cancer Flashcards
(26 cards)
what is the epidermis
stratified ephilial tissue that forms outermost protective layer of skin - mainly made of kertonocytes (provide protection)
basal layer
basal layer of keratinocytes where cell division takes place, direct contact with underlying extracellular matric proteins/ basal lamina
cornified cells
upper most layer, protective cells, metabolically inactive shells of protein and continually lost from cell surface, replaced by process of differentiation of cells from basal layer, insoluble proteins under cells and differentiating keratinocytes move up
no wound to heal
No wound - platelets circulate and non-adhesive due to anti thrombotic factors- nitric oxide and prostacyclin
stage 1 of wound healing
hemostasis = immediate response
vascular constriction, Platelet aggregation, fibrin, degranulation
- Release of vasoconstrictors from injured cells (i.e. prostaglandins) which leads to smooth muscle cells contraction surrounding the arterioles
- Arteries supply arterioles which supply capillaries
- Capillaries have endothelial cells that form tube/blood vessel and surrounding have cells called pericytes and layer of extracellular matrix/basal cells around - no smooth muscle cells so cannot contract
- arterioles contract in response to vasoconstrictors
- Temporary stops flow of blood
- Basal lamina is exposed from capillaries
- Subendothelial matrix exposed due to rupture
- Platelets become activated and bind to each other and exposed ECM due to integrins (adhesion receptors)
- Integrins on all cells apart from mature red blood cells- transmembrane proteins and made of alpha subunit and beta subunit
- A2b1 = binds to collagen which is in the matrix
- AIIbb3 = binds to fibrinogen = formed from fibrin which is part of the clotting response
- Activation of factor X (Xa)
- Xa cleaves prothrombin to form thrombin
- Thrombin cleaves fibrinogen into fibrin which cross links into mesh like structure and binding of platelet to fibrin network to stop bleeding and provides substrate for cells to fall over
phase 2 of wound healing
inflammation
- Soon after wounding
- Neutrophils (multi lobed nuclei) infiltrate wound site due to signalling
- Leave circulation due to release of factors of chemokines (small molecules that act as attractant)
- Chemotactic gradient
- engulf bacteria using phagocytosis
- Intracellular granules with proteases that digest proteins, degrade bacteria that’s engulfed
- Release proteases from intracellular granules - degranulation
- Release nitric oxide and reactive oxygen
- Neutrophil extracellular traps- shot out and traps bacteria, NETosis, nets made from DNA that captures bacteria
- Essential neutrophils cleared from wound for resolution of inflammation to occur
- Apoptosis = programmed cell death after task completion, recognised by scavenger cells i.e.. Macrophages that mop up the fragments of cells
- Necrosis = not programmed
- Phagocytosis and macrophages engulf intact neutrophils
- Monocyte have surveillance activity, roll along vessel wall to look for damage, if detected then monocyte stop rolling and exit blood vessel and differentiate into macrophages
- Macrophages release pro inflammatory cytokines / signals
- Ie. MCP-1 - monocyte chemoattractant protein 1 = 1 attracts more monocytes to differentiate into M1 macrophages
third phase of wound healing
Proliferation
- Replacement of lost cells
- Macrophages = secrete growth factors including VEGF which promotes angiogenesis/ formation of new blood vessels (seen in organism development or wound healing)
- Then secrete ECM (i.e. fibronectin = deposited at site of wound as a layer which causes migration of epidermis cells to crawl over layer) which keratinocytes will migrate to wound
- Fibrocytes- cells related to monocytes that deposit ECM at wound site, unregulated manner and too much ECM leads to scarring which is important in chronic inflammatory diseases such as pulmonary fibrosis
fourth phase of wound healing
remodelling
- macrophages recognise and clear away debri and remove ECM that is not required anymore
angiogenesis =
- Formation of new blood vessels
- VEGF triggers endothelial cells that lie on damaged blood vessels and branch out and sprout from existing damaged blood vessels to supply wound site with oxygen etc
Endothelial cells have protein receptors that specifically respond to VEGF i.e. VEGFR2
