Adhesion-Mediated Squamous Cell Carcinoma Survival through Ligand-Independent Activation of Epidermal Growth Factor Receptor

Department of Stomatology, School of Medicine, University of California at San Francisco, Box 0512, Room HSW-604, San Francisco, CA 94143-0512, USA.
American Journal Of Pathology (Impact Factor: 4.59). 11/2004; 165(4):1315-29. DOI: 10.1016/S0002-9440(10)63390-1
Source: PubMed


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.

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    • "On exposure to shear stress, VE-cadherin binds to PECAM and vascular endothelial growth factor receptor (VEGFR2) and this complex may lead to integrin activation and actin cytoskeleton reorganization [39] [40]. Epidermal growth factor receptor (EGFR) forms a complex with CDH1, leading to activation of the mitogen-activated protein kinases (MAPK) pathway in epithelial cells [41] [42] with implications for cell survival [43] or EMT [44] [45]. Fibroblast growth factor receptors (FGFR) were shown to stimulate CDH2 during neurite outgrowth[46] [47], while FGF plays a critical role in the maintenance of vascular integrity by enhancing the stability of VE-cadherin at AJ sites [48]. "
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    ABSTRACT: Accumulating evidence suggests that the mechanical and biochemical signals originating from cell-cell adhesion are critical for stem cell lineage specification. In this review, we focus on the role of cadherin mediated signaling in development and stem cell differentiation, with emphasis on two well-known cadherins, cadherin-2 (CDH2) (N-cadherin) and cadherin-11 (CDH11) (OB-cadherin). We summarize the existing knowledge regarding the role of CDH2 and CDH11 during development and differentiation in vivo and in vitro. We also discuss engineering strategies to control stem cell fate decisions by fine-tuning the extent of cell-cell adhesion through surface chemistry and microtopology. These studies may be greatly facilitated by novel strategies that enable monitoring of stem cell specification in real time. We expect that better understanding of how intercellular adhesion signaling affects lineage specification may impact biomaterial and scaffold design to control stem cell fate decisions in three-dimensional context with potential implications for tissue engineering and regenerative medicine. Copyright © 2015. Published by Elsevier B.V.
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    • "In accord with our findings, Lu and colleagues found that forced expression of PROX1 in colon cancer cells also down-regulated E-cadherin expression and attenuated cell adhesion; conversely, knockdown of PROX1 restored E-cadherin expression and reduced invasiveness [24]. In the case of squamous cell carcinoma, E-cadherin-mediated cell-cell adhesion was found to induce epidermal growth factor receptor (EGFR) activation, which triggers the ERK/MAPK signaling module and further blocks down-regulation of the anti-apoptotic protein Bcl-2, promoting tumor cell survival [25]. Given the role of PROX1 in down-regulating the E-cadherin tumor-suppressor protein, it is likely that E-cadherin is involved in PROX1-stimulated proliferation and migration of tumor cells. "
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    ABSTRACT: The transcription factor PROX1 (prospero homeobox 1) has a critical role in the development of various organs, and has been implicated in both oncogenic and tumor-suppressive functions in human cancers. However, the role of PROX1 in the development of renal cell carcinomas (RCCs) has not yet been studied. Here, we reported that PROX1 expression was decreased in human RCC tissues compared with adjacent normal tissues. In RCC tissues, however, poorly differentiated RCC expressed higher PROX1 levels compared with well-differentiated RCC. In addition, the PROX1 immunostaining levels were positively correlated with tumor nuclear grade and lymph node metastasis. Further, high PROX1 expression indicated poor survival for patients. These findings imply that in the different developmental stages of RCC, PROX1 may exert distinct functions according to the specific microenvironment of tumor. Moreover, in vitro experiments revealed that PROX1 overexpression enhanced the proliferation and migration of RCC cells; conversely, PROX1 depletion by siRNA attenuated the proliferation and migration of RCC cells. Collectively, these observations suggest that PROX1 plays an important role in RCC development and progression, and PROX1 may be a novel target for prevention and treatment of RCC.
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    • "However, no direct physical interaction between E-cadherin and EGFR could be detected in the cells used, suggesting the existence of intermediate molecules [71]. In contrast, it was demonstrated that in oral squamous carcinoma cells E-cadherin can physically interact with and activate EGFR, leading to the activation of MAPK [70]. This interaction leads to EGFR-E-cadherin complex formation at cell–cell junctions and receptor oligomerisation. "
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    ABSTRACT: Treatment failure through radioresistance of tumours is associated with activation of the epidermal growth factor receptor (EGFR). Tumour cell proliferation, DNA-repair, hypoxia and metastases-formation are four mechanisms in which EGFR signalling has an important role. In clinical trials, a correlation has been demonstrated between high EGFR expression in tumours and poor outcome after radiotherapy. Inhibition of EGFR signalling pathways improves the effectiveness of radiotherapy of head and neck cancers by overcoming these main mechanisms of radioresistance. The fact that only a minority of the patients respond to EGFR inhibitors reflects the complexity of interactions between EGFR-dependent signalling pathways and the tumour microenvironment. Furthermore, many components of the microenvironment are potential targets for therapeutic interventions. Characterisation of the interaction of EGFR signalling and the tumour microenvironment is therefore necessary to improve the effectiveness of combined modality treatment with radiotherapy and targeted agents. Here, the current status of knowledge is reviewed and directions for future research are discussed.
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