Adhesion-mediated squamous cell carcinoma survival through ligand-independent activation of epidermal growth factor receptor.
The survival and growth of squamous epithelial cells require signals generated by integrin-matrix interactions. After conversion to squamous cell carcinoma, the cells remain sensitive to detachment-induced anoikis, yet in tumor cell aggregates, which are matrix-deficient, these cells are capable of suprabasal survival and proliferation. Their survival is enhanced through a process we call synoikis, whereby junctional adhesions between neighboring cells generate specific downstream survival signals. Here we show that in squamous cell carcinoma cells, E-cadherin-mediated cell-cell contacts specifically induce activation of epidermal growth factor receptor (EGFR). EGFR activation in turn triggers the ERK/MAPK signaling module, leading to elevation of anti-apoptotic Bcl-2. After intercellular adhesion, formation of adherens junctions triggers the formation of E-cadherin-EGFR complexes, correlating with EGFR transactivation. Analysis of the process with a dominant-negative EGFR mutant indicated that activation of EGFR is ligand-independent. Our data implicate cell-cell adhesion-induced activation of EGFR as a cooperative mechanism that generates compensatory survival signaling, protecting malignant cells from detachment-induced death.
Shen
Xiaodong
X
Department of Stomatology, School of Medicine, University of California at San Francisco, Box 0512, Room HSW-604, San Francisco, CA 94143-0512, USA.
Kramer
Randall H
RH
D023102:Anoikis / Q000502:physiology; D015820:Cadherins / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000378:metabolism*; D002448:Cell Adhesion / Q000502:physiology*; D002450:Cell Communication / Q000502:physiology*; D045744:Cell Line, Tumor; D002470:Cell Survival; D004789:Enzyme Activation / Q000502:physiology; D066246:ErbB Receptors / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D006801:Humans; D015151:Immunoblotting; D008024:Ligands; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D011233:Precipitin Tests; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D015533:Transcriptional Activation; D014162:Transfection
D015820:Cadherins; D008024:Ligands; D019253:Proto-Oncogene Proteins c-bcl-2; D066246:ErbB Receptors; D020928:Mitogen-Activated Protein Kinases