Cancer Flashcards
Hallmark 1: growth signal autonomy
Examples for each type of mutations which allows cancer cells to proliferate independently
Cell signalling molecules: constitutive activation of protein
Constitutive activation of signal transduction proteins → continuous intracellular signalling in the absence of receptor-ligand binding
ras
BRAF
PI3K
Process of normal cellular proliferation
- binding of GF to its specific receptor
- transient and limited activation of GF receptor
- cascade of biochemical events with eventual signal transduction to the nucleus
- induction and activation of nuclear regulatory factors that initiate DNA transcription
- expression of genes involved in cell growth and cell cycle progression
Hallmark 2: evading growth suppressors
Function of APC gene
Forms destruction complex in the absence of WNT ligands that keeps beta-catenin levels in check
Beta catenin (when elevated in intracellular concentration) will activate genes involved in cell proliferation
Cause of cancer
Accumulation of mutations on key genes that control cell growth/proliferation (gene itself or epigenome that affects the regulation of gene expression) leading to dysregulation of growth control pathways
Proto-oncogene (growth promoting)
TSG (growth inhibiting)
Genes that regulate apoptosis
Genes involved in DNA repair
Similarity between benign and malignant tumour
both autonomous, uncontrolled growth of cells which result in the formation of an abnormal tissue, and the proliferation does not cease even when stimulus is removed.
hallmark 6: activating invasion and metastasis
what is the process of invasion-metastasis cascade
- tumour growth
- loosening of tumour cells from each other, and cells become mobile (epithelial-mesenchymal transition, EMT)
- cancer cells breach the underlying basement membrane
- traverse the interstitial connective tissue
- gain access to the circulation by penetrating the vascular basement membrane
- transit through the vasculature
- extravasate from the vessels at distant sites
- form micrometastases, followed by growth into macroscopic tumours via angiogenesis
Hallmark 3: resisting cell death
Molecular pathogenesis of b cell follicular lymphoma
Juxtaposition of BCL2 gene next to the IGH gene leads to the overexpression of BCL2 protein because the promoter of IGH gene is very active in B cells
overexpression of antiapoptotic moledule BCL2 → reduces egress of cytochromie c from mitochondria → prevents cell death by apoptosis → predisposes the cells to transform into lymphoma
What is an oncogene
Mutated version of proto-oncogene that produce an aberrant protein that stimulates cell division or proliferation, even in the absence of proper growth signals
Acts in a dominant manner (requires 1 aberration)
Gain in function mutation
Increases activity/quantity of product
Hallmark 6: activating invasion and metastasis
Requirements for invasion-metastasis cascade to proceed
Inactivation of E-cadherin function and epithelial mesenchymal transition to allow for loosening of tumour cells
Secretion of proteolytic enxzymes (Eg. metalloproteinases) to allow for cancer cells to traverse the interstitial connective tissue
what are the emerging hallmarks of cancer
deregulating cellular energetics
avoiding immune destruction
Enabling factor 1: genome instability and mutation
What are the genetic charateristics of patients with MMR deficiency
Microsatellite instability (changes in length of short tandem repeating sequences throughout the genome)
Enabling factor 1: genome instability and mutation
How do defects in DNA mismatch repair mechanisms predispose a cell to cancer
Loss of MMR proteins renders DNA mismatch repair inefficient
MMR deficiency greatly increases the mutation rate → facilitates acquisition (and accumulation) of multiple mutations in oncogenes and tumour suppressor genes → generates hypermutable phenotype → promoting the process of carcinogenesis
Parameters of GRADING of cancer?
Parameters include architecture, cell morphology and mitotic activity.
Grade of the tumour correlates with the degree of maligancy of the of the tumour and therefore with the prognosis of the cancer
which parameter depends on which cell type you’re accessing.
eg. for prostate you’re more interested in architecture.
Hallmark 6: activating invasion and metastasis
Requirements for invasion-metastasis cascade to proceed
Inactivation of E-cadherin function and epithelial mesenchymal transition to allow for loosening of tumour cells
Secretion of proteolytic enxzymes (Eg. metalloproteinases) to allow for cancer cells to traverse the interstitial connective tissue
