Metastasis Flashcards
EMT in wound healing ?
Growth factor TGF-Beta induces EMT by upregulating transcription factors (Snail, slug). These supress epithelial markers (E-cadherin) and promote mesenchymal markers (N-cadherin). Fibroblasts are also differentiated into myofibroblasts, repairing and remodelling tissue. This causes a favorable environment for tumors to appear (angiogenesis)
Seeding from primary tumor ?
Cancer cells invade surrounding tissues by breaking down the ECM between tissues. They can then intravasate : penetrate vessels = entering circulatory or lymphatic systems
How do CTCs survive ?
- Resistance to shear forces : Blood flow exert forces, CTCs can have increased flexbility and diff. cell shapes to avoid physical damage
- Immune evasion : Downregulating MHC1 (NK cells) and upregulating PD-L1 (cytotoxic T cell)
- Anoikis (cell death triggered by loss of cell adhesion to ECM) resistance
- Clusters formation : better survival and shear force res., extravasate more
- Express survival pathways to counter cell apoptosis
CTC extravasation ?
CTCs stop at a vessel wall, and undergo transendothelial migration to penetrate the endothelial cell layer. They then form micrometastases = proliferate and become secondary tumors
Dormancy ?
CTCs arrest their cell cycle. Niche signaling (ECM, TGF-Beta) promote dormancy. Hypoxia promote cell cycle arrest and dormancy as well. Autophagy (recycle cellular components) to survive.
What can wake up dormant cells ?
Hormonal changes, stress (norepinephrine), Wnt pathway, reduction in immune surveillance, tissue injury etc.
What are the implications of tumor heterogeneity ?
Tumor heterogeneity means a diverse cell population within a single, or diverse tumors across body.
- Biopsy cannot capture the full extent of the heterogeneity.
- Prognostic difficult
- Drug resistance
- Adaptive resistance (natural selection)
- Combination therapies should be explored
What is a wound healing assay ?
Experiment where cells are cultured until confluence. A scratch is inflicted, and the migration of the cells into the cell-free area or wound, is analysed. Analysis can be either done manually by measuring wound width or with an analysis software.
Useful for assessing anti-cancer drugs.
Cell tracking assay ?
Cells are labeled with fluorescent dyes and their migration is recorded. Good for testing anti-cancer drugs on cell motility and proliferation.
Transwell cell invasion assay ?
Experiment mimicking cell invasion in tissues. Top chamber membrane coated with ECM or a mimicking coating. Chemoattractant in bottom chamber.
Good for evaluating anti-cancer drugs targeting cell invasion and metastasis.
Cell spreading assay ?
Study cell adhesion on coating, and how they spread
Metastasis mimicking microenvironment ?
Advanced in vitro or in vivo model closely replicating conditions cancer cells encounter when they spread. Many models exist.
More accurate than traditional 2D cultures, can control the conditions (hypoxia, growth factors, cytokines etc.), but very complex and costly, no whole-organism interactions.
Why is bone marrow a reservoir for DTCs ?
- Environment rich in blood supply
- Hypoxic zones : signals to go dormant
- Relatively immunosuppressed environment
- Involved signaling pathways : TGF-B, Wnt, Notch = induce quiescent state
What is a liquid biopsy ?
Technique where bodily fluid is taken (blood, urine, cerebrospinal fluid…) and analyzed for :
- CTCs
- cell-free DNA : DNA fragments released by apoptotic and necrotic cells
- circulating tumor DNA : DNA fragments of tumors with mutations characteristic of the cancer
- EVs : proteins, lipids, miRNA : informs on cell origin and tumor status
BRCA1 gene ?
BRCA1-methylation on ctDNA correlates with improved survival of patients with ovarian cancer.
