Role of tumor-derived proinflammatory cytokines GM-CSF, TNF-alpha, and IL-12 in the migration and differentiation of antigen-presenting cells in cervical carcinoma.
BACKGROUND
Proinflammatory cytokines are important in modifying the activity, differentiation, and migration of antigen-presenting cells and may influence the survival of cancer patients. The study assessed whether GM-CSF, TNF-alpha, and IL-12, produced by cervical cancer cells, are important for the activity, differentiation, and migration of antigen-presenting cells.


METHODS
In 90 patients with cervical carcinoma the number of monocytes/tumor-associated macrophages (TAM), mature dendritic cells (DC), and Langerhans cells (LHC) was determined using immunohistochemistry. An RNA in situ hybridization technique was used to measure the expression level of GM-CSF, TNF-alpha, IL-12p35, and IL-12p40.


RESULTS
TAM were detected intraepithelial as well as in the stroma of the tumor. LHC were only detected intraepithelial and mature DC only in the tumor stroma. The number of TAM correlated positively with the number of mature DC. The expression levels of GM-CSF and TNF-alpha correlated positively with the number of TAM and DC. TNF-alpha showed a negative correlation with the number of LHC. A significant correlation between the expression of functional IL-12 (IL-12p40) and stromal TAM was found. The expression of GM-CSF, TNF-alpha, and IL-12p40 did not correlate significantly with disease-free survival. However, high IL-12p40 expression was associated with a favorable cumulative overall survival.


CONCLUSIONS
The results suggest that GM-CSF as well as TNF-alpha, produced by cervical carcinoma cells, may play a role in the differentiation of monocytes into mature DC. Furthermore, TNF-alpha may influence the migration of LHC from the tumor.
Zijlmans
Henry J M A A
HJ
Department of Pathology, Leiden University Medical Center, Leiden, Netherlands.
Fleuren
Gert Jan
GJ
Baelde
Hans J
HJ
Eilers
Paul H C
PH
Kenter
Gemma G
GG
Gorter
Arko
A
D000230:Adenocarcinoma / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D000328:Adult; D000368:Aged; D000938:Antigen-Presenting Cells / Q000276:immunology*; D018196:Carcinoma, Adenosquamous / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation; D002465:Cell Movement; D003713:Dendritic Cells / Q000276:immunology; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism*; D006801:Humans; D007124:Immunoenzyme Techniques; D017403:In Situ Hybridization; D053762:Interleukin-12 Subunit p40 / Q000378:metabolism*; D007801:Langerhans Cells / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology; D015347:RNA Probes; D015996:Survival Rate; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D002583:Uterine Cervical Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000473:pathology
D053762:Interleukin-12 Subunit p40; D015347:RNA Probes; D014409:Tumor Necrosis Factor-alpha; D016178:Granulocyte-Macrophage Colony-Stimulating Factor