Abstract 4099: BMP4 and BMP5 in pancreatic cancer: novel bidirectional players

Abstract

Abstract Bone morphogenetic proteins (BMP) are signaling molecules involved in diverse developmental phases and are able to regulate cell growth, apoptosis and differentiation. For the last decade, they have also been increasingly in focus in cancer research. Studies have demonstrated that BMPs are able to both promote and inhibit cancer progression. In pancreatic cancer, there are only very few papers that have evaluated the role of BMP signaling. In this work, we have first determined the expression of seven BMP ligands (BMP2- BMP8) and six BMP specific receptors in 16 pancreatic cancer cell lines and in 4 normal pancreatic tissues using qRT-PCR. Expression of six BMP specific receptors was seen in all pancreatic cancer cell lines as well as in normal pancreas samples indicating that these cells are able to respond to BMP signals. Transcripts of the ligands BMP2, BMP3, BMP6 and BMP7 were detected at similar expression levels in both cancer and normal sample groups. The relative expression levels of BMP5 and BMP8 were significantly decreased in cancer cell lines compared to the normal pancreas samples. Interestingly, in a subset (4/16) of the cancer cell lines BMP4 was detected at highly elevated expression level whereas in rest of the cancer and in all normal samples its expression was barely detectable. We chose to study further the potential role of BMP4 and BMP5 signaling in pancreatic cancer pathogenesis. Changes in cell growth, migration, and invasion were examined in five pancreatic cancer cell lines (AsPC-1, SU.86.86, MIAPaCa-2, HPAF-II, and PANC-1) after recombinant BMP4 or BMP5 treatment. BMP5 treatment reduced cell number in three cell lines up to 36% (MIAPaCa-2, HPAF-II, and PANC-1). BMP4 decreased growth in four cell lines with the most distinct difference seen in MIAPaCa-2 and PANC-1 cells (30% or 79% decrease in cell number, respectively). BMP5 and BMP4 induced growth inhibition were both mainly due the alterations in cell cycle. Despite the growth inhibitory effect, BMP5 simultaneously increased the migration and invasion of two cell lines (MIAPaCa-2 and HPAF-II). Similarly, BMP4 increased migration and invasion of three cell lines with clear growth reduction. BMP4 treatment resulted in 3.5-fold increase of invaded MIAPaCa-2 cells and 10.8-fold increase of invaded PANC-1 cells. All cell lines with phenotypic changes showed activation of the canonical SMAD pathway. In addition, phosphorylation of MAP-kinases p38 and ERK1/2 was detected in MIAPaCa-2 cells after BMP4 and BMP5 stimulation. Taken together, BMP4 and BMP5 are able to both inhibit the growth and promote migration and invasion of the same pancreatic cell line. In this regard they resemble a closely related cytokine, transforming growth factor β, with a demonstrated dual function in cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4099.