Part 1: Foundations of Cancer

What is Cancer?

Cancer is a group of diseases marked by uncontrolled cell growth and the ability of abnormal cells to invade nearby tissues and spread (metastasize) to distant organs. Unlike normal cells, cancer cells bypass growth control signals, resist cell death, and keep dividing without limit. These cells develop a set of traits known as the hallmarks of cancer (Roizen, 2012). These hallmarks include:

• Sustaining proliferative signaling: Cancer cells grow and divide without depending on normal growth signals.
• Evading growth suppressors: They ignore signals that usually slow down or stop cell division.
• Resisting cell death: They avoid apoptosis, which normally removes damaged or unneeded cells.
• Inducing angiogenesis: They form new blood vessels to supply oxygen and nutrients to the tumor.
• Enabling replicative immortality: They divide indefinitely, unlike normal cells that stop after a certain point.
• Activating invasion and metastasis: They spread to other parts of the body beyond the original site.
• Reprogramming cellular metabolism: They change their metabolism to support continuous growth.
• Evading immune destruction: They hide from or resist attacks by the immune system.

Cell Cycle and its Regulation

a. Overview of the Cell Cycle

The cell cycle is a series of stages that a cell goes through as it grows and divides. It begins with the G1 phase (Gap 1), where the cell grows and actively synthesizes proteins and organelles. During this phase, the cell also prepares for DNA replication. At a critical decision point, the cell either continues into the next phase (S phase) or exits the cycle and enters a resting state known as the G0 phase. In G0, the cell stops dividing. Some cells, like neurons, remain in G0 permanently, while others, such as liver cells, may reenter the cycle when needed (Sherr, 2000).

b. Key Regulatory Proteins and Complexes

The cell cycle is tightly regulated by specific proteins known as cyclins and cyclin-dependent kinases (CDKs). CDKs are enzymes that become active only when bound to particular cyclins. These cyclin–CDK complexes are responsible for driving the cell through the different phases of the cycle by phosphorylating target proteins that promote progression (Sherr, 2000; Knudsen et al., 2022).

Each phase of the cycle is regulated by a distinct cyclin–CDK pair:

• Cyclin D–CDK4/6 controls progression through the G1 phase
• Cyclin E–CDK2 regulates the critical G1/S transition
• Cyclin A–CDK2 promotes progression through the S phase
• Cyclin B–CDK1 is responsible for the G2/M transition

Together, these complexes ensure the orderly and accurate replication and division of cells (Sherr, 2000; Knudsen et al., 2022).

Checkpoints in the Cell Cycle

Checkpoints are control mechanisms that ensure each stage of the cell cycle is completed correctly before the cell moves forward. The main checkpoints are:

1. G1/S Checkpoint

• Ensures that the DNA is not damaged before replication begins (Sherr, 2000).
• p53 activates p21, which blocks CDKs if damage is detected (Duffy et al., 2011).
• Rb protein holds back E2F when in its hypophosphorylated form, preventing the cell from progressing (Sherr, 2000).

2. Intra-S Checkpoint

• Temporarily pauses DNA synthesis in response to DNA damage (Sherr, 2000).

3. G2/M Checkpoint

• Confirms that all DNA has been correctly replicated before mitosis begins (Sherr, 2000).
• Involves regulation by CHK1/CHK2 kinases (Sherr, 2000).

Tumor Suppressors and Oncogenes in Cell Cycle Regulation

a. Tumor Suppressors

• p53: Called the “guardian of the genome,” it can pause the cell cycle, trigger cell aging (senescence), or cause cell death (apoptosis) when there’s DNA damage (Duffy et al., 2011).
• Rb: Stops the cell from entering the S phase too early by holding back a protein called E2F (Sherr, 2000).

b. Oncogenes

• Cyclin D1: Often found in high amounts in breast cancer and lymphomas (Finn et al., 2009).
• CDK4/6: Frequently increased in glioblastomas and melanomas, speeding up cell division (Finn et al., 2009).

Cell Cycle Dysregulation in Cancer

In cancer, the cell cycle checkpoints are often turned off or don’t work properly. This means cells can keep dividing even when there’s DNA damage or chromosome problems (Knudsen et al., 2022). Some common examples include:

• Loss of p53: This happens in more than 50% of human cancers. Without p53, damaged cells don’t stop or die—they keep multiplying (Duffy et al., 2011).
• Overactive CDK4/6: These proteins can cause too much phosphorylation of Rb, allowing the cell to move into the S phase too early (Sherr, 2000).
• Excess Cyclin D: Leads to continuous cell growth by speeding up the G1 phase and is seen in several cancers like breast cancer and lymphomas (Finn et al., 2009).

References

1. Duffy, M. J. et al. (2011). Clinical Proteomics.
2. Finn, R. S. et al. (2009). Breast Cancer Research.
3. Knudsen, E. S. et al. (2022). Cell Reports.
4. Roizen, M. (2012). Yearbook of Anesthesiology and Pain Management.
5. Sherr, C. J. (2000). PubMed.