Cervical squamous carcinoma cells are resistant to the combined action of tumor necrosis factor-α and histamine whereas normal keratinocytes undergo cytolysis

Nicolae-Costin Diaconu¹ , Jaana Rummukainen² , Mikko Mättö³ , Anita Naukkarinen² , Rauno J Harvima¹ , Jukka Pelkonen³ and Ilkka T Harvima¹

¹Department of Dermatology, University of Kuopio, Kuopio, Finland

²Department of Pathology, Kuopio University Hospital, Kuopio, Finland

³Department of Clinical Microbiology, University of Kuopio, Kuopio, Finland

author email corresponding author email

BMC Cancer 2008, 8:46doi:10.1186/1471-2407-8-46


Published:	7 February 2008

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-α are potent preformed mast cell mediators and they can act simultaneously after release from mast cells. Thus, the effect of TNF-α and histamine on cervical carcinoma cell lines was studied.

Methods and results

TNF-α 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-α and histamine in combination showed no additional effect over that by TNF-α alone, although SiHa cells were even pretreated with a protein synthesis inhibitor. Furthermore, TNF-α-sensitive ME-180 carcinoma cells were also resistant to the combination effect of TNF-α and histamine. In comparison, TNF-α 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-α 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.

Conclusion

SiHa and ME-180 cells are resistant to the cytolytic effect of TNF-α 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-α could even enhance carcinoma cell migration.