-Tip cells are specialized endothelial cells that lead the process of angiogenesis, guiding new blood vessel formation = - Directional Migration – Tip cells extend filopodia, sensing VEGF gradients and guiding the sprouting vessel toward oxygen-deprived tissue, interact with stalk cells
-stalk cells = divide to elongate branches
Re-epithelialization
- Damage is resupplied with epithelial cells to reform protective layer
- Hair follicle is where most epidermal stem cells are found, lining of the hair follicle
- Epidermal stem cells needed to maintain loss and renewal of keratinocytes and cells of epidermis through proliferation of stem cells to form daughter cells
- Stem cells in basal layer of epidermis too
- Stem cells migrate out of follicle to wound site and populate divide and differentiate
- Epidermal cells secret TGF-b (growth factor) which binds to cognate receptors on dermal fibroblast (found in dermis) that triggers it to become myofibroblast (contractile cells to contract in) pulls in edges of wound
- some become adipocytes
- Proliferation migration and differentiation of epidermal keratinocytes on ECM to re epithelialize and close wound
ECM and functiond
- cell cell adhesion and cell to ECM adhesion are essential for normal tissue structure and function
-complex network of secreted proteins and carbohydrates that fills the space between cells
-connective tissue the macromolecules that make up the ECM are secreted mainly by cells called fibroblasts - basal lamina synthesized by cells that rest on it i.e. basal keratinocytes of the epidermis
functions : space filler, tissue organiser, protective, cell migration, regulation of cell function
background of cancer
tumours arise from normal tissue
devlopment is a multi step process
carcinomas are cancers of epithelial tissue and responsible for 80% of cancer realted deaths
- squamous cell carcinomas arise from epithelial cells that form protective layers (skin, fungus etc)
- adenocarcinomas = arise from specialised epithelial cells that secrete substances into ducts (breasts, colon, prostate)
Hallmark 1 of cancer
sustaining proliferative signalling
- Normal cells proliferation tightly regulated and divide under careful regulated conditions with whole host of factors taken into account before division
- Cancer cells chronic proliferation where they lose control to stop cell dividing
- Ras is a normal cellular gene that plays a pivotal role in controlling cell proliferation
- is protein that transmits signals to nucleus to start transcription
- Ras mutated is permanently switched on and drives cell proliferation with no external cues or checks
Ras is an oncogene - mutated gene that has the potential to cause cancer, unchecked proliferation
hallmark 2
evading growth suppressors
-cell cycle is tightly regulated and series of checkpoints act as barriers to make sure DNA is replicated favourably
- normal cell cycle is lost during cancer and tumour suppresser genes (p53 and Rb) are commonly mutated in cancer
- contact inhibition = in normal cells if gap then cells will divide to fill the space but then once contact made then contact inhibition occurs, epithelial cells attached to extracellular matric via integrins and cells divide and contact neighbours to stop dividing, E-cadherin protein expressed on epithelial cells and involved
- cancer cells have mutation or loss of e-cadherin so cells grow on top of each other and disrupted cell cell adhesion
hallmark 3
activating invasion and metastasis
- invasion refers to invading surrounding cells but metastasis refers to reaching circulation and transported around body
- EMT = epithelial to mesenchymal transition, normal part of development where cells go to different sites, in order they switch pheotype from epithilial to mesochenyl cells which are migratory, when transported through circulation and leave (extravasation) they form micrometastasis and then colonise into macrometastis, undergo reverse process once reach site so they switch back to epithelial to set up clusters of secondary tumours
- stromal cells contribute to invasion by sending cytokines that enhance cell survival
- macrophages = secrete enzyme that break down ECM, cells sit on ECM so need to degrade it, ie. MMP/ metalloproteinases
- mesenchymal stem cells in tumour stroma secrete CCL5 which stimulates tumour cell invasion
- ameboid =low adhesion and high contractility, enabling cells to squeeze through gaps without extensive matrix remodeling.
