Cancer Biology and Cell Cycle Control

Cancer Cell Characteristics

• Cancer cells exhibit several distinct characteristics:
  • They grow without external signals.
  • They do not undergo apoptosis (programmed cell death) when damaged or old.
  • They pile on top of each other, forming masses.
  • They develop their own vasculature (angiogenesis) to supply nutrients.
  • They can metastasize, spreading to other parts of the body.

Cell Cycle Review

• The cell cycle is a tightly controlled process with distinct phases:
  • Interphase:
  • G₀: Non-dividing state.
  • G₁: Cell growth and preparation for DNA replication.
  • S: DNA replication occurs.
  • G₂: Further growth and preparation for mitosis.
  • M Phase:
  • Mitosis: Nuclear division (prophase, prometaphase, metaphase, anaphase, telophase).
  • Cytokinesis: Cell division.
• The steps of the cell cycle are very tightly controlled.
• The process starts with a mother cell, and ends with two daughter cells.

Cyclin-Dependent Kinases (CDKs) and Cyclins

• CDKs (Cyclin-Dependent Kinases):
  • Always present in the cell.
  • Not always functional; their activity depends on cyclins.
• Cyclins:
  • Present only during specific stages of the cell cycle.

Regulation of CDKs by Cyclins and Phosphorylation

• Cyclin Binding: Cyclins bind to CDKs, forming a CDK-cyclin complex.
• Phosphorylation:
  • The CDK-cyclin complex can then phosphorylate target proteins, activating or inactivating them.
  • Phosphorylation can either activate or inactivate CDKs, depending on the specific CDK and the site of phosphorylation.

Example: Lamins

• Phosphorylation of Lamins:

  • CDKs phosphorylate lamins, which are components of the nuclear envelope.
  • This phosphorylation causes lamins to become soluble.
  • Consequently; leading to the dissolution of the nuclear membrane during cell division.

• Dephosphorylation:

  • Phosphatases remove phosphate groups, reversing the effects of CDK phosphorylation.

CDK Activation and Inactivation via Phosphorylation

• CDKs can be phosphorylated to affect their function.
• Phosphorylation at one site can inactivate CDK (e.g., CDC2 in yeast).
• Dephosphorylation at another site can activate CDK (e.g., CDC2 in yeast).

Retinoblastoma Pathway

• The retinoblastoma pathway illustrates the complexity of cell cycle control.
• CDKs and cyclins promote cell growth in this pathway.

Cell Cycle Checkpoints

• Checkpoints prevent cell growth if there are issues with:
  • DNA damage (G1 and G2 checkpoints).
  • Microtubule attachment (M checkpoint).
• These checkpoints serve as quality control mechanisms.

G1 Checkpoint and p53

• p53's Role:

  • Environmental mutagens cause DNA damage, such as double-strand breaks.
  • Double-strand breaks induce the p53 gene, leading to p53 protein synthesis.
  • p53 functions as a transcription factor.

• p53's Actions:

  1. Activates genes that promote DNA repair.
  2. Activates genes that arrest cell division, repressing genes required for cell division.
  3. Activates genes that promote apoptosis if the damage is irreparable.

• Outcomes:

  • p53 causes cell cycle arrest via CDK/Cln to allow time for DNA repair.
  • Without p53, there is no time for repair, leading to accumulation of mutations.
  • If there is too much damage, p53 induces apoptosis.

G2 and M Checkpoints

• G2 Checkpoint:
  • Arrests the cell cycle to provide time to repair DNA damage.
• M Checkpoint:
  • Arrests the cell cycle to ensure proper microtubule attachment, preventing non-disjunction.

Extracellular Signals and Cell Growth

• Extracellular signals can promote cell growth through:
  • Protein shape changes and modifications.
  • Growth factors.
  • Growth factor receptors.
  • Intracellular signaling factors.
  • Transcription factors.

Tumor Suppressor Genes

• Genes that encode proteins that prevent cell growth (e.g., checkpoints) or repair DNA damage are called tumor suppressor genes.
• They maintain genome integrity.

Proto-oncogenes

• Genes that encode proteins that promote cell growth (e.g., CDKs/Clns or extracellular signaling proteins) are called proto-oncogenes.

Oncogenes

• All genes are susceptible to spontaneous or induced mutations.
• A mutation in a proto-oncogene produces a mutant form called an oncogene.
• Tumor suppressor genes with mutations are called mutant tumor suppressor genes.

Translocation Example: Philadelphia Chromosome

• The translocation causes chronic myelogenous leukemia.
• Mechanism:
  • Normal chromosomes 9 and 22 undergo an abnormal crossover.
  • This results in the Philadelphia chromosome, which contains a fusion gene called bcr-abl.
  • The abl oncogene promotes cell growth constitutively (ALWAYS).

Tumor Suppressor Genes and Recessive Mutations

• Mutant tumor suppressor genes cannot prevent cell growth because their function is lost (recessive).
• However, they can appear dominant in a pedigree because only one "hit" (mutation) is required in a cell to make it homozygous recessive for the loss-of-function mutation.

Epigenetic Changes in Cancer

• Epigenetic changes that affect gene expression are also involved in cancer, leading to over- or under-expression of genes.

Table 25.5: Mutations in Genes Encoding Chromatin-Modifying Proteins

Progression of Colon Cancer

• Many mutations must arise in cell cycle control genes in the same cell for cancer to progress.
• Steps:
  1. Normal mucosa cells of the colon.
  2. Loss of APC tumor-suppressor gene on chromosome 5 leads to cell division continuing.
  3. Small polyp (benign).
  4. Class I adenoma (benign).
  5. Activation of ras oncogene on chromosome 12.
  6. Class II adenoma (benign).
  7. Loss of DCC tumor-suppressor gene on chromosome 18.
  8. Class III adenoma (benign).
  9. Loss of p53 tumor-suppressor gene on chromosome 17.
  10. Class IV carcinoma (malignant).
  11. Other mutations lead to metastasis.

Cancer Cell Karyotypes

• Cancer cell karyotypes barely look human due to loss of checkpoint control, leading to aneuploidy and rearrangements.

Cancer Treatments

• Treatments for cancer include:
  • Radiation.
  • Chemotherapy.
  • Radiochemotherapy.
  • Radioimmunotherapy.

Molecular Profiling for Better Treatments

• Gene expression profiling can identify distinct types of diffuse large B-cell lymphoma.
• Cluster analysis helps in molecular profiling.
• Patient outcomes vary based on the type of lymphoma (Germinal center B-like cells vs. Activated B-like cells).

Recent Breakthroughs in Cancer Treatment

• There have been new breakthroughs in the fight against cancer as of February 27, 2025, according to the World Economic Forum.