Overview
This lecture explores the complex interactions between tumor cells, endothelial cells, and the gut microbiome in promoting cancer metastasis, with particular focus on gastrointestinal cancers and implications for therapy.
Cancer Metastasis and the Tumor Microenvironment
- Metastasis is a multi-step process where tumor cells spread and colonize distant organs.
- The tumor microenvironment (TME) consists of cancerous and non-cancerous cells, including fibroblasts, immune cells, and endothelial cells (ECs).
- Non-cancerous cells in the TME can promote tumor growth and metastasis.
- The pre-metastatic niche (PMN) refers to a microenvironment in distant organs that supports incoming tumor cells.
Pre-Metastatic Niche Formation
- PMNs form before tumor cells arrive, driven by tumor-secreted factors and bone marrow-derived cells.
- Increased vascular permeability and ECM remodeling are key steps in PMN formation.
- Stromal cells, fibroblasts, and specific proteins (e.g., S100, periostin, versican, collagen) assist PMN development and tumor cell seeding.
Endothelial Cells in Metastasis
- Metastasis involves tumor cell intravasation (entry) and extravasation (exit) across the endothelial barrier.
- ECs are altered by tumor factors (e.g., VEGF, TGF-β) to increase barrier permeability.
- Dysfunctional ECs promote inflammation and metastasis, while healthy ECs can inhibit progression.
- Chemokines and adhesion molecules facilitate tumor cell migration and adhesion to ECs.
Gut Microbiota’s Role in Cancer and Metastasis
- Gut microbiota (GM) dysbiosis is linked to gastrointestinal tumor development, especially colorectal and gastric cancers.
- Microbial metabolites (e.g., LPS, vacuolating toxin A, LCA) induce angiogenesis and increase vascular permeability, aiding metastasis.
- Some probiotics and bacterial products can inhibit angiogenesis and suppress tumor growth.
- Bacterial extracellular vesicles (BEVs) can cross barriers and reach systemic circulation, affecting distant organs and immune responses.
Interaction with Immunotherapy and Endothelium
- Immune checkpoint inhibitors (CPIs) enhance anti-tumor immunity but only work in some patients.
- The GM influences the efficacy of CPIs; higher microbiota diversity increases response rates.
- Specific bacteria (e.g., Bacteroides, Bifidobacterium, Faecalibacterium) enhance CPIs effectiveness via immune modulation.
- The endothelium and GM interact via bacterial metabolites, influencing vascular health and response to therapy.
- Metabolite examples: TMAO promotes thrombosis, SCFAs regulate immunity, H2S/NO/CO act on vascular tone.
Combined Therapeutic Strategies
- Combining anti-angiogenic therapy with CPIs and GM manipulation may enhance treatment responses.
- Anti-VEGF agents can boost immune cell infiltration and tumor control when used with CPIs.
- Clinical studies show improved survival in cancers treated with combined CPI and anti-VEGF therapy, suggesting the benefit of targeting all three pathways.
Key Terms & Definitions
- Metastasis — Spread of cancer cells from the original site to distant organs.
- Endothelial cells (ECs) — Cells lining blood vessels, regulating permeability and angiogenesis.
- Tumor microenvironment (TME) — The cellular environment around a tumor, including non-cancerous cells.
- Pre-metastatic niche (PMN) — Distant tissue microenvironment primed to support cancer cell colonization.
- Gut microbiota (GM) — The community of microorganisms living in the gastrointestinal tract.
- Angiogenesis — Formation of new blood vessels from existing vasculature.
- Immune checkpoint inhibitors (CPIs) — Drugs that block proteins inhibiting immune responses against tumors.
Action Items / Next Steps
- Review the mechanisms of PMN formation and how they facilitate metastasis.
- Study the effects of specific gut microbiota on endothelial function and tumor progression.
- Read about combined therapeutic approaches targeting the microbiome, angiogenesis, and immune checkpoints.