Discuss how changes in control of the cell cycle contribute to cancer development Cancer is a multifarious disease, with a common feature that most tumours harbour one or more genetic mutations that allow them to advance outside their normal growth restr

Discuss how changes in control of the cell cycle contribute to cancer development

Cancer is a multifarious disease, with a common feature that most tumours harbour one or more genetic mutations that allow them to advance outside their normal growth restraints. This proliferation is normally harnessed by the control of the cell division cycle, which in turn, is majorly regulated by the cyclin dependent kinases (Cdks) family of serine/threonine kinases and their regulatory partners, the cyclins (Errico, et al., 2009). In this essay, the roles of Cdks, cyclin complexes, regulatory proteins and other cell-cycle regulatory processes will be underlined, followed by an analysis of the genetic lesions in these regulators which may contribute to tumorigenesis.

Fundamentally, cancer, or a neoplasm is a disease where cellular proliferation is no longer under normal growth control. The growth of this clone of cells exceeds, and is uncoordinated with that of normal surrounding tissues (NHS, 2009). Ultimately, this deregulation of growth and division of the cancer cells disrupts and interferes with the normal functioning of the body, either at its origin or through spreading to another location, eventually resulting in the potential death of the sufferer if left untreated. Other complex characteristics include the ability of the cancer cells to induce vascularisation of the tumour in order to receive oxygen and nutrients (angiogenesis), thus sustaining their survival. They can also disperse from the site of origin and travel to distant parts of the body by metastasis and also display the ability to suppress programmed cell death (apoptosis) (Okudela, et al, 2009) Such atypical proficiencies are also detailed further in this essay.

To appreciate both the phenomenon and capacity for a cell to develop into a cancerous cell, it is pivotal to understand the concept of cell proliferation and how it is controlled. Populations of cells in complex organisms, such as humans, undergo replacement and turnover of their macromolecular compounds. This is known as cell renewal. Exceptional to this are cardiac muscle and many nerve cells, which are mitotically inactive, but even such differentiated cells replenish their molecules and structures under the influence of appropriate stimuli (Avers, 1986). At the core of cellular proliferation is the cell division cycle, the process by which a cell grows, replicates its DNA and then divides to produce two genetically identical daughter cells. This intricate process is divided into four sequential phases, as depicted by the diagram below (Figure 1:1).

Figure 1:1 The Cell Cycle, representing the critical G1, S, G2 and M phases

The M phase is devoted to mitosis, and the G1, S, and G2 phases constitute the biosynthetically active time of interphase. DNA replication takes place during S phase, and it is separated from mitosis by the pre-replication G1 phase and the post-replication premitotic G2 phase, or time gaps (Lodish, et al., 2000). Cellular activities occurring during mitosis, which includes prophase, prometaphase, metaphase, anaphase, telophase and cytokinesis are outlined in Appendix 1:1. The proportion of a cell cycle occupied by each phase varies, but the mitotic phase is usually brief. The G1 phase is the most variable in duration in different kinds of cells; it may even be lacking in some cell cycles. The two most important of these are the S phase and mitosis (M), the key concept of the cell cycle is that S phase must always follow M phase and that M phase must not commence until S phase has been completed. Underlining that DNA replication must not commence until mitosis is complete, ensuring that the integrity of the genome is maintained. Additionally, there is a fifth state, the G0 (known as quiescence) into which the cell may reversibly exit from G1, if it is deprived of the appropriate and correct growth-promoting signals (Cell Cycle Research, 2007).

The movement through each phase of the cell cycle and transition from one phase to the next is controlled at a number of positions within the cell division cycle known as checkpoints. Checkpoints are intricate sensor mechanisms within the cell which monitor the cellular environment and determine whether appropriate conditions have been fulfilled before it progresses further through the cell division cycle (Beck, et al., 2009). Ergo a major function of these checkpoints is to oversee that the integrity of the genome remains intact throughout the cell cycle. This assures that cellular growth and the coordination of DNA synthesis with cell-size increase and cytokinesis are monitored and do not fall out of regulated synchrony (Lodish, et al., 2000). Each checkpoint is made up of three critical components. Firstly is a sensor mechanism that detects abnormal or incomplete cell cycle events such as DNA damage. Following is the signal transduction pathway, which carries the signal from the sensor to the third component, the effector that can invoke a cell cycle arrest until the problem has been resolved (WormBook, 2007). The major cell cycle checkpoints are depicted in Figure 1:2 below:

The first checkpoint occurs at the G1/S phase transition and is a major sensor of DNA damage. The cell may also arrest later in S phase due to incomplete DNA replication or again, damage to the DNA. Next is the G2/M checkpoint, which monitors the conformity of DNA replication and like the G1/S checkpoint is an important sensor of DNA damage. This is followed by the spindle checkpoint, which is invoked during mitosis if a functional mitotic spindle has not been formed appropriately (McKinnell, et al., 2006).

