Hepatocellular Carcinoma Cells and Their Fibrotic Microenvironment

GARCÍA, MARIANA G. ; BAYO, JUAN ; BOLONTRADE, MARCELA F. ; SGANGA, LEONARDO ; MALVICINI, MARIANA; ALANIZ, LAURA ; AQUINO, JORGE ; FIORE, ESTEBAN ; RIZZO, MANGLIO M. ; RODRIGUEZ, ANDRÉS ; LORENTI, ALICIA ; ANDRIANI, OSCAR ; PODHAJCER, OSVALDO; MAZZOLINI, GUILLERMO.

MOLECULAR PHARMACEUTICS

AMER CHEMICAL SOC

Lugar: Washington, DC; Año: 2011 vol. 8 p. 1538 - 1548

1543-8384

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 themain source of the extracellularmatrix 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 fromestablished HCC cell lines were found to induce higher levels of hMSCmigration than CM derived from fresh patient tumor samples. In addition, after exposure to CMfromHCC 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 hMSCsmigrated 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 ofhMSCs localized in the liver was higher in comparisonwith healthy animals. A very low signal was found in lungs and spleens, indicating that liver tumors are able to recruit themat high efficiency. Taken together our results indicate thatHCC and HSC cells produce factors that efficiently induce hMSCmigration toward tumormicroenvironment in vitro and in vivo and makeMSCs candidates for cell-based therapeutic strategies to hepatocellular carcinoma associated with fibrosis.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 themain source of the extracellularmatrix 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 fromestablished HCC cell lines were found to induce higher levels of hMSCmigration than CM derived from fresh patient tumor samples. In addition, after exposure to CMfromHCC 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 hMSCsmigrated 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 ofhMSCs localized in the liver was higher in comparisonwith healthy animals. A very low signal was found in lungs and spleens, indicating that liver tumors are able to recruit themat high efficiency. Taken together our results indicate thatHCC and HSC cells produce factors that efficiently induce hMSCmigration toward tumormicroenvironment in vitro and in vivo and makeMSCs candidates for cell-based therapeutic strategies to hepatocellular carcinoma associated with fibrosis.