title: Expression of folate receptors alpha and beta in normal and cancerous gynecologic tissues: correlation of expression of the beta isoform with macrophage markers.
abstract: BACKGROUND
  Folate receptor alpha (FOLR1/FRA) is expressed in a number of epithelial cancers and in particular epithelial ovarian cancer (EOC), especially of the serous histotype. Recent studies have shown that EOC originates from the fallopian tube fimbriae rather than from epithelial cells lining the ovary. We have previously shown by immunohistochemistry a strong correlation between FRA expression in EOC and normal and fallopian adenocarcinoma. Folate receptor beta (FOLR2/FRB) has been described to be expressed by macrophages both in inflammatory disorders and certain epithelial cancers. Given the high sequence identity of these two folate receptor family members we sought to investigate the architectural and cell-specific expression of these two receptors in gynecologic tissues.
  
  
  METHODS
  RNA scope, a novel chromogenic in situ hybridization assay tool, was used to examine expression of the alpha (FOLR1) and beta (FOLR2) isoforms of folate receptor relative to each other as well as to the macrophage markers CD11b and CD68, in samples of normal fallopian tube and fallopian adenocarcinoma as well as normal ovary and EOC.
  
  
  RESULTS
  We demonstrated expression of both FOLR1 and FOLR2 in EOC, normal fallopian tube and fallopian adenocarcinoma tissue while very little expression of either marker was observed in normal ovary. Furthermore, FOLR2 was shown to be expressed almost exclusively in macrophages, of both the M1 and M2 lineages, as determined by co-expression of CD11b and/or CD68, with little or no expression in epithelial cells.
  
  
  CONCLUSIONS
  These findings further substantiate the hypothesis that the cell of origin of EOC is tubal epithelium and that the beta isoform of folate receptor is primarily restricted to macrophages. Further, macrophages expressing FOLR2 may represent tumor associated or infiltrating macrophages (TAMs) in epithelial cancers.
authors.affiliation: Translational Medicine and Diagnostics, Morphotek, Inc, Exton, USA. doshannessy@morphotek.com.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: O'Shannessy
authors.affiliation: Translational Medicine and Diagnostics, Morphotek, Inc, Exton, USA. esomers@morphotek.com.
authors.forename: Elizabeth B
authors.initials: EB
authors.lastname: Somers
authors.affiliation: Pharma Assay Services, Advanced Cell Diagnostics, Inc, Hayward, USA. lwang@acdbio.com.
authors.forename: Li-Chong
authors.initials: LC
authors.lastname: Wang
authors.affiliation: Pharma Assay Services, Advanced Cell Diagnostics, Inc, Hayward, USA. hwang@acdbio.com.
authors.forename: Hongwei
authors.initials: H
authors.lastname: Wang
authors.affiliation: Pharma Assay Services, Advanced Cell Diagnostics, Inc, Hayward, USA. rhsu@acdbio.com.
authors.forename: Ruby
authors.initials: R
authors.lastname: Hsu
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000096:biosynthesis* / Q000235:genetics; D015214:Antigens, Differentiation, Myelomonocytic / Q000096:biosynthesis* / Q000235:genetics; D039481:CD11b Antigen / Q000096:biosynthesis* / Q000235:genetics; D000077216:Carcinoma, Ovarian Epithelial; D005187:Fallopian Tubes / Q000378:metabolism / Q000473:pathology; D005260:Female; D058975:Folate Receptor 1 / Q000096:biosynthesis* / Q000235:genetics; D058976:Folate Receptor 2 / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008875:Middle Aged; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics* / Q000473:pathology; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology; D059016:Tumor Microenvironment / Q000235:genetics; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D039481:CD11b Antigen; D058975:Folate Receptor 1; D058976:Folate Receptor 2; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C548696:FOLR1 protein, human; C000610095:FOLR2 protein, human; C509295:ITGAM protein, human