title: Cervical squamous carcinoma cells are resistant to the combined action of tumor necrosis factor-alpha and histamine whereas normal keratinocytes undergo cytolysis.
abstract: BACKGROUND
  Previous reports showed that mast cells can typically be found in the peritumoral stroma of cervix carcinomas as well as in many other cancers. Both histamine and TNF-alpha are potent preformed mast cell mediators and they can act simultaneously after release from mast cells. Thus, the effect of TNF-alpha and histamine on cervical carcinoma cell lines was studied.
  
  
  RESULTS
  TNF-alpha alone induced slight growth inhibition and cell cycle arrest at G0/G1 phase in SiHa cells, but increased their migration. Histamine alone had no effect on cells. In addition, TNF-alpha and histamine in combination showed no additional effect over that by TNF-alpha alone, although SiHa cells were even pretreated with a protein synthesis inhibitor. Furthermore, TNF-alpha-sensitive ME-180 carcinoma cells were also resistant to the combination effect of TNF-alpha and histamine. In comparison, TNF-alpha or histamine alone induced growth inhibition in a non-cytolytic manner in normal keratinocytes, an effect that was further enhanced to cell cytolysis when both mediators acted in combination. Keratinocytes displayed strong TNF receptor (TNFR) I and II immunoreactivity, whereas SiHa and ME-180 cells did not. Furthermore, cervix carcinoma specimens revealed TNF-alpha immunoreactivity in peritumoral cells and carcinoma cells. However, the immunoreactivity of both TNFRs was less intense in carcinoma cells than that in epithelial cells in cervical specimens with non-specific inflammatory changes.
  
  
  CONCLUSIONS
  SiHa and ME-180 cells are resistant to the cytolytic effect of TNF-alpha and histamine whereas normal keratinocytes undergo cytolysis, possibly due to the smaller amount of TNFRs in SiHa and ME-180 cells. In the cervix carcinoma, the malignant cells may resist this endogenous cytolytic action and TNF-alpha could even enhance carcinoma cell migration.
authors.affiliation: Department of Dermatology, University of Kuopio, Kuopio, Finland. nicolae-costin.diaconu@kuh.fi
authors.forename: Nicolae-Costin
authors.initials: NC
authors.lastname: Diaconu
authors.forename: Jaana
authors.initials: J
authors.lastname: Rummukainen
authors.forename: Mikko
authors.initials: M
authors.lastname: Mättö
authors.forename: Anita
authors.initials: A
authors.lastname: Naukkarinen
authors.forename: Rauno J
authors.initials: RJ
authors.lastname: Harvima
authors.forename: Jukka
authors.initials: J
authors.lastname: Pelkonen
authors.forename: Ilkka T
authors.initials: IT
authors.lastname: Harvima
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy*; D016923:Cell Death / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003603:Cytotoxins / Q000008:administration & dosage; D004273:DNA, Neoplasm / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D005260:Female; D006632:Histamine / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects* / Q000502:physiology; D008297:Male; D008875:Middle Aged; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000494:pharmacology*; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy*
chemical_list: D003603:Cytotoxins; D004273:DNA, Neoplasm; D014409:Tumor Necrosis Factor-alpha; D006632:Histamine