Proof of prometastatic niche induction by hepatic stellate cells

• Published in: The Journal of surgical research Vol. 194; no. 2; pp. 496 - 504
• Main Authors: Eveno, Clarisse, PhD, MD, Hainaud, Patricia, PhD, Rampanou, Aurore, BA, Bonnin, Philippe, PhD, MD, Bakhouche, Sana, BA, Dupuy, Evelyne, PhD, MD, Contreres, Jean-Olivier, PhD, Pocard, Marc, PhD, MD
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.04.2015
• Subjects: Actins - metabolism; Activated hepatic stellate cells; Angiogenesis; Animals; Biomarkers - metabolism; Carcinoma - pathology; Carcinoma, Hepatocellular - physiopathology; Colorectal liver metastases; Colorectal Neoplasms - pathology; Desmin - metabolism; Endothelial Cells - physiology; Female; Hepatic Stellate Cells - physiology; Human Umbilical Vein Endothelial Cells; Humans; Ki-67 Antigen - metabolism; Laminin - metabolism; Liver Neoplasms, Experimental - metabolism; Liver Neoplasms, Experimental - secondary; Metastatic niche; Mice, Inbred C57BL; Mice, SCID; Microenvironment; Neoplasm Metastasis; Neovascularization, Pathologic - metabolism; Platelet Endothelial Cell Adhesion Molecule-1 - metabolism; Surgery; Metastatic niche; Angiogenesis; Activated hepatic stellate cells; Colorectal liver metastases; Microenvironment
• ISSN: 0022-4804; 1095-8673
• DOI: 10.1016/j.jss.2014.11.005

Abstract Background An interaction between tumor cells and the microenvironment, as well as the development of angiogenesis, are required to form liver metastases (LMs). Material and methods Immunofluorescence detection of α-smooth muscle actin, desmin, Ki67, laminin, and CD31 was used to analyze the kinetics of tumor angiogenesis determinants, especially the contribution of hepatic stellate cells (HSCs) to angiogenesis in hepatic metastasis produced by intrasplenically injected LS174 colorectal cancer cells. Immunostaining was performed at various times (days 9, 14, 28, and 39). Results At the earliest stage, micrometastases consisted of proliferating cancer cells, a well-organized network of activated HSCs and laminin deposits. No vascular network was observed. As the LMs grew in size, an organized vascular network appeared; the laminin network colocalized with CD31 immunostaining. At the later stages, all the immunostained markers became peripheral as a central necrosis developed. Purified activated HSCs isolated from transgenic mice livers developing hepatocellular carcinoma secreted laminin and showed enhanced human umbilical vein EC network formation in a Matrigel assay. In a coinjection LM experiment, activated HSCs enhanced the metastatic process. Moreover, colorectal LMs from six patients were analyzed, and a pattern of marker distribution similar to the coinjection experiment was found in human LMs. Conclusions For the first time, our results show that HSCs play a crucial role in organizing and accelerating the progression of metastasis in modulating the prometastatic niche, interacting with colorectal cancer cell recruitment, and the organization of angiogenesis during colorectal LM development. Therefore, HSCs may be an early therapeutic target in colorectal cancer therapies.