W3L3 Flashcards
Cell-Cell Junctions in Cancer
Carcinoma
- Cancer of skin or tissues that line internal organs
Subtypes
- adenocarcinoma
- basal cell carcinoma
- squamous cell carcinoma
- etc.
Metastasis
- Migration of tumor cells from tissue of origin (primary site) to other parts of the body
Question: How can tumor cells that are epithelial in origin migrate and invade?
Answer: Via a Process that includes Epithelial to Mesenchymal Transition (EMT)
Epithelial vs. Mesenchymal Cells
Epithelial cell (has tight junction, desmosomes, gap junction)
- Highly differentiated
- Actin is cortical, making ep cell very rigid
- Expresses epithelial proteins (markers)
- Associated with other cells
- Non-migratory
Mesenchymal cell (has focal adhesion, lammellpodium, leading edge, trailing edge)
- Relatively undifferentiated
- Actin is in stress fiber form
- Expresses mesenchymal proteins (markers)
- Not associated with other cells
- Very migratory
- Actin stress fibers associate with focal adhesions and pull the cell along
Normal situation:
During wound, ep cells need to de-differentiate to become more mesenchymal so they can migrate into the wound and repopulate. Once the inflammation and cytokines and macrophages are gone, it does not have the pressure to remain mesenchymal so the cells become differentiated again as ep cells
Tumor situation:
The above scenario occurs, except the cells use the opportunity to migrate and metastasize
Cell-Cell Junctions in Cancer (MET and EMT)
MET = mesenchymal to epithelial transition
EMT = epithelial to mesenchymal transition
Epithelial markers
- e-cadherin
- claudins
- occludin
- desmoplakin
- cytokeratin-8, -9, and -18
Mesenchymal markers
- fibronectin
- vimentin; Vimentin is malleable intermediate filament, allows cell to migrate over uneven terrain
EMT effectors
- growth factors
- cytokines
- ECM
MET effectors
- adhesion
- cortical actin microfilaments
- Epithelial cell
EMT - Tight-junction dissociation
EMT - Adherent-junction and desmosome dissociation
EMT - Mesenchymal cells
MET - Initial E-cadherin adhesive contact
MET - Cortical-actin-cytoskeleton reorganization
- adherent-junction assembly
MET - Desmosome association
MET - Tight-junction formation
- completion of cell-polarity programme
MET
to step 1
Hyperplasia vs Dysplasia
Hyperplasia = uncontrolled growth
Dysplasia = looks weird
Epithelial Cell Properties
Cells bound tightly together into sheets called epithelia
ECM is rare (except for Basal Lamina)
Derived from all 3 germ layers
- Ectoderm- Epidermis
- Mesoderm- Inner lining of body cavity
- Endoderm- Gastrointestinal tract
Often functions as a barrier from external environment, and self from non-self
All 3 germ layers can become ep cells
Ep cells are all over body
Types of Epithelial Cells
- Simple squamous
- alveoli
- bowman’s capsule
- endothelial cells - Simple cuboidal
- kidney tubule
- lining of exocrine glands
- part of pancreas - Simple columnar
- small intestine - Stratified squamous
- epidermis
- esophagus and mouth lining - Stratified cuboidal
- sweat glands
- salivary glands - Stratified columnar
- urethra
Absorptive Epithelia Properties
Main property is transport
Polar (apical and basolateral membranes)
Barrier function (allows selective movement of molecules)
Increased surface area (microvilli)
Avascular
- They are surrounded by stroma (ECM and fibroblasts)
Tight junctions may impede paracellular transport
Diffusion
- down concentration gradient
- passive transport
- small, hydrophobic
- hydrophilic molecules need channels
Facilitated Diffusion
- down concentration gradient (passive)
- uses protein-mediated transport (carriers)
- no energy required (ATP)
- Specific
- limited capacity- can be saturated
- can be competitively inhibited
Active Transport
- Molecules moving against concentration gradient directly coupled to the hydrolysis of ATP
- Specific
- limited capacity- can be saturated
- can be competitively inhibited
- For e.g., Na+/K+ pump
Secondary Active Transport
- Molecule “1” moves up its concentration gradient coupled to Molecule “2” going down its concentration gradient
- ATP is necessary to generate Molecule “2” gradient
- For e.g., Na+/Glucose symporter
Gastrointestinal Tract
- Nutrient extraction from the lumen of the small intestine requires specific transporters in the absorptive epithelia
- Similar to reabsorption of nutrients/ions in the kidney tubules
- Mostly small intestine since it has tight junctions
- Duodenum is a bit leakier
- Glucose and water is greatly absorbed in small intestine
Glucose Transport
- Glucose across apical membrane
- Glucose in the gut is relatively low in concentration, so you need to move it against its concentration gradient to get glucose inside the cell.
- Since it is difficult to move against conc gradient, can do secondary active transport with sodium. Sodium is high in gut and low in cell.
- As sodium goes in, glucose also goes in; this occurs at apical surface of cell
- no energy involved in this step, no ATP since sodium goes along with its conc gradient, bringing glucose with it afterwards
- Glucose goes across basolateral membrane of cell to extracellular fluid
- no transporter needed bc glucose is higher in cell and lower outside of cell, so going outside of cell is easy
- glucose uniporter - Re-establishment of Na+ gradient
- energy needed to make sodium gradient, ATP
- need to keep inside of cell with low Na+ to maintain original conc gradient, so we need to pump out the excess cellular Na+ that went in during step 1
- occurs at basolateral membrane, right next to the extracellular fluid
Characteristics of Secondary Active Transporters
Protein mediated
Limited capacity; can be saturated
Can be inhibited
Can transport more than one molecule (# or type)
One molecule must move down its concentration gradient
i.e. Glucose-sodium symporter. Sodium moves down conc gradient.
Family of Transporters-Glucose/ Na+: Sodium Glucose Linked Transporter (SGLT)
Sodium Glucose Linked Transporter (SGLT)
SGLT1- high affinity, transports either glucose or galactose with 2 Na+ ions (expressed in intestine, kidney) (mostly transports glucose though)
SGLT2- lower affinity, high capacity transporter, only transports glucose with 1 Na+ ion (expressed in kidney)
SGLT3- Glucose sensor (intestine, brain)
- does not transport glucose, but senses it
- brain needs glucose sensors, bc it gets first dibs on any glucose in the system. No glucose in brain = passing out
