ECTS Abstracts (2015) 1 P98

ALK1Fc suppresses tumour growth by inhibiting angiogenesis and Notch signalling in human prostate cancer

Eugenio Zoni1, Sofia Karkampouna2, Laurens van Meeteren2, Marie Jose Goumans2, Peter Gray3, Gabri van der Pluijm1, Peter ten Dijke2 & Marianna Kruithof-de Julio2,4


1Dept. of Urology, Leiden University Medical Centre, Leiden, The Netherlands; 2Dept. of Molecular Cell Biology, Leiden University Medical Centre, Leiden, The Netherlands; 3Clayton Foundation Laboratories for Peptide Biology, The Salk Institute for Biological Studies, La Jolla, CA, USA; 4Dept. of Dermatology, Leiden University Medical Centre, Leiden, The Netherlands.


Prostate cancer is the second most common cancer in men worldwide. Lethality is almost inevitable due to the consequences of metastasis. Therefore, understanding the molecular pathways that underlie the emergence and spread of metastases from primary tumours are of great biological and clinical value. Our studies focus on the role of activin receptor–like kinase-1 (ALK1), a key regulator of tumour angiogenesis. ALK1 is a type I receptor in the transforming growth factor-β (TGFβ) superfamily with high affinity for its ligands Bone morphogenetic protein (BMP) 9 and 10 inducing phosphorylation of Smad1 and/or Smad5. Interestingly, its effect can be mediated also by ALK2/Smad1/Smad4 pathway. We employed a soluble chimeric protein (ALK1Fc) containing the human ALK1 extracellular domain that binds with high affinity BMP9 and BMP10, thus, preventing activation of endogenous ALK1, ALK2 and downstream signalling. Here we show for the first time in prostate cancer that ALK1Fc reduces BMP9- mediated signalling and decreases proliferation in vitro by disrupting the induction of Notch signalling, another major key pathway involved in prostate cancer development, progression and bone metastasis. In line with these observations we further demonstrate that ALK1Fc reduced tumour growth by impairing angiogenesis and affecting proliferation of human prostate cancer cells in vivo. Taken together this data suggest BMP9 as a possible therapeutic target and thus justifies the continued clinical development of drugs blocking ALK1 and ALK2 receptor activity.

Disclosure: The authors declared no competing interests.

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