Cancer Biology and Mechanisms

Goals of Understanding Cancer

  1. Define cancer and understand the process that leads to a cell becoming "cancerous."

  2. Describe the normal functions at each of the three cell cycle checkpoints and know how the loss of control at these checkpoints contributes to cancer.

  3. Define key terms, including proto-oncogenes, oncogenes, and tumor suppressor genes, and explain the mechanisms that lead to cancer.

Understanding Cancer as a Genetic Disease

  • Cancer is fundamentally a genetic disease characterized by mutations or abnormal gene expression, leading to loss of cell cycle control, especially in somatic cells.

  • Common cancers frequently arise through various mutations that cause uncontrolled cellular proliferation.

Cell Cycle Checkpoints

The cell cycle consists of several checkpoints that ensure proper cell division and function. The three primary checkpoints are as follows:

G1/S Checkpoint

  • Monitors the size of the cell and the integrity of its DNA.

  • A decision is made whether the cell can proceed to divide based on:

    • The cell being large enough

    • Identification of any mutations present in the DNA

G2/M Checkpoint

  • Checks DNA synthesis and damage before mitosis occurs.

  • The presence of mutations or errors will prevent the cell from advancing to the mitotic phase.

M Checkpoint

  • Oversees spindle formation and the attachment of spindle fibers to kinetochores.

  • Ensures that chromosomes are appropriately aligned and attached for successful division.

Consequences of Damaged Cells

  • If checkpoint requirements are not met at these stages, the cell can either:

    • Exit the cell cycle to repair damage

    • Proceed to apoptosis (programmed cell death) if the damage is irreparable.

Apoptosis

  • Apoptosis is a controlled process that occurs when a cell's DNA or structural integrity is significantly compromised.

  • This mechanism allows cells with severe damage to be eliminated, thereby preventing cancer development.

  • The process involves taking the cell apart to facilitate phagocytosis by immune cells.

Bcl2 Family Proteins

  • The Bcl2 family consists of pro-apoptotic and anti-apoptotic proteins that regulate apoptotic pathways.

  • Bcl2: Prevents apoptosis (inactive complex).

  • BAX: Promotes apoptosis (active complex).

    • The balance between these proteins is crucial for maintaining cell homeostasis and preventing tumorigenesis.

Genes Altered in Cancer Cells

There are two key classes of genes that, when mutated, contribute to cancer development:

Proto-oncogenes

  • Define proto-oncogenes as genes whose products promote cell growth and division under normal conditions.

  • When mutated into oncogenes, they contribute to cancer progression by causing uncontrolled cell growth.

  • An example is the ras proto-oncogene, which regulates cell growth and division.

Ras Oncogene Pathway

  1. Binding of growth factor to a cell-surface receptor initiates a cascade.

  2. The growth factor receptor catalyzes the exchange of GDP for GTP in the inactive Ras protein, activating it.

  3. The active Ras protein transmits signals through several downstream kinases.

    1. Ultimately, signals are sent to transcription factors to activate or repress gene transcription in response to growth signals.

  • If a mutation renders Ras continuously active (an oncogene), cell growth becomes uncontrolled.

  • Tumors can form due to either benign growth (non-invasive) or malignant growth (invasive, affects surrounding tissues).

Tumor-Suppressor Genes

  • Tumor-suppressor genes play a critical role in regulating the cell cycle and promoting apoptosis.

  • When mutated, these genes can become nonfunctional, leading to a loss of control at cell cycle checkpoints.

p53 Tumor-Suppressor Gene

  • The p53 gene is one of the most frequently mutated genes in human cancers, involved in about 50% of all cancers.

  • While p53 is continuously synthesized, it is rapidly degraded, maintaining low levels under normal conditions.

  • Cellular stress, such as DNA damage, increases p53 levels, leading to cell cycle arrest or apoptosis.

Mechanism of p53 Action

  • When DNA damage occurs, p53 accumulates and activates the transcription of various target genes involved in repair processes and apoptosis, such as p21 and BAX.

Cancer Stem Cells and Epigenetics

  • Cancer may also involve stem cells undergoing epigenetic changes leading to genetic mutations.

  • Cancer stem cells can remain quiescent but undergo uncontrolled growth, leading to metastasis.

Epigenetic Modifications

  • DNA methylation and histone acetylation are significant epigenetic changes that affect gene expression.

  • In normal cells, tumor suppressor genes regulate cell cycle and apoptosis.

  • In cancer, alterations can include:

    • Tumor suppressor genes becoming methylated and silenced

    • Proto-oncogenes being expressed due to loss of regulatory controls.

Conclusion

  • Understanding the intricate roles of oncogenes, tumor suppressor genes, and the mechanisms of cell cycle regulation can aid in the development of novel cancer therapies and prevention strategies.