title: Targeting the TGFβ pathway for cancer therapy.
abstract: The TGFβ signaling pathway has pleiotropic functions regulating cell growth, differentiation, apoptosis, motility and invasion, extracellular matrix production, angiogenesis, and immune response. TGFβ signaling deregulation is frequent in tumors and has crucial roles in tumor initiation, development and metastasis. TGFβ signaling inhibition is an emerging strategy for cancer therapy. The role of the TGFβ pathway as a tumor-promoter or suppressor at the cancer cell level is still a matter of debate, due to its differential effects at the early and late stages of carcinogenesis. In contrast, at the microenvironment level, the TGFβ pathway contributes to generate a favorable microenvironment for tumor growth and metastasis throughout all the steps of carcinogenesis. Then, targeting the TGFβ pathway in cancer may be considered primarily as a microenvironment-targeted strategy. In this review, we focus on the TGFβ pathway as a target for cancer therapy. In the first part, we provide a comprehensive overview of the roles played by this pathway and its deregulation in cancer, at the cancer cell and microenvironment levels. We go on to describe the preclinical and clinical results of pharmacological strategies to target the TGFβ pathway, with a highlight on the effects on tumor microenvironment. We then explore the perspectives to optimize TGFβ inhibition therapy in different tumor settings.
authors.affiliation: INSERM U728 & U773 and Department of Medical Oncology, Beaujon University Hospital (AP-HP - PRES Paris 7 Diderot), 100 boulevard du Général Leclerc, 92110 Clichy, France.
authors.forename: Cindy
authors.initials: C
authors.lastname: Neuzillet
authors.affiliation: AAREC Filia Research, Translational Department, 1 place Paul Verlaine, 92100 Boulogne-Billancourt, France.
authors.forename: Annemilaï
authors.initials: A
authors.lastname: Tijeras-Raballand
authors.affiliation: AAREC Filia Research, Translational Department, 1 place Paul Verlaine, 92100 Boulogne-Billancourt, France.
authors.forename: Romain
authors.initials: R
authors.lastname: Cohen
authors.affiliation: Department of Pathology, Beaujon University Hospital (AP-HP - PRES Paris 7 Diderot), 100 boulevard du Général Leclerc, 92110 Clichy, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Cros
authors.affiliation: INSERM U728 & U773 and Department of Medical Oncology, Beaujon University Hospital (AP-HP - PRES Paris 7 Diderot), 100 boulevard du Général Leclerc, 92110 Clichy, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Faivre
authors.affiliation: New Drug Evaluation Laboratory, Centre of Experimental Therapeutics and Medical Oncology, Department of Oncology, Centre Hospitalier Universitaire Vaudois (CHUV) Lausanne, Switzerland.
authors.forename: Eric
authors.initials: E
authors.lastname: Raymond
authors.affiliation: New Drug Evaluation Laboratory, Centre of Experimental Therapeutics and Medical Oncology, Department of Oncology, Centre Hospitalier Universitaire Vaudois (CHUV) Lausanne, Switzerland. Electronic address: armand.de-gramont@chuv.ch.
authors.forename: Armand
authors.initials: A
authors.lastname: de Gramont
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000378:metabolism; D002986:Clinical Trials as Topic / Q000379:methods; D016503:Drug Delivery Systems / Q000379:methods* / Q000639:trends; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D016212:Transforming Growth Factor beta
keywords: Angiogenesis; Fibrosis; Metastasis; Microenvironment; TGFβ inhibitors; Tumor-stroma interactions