title: Hepatocellular carcinoma cells and their fibrotic microenvironment modulate bone marrow-derived mesenchymal stromal cell migration in vitro and in vivo.
abstract: Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third cause of cancer-related death. Fibrogenesis is an active process characterized by the production of several proinflammatory cytokines, chemokines and growth factors. It involves the activation of hepatic stellate cells (HSCs) which accumulate at the site of injury and are the main source of the extracellular matrix deposits. There are no curative treatments for advanced HCC, thus, new therapies are urgently needed. Mesenchymal stromal cells (MSCs) have the ability to migrate to sites of injury or to remodeling tissues after in vivo administration; however, in several cancer models they demonstrated limited efficacy to eradicate experimental tumors partially due to poor engraftment. Thus, the aim of this work was to analyze the capacity of human MSCs (hMSCs) to migrate and anchor to HCC tumors. We observed that HCC and HSCs, but not nontumoral stroma, produce factors that induce hMSC migration in vitro. Conditioned media (CM) generated from established HCC cell lines were found to induce higher levels of hMSC migration than CM derived from fresh patient tumor samples. In addition, after exposure to CM from HCC cells or HSCs, hMSCs demonstrated adhesion and invasion capability to endothelial cells, type IV collagen and fibrinogen. Consistently, these cells were found to increase metalloproteinase-2 activity. In vivo studies with subcutaneous and orthotopic HCC models indicated that intravenously infused hMSCs migrated to lungs, spleen and liver. Seven days post-hMSC infusion cells were located also in the tumor in both models, but the signal intensity was significantly higher in orthotopic than in subcutaneous model. Interestingly, when orthotopic HCC tumors where established in noncirrhotic or cirrhotic livers, the amount of hMSCs localized in the liver was higher in comparison with healthy animals. A very low signal was found in lungs and spleens, indicating that liver tumors are able to recruit them at high efficiency. Taken together our results indicate that HCC and HSC cells produce factors that efficiently induce hMSC migration toward tumor microenvironment in vitro and in vivo and make MSCs candidates for cell-based therapeutic strategies to hepatocellular carcinoma associated with fibrosis.
authors.affiliation: Gene Therapy Laboratory, School of Medicine, Austral University, Av Presidente Perón 1500, B1629ODT Derqui-Pilar, Buenos Aires, Argentina.
authors.forename: Mariana G
authors.initials: MG
authors.lastname: Garcia
authors.forename: Juan
authors.initials: J
authors.lastname: Bayo
authors.forename: Marcela F
authors.initials: MF
authors.lastname: Bolontrade
authors.forename: Leonardo
authors.initials: L
authors.lastname: Sganga
authors.forename: Mariana
authors.initials: M
authors.lastname: Malvicini
authors.forename: Laura
authors.initials: L
authors.lastname: Alaniz
authors.forename: Jorge B
authors.initials: JB
authors.lastname: Aquino
authors.forename: Esteban
authors.initials: E
authors.lastname: Fiore
authors.forename: Manglio M
authors.initials: MM
authors.lastname: Rizzo
authors.forename: Andrés
authors.initials: A
authors.lastname: Rodriguez
authors.forename: Alicia
authors.initials: A
authors.lastname: Lorenti
authors.forename: Oscar
authors.initials: O
authors.lastname: Andriani
authors.forename: Osvaldo
authors.initials: O
authors.lastname: Podhajcer
authors.forename: Guillermo
authors.initials: G
authors.lastname: Mazzolini
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism* / Q000473:pathology; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology / Q000628:therapy; D002448:Cell Adhesion; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement; D017077:Culture Media, Conditioned; D004730:Endothelium, Vascular / Q000378:metabolism; D055166:Hepatic Stellate Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008103:Liver Cirrhosis / Q000209:etiology / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology / Q000628:therapy; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000378:metabolism; D018874:Spheroids, Cellular / Q000378:metabolism / Q000473:pathology; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays
chemical_list: D017077:Culture Media, Conditioned; D009363:Neoplasm Proteins; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2