Epidermal growth factor receptor(EGFR) controls a wide range of cellular processes, and aberrant EGFR signaling as a result of receptor overexpression and/or mutation occurs in many types of cancer. Tumor cells in non...Epidermal growth factor receptor(EGFR) controls a wide range of cellular processes, and aberrant EGFR signaling as a result of receptor overexpression and/or mutation occurs in many types of cancer. Tumor cells in non-small cell lung cancer(NSCLC) patients that harbor EGFR kinase domain mutations exhibit oncogene addiction to mutant EGFR, which confers high sensitivity to tyrosine kinase inhibitors(TKIs). As patients invariably develop resistance to TKIs, it is important to delineate the cell biological basis of mutant EGFR-induced cellular transformation since components of these pathways can serve as alternate therapeutic targets to preempt or overcome resistance. NSCLC-associated EGFR mutants are constitutively-active and induce ligandindependent transformation in nonmalignant cell lines. Emerging data suggest that a number of factors are critical for the mutant EGFR-dependent tumorigenicity, and bypassing the effects of TKIs on these pathways promotes drug resistance. For example, activation of downstream pathways such as Akt, Erk, STAT3 and Src is critical for mutant EGFR-mediated biological processes. It is now well-established that the potency and spatiotemporal features of cellular signaling by receptor tyrosine kinases such as EGFR, as well as the specific pathways activated, is determined by the nature of endocytic traffic pathways through which the active receptors traverse. Recent evidence indicates that NSCLCassociated mutant EGFRs exhibit altered endocytic trafficking and they exhibit reduced Cbl ubiquitin ligasemediated lysosomal downregulation. More recent work has shown that mutant EGFRs undergo ligand-independent traffic into the endocytic recycling compartment, a behavior that plays a key role in Src pathway activation and oncogenesis. These studies are beginning to delineate the close nexus between signaling and endocytic traffic of EGFR mutants as a key driver of oncogenicprocesses. Therefore, in this review, we will discuss the links between mutant EGFR signaling and endocytic properties, and introduce potential mechanisms by which altered endocytic properties of mutant EGFRs may alter signaling and vice versa as well as their implications for NSCLC therapy.展开更多
Head and neck squamous cell carcinoma(HNSCC)is a very aggressive disease with a poor prognosis for advanced-stage tumors.Recent clinical,genomic,and cellular studies have revealed the highly heterogeneous and immunosu...Head and neck squamous cell carcinoma(HNSCC)is a very aggressive disease with a poor prognosis for advanced-stage tumors.Recent clinical,genomic,and cellular studies have revealed the highly heterogeneous and immunosuppressive nature of HNSCC.Despite signifcant advances in multimodal therapeutic interventions,failure to cure and recurrence are common and account for most deaths.It is becoming increasingly apparent that tumor microenvironment(TME)plays a critical role in HNSCC tumorigenesis,promotes the evolution of aggressive tumors and resistance to therapy,and thereby adversely affects the prognosis.A complete understanding of the TME factors,together with the highly complex tumor-stromal interactions,can lead to new therapeutic interventions in HNSCC.Interestingly,different molecular and immune landscapes between HPV^(+ve) and HPV^(-ve)(human papillomavirus)HNSCC tumors offer new opportunities for developing individualized,targeted chemoimmunotherapy(CIT)regimen.This review highlights the current understanding of the complexity between HPV^(+ve) and HPV^(-ve) HNSCC TME and various tumor-stromal cross-talk modulating processes,including epithelial-mesenchymal transition(EMT),anoikis resistance,angiogenesis,immune surveillance,metastatic niche,therapeutic resistance,and development of an aggressive tumor phenotype.Furthermore,we summarize the recent developments and the rationale behind CIT strategies and their clinical applications in HPV^(+ve) and HPV^(-ve) HNSCC.展开更多
基金Supported by the NIH grant to Band H,No.CA99163,CA87986,CA105489 and CA116552a Department of Defense grant to Band H,No.W81WH-11-1-0167+4 种基金the NIH grant to Band V,No.CA96844 and CA144027Department of Defense grant to Band V,No.W81XWH-07-1-0351 and W81XWH-11-1-0171the Nebraska Department of Health and Human Services LB-506 grant to Band H,No.2014-01the NCI Core Support Grant to the UNMC Buffett Cancer CenterBielecki TA was a predoctoral trainee under the NCI Institutional Cancer Biology Training Grant,No.CA009476
