Cell-cell and cell-ECM interactions in cancer

• Cancer metastasis


  The spread of cancer cells to other parts of the body and forming secondaries in the new organ/tissue
• Cancer metastasis


  The spread of cancer cells to other parts of the body and forming secondaries in the new organ/tissue
• Cancer metastasis


  The spread of cancer cells to other parts of the body and forming secondaries in the new organ/tissue
• Cancer metastasis is the leading reason that causes death of patients with cancer
• Most patients would already have micro-metastasis at the time of diagnosis
• Cancer metastasis


  The spread of cancer cells to other parts of the body and forming secondaries in the new organ/tissue
• Cancer metastasis is the leading reason that causes death of patients with cancer
• Most patients would already have micro-metastasis at the time of diagnosis
• Micro-metastasis


  Metastasis that cannot be seen with conventional method but microscopic methods
• Macro-metastasis


  Metastasis that can be seen by routine examination methods
• Almost all patients will develop metastatic disease, which ultimately leads to mortality
• Over 90% of patients with solid cancers died of metastasis related conditions
• Main cellular structures in the cell-cell junction regions

  • Cell adhesion
  • Cell-matrix adhesions
  • Barrier and cell adhesion
  • Intercellular communications and cell adhesions

  
• Adherent junctions (belt junctions, characterised by Cadherins)

  • Cadherin family
  • Type 1 including E, N and R
  • Synthesised as precursor
  • Have 5 tandemly arranged domains
  • 4 Ca binding pockets
  • His-Ala-Val motif
  • Actin cytoskeleton
• E (epithelial) - cadherin


  • Widely expressed in normal epithelial cells
  • One of the strongest cell-cell mechanisms in epithelial cells

  
• Disruption of the E-cadherin mediated cell cell adhesion

  Impacts the fate of the cells, they gain ability to metastasise
• Beta-catenin


  • Links Cadherins to actin cytoskeleton to allow a strong response in the EC environment
  • If allowed to accumulate (due to failure to form degradation complex), can enter the nucleus
• Biomarkers for EMT (Epithelial mesenchymal transition) include Wnt competence, E-Cadherin degradation/endocytosis, cytoplasmic/nuclear B-catenin, loss of epithelial markers, expression of vimentin, RhoB and MMPs

  
• Type 2 cadherins


  • VE, K, OB, M
  • Synthesised as precursor
  • Have 5 tandemly arranged EC domains
  • 4 Ca binding pockets
  • Non-HAV motif
  • Catenins
  • Actin cytoskeleton

  
• VE-Cadherin


  • Exclusively expressed in endothelial cells
  • A cell-cell adhesion regulator in vascular endothelial cells
  • Together with tight junctional structure, controls the paracellular permeability to macromolecules and cells
  • A keen and key angiogenesis regulator

  
• Desmosomal cadherins


  • Desmogleins and desmocollins
  • Located in desmosomes only
  • Non-HAV motif
  • CAR F/YAT/S motif
  • Plakoglobin/desmoplakin/plectin
  • Intermediate filaments (such as keratin and desman)

  
• Desmosomes


  • Specialised cell-cell junction
  • Formed between 2 epithelial cells and other cells such as heart or muscle cells
  • Important cell cell adhesion structure
  • Characterised by dense plaques of proteins, into which intermediate filaments of the 2 adjoining cells insert

  
• Pemphigus


  • Rarely occurring autoimmune disease of the skin
  • Loose junction between the cells > body fluids can leak into the skin > blisters
• • Loss and reduction of desmosomes in cancer cells
  • Abnormal distribution of desmosomes Cadherins in cancer cells
• Hemidesmosomes


  • Historically similar to desmosomes
  • Unique cellular location
  • Different molecular composition
  • Different cellular function

  
• Ig superfamily adhesion molecules

  • VCAM, NCAM, ICAM, nectin and nectin-like Nec1 family, Activated leukocyte CAM CD166
  • Anchored to actin cytoskeleton by ERM
  • Can bind to wide range of adhesion molecules L1CAM, ALCAM and integrins

  
• Increased levels of ALCAM associated with decreased survival of pancreatic cancer
• Tight junctions


  • Most apical structure
  • Commonly seen in epithelial, endothelial and transitional cells
  • Controlling the paracellular permeability/passages to macromolecules and penetrating cells
  • Creating barrier and maintain distinct tissue spaces
  • Charge-dependent and size-dependent
  • Also act as cell cell adhesion mechanism

  
• Claudin 1, occludin and junctional adhesion molecule

  First 2 in BBB
• Claudin 16 (paracellin-1)


  Uniquely expressed in kidney epithelial cells and mutated in HHS
• • HHS (Hypomagnesemia Hypercalciuria Syndrome) - result of Mg wasting, failed absorption of Mg and Ca, unregulated loss of Mg and Ca from the urine
  • Clinical features: growth retardation, renal failure
• Cell-matrix adhesion in cancer and the focal adhesion complex

  • Critical influence over the migration and the living fate of the cells
  • Main structure in cell-matrix interactions
• Integrins


  • Different integrins interact with different EC structures
• Anoikis


  The loss of adhesion to a cell will drive it towards apoptosis
• FAK inhibitors can cause increased cell-matrix adhesion and RGD Abs to target integrin-mediated activation of FAK > increased cell-matrix adhesion > decreased motility and spreading
• FAK is over-expressed/activated in most solid tumours and a target for cancer therapies
• Peritoneal (transcoelomic) metastasis is largely seen in the peritoneal and pleural cavities, a fertile 'soil' environment for certain cancers to seed
• Peritoneal spread is made of approx 60% from gynaecological, 23% from GI, 14% from breast cancers and other tumour types
• Increased levels of ALCAM associated with increased peritoneal metastasis in pancreatic and gastric cancer accompanied with decreased survival rates
• No effective specific therapies for peritoneal metastasis, only systemic and regional chemo therapies, radiotherapy, and other options like perioperative irrigation/washings