To highlight also, there is the restriction point (R) which occurs between mid and late G1 phase. It is the point at which the cell determines whether it has received the necessary growth signals (extracellular in origin) so that it can transit out of G1 into the S phase, in doing so replicate its DNA and complete one cycle of cell division. If cells are sufficient, they pass the R point and for the remainder of that cell cycle will not require such signals (Beck, et al., 2009). Contrastingly, if the cell has received insufficient cues, it does not pass the restriction point, thus instead enter the G0 phase. Although this checkpoint does not specifically ascertain whether the genome is intact, it is an essential control point which restrains cell proliferation (thence, cancer) if appropriate growth signals have not been received.

Cyclins, Cdks, and the Rb protein are all elements of the control system that regulate passage through the restriction point. The ability of these proteins to check cell-cycle progression, and hold cells in quiescence or even lead cells to commit suicide unless conditions are appropriate, means that they can prevent cells from becoming cancerous. Altered regulation of expression of at least one cyclin as well as mutation of several proteins that negatively regulate passage through the restriction point can be oncogenic (Berg, et al., 2002).

In emphasis, if these cell cycle checkpoints are not in place then inappropriate ...

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In emphasis, if these cell cycle checkpoints are not in place then inappropriate proliferation can occur - the hallmark of cancer. It is also known that probably all human tumours harbour genetic alterations in the genes that control cell cycle progression and checkpoint function (Cooper, et al., 2004).

At the core of the mammalian cell division cycle is the cyclin dependent kinase family. In mammalian cells, different Cdks are active and required at different phases of the cell cycle. The responsibility of Cdks is to control cell cycle progression through phosphorylation of proteins that function at specific cell cycle stages. There is a complex variety of Cdks operating in the cell cycle, each operating in its own phase. The cyclins combine with their cognate kinases causing a conformational change which, together with a single phosphorylation, activates the Cdk. At the start of each cycle phase, genes have to be activated so that the appropriate cyclins are synthesized (Hutchinson, et al., 1995). If this does not happen, the cycle cannot proceed through that specific phase. At the end of each phase, the cyclins are destroyed by proteasomes and new cyclin synthesis specific for the next phase is needed. This highlights such an expensive way to achieve control but it is a decisive procedure leaving no room for partial inactivation; as emphasized, cell-cycle control, above all, has to be decisive given the potential dangerous consequences of errors (Mulambres, et al., 2009).

An example is the product of the retinoblastoma tumour suppressor gene; pRb is a key regulator of G1 progression and possesses 16 potential sites of Cdk phosphorylation. In early G1, pRb is found in low phosphorylated state and tightly binds and represses the activity of the E2F family of transcription factors which are functionally required for the expression of genes necessary for S phase. Additionally, pRb becomes phosphorylated at the Cdk consensus sites, disrupting its interaction with the E2F proteins, allowing E2F dependent transcription to occur. This is required in order for the cell to pass through the restriction point late in G1 phase (Tyson, et al., 2001). The phosphorylation of pRb at the Cdk consensus sites appears to be a sequential process, initiated by Cdk4 and Cdk6 each acting in association with one of three related cyclin subunits D1, D2 and D3. In doing so, it allows expression of cyclin E by disrupting the interaction of pRb with proteins known as histone deactylases, which are involved in chromatin remodelling. Furthermore, the expression of cyclin E allows the formation of active Cdk2/ cyclin E complexes that continue to phosphorylate pRb. This leads to disruption of the pRb-E2F interaction such that E2F is a requirement for the cell to progress from G1 into S phase (Sashai, et al., 2002).