文摘Epidermal growth factor receptor(EGFR) controls a wide range of cellular processes, and aberrant EGFR signaling as a result of receptor overexpression and/or mutation occurs in many types of cancer. Tumor cells in non-small cell lung cancer(NSCLC) patients that harbor EGFR kinase domain mutations exhibit oncogene addiction to mutant EGFR, which confers high sensitivity to tyrosine kinase inhibitors(TKIs). As patients invariably develop resistance to TKIs, it is important to delineate the cell biological basis of mutant EGFR-induced cellular transformation since components of these pathways can serve as alternate therapeutic targets to preempt or overcome resistance. NSCLC-associated EGFR mutants are constitutively-active and induce ligandindependent transformation in nonmalignant cell lines. Emerging data suggest that a number of factors are critical for the mutant EGFR-dependent tumorigenicity, and bypassing the effects of TKIs on these pathways promotes drug resistance. For example, activation of downstream pathways such as Akt, Erk, STAT3 and Src is critical for mutant EGFR-mediated biological processes. It is now well-established that the potency and spatiotemporal features of cellular signaling by receptor tyrosine kinases such as EGFR, as well as the specific pathways activated, is determined by the nature of endocytic traffic pathways through which the active receptors traverse. Recent evidence indicates that NSCLCassociated mutant EGFRs exhibit altered endocytic trafficking and they exhibit reduced Cbl ubiquitin ligasemediated lysosomal downregulation. More recent work has shown that mutant EGFRs undergo ligand-independent traffic into the endocytic recycling compartment, a behavior that plays a key role in Src pathway activation and oncogenesis. These studies are beginning to delineate the close nexus between signaling and endocytic traffic of EGFR mutants as a key driver of oncogenicprocesses. Therefore, in this review, we will discuss the links between mutant EGFR signaling and endocytic properties, and introduce potential mechanisms by which altered endocytic properties of mutant EGFRs may alter signaling and vice versa as well as their implications for NSCLC therapy.
基金This study was supported by Ramalingaswami Fellowship(Grant number:D.O.NO.BT/HRD/35/02/2006)from the Department of Biotechnology,Government of India,New Delhi to Muzafar A.MachaMohammad Haris is funded by a grant(5071012001)from Sidra Medicine Doha,QatarAjaz A.Bhat is supported by Sidra Medicine internal grant(5011041002).We thank Dr.Vineeta Tanwar(Ohio State University,Columbus,Ohio,USA)for her professional assistance in editing the paper.
文摘Head and neck squamous cell carcinoma(HNSCC)is a very aggressive disease with a poor prognosis for advanced-stage tumors.Recent clinical,genomic,and cellular studies have revealed the highly heterogeneous and immunosuppressive nature of HNSCC.Despite signifcant advances in multimodal therapeutic interventions,failure to cure and recurrence are common and account for most deaths.It is becoming increasingly apparent that tumor microenvironment(TME)plays a critical role in HNSCC tumorigenesis,promotes the evolution of aggressive tumors and resistance to therapy,and thereby adversely affects the prognosis.A complete understanding of the TME factors,together with the highly complex tumor-stromal interactions,can lead to new therapeutic interventions in HNSCC.Interestingly,different molecular and immune landscapes between HPV^(+ve) and HPV^(-ve)(human papillomavirus)HNSCC tumors offer new opportunities for developing individualized,targeted chemoimmunotherapy(CIT)regimen.This review highlights the current understanding of the complexity between HPV^(+ve) and HPV^(-ve) HNSCC TME and various tumor-stromal cross-talk modulating processes,including epithelial-mesenchymal transition(EMT),anoikis resistance,angiogenesis,immune surveillance,metastatic niche,therapeutic resistance,and development of an aggressive tumor phenotype.Furthermore,we summarize the recent developments and the rationale behind CIT strategies and their clinical applications in HPV^(+ve) and HPV^(-ve) HNSCC.
