Myofibroblasts enable invasion of endothelial cells into three-dimensional tumor cell clusters: a novel in vitro tumor model

• Published in: Cancer chemotherapy and pharmacology Vol. 52; no. 4; pp. 263 - 269
• Main Authors: WALTER-YOHRLING, Jennifer, PRATT, Bruce M, LEDBETTER, Steve, TEICHER, Beverly A
• Format: Journal Article
• Language: English
• Published: Berlin Springer 01-10-2003; Springer Nature B.V
• Subjects: Adult; Angiogenesis Inhibitors - pharmacology; Antineoplastic Agents, Phytogenic - pharmacology; Biological and medical sciences; Cell Line, Tumor; Cells, Cultured; Dissemination; Endothelial Cells - pathology; Fibroblasts - pathology; Humans; Immunohistochemistry; Indoles - pharmacology; Medical sciences; Metalloproteases - antagonists & inhibitors; Neoplasm Invasiveness - pathology; Neoplasm Invasiveness - prevention & control; Neoplasms - pathology; Paclitaxel - pharmacology; Protease Inhibitors - pharmacology; Pyrroles - pharmacology; Stromal Cells - drug effects; Stromal Cells - pathology; Tumor cell; Tumors; Human; Cell culture; Endothelial cell; Migration; Myofibroblast; Tumor stroma; Cell cell interaction; In vitro; Invasion; Angiogenesis; Angiogenesis ÷ Inhibitors; Dissemination; Tumor progression; In vitro model; Models; Neovascularization; Mechanism of action; Tumor cell
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-003-0664-2

In an effort to study the importance of stromal involvement in angiogenesis, we developed a novel, multicellular model that utilizes three of the primary cell types involved in tumor angiogenesis.
Fluorescently labeled human microvascular endothelial cells (HMVECs), 10T1/2 cells and myofibroblasts were incubated in the presence of a three-dimensional tumor cell cluster resuspended in collagen and embedded in Matrigel.
HMVECs cultured in the presence of a human SKOV-3 ovarian carcinoma tumor cell cluster, surrounded the tumor cell cluster, while myofibroblasts invaded the cluster, localizing within the tumor cell mass. In contrast, 10T1/2 cells, a pluripotent mouse mesenchymal cell line with pericyte-like properties, did not demonstrate the same invasive phenotype. HMVECs cultured in the presence of myofibroblasts invaded the tumor cell cluster and colocalized with the myofibroblasts as demonstrated by fluorescent microscopy and immunohistochemistry. The angiogenesis inhibitors SU6668 and paclitaxel inhibited stromal invasion, while a broad-spectrum matrix metalloproteinase inhibitor did not.
This model emphasizes the critical interaction between endothelial cells and myofibroblasts and provides a more complete in vitro model for studying angiogenesis and tumor progression.