood of becoming malignant and equivalent cancer suppression mechanisms, some evidence suggests that larger animals with more cells are more susceptible to cancer than smaller ones, especially given that cell sizes in large and small animals are comparable. This association holds true within the same species with taller individuals (Green et al., 2011; Nunney, 2018) and larger dogs or cats (Dobson, 2013; Dorn et al., 1968) having a higher cancer risk than their smaller counterparts. Therefore, body size and longevity appear to have a link to the likelihood of developing cancer within the same species. However, no correlation was found between cancer and body size or longevity when different species were compared. This lack of correlation is often referred to as the ‘Peto’s Paradox’ (Caulin & Maley, 2011; Peto et al., 1975). In spite of variances in body size, the frequency of cancer is actually remarkably consistent across species at around 5%. The solution to Peto's Paradox seems rather straightforward: large-bodied, long-lived species have evolved enhanced cancer protection mechanisms. However, it has proven challenging to identify and characterize the mechanisms underlying the evolution of enhanced cancer safeguarding mechanisms in larger animals (Seluanov et al., 2008; Sulak et al., 2016). This is because it requires a comparison of the cancer risk and genetic information of a broad collection of animals that are evolutionarily related but have significantly different body sizes, i.e., animal lineages where large-bodied species originated from small-bodied species.

Figure 6 - Peto’s Paradox: how evolution has solved the cancer riddle ('Peto's Paradox', n.d).

Because they evolved relatively recently from an ancestral lineage of smaller-bodied animals (Afrotherians), elephants and their close, massive-bodied relatives (Proboscidea) represent a particularly fascinating lineage for understanding the processes driving increased cancer resistance. Vazquez and Lynch (2021) solved the riddle of Peto's paradox by comparing the genomes of elephants, woolly mammoths, mastodons, and their small-body relatives (marmot hyraxes, manatees, and armadillos). According to the findings of Vazquez and Lynch, the evolution of elephants was accompanied by the acquisition of extra sets of tumor suppressor genes that help repair the genetic and cellular damage driving healthy cells to become malignant. Duplication of tumor suppressor genes reduced intrinsic cancer risk, which supported the growth of larger bodies (Vazquez & Lynch, 2021).


The link between the cell cycle and cancer is rather straightforward: the cell cycle machinery controls cell proliferation and cancer is a disorder defined by abnormal cell proliferation. In the human body the majority of cells are not cycling but rather remain inactive or at rest. Only a small proportion of cells are actively cycling or proliferating, and they are mostly located in tissues that can self-renew, such as epithelia and bone marrow. Cell cycle deregulation is the main source of the aberrant cell proliferation that characterizes cancer, which is primarily driven by successive mutations and genomic instability. Such a lack of regulation is what fuels tumor cells to their proliferative edge by allowing them to skip rest. Furthermore, the endless potential of cancer cells to divide is linked to a vicious cycle in which cells lose sensitivity to signals instructing when to proliferate, differentiate, or die. The combination of altered features makes it incredibly challenging to identify which alterations are most likely to cause cancer. Comprehending the molecular processes underlying cell cycle commitment and re-entry could provide crucial insights into how healthy cells turn tumorigenic and how novel anticancer strategies might be designed to prevent or eventually target the disease's earliest stages.

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