Modulation of tumour angiogenesis by targeting p38 MAPK signalling in tumour-associated macrophages

Hyde, Caroline A. C.; Kumar, Sushil; Steiner, Rudolf and Schwendener, Reto A. (2009). Modulation of tumour angiogenesis by targeting p38 MAPK signalling in tumour-associated macrophages. In: Molecular and Cellular Mechanisms of Angiogenesis, 15-17 Jul 2009, University of Chester, The Biochemical Society.


Cellular crosstalk between cancer cells and tumour-associated macrophages (TAMs) plays an important role in tumour growth and metastasis by promoting tumour angiogenesis.
Western blot analyses of cell lysates from in vitro studies revealed that RAW macrophages co-cultured with Murine Lewis lung carcinoma (LLC) cells display elevated levels of p38 MAPK (p38) activation. To further investigate this signalling pathway we used the p38 inhibitor BIRB796. Exposure of cancer cells to macrophage-conditioned medium pre-incubated with BIRB796 showed a clear dose-dependent increase in apoptosis. By preparing liposomal formulations of BIRB796 (Lip-BIRB796) we can spare normal cells from the drug’s cytotoxic effects and specifically target p38 signalling in phagocytic macrophages. In vitro cytotoxicity studies revealed an increased chemosensitivity to doxorubicin treatment when macrophage/cancer cell co-cultures were treated with Lip-BIRB796 prior to doxorubicin exposure. Furthermore, in vivo CAM assays were able to demonstrate both a marked increase in angiogenesis in CAMs inoculated with RAW and LLC cell co-cultures as compared to the respective monocultures and a significant decrease where these co-cultures were treated with Lip-BIRB796.
To conclude, our results suggest that p38 is a promising target in TAMs for cancer adjuvant therapy.

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