Human cytomegalovirus and mucoepidermoid carcinoma of salivary glands: cell-specific localization of active viral and oncogenic signaling proteins is confirmatory of a causal relationship

Exp Mol Pathol. 2012 Feb;92(1):118-25. doi: 10.1016/j.yexmp.2011.10.011. Epub 2011 Nov 10.

Abstract

Human cytomegalovirus (hCMV) infection is common. Although still controversial, there is growing evidence that active hCMV infection is associated with a variety of malignancies, including brain, breast, lung, colon, and prostate. Given that hCMV is frequently resident in salivary gland (SG) ductal epithelium, we hypothesized that hCMV would be important to the pathogenesis of SG mucoepidermoid carcinoma (MEC). This was initially supported by our finding that purified CMV induces malignant transformation in SG cells in an in vitro mouse model, and utilizes a pathogenic pathway previously reported for human MEC. Here we present the histologic and molecular characterizations of 39 human SG MECs selected randomly from a repository of cases spanning 2004-2011. Serial sections were obtained from formalin-fixed, paraffin embedded, tissue blocks from previous incisional or excisional biopsies. Immunohistochemical assays were performed for active hCMV proteins (IE1 and pp65) and the activated COX/AREG/EGFR/ERK signaling pathway. All four prospective causal criteria for viruses and cancer are fully satisfied: (1) protein markers for active hCMV are present in 97% of MECs; (2) markers of active hCMV are absent in non-neoplastic SG tissues; (3) hCMV-specific proteins (IE1, pp65) are in specific cell types and expression is positively correlated with severity; (4) hCMV correlates and colocalizes with an upregulation and activation of an established oncogenic signaling pathway (COX/AREG/EGFR/ERK). Thus, the evidential support reported here and previously in a mouse model is strongly confirmatory of a causal relationship between hCMV and SG mucoepidermoid carcinoma. To our knowledge, this is the first demonstration of hCMV's role in human oncogenesis that fully responds to all of Koch's Postulates as revised for viruses and cancer. In the absence of any contrary evidence, hCMV can reasonably be designated an "oncovirus."

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Amphiregulin
  • Animals
  • Antigens, Viral / analysis
  • Antigens, Viral / metabolism
  • Carcinoma, Mucoepidermoid / pathology
  • Carcinoma, Mucoepidermoid / virology*
  • Cyclooxygenase 2 / analysis
  • Cyclooxygenase 2 / metabolism
  • Cytomegalovirus / isolation & purification
  • Cytomegalovirus / metabolism*
  • Cytomegalovirus / physiology
  • Cytomegalovirus Infections / complications*
  • Cytomegalovirus Infections / immunology
  • Cytomegalovirus Infections / pathology
  • EGF Family of Proteins
  • ErbB Receptors / analysis
  • ErbB Receptors / metabolism
  • Female
  • Glycoproteins / analysis
  • Glycoproteins / metabolism
  • Humans
  • Immediate-Early Proteins / analysis
  • Immediate-Early Proteins / metabolism
  • Immunohistochemistry
  • Intercellular Signaling Peptides and Proteins / analysis
  • Intercellular Signaling Peptides and Proteins / metabolism
  • MAP Kinase Signaling System / physiology
  • Male
  • Middle Aged
  • Phosphoproteins / analysis
  • Phosphoproteins / metabolism
  • Salivary Gland Neoplasms / pathology
  • Salivary Gland Neoplasms / virology*
  • Salivary Glands / pathology
  • Salivary Glands / virology
  • Viral Matrix Proteins / analysis
  • Viral Matrix Proteins / metabolism
  • Viral Proteins / analysis*
  • Viral Proteins / metabolism
  • Young Adult

Substances

  • AREG protein, human
  • Amphiregulin
  • Antigens, Viral
  • Areg protein, mouse
  • EGF Family of Proteins
  • Glycoproteins
  • IE1 protein, cytomegalovirus
  • Immediate-Early Proteins
  • Intercellular Signaling Peptides and Proteins
  • Phosphoproteins
  • Viral Matrix Proteins
  • Viral Proteins
  • cytomegalovirus matrix protein 65kDa
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • EGFR protein, human
  • ErbB Receptors