Cellular Mechanisms in Cancer: Pathways, Genes, and Therapies

Posted on Sep 10, 2025 in Biology

Cellular Pathways

This section details key cellular signaling pathways and processes fundamental to cell function and often dysregulated in cancer.

MAPK Pathway

The Mitogen-Activated Protein Kinase (MAPK) pathway promotes cell growth, proliferation, differentiation, survival, and resistance to apoptosis. Its activation cascade is as follows:

  1. Raf activates Ras.
  2. Ras activates MEK (MKK).
  3. MEK activates ERK.
  4. ERK activates RSK.
  5. RSK (in the nucleus) activates CREB.

Caspases and Apoptosis

Caspases are enzymes that play a key role in programmed cell death (apoptosis). The process involves:

  1. Initiator procaspases aggregate and activate each other.
  2. This initiates cytochrome c release from mitochondria.
  3. Cytochrome c binds to Apaf-1, triggering procaspases to become active caspases.
  4. A chain reaction of caspases leads to cell death.

Targeting apoptosis is a strategy in cancer treatment, for example, by inhibiting Bcl-2/x or upregulating Bax/Bak.

Cyclins and CDKs

Cyclins and Cyclin-Dependent Kinases (CDKs) bind together, triggering a cascade of phosphorylation that drives the cell cycle. This process can be inhibited by:

  • Proteins p16 or p21.
  • Phosphorylating CDK at Threonine 14 (Thr14) and Tyrosine 15 (Tyr15).

Cellular Receptors

Receptors are crucial for cells to receive and respond to external signals.

G-Protein Coupled Receptors

These receptors have alpha (α), beta (β), and gamma (γ) subunits. Their activation mechanism includes:

  1. The alpha subunit exchanges GDP for GTP.
  2. The alpha subunit dissociates from the beta and gamma subunits.
  3. GTP hydrolyzes to GDP and a phosphate, which can then be used by kinases to activate downstream proteins.
  4. The complex eventually returns to its normal, inactive state.

Receptor Tyrosine Kinases

Receptor Tyrosine Kinases (RTKs) are vital for cell growth and differentiation. Their activation involves:

  1. Two receptors dimerize upon ligand binding.
  2. Cross-phosphorylation occurs between tyrosine residues on the receptors.
  3. ATP binds, leaving a phosphate group and becoming ADP.
  4. This phosphorylates proteins that activate downstream pathways.

Key Genes in Cell Regulation

Genes play a critical role in controlling cell growth, division, and death. Dysregulation of these genes is central to cancer development.

Oncogenes

Oncogenes are genes that promote the cell cycle and cell proliferation. Examples include:

  • HER2: Signals cells to grow and divide.
  • Ras: Promotes the MAPK pathway (can be inhibited by SOS).
  • EGFR: A growth factor receptor that binds to receptor tyrosine kinases, regulating cell growth, survival, proliferation, and differentiation.
  • Bcl-2/x: Anti-apoptotic proteins that inhibit the release of cytochrome c, thereby preventing cell death.

Tumor Suppressor Genes

Tumor suppressor genes hinder the cell cycle and promote apoptosis, acting as the ‘brakes’ on cell division. Examples include:

  • p53: Forms an inhibitor that inactivates cyclin/CDK complexes.
  • Rb: Binds to E2F, stopping the S-phase checkpoint. It also recruits HDACs, which keep chromatin condensed, silencing transcription.
  • BRCA1: Involved in repairing double-strand DNA breaks through homologous recombination, controlling cell cycle checkpoints, and helping prevent harmful mutations from accumulating. Mutations can lead to genomic instability.
  • Bax/Bak: Pro-apoptotic proteins that induce the release of cytochrome c.

Cancer Hallmarks

These are the fundamental biological capabilities acquired by cancer cells during their development.

Evading Growth Suppressors

Cancer cells inhibit the ‘brakes’ of cell division and inactivate tumor suppressor pathways, leading to an unchecked cell cycle. This often involves dysregulation of genes like:

  • p53
  • Rb
  • BRCA1/2

Cancer cells also ignore contact inhibition, allowing uncontrolled growth.

Sustaining Proliferative Signaling

Cancer cells keep the ‘gas pedal’ on for growth by overexpressing growth factors or overactivating receptors. Signaling can remain active even without a ligand if the receptor is mutated. Key players include:

  • Ras
  • HER2
  • Cyclin D

Avoiding Apoptosis

Cancer cells bypass the cell’s natural mechanism for self-destruction, preventing tumor spread. This can involve:

  • Inactivating Bax.
  • Overexpressing Bcl-2.
  • Upregulating survival pathways like Akt.

Necrosis: Unlike apoptosis, necrosis is an unorganized form of cell death. Tumor cells can benefit from necrosis as dying cells release signals that support tumor growth and survival, potentially leading to a chain reaction of necrosis.

Enabling Replicative Immortality

Cancer cells bypass the normal cell replication limit, allowing them to divide indefinitely and avoid senescence. This is often achieved by:

  • Overexpressing TERT, which leads to telomerases constantly lengthening telomeres.

Telomerase: A protective cap at the end of chromosomes that normally shortens with each cell division, limiting replication.

Cancer Treatment Strategies

Various approaches are used to target cancer cells and their underlying mechanisms.

  • CRISPR-Cas9 and dCas9: Gene editing tools that can potentially upregulate or silence specific cancerous genes.
  • RNA interference (RNAi): Helps silence certain cancerous genes by degrading their mRNA.
  • Small Molecule/Antibody Competitive Inhibitors: Inhibit proteins that promote the cell cycle or other pro-cancerous pathways.
  • Antisense Oligonucleotides (ASOs): Inhibit translation of specific mRNA sequences, thereby reducing the production of harmful proteins.

Pharmacological Concepts

Understanding these concepts is crucial for developing and evaluating cancer therapies.

Maximum Tolerated Dose (MTD)

The highest dose of a drug that a patient can tolerate without experiencing unacceptable severe side effects.

Selectivity Index (SI)

An equation that models how toxic a drug is to pathogens (or cancer cells) versus normal cells. It is calculated as:

SI = MTD (concentration that kills 50% of healthy cells) / Effective Dose (concentration that achieves 50% of desired effects)

  • SI > 10: The drug is significantly more toxic to the target (pathogen/cancer cells) than to normal cells, indicating a safer profile.
  • SI < 2: The drug is more toxic to healthy cells, suggesting a less safe profile.

Improved Selectivity

The goal of making a treatment specifically target only the desired cells or pathways, minimizing harm to healthy tissues.

Survival Rate

A measure of how long patients survive after diagnosis or treatment. A high survival rate, especially when combined with a high Selectivity Index and low toxicity, indicates a successful treatment.