title: Molecular signature and therapeutic perspective of the epithelial-to-mesenchymal transitions in epithelial cancers.
abstract: The mechanisms involved in the epithelial to mesenchymal transition (EMT) are integrated in concert with master developmental and oncogenic pathways regulating in tumor growth, angiogenesis, metastasis, as well as the reprogrammation of specific gene repertoires ascribed to both epithelial and mesenchymal cells. Consequently, it is not unexpected that EMT has profound impacts on the neoplastic progression, patient survival, as well as the resistance of cancers to therapeutics (taxol, vincristine, oxaliplatin, EGF-R targeted therapy and radiotherapy), independent of the "classical" resistance mechanisms linked to genotoxic drugs. New therapeutic combinations using genotoxic agents and/or EMT signaling inhibitors are therefore expected to circumvent the chemotherapeutic resistance of cancers characterized by transient or sustained EMT signatures. Thus, targeting critical orchestrators at the convergence of several EMT pathways, such as the transcription pathways NF-kappaB, AKT/mTOR axis, MAPK, beta-catenin, PKC and the AP-1/SMAD factors provide a realistic strategy to control EMT and the progression of human epithelial cancers. Several inhibitors targeting these signaling platforms are already tested in preclinical and clinical oncology. In addition, upstream EMT signaling pathways induced by receptor and nonreceptor tyrosine kinases (e.g. EGF-R, IGF-R, VEGF-R, integrins/FAK, Src) and G-protein-coupled receptors (GPCR) constitute practical options under preclinical research, clinical trials or are currently used in the clinic for cancer treatment: e.g. small molecule inhibitors (Iressa: targeting selectively the EGF-R; CP-751,871, AMG479, NVP-AEW541, BMS-536924, PQIP, AG1024: IGF-R; AZD2171, ZD6474: VEGF-R; AZD0530, BMS-354825, SKI606: Src; BIM-46174: GPCR; rapamycin, CCI-779, RAD-001: mTOR) and humanized function blocking antibodies (Herceptin: ErbB2; Avastin: VEGF-A; Erbitux: EGF-R; Abegrin: alphavbeta3 integrins). We can assume that silencing RNA and adenovirus-based gene transfer of therapeutic miR and dominant interferring expression vectors targeting EMT pathways and signaling elements will bring additional ways for the treatment of epithelial cancers. Identification of the factors that initiate, modulate and effectuate EMT signatures and their underlying upstream oncogenic pathways should provide the basis of more efficient strategies to fight cancer progression as well as genetic and epigenetic forms of drug resistance. This goal can be accomplished using global screening of human clinical tumors by EMT-associated cDNA, proteome, miRome, and tissue arrays.
authors: INSERM U673, Molecular and Clinical Oncology of Solid Tumors, Université Pierre et Marie Curie-Paris 6, Faculté de Médecine, Hôpital Saint-Antoine, 75571 Paris Cedex 12, France.
authors: Michèle
authors: M
authors: Sabbah
authors: Shahin
authors: S
authors: Emami
authors: Gérard
authors: G
authors: Redeuilh
authors: Sylvia
authors: S
authors: Julien
authors: Grégoire
authors: G
authors: Prévost
authors: Amazia
authors: A
authors: Zimber
authors: Radia
authors: R
authors: Ouelaa
authors: Marc
authors: M
authors: Bracke
authors: Olivier
authors: O
authors: De Wever
authors: Christian
authors: C
authors: Gespach
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002470:Cell Survival; D054338:Cell Transdifferentiation / Q000187:drug effects / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019008:Drug Resistance, Neoplasm; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D015316:Genetic Therapy; D006801:Humans; D008648:Mesoderm / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents