Tumour Microenvironment and Metabolism Lecture Notes

Tumour Microenvironment

• Definition: Refers to the immediate, local environment of the tumour, including various supporting elements surrounding the cancer cells.
• Key Components: Cancer cells, inflammatory cells, blood vessels, fibroblasts, extracellular matrix (ECM), and signaling molecules.
• Analogy: A tumour is seen as a 'wound that does not heal' (Dvorak, NEJM 1986), which is characterized by chronic inflammation, persistent hypoxia, and ongoing angiogenesis.

Wound Healing Process Breakdown

1. Hemostasis

   • Platelets enter blood vessel breaches.
   • Blood vessels become leaky, allowing plasma proteins to enter.
   • Platelets activate clotting factors, forming platelet plugs and fibrin clots to stop bleeding.

2. Inflammation

   • Inflammatory cells, including neutrophils and macrophages, enter the wound from the bloodstream.
   • Neutrophils fight infection and secrete cytokines to recruit further immune/inflammatory cells.
   • Macrophages clear debris and secrete growth factors (like TGF-β, VEGF) to promote tissue repair and angiogenesis.

3. Proliferation and Remodeling

   • Epithelial cells migrate into the wound site, proliferating and covering the area while producing extracellular matrix components (e.g., collagen).
   • Fibroblasts in connective tissue participate in wound healing, contract the wound, produce ECM, and secrete signaling molecules.

Tumours as Non-Healing Wounds

• Tumour cells exhibit characteristics similar to chronic wounds:
  • Chronic inflammation leads to cancer-associated fibroblasts and immune evasion.
  • Sustained hypoxia results in ongoing angiogenesis to restore blood supply (HIF1α activation).
  • Promotes cancer cell survival, proliferation, and metastasis.

Cancer Cell Metabolism

• Definition: Series of biochemical reactions responsible for energy generation, biomolecule production, and waste elimination.
• Influence of the Tumour Microenvironment:
  • Increased energy demands due to rapid proliferation.
  • Impaired access to oxygen and nutrients, competition for resources, and poor blood supply.

Aerobic vs Anaerobic Metabolism

• Normal Metabolism:

  • Glucose is converted into pyruvate, then into acetyl-CoA, entering the TCA (Krebs) cycle, generating approximately 32 ATP per glucose.

• Anaerobic Glycolysis:

  • Under hypoxic conditions, pyruvate is turned into lactate, yielding only 2 ATP.
  • This shift is known as the Warburg phenomenon, where tumours preferentially use glycolysis for ATP generation even in the presence of oxygen.

Oncogenic Signaling and Warburg Phenomenon

• Oncogenic pathways (e.g., PI3K/AKT/mTOR) upregulate HIF1α, promoting lactate production over oxidative phosphorylation, essential for rapid cell proliferation and biomolecule synthesis.

Clinical Applications

• PET Scans: Tumours consume glucose at a higher rate; injected with 18F-deoxyglucose (FDG) helps visualize cancer distribution based on glucose metabolism.

Glutamine Metabolism

• Some cancers rely on glutamine for ATP and biomolecule generation, regulated by oncogenes like MYC.

Autophagy in Tumour Cells

• Process where cells digest their own organelles and biomolecules, activated under stress (hypoxia, nutrient deprivation), serving as a survival mechanism.

Effects of TCA Cycle Gene Mutations

• Mutations in TCA cycle genes can serve as tumour suppressors or oncogenes, contributing to cancer predisposition through a 'pseudo-hypoxic' phenotype.
• Mutant IDH1/IDH2: Converts α-KG to D-2-HG, leading to epigenetic changes and inhibition of differentiation.

Summary: Altered Metabolism in Cancer Cells

• Metabolic adaptations driven by hypoxia, nutrient demands, oncogenes, and loss of suppressors.
• Shift to glycolysis for energy production (Warburg phenomenon).
• Increased glutamine utilization and enhanced autophagy as survival mechanisms.
• Targeting altered metabolism in cancer treatment, exemplified by IDH inhibitors (e.g., vorasidenib) in clinical trials.