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Lecture 27

BIO315H5 Lecture 27: BIO315 - Lecture 27

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Hai- Ying Mary Cheng

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Lecture 27
pI3K/mTOR pathway:
Must be increase in cell growth to keep up with cell division
Starts with RTK at the cell plasma membrane (ex. IGFR) that activates the PI3K (lipid
kinase that converts PIP2 to PIP3) that leads to activation of protein kinase Akt, which
activates mTOR (another kinase) that mediates increased protein synthesis and can
increase uptake of glucose from extracellular space by increasing expression of glucose
Cells need glucose for energy and building blocks - increased glycolysis from Warburg
Increased pyruvate and lipid synthesis
Anything that participates in a positive manner in this pathway is considered a proto-
oncogene because by making the overactivity of this pathway promotes cell growth
Ex. RTKs, PI3K
Anything that puts a break on this pathway is a tumour suppressor gene
Ex. PTEN - phoshatase of PIP3 -> PIP2?
P53 pathway:
Usually expressed in low abundance
After pathway is turned on, levels increase and p53 act as transcriptional activator of
genes in cell cycle arrest and apoptosis
DNA Damange: ATM/ATR pathway?, MDM2
P53 = tumour suppressor
Origins of genome instability
Reason why cancer cells are genomically instable differs between cancer types
Ex. breast cancer - high level of inactivation of BRCA1 and BRCA2 (breast
cancer-associated genes). Mutations or epigenetic silencing. Needed to repair
ds-breaks through homologous recombination, so cells wont be able to fix
damaged DNA
Ex. colorectal cancer - mutations of DNA mismatch repair genes
Different cancers use different routes:
Ras/MAPK kinase pathway
Pathways have distinct upstream regulators at level of receptors
Ex. glioblastoma can have mutations at EGFR that is upstream of Ras
Cancer-critical genes
Can be studied and discovered from genetic models - mouse models
If you think a gene is involved in cancer development, you can knockout or
overexpression that gene in a mouse - transgenic model
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Functions of cancer-critical genes
Graph: all overexpression of genes. Rapid decrease in tumour-free mice with double
Heterogenous mutations
Rounds of random mutations followed by natural selection
One of the descendants acquire a second mutation that gives it a bigger advantage and
lets it proliferate more
Mutations that don’t help with proliferation don’t become the dominant clone in the tumor
Driver mutations
Cause of tumour development
Passenger mutations - don’t confer selective advantage and are not selected for
Over time can get diluted out while driver mutations become dominant
Recent common ancestor - here is the ancestral mutation
Blackbox of cancer metastasis
Cancer metastasis - When cancer in primary tumour escapes from its primary site where
it initially grew and ends up in foreign sites at other tissues
Two major steps in metastasis:
Invasion (when the cancer cells in primary site start to invade the surrounding
tissue that has normal cells) - before this state, oncologists will see a solid mass
with smooth edges. Invasiveness comes because the cancer cells have lost
certain genes for cell-to-cell adhesion. Similar to process called EMT - changes
in expression of adhesion molecules like cadherins. Invasion comes as lose of
cadherin expression (tumour suppressor gene)
Colonization - must successfully populate a foreign site - become independent of
factors from the primary site
Micrometastasis - attempt to grow colonies that are unsuccessful due to
lack of dependent local factors from original microenvironment
Tumour angiogenesis - formation of new blood vessels into a tumour mass
Once a tumor reaches a certain mass, the centre of the mass will become
hypoxic and it will be harder for nutrients to reach the centre of the mass
Triggers formation of new blood vessels - poorly constructed, leaky, and make it
easy for tumour cells to get into the bloodstream
1) Aid in metastasis and 2) bring oxygen and nutrients into centre of mass
Triggered by hypoxia or low O2 levels
Cancer stem cells
Most primitive cells
Normally in stem cells, Two important properties: totipotency (can differentiate into
different cell types) and self-renewal (divide in asymmetric fashion - one cell is a stem
cell and the other cell is the transient-amplifying cell; can divide indefinitely and will
never lose the original cell)
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