title: Cytomegalovirus-induced salivary gland pathology: AREG, FGF8, TNF-α, and IL-6 signal dysregulation and neoplasia.
abstract: Mucoepidermoid carcinoma (MEC) is the most common malignant tumor originating in major and minor salivary glands (SGs). Although the precise multifactorial etiology of human SG-MEC is largely unknown, we have recently shown that cytomegalovirus (CMV) is an important component of MEC tumorigenesis. Despite the well-documented overexpression of the EGFR → ERK signaling pathway in SG-MEC, there has been limited to no clinical success with inhibition of this pathway. Using our previously characterized mouse model of CMV-induced SG dysplasia/neoplasia, we report that inhibitors of the EGFR → ERK pathway do not ameliorate or rescue well-established pathology, either singly or in combination, but they do inhibit the evolution of progressive pathogenesis ("disease tolerance") in the face of mounting CMV burden. Failure to rescue SG pathology, suggested a possible increase in the ligand levels of alternative pathways that share cell proliferation and survival effectors (e.g. ERK and PI3K). Here we present evidence of a highly significant upregulation of ligands for the EGFR, FGFR, IL-6R, and TNFR signaling pathways, all of which converge upon the Raf/MEK/ERK amplifier module. This explains our finding that even in the presence of the highest nontoxic dose of an ERK phosphorylation inhibitor, pERK is undiminished. Given the considerable pathway crosstalk, a deep understanding of subversion and dysregulation of the SG interactome by CMV is a priori quite daunting. Circumventing this dilemma, we present evidence that concurrent inhibition of ERK phosphorylation (U0126) and CMV replication (acyclovir) obviates progressive pathogenesis and results in complete SG rescue (tumor regression). These findings provide a mechanistic foundation for potential clinical trials that utilize similar concurrent treatment with extant FDA-approved drugs.
authors: Laboratory for Developmental Genetics, USC, Los Angeles, CA 90089-0641, USA. mmelnick@usc.edu
authors: Michael
authors: M
authors: Melnick
authors: Krysta A
authors: KA
authors: Deluca
authors: Parish P
authors: PP
authors: Sedghizadeh
authors: Tina
authors: T
authors: Jaskoll
mesh_terms: D000212:Acyclovir / Q000494:pharmacology; D066258:Amphiregulin; D000818:Animals; D018277:Carcinoma, Mucoepidermoid / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D003588:Cytopathogenic Effect, Viral; D004195:Disease Models, Animal; D066255:EGF Family of Proteins; D066246:ErbB Receptors / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005260:Female; D051524:Fibroblast Growth Factor 8 / Q000378:metabolism; D006023:Glycoproteins / Q000378:metabolism; D006566:Herpesviridae Infections / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D020935:MAP Kinase Signaling System; D051379:Mice; D008810:Mice, Inbred C57BL; D018146:Muromegalovirus / Q000187:drug effects / Q000502:physiology*; D009924:Organ Culture Techniques; D010766:Phosphorylation; D013363:Submandibular Gland / Q000378:metabolism / Q000473:pathology* / Q000821:virology*; D013365:Submandibular Gland Neoplasms / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation
chemical_list: C587848:AREG protein, human; D066258:Amphiregulin; C587849:Areg protein, mouse; D066255:EGF Family of Proteins; C496457:Fgf8 protein, mouse; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D051524:Fibroblast Growth Factor 8; C541485:EGFR protein, mouse; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; D000212:Acyclovir