Tumour Cells part 3 Flashcards
Tumour cells, like oxygen-starved tissues, stimulate angiogenesis
Also seen, e.g., in inflammation and wound healing
- HIF (Hypoxia-inducible factor) is a transcription factor expressed when oxygen tension is low
- Vascular endothelial growth factor (VEGF) is made in response
- Tumours use this pathway (but remain hypoxic)
- Blockade of VEGF can be used to limit the growth of some tumours (and other types of abnormal blood vessel growth, e.g., in macular degeneration, a cause of blindness)
Invasion and Metasis
Invasion and metastasis involve additional changes in cell behaviour
Cross basement membrane (specialised enzymes)
Migrate across blood and lymph vessel walls (changes in adhesion, cytoskeleton)
Invade and survive in different tissues
Recruit fibroblasts and inflammatory (white blood) cells (subvert inflammatory and wound healing responses to tissue injury)
Recruit growth of new blood vessels (tumour angiogenesis)
The concept of the cancer stem cell
Mutations must accumulate in longlived cells
- Loss of genome stability aids this process, and allows drug-resistant variants to emerge
- Most tumour cells proliferate actively, but few can regenerate a tumour when transplanted into immunodeficient animals
- Treatment directed against dividing cells often shrinks the tumour but does not kill all cancer stem cells relapse
- Stem cells are often multidrugresistant, thus harder to kill
- Profound implications for treatment!
Cancer stem cells may divide less frequently and are harder to kill by treatments that target excessive cell growth (multidrug-resistant)
May account for tumour relapse New approaches to therapy needed
Stem C cells
Cancer stem cells may divide less frequently and are harder to kill by treatments that target excessive cell growth (multidrug-resistant)
May account for tumour relapse New approaches to therapy needed
What are some of the treatments of C ?
Surgery
Chemotherapy
radiotherapy
What are some of the effects /disadvantges ?
Not all tumours are operable •
Radiotherapy is only effective in few tumours
- Chemotherapy does not kill all cancer cells (risk of relapse
- Chemotherapy does not distinguish between cancer cells and healthy dividing cells (hair, colon epithelium
Cancer develops resistance to chemotherapy
Obstacles to c therapy
Many tumours re-emerge after successful initial therapy, then relapse as drug-resistant variants
The ability to mutate is a mechanism for generating drug resistance This can be made less likely by combination therapy
Multidrug resistance can come from increased expression of transmembrane proteins, which actively pump out many cytotoxic drugs
News strategies for cancer treatment
Oncogene addiction
Precision medicine
Gene therapy
Synthetic lethality
Immunotherapy
Targeting the cancer stem cells
Epigenetic inhibitors
Cancer treatment: Oncogene addiction
Cancer treatment: Oncogene addiction
• Aimed to block fusion protein •
80% of patients showed disappearance of cells carrying Philadelphia chromosome
gene therapy p53
Lung cancer clinical trials on p53 therapies have demonstrated notable success. Phase I and II studies proved that this treatment is not only safe, but also far less harmful to healthy cells than chemotherapy.
After three months, 63 percent of patients had no detectable signs of cancer.
Stem cell therapy in cancer: bone marrow transplantation
Not a treatment for cancer •
But a treatment for side effects of anti-cancer drugs
All blood cells ultimately originate from a stem cell in the bone marrow
A way to replace blood cells after intensive chemotherapy: Bone marrow transplantation
To treat genetic or toxin-induced defects in blood cell renewal Allows more aggressive chemotherapy in patients with leukaemias/lymphomas (which also kills normal BM)
From same donor (autologous) or another donor (allogeneic) Whole bone marrow or blood-forming stem cells
Cells are harvested from bone marrow and transfused into a vein Cells normally circulate in blood and migrate spontaneously to correct location (they “know” where to go)
Summary: cell replacement therapy
Best established for human blood
Transfuse bone marrow (whole or purified stem cells)
Restores entire blood forming system
Permanent replacement, but many issues
What are the cellular outcomes of p53 activation? •
P53 can induce temporary and permanent arrest of cell cycle, DNA damage repair and apoptosis
Name a target gene of p53.
p21
Is RB a transcription factor?
No RB is an inhibitory proteins that binds and sequester E2F
