Carcinogenesis Advance Access published online on August 29, 2003
Carcinogenesis, doi:10.1093/carcin/bgg153
© 2003 by Oxford University Press
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CANCER BIOLOGY
1 Institute for Biochemistry and Molecular Biology I, Heinrich-Heine-University, D-40225 Düsseldorf, Germany
* Corresponding author. E-mail: PeterBrenneisen{at}web.de.
Received 2 May 2003
; revised 14 July 2003
; accepted 14 August 2003
Loss of gap junctional intercellular communication (GJIC) is a characteristic of cancer cells. Since a coordinated interaction of epithelial tumor cells with stromal cells is a prerequisite for tumor invasion and metastasis, the present study was designed to test the hypothesis that skin-derived tumor cells may modulate homologous and heterologous GJIC. While homologous GJIC of human dermal fibroblast as well as epidermal keratinocytes was detected, no communication was measured between SCL-1 cells derived from squamous cell carcinoma of human skin. Interestingly, cocultures of dermal fibroblasts and SCL-1 tumor cells in serum-containing medium resulted in a 52-70% lowering of the number of communicating fibroblasts. Furthermore, incubation of confluent fibroblast cultures with serum-free supernatant fractions (20-30 kDa) from tumor cells, termed 20/30-fraction, lowered the homologous gap junction communication of fibroblasts by over 90%. This novel aspect of downregulated homologous GJIC of dermal fibroblasts, which is reversible, was neither mediated by alteration of the expression of connexin43, the major gap junctional protein of dermal fibroblasts, nor by aberrant localization of connexin43 in the plasma membrane. Furthermore, posttranslational modifications of connexins such as phosphorylation was not measured by mobility shift studies. Tumor cell-mediated GJIC downregulation between fibroblasts was suppressed using EGTA-containing serum-free tumor cell-derived supernatants suggesting that calcium ions (Ca2+) might mediate the transduction of this effect. The involvement of Ca2+ in downregulation of homologous GJIC of fibroblasts was supported by an increase in fluorescence intensity of the intracellular calcium-sensitive indicator Fura-2 upon treatment of fibroblasts with the active 20/30-fraction. In conclusion, these data establish homologous GJIC of (stromal) fibroblasts as a parameter modulated by paracrine acting factor(s) of epithelial tumor cells during tumor-stroma interaction of skin cells.
connexin, gap junction, fibroblast, keratinocyte, tumor-stroma, cancer
Modulation of homologous gap junctional intercellular communication of human dermal fibroblasts via paracrine factor(s) generated by squamous tumor cells
2 Clinic for Gastroenterology, Hepatology, and Infectiology, Heinrich-Heine-University, D-40225 Düsseldorf, Germany
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