Advanced research has shown that cancer cells usually carry mutations that affect the final step in mitogenic signaling, where there is an increased G1/S gene expression that is driven by gene regulatory proteins of the E2F family. These proteins are normally harnessed by members of the pRb protein family, and mitogens release the brakes on cell-cycle entry by stimulating G1 and G1/S-Cdk activities, which trigger the phosphorylation of pRb proteins. In such cancer cells, the pRb brakes are lost or defective, resulting in E2F-dependent G1/S expression even in the absence of mitogens (Pavletich, 1999).

Research has also highlighted that it is likely that all cancer cells carry a mutation that disrupts some feature of pRb control. Such dominant oncogenic mutations can occur in the cyclins and Cdks that promote pRb phosphorylation. An example is the cyclin D or Cdk4 which are overproduced in some tumours as a result of gene amplification or other cellular mechanisms. Cdk4 can also carry point mutations that render it insensitive to the Cdk inhibitors of the INK4 family, which normally help restrain the kinase. More frequently, tumour cells lose the gene for p16INK4a, which is among the most common defects in human cancers. This gene was the first tumour suppressor to be identified, in a search for the genetic backbone of retinoblastoma, a congenital syndrome that leads to cancers of the retina. The frequencies of mutations in pRb pathway components in human cancers are shown in table 1:1 below:

Table 1:1 The frequency of mutations in pRb pathway components in human cancers

The G1 phase of the cell cycle is a critical time where extracellular signals both positive and negative are integrated into regulation of the cell cycle progression. This occurs until the restriction point at which time the cell becomes committed to one round of cell division. As previously described, if the cell does not receive the appropriate cues during G1, it cannot pass the restriction point and will instead enter the quiescent state, G0. At the molecular level, it is the cyclin D-dependent kinases that act as integrators of these extracellular signals. An example of this is that cyclin D1 can be induced by both the Ras and p13 kinase signalling pathways, thus promoting G1 progression. Therefore, the cyclin D-dependent kinases, their regulators and pRb are a focal point of control for G1 progression and so unsurprisingly, their links with cancer are very strong. This link starts with the signalling pathways which regulate cyclin D-dependent kinase activity. For instance, the Ras genes, the PIK3CA gene encoding the p110α subunit of p13 kinase and the tumour suppressor gene PTEN which acts as a lipid phosphatase and reverses the p13 kinase reaction, have all been shown to be mutated in cancer. All these genetic alterations have the capability to cause activation of the cyclin D-dependent kinases leading to inappropriate phosphorylation of pRb and misregulation of the restriction point. Downstream the cyclin D-dependent kinases, their regulators, as well as the gene encoding pRb itself (RB) are all cancer targets. To underline therefore is that most tumours contain a genetic alteration in one of these genes. Cyclin D1 was first isolated as the BCL1 gene, found at the t (11; 14) translocation in mantle cell lymphoma. Augmentation of the cyclin D1 locus 11q3, has also been identified in a number of cancer types including breast, glioma and lung. Amplification of Cdk4 has also been identified, whilst low levels of the CKI p27KIP1 protein have been shown to indicate poor prognosis in both colon and breast cancer (Welsh, et al., 2001).

In considering all these genetic alterations it is clear to see that one common denominator is that they all have the ability to promote inappropriate phosphorylation and inactivation of pRb. As for the RB gene itself, mutation or deletion is a common occurrence in cancer, thus directly revoking the requirement for cyclin D-dependent kinase activity during G1. Importantly to note also is that in some tumour types there appears to be a mutually exclusive behaviour in the genetic alterations on the p16INK4A/ cyclin D/ pRb pathway. An example of this is in lung cancer where tumours tend to harbour either deletions or mutations in RB or CDKN2 encoding p16INK4A, but not in both. This suggests in certain circumstances, genetic alteration in one member of this pathway is a sufficient contribution to tumour progression (Pavletich, 1999).

Although many cellular stresses can invoke cell cycle checkpoints (hypoxia, DNA damage, nucleotide deprivation, to name a few), the checkpoint pathways for G1/S, S and the G2/M transition are those which are invoked in response to DNA damage caused by double strand breaks in the DNA (DSBs). This type of DNA damage can be brought about by a number of agents of which ionizing radiation, genotoxic chemicals and reactive oxygen species are three major culprits. As DSBs affect the integrity of the genome, which if not maintained correctly can lead to cancer.

