title: Symptomatic Improvement in Human Papillomavirus-Induced Epithelial Neoplasia by Specific Targeting of the CXCR4 Chemokine Receptor.
abstract: Human papillomavirus (HPV) infection is estimated to be the causal agent in 5% of all human cancers and is the leading cause of genital warts, which is the most common sexually transmitted viral disease. Currently, there are no medications to treat HPV infection, and therapeutic strategies primarily target HPV-related cancer rather than viral infection. HPV infection has severe effects on patients who display selective susceptibility to the virus in the context of primary immunodeficiencies, such as the warts, hypogammaglobulinemia, infections, and myelokathexis syndrome, which is caused by dysfunctions of CXCR4, the receptor for the CXCL12 chemokine. In this study we showed in a transgenic mouse model of HPV-induced epidermal neoplasia the beneficial effects of Cxcl12/Cxcr4 pathway blockade with the selective CXCR4 antagonist AMD3100. Daily treatment with AMD3100 for 28 days potently reduced the abnormal ear epidermal thickening in all mice. This effect was associated with reductions in keratinocyte hyperproliferation and immune cell infiltration, both of which are linked to neoplastic progression. Moreover, we observed the abnormal coordinate expression of Cxcl12 and p16INK4a (a surrogate marker of HPV-induced cancers) in dysplastic epidermal keratinocytes, which was inhibited by AMD3100 treatment. These results provide strong evidence for the therapeutic potential of CXCL12/CXCR4 pathway blockade in HPV-induced pathogenesis.
authors.affiliation: UMR996-Inflammation, Chemokines and Immunopathology, Inserm, Univ Paris-Sud, Université Paris-Saclay, Clamart, France.
authors.forename: Floriane
authors.initials: F
authors.lastname: Meuris
authors.affiliation: UMR996-Inflammation, Chemokines and Immunopathology, Inserm, Univ Paris-Sud, Université Paris-Saclay, Clamart, France; US31-UMS3679-Plateforme PHIC, Institut Paris-Saclay d'Innovation Thérapeutique (IPSIT), Inserm, CNRS, Univ Paris-Sud, Université Paris-Saclay, Clamart, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Gaudin
authors.affiliation: UMR996-Inflammation, Chemokines and Immunopathology, Inserm, Univ Paris-Sud, Université Paris-Saclay, Clamart, France.
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Aknin
authors.affiliation: UMR996-Inflammation, Chemokines and Immunopathology, Inserm, Univ Paris-Sud, Université Paris-Saclay, Clamart, France.
authors.forename: Patrice
authors.initials: P
authors.lastname: Hémon
authors.affiliation: UMR996-Inflammation, Chemokines and Immunopathology, Inserm, Univ Paris-Sud, Université Paris-Saclay, Clamart, France; Service d'Anatomie et de Cytologie Pathologique, Hôpital Robert Debré, Université Paris Diderot, Paris, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Berrebi
authors.affiliation: UMR996-Inflammation, Chemokines and Immunopathology, Inserm, Univ Paris-Sud, Université Paris-Saclay, Clamart, France. Electronic address: francoise.bachelerie@u-psud.fr.
authors.forename: Françoise
authors.initials: F
authors.lastname: Bachelerie
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001596:Benzylamines; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D000080027:Cyclams; D004195:Disease Models, Animal; D006571:Heterocyclic Compounds / Q000494:pharmacology*; D006801:Humans; D007150:Immunohistochemistry; D015603:Keratinocytes / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D058990:Molecular Targeted Therapy; D027383:Papillomaviridae / Q000472:pathogenicity; D030361:Papillomavirus Infections / Q000188:drug therapy* / Q000235:genetics; D011897:Random Allocation; D019718:Receptors, CXCR4 / Q000187:drug effects / Q000235:genetics*; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000821:virology*
chemical_list: D001596:Benzylamines; D000080027:Cyclams; D006571:Heterocyclic Compounds; D019718:Receptors, CXCR4; C088327:plerixafor