Asymmetry & Cancer Stem CElls Flashcards
What are the 6 hallmarks of cancer?
They are biological capabilities
- Sustaining proliferative signalling
- Evading growth suppressors
- Resisting cell death
- Enabling replicative immortaility
- Inducing angiogenesis
- Activating invasion and metastasis
What don’t the hallmarks of cancer tell us?
Non of them help us understand how cancer arises
What is the first cels that drives the start of cancer?
They are all just characteristsics of cancer cells
What were the previous ideas of the origin of cancer?
Oncogenes
Tumour suppressor genes
Mutations controlling the cell cycle
Theory that progressive growth of tumours was dependent on blood supply = angiogenesis
Triggered by failure of programmed cells death = apoptosis
Does aneuploidy cause cancer?
No it is a consequence of cancer
What does Harris H. propose the origin of cancer is?
Theory = initiating even in formaiton of malignant tumour is a block to some critical step in process of normal differentiation
Cancer is not a disease of mulitplication but differentiation
What is the logic behind thinking cancer is a disease of differentiation?
The reasons for this theory = Steady state of al cells is not “rest” but exponential multiplication
Only one natural process that restains exponential multiplication = differentiation
If cells do not require stimulation in order to multiply exponentially then the disordered cell multiplication seen in malignant tumours must be the result of an error in differentiation
Why aren’t all cells in our body equally likely to develop cancer?
Certain fraction = due to lifestyl (e.g smoking tagets lungs)
Theory = rate of stem cell division increases risk of devloping cancer because more mutation error risk
Checkpoint quality can decrease???
Only 1/3 of the variation in cancer risk among tissues = due to env factors or inherited predisposition
Majority is due to random mutation arising during DNA replication in normal, non-cancerous stem cells
What is neoplasia/neoplasm?
An abnormal mass of tissue that forms when cells grow and divide more than they should or do not die when they should.
Neoplasms may be benign (not cancer) or malignant (cancer). Benign neoplasms may grow large but do not spread into, or invade, nearby tissues or other parts of the body.
Malignant neoplasms can spread into, or invade, nearby tissues. They can also spread to other parts of the body through the blood and lymph systems. Also called tumor.
What outcome did the find when deleting APC in intestinal stem cells vs in transit-amplifying cells?
Deleting APC in stem cells caused cancer
Deleting APC in transit-amplifying cells did not cause tumour
What is APC?
Tmour suppressor gene that regulates Wnt
What is a transit-amplifying cell?
A type of progenitor cell found in various tissues
They arise from stem cells and undergo rapid proliferation to generate differentiated cells.
These cells have a limited lifespan and are characterized by a high rate of division, but they do not self-renew like stem cells.
Instead, their role is to quickly amplify cell numbers before they differentiate into the specific cell types of the tissue, such as enterocytes, goblet cells, or Paneth cells in the intestine.
What is tested to see if cancer is a disease of differentiation?
Test if failed asymmetric stem cell division can cause tumour-like growth
What is Numb?
Tumour suppressor
What does Numb regulate?
Regulates asymmetric cell division
During ACD, Numb is asymmetrically distributed between the two daughter cells. In one daughter cell, Numb inhibits the Notch signaling pathway. Notch signaling is crucial for maintaining stem cell-like properties and promoting cell proliferation. In the daughter cell that inherits Numb, the inhibition of Notch signaling leads to differentiation.
How does Numb inhibit Notch?
Numb directly interacts with Notch receptor in PEST domain
Once Numb binds to the Notch receptor, it facilitates endocytosis of the Notch receptor. Endocytosis is the process by which the cell internalizes proteins from the cell membrane into vesicles.
Numb’s role in endocytosis is partly mediated through its association with other proteins involved in vesicle trafficking. Numb helps recruit the AP-2 adaptor complex, which is involved in clathrin-mediated endocytosis, leading to internalization of the Notch receptor into the cell.
Once the Notch receptor is internalized, Numb facilitates its ubiquitination (marking it for degradation) through its interaction with the E3 ubiquitin ligase complex.
The ubiquitination of Notch signals for its degradation in the proteasome, a protein complex responsible for breaking down unneeded or damaged proteins. This degradation reduces the levels of active Notch in the cell, thereby inhibiting its ability to transduce signals.
How does Numb end up in ONLY one daughter cells?
Before division, the cell establishes polarity using the PAR complex.
The PAR complex helps orient the mitotic spindle along the apical-basal axis of the cell.
The protein Numb is localized to the basal region by interacting with the PAR-2 complex
What are the characteristiscs of tumour-like growths after failed assymetric stem cell division?
Genome instability
Show centrosome amplificaiton
Are immortal
Kill the host
How did they test if failed asymmetric stem cell division caused tumour growth?***
Mutating key genes involved in asymmetric division (e.g., Numb, Par3, aPKC).
Observing mutant Drosophila for tumor-like growths in tissues where asymmetric division is critical (e.g., the neuroepithelium).
Confirming tumor formation through in vivo observations of abnormal cell proliferation and loss of differentiation.
Performing histological analysis to identify tumor-like structures and confirming the role of Notch signaling in the process.
What was the experimental proof that stem cells can be the cell-of-origin of cancer?
Lgr5+ intestinal stem cells
What is the problems with many cancers after being treated?
They reappear
Why are tumours so difficult to get rid of?
Very heterogeneic
How can heterogeneity be measured?
scRNAseq
What is the hypothesis of the cause of cancer heterogeneity?
Cancer stem cells fuel the heterogeneity
What is the difference between stem cells and transit amplifying cells?
Stem cells = mostly quiescent, cery low division rate
TA cells = fast disivion rate
