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Open Access Research

Cytomegalovirus-induced salivary gland pathology: resistance to kinase inhibitors of the upregulated host cell EGFR/ERK pathway is associated with CMV-dependent stromal overexpression of IL-6 and fibronectin

Michael Melnick1, Parish P Sedghizadeh2, Krysta A Deluca1 and Tina Jaskoll1*

Author Affiliations

1 Laboratory for Developmental Genetics, University of Southern California, 925 W 34th Street, MC-0641, Los Angeles, CA 90089-0641, USA

2 Oral and Maxillofacial Pathology, Division of Diagnostic Sciences, University of Southern California, Los Angeles, CA, USA

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Herpesviridae 2013, 4:1  doi:10.1186/2042-4280-4-1

Published: 23 January 2013

Abstract

Background

Recently we identified a relationship between human cytomegalovirus (hCMV) and human salivary gland (SG) mucoepidermoid carcinoma (MEC) in over 90% of cases; tumorigenesis in these cases uniformly correlated with active hCMV protein expression and an upregulation of the EGFR → ERK pathway. Our previously characterized, novel mouse organ culture model of mouse CMV (mCMV)-induced tumorigenesis displays a number of histologic and molecular characteristics similar to human MEC.

Methods

Newborn mouse submandibular glands (SMGs) were incubated with 1 × 105 PFU/ml of lacZ-tagged mCMV RM427+ on day 0 for 24 hours and then cultured in virus-free media for a total of 6 or 12 days with or without EGFR/ERK inhibitors and/or aciclovir. SMGs were collected for histology, immunolocalization (pERK, FN, IL-6), viral distribution, or Western blot analysis (pERK).

Results

Here we report: (1) mouse SMG tumors soon exhibit an acquired resistance to EGFR/ERK pathway kinase inhibitors, alone or in combination; (2) long term tumor regression can only be sustained by concurrent inhibitor and antiviral treatment; (3) CMV-dependent, kinase inhibitor resistance is associated with overexpression of fibronectin and IL-6 proteins in abnormal stromal cells.

Conclusions

Acquired resistance to kinase inhibitors is dependent upon CMV dysregulation of alternative pathways with downstream effectors common with the targeted pathway, a phenomenon with important therapeutic implications for human MEC of salivary glands.

Keywords:
Cytomegalovirus; Salivary gland; Tumorigenesis; EGFR; ERK; Fibronectin; Interleukin 6