Mitosis is the time in a cell when newly replicated DNA (condensed sister chromatids) is segregated so that the subsequent two daughter cells will have identical genomes. This is achieved through a highly organized series of events starting with chromosome condensation and culminating in cell division (see Appendix 1:1). A critical point occurs when the condensed sister chromatids become attached to the bipolar spindle emanating from the two centrosomes at opposite sides of the cell (metaphase). The two sets of identical sister chromatids are then pulled to opposite poles (anaphase), a nuclear envelope reform around each of set of chromatids (telophase) ready for cell division (cytokinesis). If mis-segregation of the sister chromatids occurs, then the resulting daughter cells will have an incorrect number of chromosomes (aneuloploidy), a pheontype commonly observed in cancer and believed to contribute to the malignant phenotype of the tumour. Thus mitosis would be hypothesized to be an important target of genetic mutation in cancer and recent discoveries bear this out.

Phenotypic defects in the centrosomes, the organising centres of the bipolar spindle, have been reported in many forms of cancer. Scientists believe that one possible cause of this is the Aurora2/ STK15/ BTAK kinase, which is centrosome associated during interphase and both centrosome and spindle associated during mitosis. The gene is overexpressed in colorectal carcinomas and maps to a region on chromosome 20 found frequently amplified in a number of tumour types (Hutchinson, et al., 1995).

Chromatid attachment to the bipolar spindle is essential for correct mitosis and if defective, invokes the mitotic spindle checkpoint at the metaphase-anaphase transition. During normal mitosis, as the last chromatid becomes attached to the spindle, the APC E3 ligase becomes active. This requires association with the Cdc20 regulatory subunit and phosphorylation by CDC2/ cyclin B. Once active, APC/Cdc20 initiates degradation of securin, a protein associated with the mitotic protease, Separin. After degradation of Securin, Separin is released and cleaves proteins involved in sister chromatid cohesion, thus allowing their separation. Human Securin is identical to the product of the pituitary tumour-transforming gene (PTTG), which is overexpressed in some tumours. However, no direct link between separin and cancer has yet been identified (Lodish, et al, 2000).

The genetic changes that contribute to cancer development are also due to the loss of the functional genes that protect cells against uncontrolled cell division, the tumour-suppressor genes. Mutation of these genes does not itself lead to uncontrolled cell growth, but removal of their protective effect means that if oncogenes become activated, cells are more likely to make the progression to the cancerous state.

Tumour derived growth factor β (TGFβ) is secreted by most body cells and has a diverse range of biological activities. Loss of TGFβ- mediated growth inhibition contributes to the development and progression of a variety of tumours (Paradali, et al., 2007).

TGFβ signals through the sequential activation of two cell-surface receptors, termed type I and type II, both of which have intrinsic serine/threonine protein kinase activity. The binding of TGFβ induces formation of a complex of the type I and type II receptors and phosphorylation and activation of the type I and type II receptor kinase (Blerie, et al., 2006). Smad proteins are the key intracellular signal transducers in the pathway downstream from the TGFβ receptors. The ligand-activated type I receptor phosphorylates conserved serines at the C-terminus of either Smad2 or Smad3, which enables them to bind to one or more molecules of Smad4, a common partner for all phosphorylated Smads involved in signaling by both TGFβ and bone morphogenic proteins. These Smad complexes then enter the nucleus and activate transcription of a variety of genes. One important gene induced by TGFβ encodes p15. This G1 cyclin-kinase inhibitor displaces p27 from the Cdk4-cyclin D complex, freeing p27 to bind to and inhibit the Cdk2 cyclin E complex, which is required for entry into the S phase. Thus by inducing expression of p15, TGFβ causes the cell to arrest in G1 (Stover, et al., 2007).

Many tumours contain inactivating mutations in either the TGFβ receptors or the Smad proteins, and thus are resistant to growth inhibition by TGFβ. Most human pancreatic cancers contain a deletion in the gene encoding Smad4. Retinoblastoma, colon and gastric cancer, hepatoma, and some T- and B-cell malignancies are unresponsive to TGFβ growth inhibition. This loss of responsiveness to TGFβ can be restored by combinant expression of the ‘missing’ protein. Mutations in Smad2 also commonly occur in several types of human tumours (Bronstein, et al., 2009).

