title: BMP signaling promotes the growth of primary human colon carcinomas in vivo.
abstract: Human colon carcinomas (CCs) represent a growing worldwide problem. One of the pathways that has been negatively implicated in the genesis of CCs is triggered by bone morphogenetic protein (BMP) ligands, which activate BMP receptors leading to the function of SMAD proteins in the nucleus. BMP signaling is altered in familial human polyposis, and mice with compromised BMP signaling in the intestine develop tumors. Here, we have re-evaluated the presence and roles of BMP signaling in advanced sporadic human CCs, using both primary tumors and established cell lines, and directly modulating BMP pathway activity in a cell-autonomous manner using constitutively active and dominant-negative BMP receptor Ib forms. We find evidence for active endogenous BMP signaling in all primary CC samples and for its role in promoting primary CC tumor growth and CC cell survival and proliferation in vivo in xenografts. In vitro, we also document autonomous and non-autonomous effects of enhanced BMP receptor activity on gap closure in culture, suggesting possible roles in invasion. Caution should thus be exerted in trying to augment or restore its activity for therapeutic purposes. In contrast, we raise the possibility that blockade of BMP signaling might have beneficial effects against at least a subset of advanced colon cancers.
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva School of Medicine, 8242 CMU, 1 rue Michel Servet, CH-1211 Geneva, Switzerland.
authors.forename: Aiala
authors.initials: A
authors.lastname: Lorente-Trigos
authors.forename: Frédéric
authors.initials: F
authors.lastname: Varnat
authors.forename: Alice
authors.initials: A
authors.lastname: Melotti
authors.forename: Ariel
authors.initials: A
authors.lastname: Ruiz i Altaba
mesh_terms: D000818:Animals; D017209:Apoptosis; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000378:metabolism; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D002277:Carcinoma / Q000378:metabolism*; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D003110:Colonic Neoplasms / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D015513:Oncogene Proteins / Q000502:physiology; D015398:Signal Transduction; D051898:Smad1 Protein / Q000378:metabolism; D051902:Smad5 Protein / Q000378:metabolism; D051904:Smad8 Protein / Q000378:metabolism; D015534:Trans-Activators / Q000502:physiology; D014183:Transplantation, Heterologous; D000071676:Zinc Finger Protein GLI1
chemical_list: D019485:Bone Morphogenetic Proteins; D015513:Oncogene Proteins; D051898:Smad1 Protein; D051902:Smad5 Protein; D051904:Smad8 Protein; D015534:Trans-Activators; D000071676:Zinc Finger Protein GLI1; D052005:Bone Morphogenetic Protein Receptors, Type I