Cell-Based Targeted Therapy Notes

Cell-Based Targeted Therapy

Conventional Therapy vs. Targeted Therapy

Conventional Therapy

  • Non-specific: targets both cancer and healthy cells.

  • High risk of side effects due to damage to healthy cells.

  • Cost-effective: generally less expensive.

  • Widely available.

How it Works:

  • Targets fast-dividing cells, which include both tumor cells and healthy cells.

  • Can lead to significant side effects due to the damage of healthy cells.

  • May not target cancer stem cells (non-dividing), potentially leading to cancer relapse.

Targeted Therapy

  • Specific: precisely targets cancer cells.

  • Low risk of side effects due to specificity.

  • More expensive than conventional therapy.

  • Availability may be limited.

How it Works:

  • Aims to achieve long-term remission by specifically targeting tumor cells.

  • Results in fewer side effects by sparing healthy cells.

Radiotherapy and Cancer Stem Cells

  • Radiotherapy can 'awaken' cancer stem cells, leading to tumor relapse and metastasis.

  • Effective treatment initially shrinks or eliminates the tumor, but some quiescent cancer stem cells (CSCs) survive.

  • These awakened CSCs can become metastatic.

CSC Response to Radiotherapy

  • Initial Treatment:

    • Tumor shrinking or disappearance.

  • Failed Treatment:

    • Quiescent CSCs are awakened.

    • These awakened CSCs can lead to tumor relapse.

    • Tumor has the potential to metastasize.

Tumor Microenvironment

  • Radiotherapy modifies the tumor microenvironment by inducing cytokine expression and reducing oxygen levels (increased hypoxia).

  • This modified microenvironment promotes angiogenesis, facilitates immune evasion, and creates a supportive niche for cancer stem cells, enhancing their survival and metastasis.

Key Factors

  • Cytokines:

    • EGF levels increase.

    • IL6 levels increase.

    • HGF levels increase.

    • HIF-1 levels increase.

    • VEGF levels increase.

  • Modified Microenvironment Effects:

    • Enhanced radioresistance.

    • Enhanced angiogenesis.

Cancer Stem Cell (CSC) Development

  • CSCs were first identified in leukemia (1994).

Process

  • Normal stem cells can become CSCs through a multi-step process:

    1. Initiation:

      • First hit (mutations) due to DNA damage or environmental stressors.

      • Normal stem cell transforms into a pre-CSC.

    2. Promotion:

      • Second hit (genetic/epigenetic changes).

      • Pre-CSC transforms into a CSC.

    3. Progression:

      • CSCs enhance self-renewal and proliferation, leading to resistant clones.

Two-Hit Hypothesis

  • The 'two-hit' hypothesis explains how normal cells evolve into cancer stem cells.

    • 1st Hit:

      • Mutations occur, transforming a normal stem cell into a pre-CSC.

    • 2nd Hit:

      • Further genetic or epigenetic changes transform the pre-CSC into a CSC.

Environmental Changes and Cancer Development

  • Environmental factors play a significant role in cancer development.

  • Twin studies show that even with identical genetic backgrounds, different environmental exposures can lead to different cancer outcomes.

Process

  • Normal Stem Cell:

    • 1st hit (genetic mutations) $\rightarrow$ pre-CSC.

    • 2nd hit (epigenetic/environmental changes) $\rightarrow$ CSC.

  • Example: BRCA1 promoter hypermethylation.

  • Genetic mutations can occur before birth.

  • Epigenetic/environmental changes can occur after birth.

Hypermethylation and BRCA1 Expression

  • Hypermethylation (epigenetic silencing) represses BRCA1 expression.

  • BRCA1 promoter hypermethylation is observed in malignant breast tumors (MBTs) and normal adjacent tissue (NATs).

  • MBTs:

    • 41.67% show BRCA1 promoter hypermethylation.

    • This is a biomarker of aggressiveness and a potential early event of breast tumorigenesis.

  • NATs:

    • 46.67% show BRCA1 promoter hypermethylation.

    • This may be a potential early event of epigenomic instability.

BRCA1 and Stem Cell-Based Therapy

  • BRCA1 is a critical DNA repair gene involved in maintaining genomic stability.

  • Epigenetic silencing of BRCA1 impairs the cell's ability to repair DNA, leading to genomic instability and mutations.

Implications

  • Tumor Tissue:

    • Epigenetic silencing of BRCA1 leads to transcriptional suppression.

    • Constitutive exon methylation occurs.

  • Normal Tissue:

    • BRCA1 expression is maintained through an unmethylated promoter.

    • Constitutive exon methylation occurs.

Restoring BRCA1 Function

  • Nanoparticle-based delivery of the BRCA1 gene leads to significant reductions in tumor growth in breast cancer mouse models.

    • This enhances BRCA1 expression and suppresses oncogenic pathways.

  • Epigenetic editing restores BRCA1 function.

    • Reversing promoter hypermethylation reactivates BRCA1 gene expression.

    • This enhances its tumor-suppressing activity.

Tumor Microenvironment and Immune Cells

  • Tumor cells interact with immune cells in the tumor microenvironment.

  • Tumor cells recruit and manipulate immune cells by secreting specific molecules that change immune cell behavior, turning them into pro-tumor cells.

  • Pro-tumor immune cells help cancer cells