- collective cell migration =process where groups of cells move together in a coordinated manner, maintaining cell-cell interactions while navigating through tissues.
hallmark 4
enabling repliactive immortality
- tumour immortal, normal cells have finite division number and die
hallmark 5
inducing angiogenesis
- to grow a constant need of oxygen and nutrients needed and metabolic products taken away
- needs blood vessels formed aeound tumour mass, controlled by angiogenic swicth
- switch permantlyon in tumours
- VEGF = key promotor/ pro angiogenic factor
normal tissues have thrombospondin-1 which inhibits
hallmark 6
resisting cell death
-normal cells undergo apoptosis when abnormal
- dna damage then TP53 induces
- Evade apoptosis theough mutations in pro apotoptic genes ie. p53 and activation of survival pathways
- Efferocytosis - removal of dead cells, engulfed and cleared by phagocytes but in cancer dysregulated so environment is immunosupressive
- Macrophages remove apoptotic cell and engulf, without inducing inflammotary response
hallmarks revisted
-additional hallmarks
emerging hallmarks:
1) deregulating cellular energetics
2) avoiding immune destruction
enabling characterstics
1) genome instability and mutation
2) tumour promoting inflammation
enabling characterstic = genome instability and mutation
we have efficient DNA surveillance and repair system such that spontaneous mutations are rare
- cancer cells have increased rates
DNA maintenance machinery is frequently defective in cancer as a consequence cancer cells are more sensitive to mutagenic agents and accumulation is accelerated
- cancer cells normal surveillance is compromised (p53 mutations) resulting in failure to repair damage or induce apoptosis
enabling characterstic = tumour promoting inflmmation
tumours infiltrated by cells of immune system and therefore resemble sites of inflammation
- tumour associated inflammatory response enhances tumour growth and progression
- inflmation supplies bioactive molecules to tumour microenvironments e.g. growth factors
- inflammatory cells release reactive ocygen species which are mutagenic for neighbouring cancer cells
emerging hallmarks = reprogramming energy metabolism
- reprogramming energy production away from oxidative phosphylation to glycolysis
-warburg effect = when cancer cells consume glucose into lactate to proliferate rapidly
emerging hallmark - evading immune destruction
- growing evidence for existence of anti tumour immune response in some types of cancer and therefore the evasion of immune system is hallmark
- immunosuppressed organ transplant recipients have developed donor derived tumours even though the donors are symptom free suggesting the donor immune system had been supressing the tumour
- Natural killer cells and tumour surveillance
Cells under stress lose expression of MHC class 1 the don’t kill ligand for activating receptors on NK cells
parrallels between cancer and wound healing - invasion and migration
- epithelial cells attached to ECM via adhesion molecules integrins (heterodimeric as comprised of alpha subunit non covalently attached to b subunit), active and inactive states
- cells must migrate over to plug wound and to do that switch off a6b4 and switch on other integrins ie.a5b1 a fibronectin receptor
re epithelisation has occured then a5b1 is swicthed off and a6b4 is swicthed back on, epidermal specific knockout of b1 integrins in mice results in impaired wound healing
-malignant melonoma = tumour of melanocytes, pigment producing cells, physically attached to surrounding cells via e-cadherin, in melonoma = migrate to distant sites via detaching from epithelial cells by switching expression of mols in cell cell adhesion, n cadherin swicthed on which does not interact with surrounding keronocytes, fibroblasts express n cadherin and endothelial cells, melanocyte now melonoma cell and can migrate
inflammation parallels between wound healing and cancer
- rudolf virchow founded cellular pathology, arose cancer cells arose from normal cells, some carcinomas inflitrated by white blood cells (macrophages), development linked to chronic irritation of tissues
- some examples that cancers are consequence of long term inflammation i.e. oesphegal cancer linked to inflmamtion in oesphagus
high inflamatry cells in tumour can impact prognosis, higher immune cells inflitrating the poorer the prognosis ie. ovarian and colon cancer
