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BBB seminar: Carl-Henrik Heldin

Signal transduction via receptors for PDGF and TGF-β - possible targets in tumor therapy


Carl-Henrik Heldin
Ludwig Institute for Cancer Research, Uppsala University, Sweden


Platelet-derived growth factor (PDGF) and transforming growth factor-β (TGF-β) affect cell growth, survival and migration, and have important functions during embryonal development.

PDGF isoforms exert their cellular effects via two structurally similar tyrosine kinase receptors. We investigate the signal transduction mechanisms downstream of PDGF receptors which mediate PDGF's effects. We also study the effect of receptor internalization and trafficking on its signaling capacity. Overactivity of the PDGF signaling pathway is associated with disease, e.g. certain malignancies. We have explored the use of PDGF antagonists in tumor treatment, and found significant inhibition of tumor growth in animal models of tumors driven by autocrine PDGF production. In addition, we have observed that inhibition of paracrine PDGF stimulation of stromal fibroblasts and vessel pericytes affects tumor interstitial fluid pressure and tumor angiogenesis.

TGF-β has a more complicated role in cancer; initially it is a tumor suppressor through its ability to inhibit growth and to promote apoptosis of tumor cells. At later stages, when tumor cells become resistant to the cytostatic effects of TGF-β, it has tumor promoter effects through stimulation of epithelial-to-mesenchymal transition of tumor cells, stimulation of angiogenesis and suppression of the immune system. We are currently delineating the signaling pathways involved in the cytostatic and apoptotic effects of TGF-β, as well as in its effects on epithelial-to-mesenchymal transition which is linked to increased invasiveness. Our aim is to explore the possible use of TGF-β antagonists in tumor treatment.

Selected publications:

Heldin C-H, Rubin K, Pietras K and Östman A. High interstitial fluid pressure – an obstacle in cancer therapy. Nat. Rev. Cancer 4: 806-813, 2004.

Moustakas A and Heldin C-H. Non-Smad TGF-β signals. J. Cell. Sci. 118: 3573-3584, 2005.

ten Dijke P and Heldin C-H, eds. (2006). Smad Signal Transduction. Proteins and Cell Regulation, Springer Verlag, Dordrecht, Germany, Vol. 5, pp. 1-473.

Host: Rolf Kåre Reed <rolf.reed@biomed.uib.no>, Department of Biomedicine