The Cell Line-Dependent Diversity in Initial Morphological Dynamics of Pancreatic Cancer Cell Peritoneal Metastasis Visualized by an Artificial Human Peritoneal Model

Abstract

Background: Pancreatic ductal adenocarcinoma is considered as one of the most malignant types of cancer with rapid metastasis and invasion of the cancer cells, having peritoneal metastasis (PM) as a dominant factor of poor prognosis. Although the prevention of peritoneal dissemination would result in the inhibition of the initial metastatic process and contribute in improving the poor prognosis of the pancreatic cancer, the initial dynamics of PM are still unclear because of the lack of adequate models in studying the morphological and molecular details of pancreatic cancer cells. Materials and methods: The artificial human peritoneal tissue (AHPT) that can be applied in studying for the spatial dynamics of cancer PM in vitro has been established previously. In this study, the initial dynamics of the three pancreatic cell lines, undifferentiated carcinoma MIA PaCa-2, poorly differentiated adenocarcinoma Panc-1, and moderately differentiated adenocarcinoma BxPC3 on AHPT are examined. Results: In a morphological analysis using light and electron microscopy, MIA PaCa-2 cells spread on the mesothelial layer with disruption of the sheet structure and infiltrated into the stroma-like tissue in AHPT. On the other hand, BxPC3 cells changed shapes from round into flat ones with rapid proliferation and formed sheet structure at the surface of the tissue replacing the mesothelial layer without vertical invasion into the tissue. Panc-1 cells demonstrated the intermediate characteristics of MIA PaCa-2 and BxPC3 on AHPT. These diverse morphological characteristics were verified by the correspondence with the results

A human ex vivo coculture model to investigate peritoneal metastasis and innovative treatment options

“…Moreover, clinically relevant models to investigate PM and possible treatment options apart from animal models are still scarce [ 15 , 17 , 33 , 34 ]. Recently Asano and colleagues developed an artificial human peritoneal tissue (AHPT) model to investigate PM of different cancer types [ 18 ], [ 19 ], [ 20 ]. This bottom-up approach consists of a mesothelial cell layer resting on several layers of human fibroblasts and tubular arranged endothelial cells connected via the cell-accumulation technique [ 34 ].…”

“…Current research lacks a suitable human experimental ex vivo model to investigate new therapeutic reagents for HIPEC, as well as the mechanisms underlying PM formation. Existing ex vivo models include inverted bovine urinary bladders used to optimize intraperitoneal drug delivery [ 12 ], mouse peritoneum as a scaffold for human tumor cells [ 13 ], combined models of human mesothelial and fibroblast cells with rat extracellular collagen matrices [ 14 ] as well as mere human models from healthy donors [ 15 ], [ 16 ], [ 17 ] or artificial models [ 18 ], [ 19 ], [ 20 ]. However, these animal or combined models do not fully reflect the tumor biology including the tumor microenvironment in humans.…”