The proficiency of TGFβ signalling pathway also induces expression of the genes encoding many extracellular matrix proteins, such as collagen and plasminogen activator inhibitor-1, an inhibitor that degrades the matrix proteins. Such an ability to synthesize these proteins indicate a contribution to metastasis, allowing tumour cells to escape, since less matrix will be synthesized by the cells and the matrix that is present may be degraded by inappropriately activated proteases (Jakowlew, 2006).

Another key tumour-suppressor gene is TP53, encoding the tumour suppressor protein, p53. It is the absence of a normal protective p53 protein that favours cancer development, rather than p53 mutant promoting cancer. p53 is described as the guardian of the genome. Defective p53 genes are involved in the development of over half of all human cancers. If only one p53 gene is deficient there is still functional p53 protein coded for by the other gene, so that mutation of both genes is needed to lose the protective effect. The mutations are recessive (Lim, et al., 2009).

In consideration of a normal cell in early G1 phase, if appropriate mitogenic factors are present, the latter will activate genes leading to the production of the G1-specific cyclins, which activates the Cdks. In the normal cell, the amount of p53 protein is low and inactive and the cycle can proceed. If the DNA is damaged however, the p53 gene is activated and more p53 protein is activated. p53, in the presence of damaged DNA, becomes phosphorylated on a serine residue which both activates it and decreases its rate of destruction. The protein is a transcription factor that activates another gene (p21) whose protein product inactivates the G1-specific Cdk activity. This arrests the cycle at the restriction point, giving time for the DNA to be repaired. If this is done, the p53 gene is no longer activated and the level of p53 protein returns to its low level and the cycle continues normally. If the DNA damage is not repaired, the p53 signals the cell to self-destruct by the apoptotic mechanism (p53-Research, 2009).

In the absence of functional p53 genes, the cycle is not arrested and the apoptosis signal is not delivered, so a cell with abnormal DNA is allowed to replicate, thus increasing the chance of cancer developing (Lim, et al., 2009).

Apoptosis is another key factor underpinning the cell cycle control and resistance towards it allows the survival of malignant cells. Cancer results if there is too little apoptosis and cells grow faster and live longer than normal cells (Schulze-Bergkamen, et al., 2004). Research has produced remarkable advances in the understanding of cancer biology and cancer genetics underpinning apoptosis. Among the most important of these advances is the realization that the genes that control it have a profound effect on the malignant phenotype. For example, it is clear that some oncogenic mutations disrupt apoptosis, leading to tumour initiation, progression or metastasis. Conversely, compelling evidence indicates that other oncogenic changes promote apoptosis, thereby producing selective pressure to override apoptosis during the multistage carcinogenesis. However, it is now documented that most cytotoxic anticancer agents induce apoptosis, raising the intriguing possibility defects in apoptotic programs contribute to treatment failure. Because the same mutation that suppresses apoptosis during tumour development also reduces treatment sensitivity, apoptosis provides a conceptual framework to link cancer genetics with cancer therapy. Intense research effort is uncovering the underlying mechanisms of apoptosis such that, in the future, it is possible that this information will produce new strategies to exploit apoptosis for therapeutic benefit (Lowe, et al., 2000)

In conclusion, by considering the role the cell cycle plays in cancer it is clear that in most cases this disease is not one derived from a single genetic mutation, but from alterations in a number of genes arising to give a specific cancer type. Until now, many of the tumour suppressor genes which play a major role in cancer have been identified through the scientific dedication of mapping a genetic locus to a chromosome and then looking for candidate genes.

Recent advancements in understanding the cell cycle reveal how fidelity is normally achieved by the coordinated activity of the cyclin-dependent kinases, checkpoint controls, and repair pathways and how this fidelity can be abrogated by specific genetic changes that control the cell cycle. Such major changes as highlighted in this essay include the loss of Rb function, loss of p16 function, overexpression of cyclin D1 and mutations in p53 which abolish G1 checkpoint control; all in which display oncogenic capacities.

Moreover, such insights into how changes in the control of the cell cycle induce cancer not only suggests molecular mechanisms for these cellular transformations but more importantly, may contribute to identify potential targets for improved cancer therapies; this taking forefront priority for such a devastating disease.

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Appendix:

Figure 1:1 showing the sequential cellular phases of Mitosis (M phase):

(Clinical Tools Inc, 2009)