Figure 3

Known molecular EMT mechanisms can be classified into 5 major overlapping categories. 1: Growth Promoting/Proliferative Pathways are driven primarily by receptor tyrosine kinases, serine/threonine kinases, and cytokine receptors (many removed for clarity). Transforming Growth factor-beta (TGF β) and epidermal growth factor (EGFR) and other receptor tyrosine kinases (RTKs; For example: TrkB, Fibroblast growth factor receptor 1(FGFR1), etc.) signal via various intracellular kinases including mitogen activated kinase (p38/MAPK); Phosphoinositol-3-kinase (PI3k/Akt); and Ras-oncogene-MEK-ERK. TGF β signaling down-stream of TGR1 and TGR1 is multifarious and can by action of phosphorylation impact multiple kinases (via the kinase Transforming Growth Factor-β-activated Kinase (TAK1)) or SMA-mothers against decapentaplegic (Smad) transcription factors. TGF β signaling is regulated by cytoplasmic kinases (Bone Morphogenic Proteins – not discussed herein), Retinoic Acid-Retinoic Acid Receptor (RAR) and is important in developmental programs and maintaining an epithelial state. 2: Key developmental pathways are activated by kinase activity described above or morphogens (Sonic Hedgehog (Shh)-Patched(Ptch)-Gli1; Notch-Jagged(Jag)-Delta-like Ligand (DLL1/4); or Wingless (Wnt)-Frizzled (Frz)-β-catenin (β-Cat). These canonical developmental pathways activate highly conserved transcriptional programs which center around Snail and Slug (5) in inducing epithelial to mesenchymal transition. Activation of Snail and Slug result in reduction of E-cadherin and diminution of adherens junctions and planar cell polarity PCP 3. 3: Reduced and epithelial cell adhesion with concomitant increases in N-Cadherin, loss of apico-basal orientation, and reorganization of the cytoskeleton via Rho/ROCK kinases (4, not shown) promotes cellular motility, infiltration, and lymphadenopathy. 4: Snail/Slug/Crumbs/Zeb signaling reduces PCP and increases cellular orientiation towards growth enhancing gradients (1; vasculature (angiogenesis; vasculogenesis) and nerves (axonogenesis; perinerual spreading and invasion). 5: Feedback mechanisms and chromatin modifications by developmental pathways (2) perpetuate frank invasion, perineural invasion, locoregional spread, and metastasis. Not Shown: Inflammatory mediators (cytokines (Interleukins (IL) and Tumor Necrosis Factor (TNF), Chemokines (CCL and CXCR)) drive pro-inflammatory cell survival and pro-migratory pathways via hypoxia-inducible factor 1 alpha (HIF-1 α) and signal transducer and activator of transcription factor (STATs).