Cellular basis of Malignancy Flashcards
What is the difference between a Malignant or Benign tumour?
Invasion
(not metastasise)
invade and hence destroy local tissues
Epithelial Tissue
Consumates communal cells
-not individualists/exist by themselves like fibroblasts
-instead form structured sheets/ducts/glands
Held together by Adherins Junctions
Change in Epithelial cells upon invasion
Invasion, requires a break/change in immaculately ordered epithelial cell structure
–> become motile and destructive
Adherens Junctions
- Hold together epithelial cells
composed of integral membrane protein E cadherins
-goes through membranes of both partner cells
-forms calcium dependant connection in the inter cellular space - E chadherin inside the cell is connected to Actin cytoskeleton
(Intercellular links connected to cytoskeleton giving cells their structure)
-via 2x intermediate proteins
a) B-catenin
b)A-catenin
1st mechanism of epithelial cell invasion
Irreversible mechanism EMT = Epithelial –> Mesenchymal Transition
-genetic or epigenetic
a) Loss of E cadherin expression (due to genetic mutation or epigenetic silencing)
b) Loss of alpha A Catenin
=
-Loss of junctions b/w cells
-Loss of cellular polarity
Lose epithelial form to form Diffuse Spreaded single cell relatively Structureless tumours
=Diffuse Gastric Carcinomas
= Diffuse Breast Carcinomas (when hereditary syndrome assoc.)
2nd mechanism of epithelial cell invasion
Reversible mechanism
-Microenvironmental mechanism
EMT = Epithelial –> Mesenchymal Transition
Primary tumour maintains differentiated feature
-Big pleomorphic nuclei
-Primary tumour/cancer
–>
a) often Metastasize and invade
-seed distance cancers which share same epithelial glandular cellular polarised structure
-can see focal dissociation of carcinoma cells (regions where structure breaks down to produce motile cells which are able to
1) first invade
Focal dissociation tends to occur at margins of tumours where inflammatory cells are
-macrophages/fibroblasts, which secretes growth factors, such as Hepatocyte Growth factor HGF
-binds to their specific receptor (HGFR is a tyrosin kinase)
-induces a signalling response, which results in phosphorylational and transcriptional events which induces motile mesenchymal phenotype
2) later Potentially form distant metastases
-forms well differentiated primary tumour structure,
-due to reverse process occurring MET Mesnechymal –> Epithelial transition (back to original state)
a) phosphorylation events (HGFR phosphorylate E cadherin and b catenin, inducing reversible breakdown of adherins junctions, enabling invasion
b) induce snail protein (migration)
-transcriptional repressor which turns off epithelial structure/gene encoding E cadherin
-signalling pathways induced by HGF and other EMT inducers, causeing reversible loss of epithelial structure, resulting in invasion and metastases
EMT re wound healing
Same thing
- similar to re-epithelialisation and wound healing
- wound healing it is beautifully coordinated and controlled
- cancer is regulated but obherently so
How are Hepatocyte Growth Factor HGF and Receptor Deregulated when cancer develops?
- Deregulated (abnormal) expression of HGFR (in aggressive tumours) –> increased signalling –> increased EMT
- CRC, Metastatic Tumours, Amplification of HGFR gene (increased copy number, protooncogen –> oncogene)
- Papillary Renal Cell Carcinoma –> Point mutations of HGFR gene (turn on tyrosine kinase activity, increasing molecular response)
- Autocrine activation of Receptor. Single tumour cell can both produce the growth factor and express the receptor –> hence drive its own mesenchymal phenotypic conversion
- Identifies important of HGF signalling as a key inducer of EMT
Mechanism of invasion
- Motility
- Production of Hydrolytic Enzymes
- break down and destroy tissues
- provide route for cancer invasion
Defining criterium of cancer
Ability to invade into normal tissues
Proteases and Heparonases are released by cancer cells
-break down/solubilise adjacent tissues
What are Growth Factors
Fibroblasts
Macrophages (e.g. HGF)
-bind to receptors and stimulate signalling
What happens after signalling is stimulated by HGFR and HGF binding?
1) induce formation of Invadopodia/Podosome on mesenchymal/invading cells
- structures that allow cells to contact ECM
- involved in contact and invasion
2) express receptor for protease called uPA urokinase-type Plasminogen Activator
- uPA activates substrate of plasmin
Plasmin
important protease
a) Thrombolytic- important for maintaining blood flow after ischaemic event/thrombis
b) Remodels Tissues: wound repair
always circulating in body as plasminogen waiting for appropriate trigger to activate
(inactive plasminogen cleaved to plasmin active protease)-must be carefully controlled
-Activated by uPA
-plasmin is able to activate class of enzymes called pro-mmP (matrix metalloproteinases) (mmP upon cleavage)
mmP
Matrix MetalloProteinases
-atleast 20 known
-v important in inflammatory responses and tissue remodelling
“metallo proteinases” as contain ZINC in active centre
-produced by variety of cells including Inflammatory cells (macrophages, neutrophils), Fibroblasts, Tumour cells
What can break down ECM Extra Cellular Matrix Proteins?
Invadopodela structure: series of 3x levels of proteases
uPA
Plasmin
mmPs
(break down fibronectins, collagens, elastins)
-the essential packing proteins that holds tissues in normal size and shape
-allows tumour cells to invade
Other Pro Tumour functions due to Proteolytic Activation
- Many Growth factors bound within ECM. These growth factors are released tumours move forward due to Invadopodea and ECM breaking down. Provides Feed Forward Stimulation for tumour behaviour (encourages and aids)
- ECM protein Laminen. When cleaves releases chemotactic fragments
- tumours can stimulate own invasion by cleaving Laminen, results in peptide fragments that will further stimulate tumour invasion - If proteases feed back and nibble on Intracellular junctions (e.g. E cadherin) will break it down Proteolytically, contributing towards tumour invasion
- Plasmin can feed back. uPA originates from progenitor pro. uPA.
- Plasmin can feedback and activate its own activator (pro. uPA) resulting sustained environment, in direction that tumour cells are progressing, maintaining tissue destruction - Invadopodea Receptors = Integrins
- link tumour cell to substrate
- helps to form directionality
- can signal into cell, promoting invasive behaviour
a) e.g. result in more expression of pro-uPA
Invadopodea
- uPA
- Plasmin
- mmP
- Receptors = Integrins
- link tumour cell to substrate
- helps to form directionality
- can signal into cell, promoting invasive behaviour
a) e.g. result in more expression of pro-uPA
Overview of Mechanism of Invason
complex of enzymes and receptors on front surface of cells contacting ECM
-enable tumour cell invasion
Tumour Hypoxia
tumours grow because induce blood supply tend to outgrow blood supply -often poorly vascularised -therefore part of tumours becomes hypoxic and necrotic -200 microns from BV cells will se