Researchers at Erasmus University Have Reported New Data on Cancer Gene Therapy (Loss of SMAD4 Alters BMP Signaling to Promote Colorectal Cancer Cell Metastasis via Activation of Rho and ROCK)
By a News Reporter-Staff News Editor at Cancer Gene Therapy Week -- Investigators publish new report on Biotechnology. According to news reporting originating from Rotterdam, Netherlands, by NewsRx correspondents, research stated, "SMAD4 frequently is lost from colorectal cancers (CRCs), which is associated with the development of metastases and a poor prognosis. SMAD4 loss is believed to alter transforming growth factor beta signaling to promote tumor progression."
Our news editors obtained a quote from the research from Erasmus University, "However, SMAD4 is also a central component of the bone morphogenetic protein (BMP) signaling pathway, implicated in CRC pathogenesis by human genetic studies. We investigated the effects of alterations in BMP signaling on the invasive and metastatic abilities of CRC cells and changes in members in this pathway in human tumor samples. We activated BMP signaling in SMAD4-positive and SMAD4-negative CRC cells (HCT116, HT-29, SW480, and LS174T); SMAD4 was stably expressed or knocked down using lentiviral vectors. We investigated the effects on markers of epithelial-mesenchymal transition and on cell migration, invasion, and formation of invadopodia. We performed kinase activity assays to characterize SMAD4-independent BMP signaling and used an inhibitor screen to identify pathways that regulate CRC cell migration. We investigated the effects of the ROCK inhibitor Y-27632 in immunocompromised (CD-1 Nu) mice with orthotopic metastatic tumors. Immunohistochemistry was used to detect BMPR1a, BMPR1b, BMPR2, and SMAD4 in human colorectal tumors; these were related to patient survival times. Activation of BMP signaling in SMAD4-negative cells altered protein and messenger RNA levels of markers of epithelial-mesenchymal transition and increased cell migration, invasion, and formation of invadopodia. Knockdown of the BMP receptor in SMAD4-negative cells reduced their invasive activity in vitro. SMAD4-independent BMP signaling activated Rho signaling via ROCK and LIM domain kinase (LIMK). Pharmacologic inhibition of ROCK reduced metastasis of colorectal xenograft tumors in mice. Loss of SMAD4 from colorectal tumors has been associated with reduced survival time; we found that this association is dependent on the expression of BMP receptors but not transforming growth factor beta receptors. Loss of SMAD4 from colorectal cancer cells causes BMP signaling to switch from tumor suppressive to metastasis promoting. Concurrent loss of SMAD4 and normal expression of BMP receptors in colorectal tumors was associated with reduced survival times of patients."
According to the news editors, the research concluded: "Reagents that interfere with SMAD4-independent BMP signaling, such as ROCK inhibitors, might be developed as therapeutics for CRC."
For more information on this research see: Loss of SMAD4 Alters BMP Signaling to Promote Colorectal Cancer Cell Metastasis via Activation of Rho and ROCK. Gastroenterology, 2014;147(1):196-328. Gastroenterology can be contacted at: W B Saunders Co-Elsevier Inc, 1600 John F Kennedy Boulevard, Ste 1800, Philadelphia, PA 19103-2899, USA. (Elsevier - www.elsevier.com; Gastroenterology - www.elsevier.com/wps/product/cws_home/623297)
The news editors report that additional information may be obtained by contacting P.W. Voorneveld, Erasmus University, Erasmus MC, Dept. of Gastroenterol & Hepatol, Rotterdam, Netherlands. Additional authors for this research include L.L. Kodach, R.J. Jacobs, N. Liv, A.C. Zonnevylle, J.P. Hoogenboom, I. Biemond, H.W. Verspaget, D.W. Hommes, K. de Rooij, C.J.M. van Noesel, H. Morreau, T. van Wezel, G.J.A. Offerhaus, G.R. van den Brink and M. Peppelenbosch (see also Biotechnology).
Keywords for this news article include: Biotechnology, Europe, Kinase, Oncology, Rotterdam, Colorectal, Netherlands, Colon Cancer, Gastroenterology, Cancer Gene Therapy, Enzymes and Coenzymes, Bone Morphogenetic Protein
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