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(American Journal of Pathology. 2002;160:1973-1980.)
© 2002 American Society for Investigative Pathology

Regular Articles

An Invasion-Independent Pathway of Blood-Borne Metastasis

A New Murine Mammary Tumor Model

Takashi Sugino^*, Takashi Kusakabe^*, Nobuo Hoshi^*, Tomiko Yamaguchi^*, Takanori Kawaguchi^*, Steve Goodison, Masayuki Sekimata, Yoshimi Homma and Toshimitsu Suzuki^*

From the Departments of Pathology^*and Biomolecular Science,School of Medicine, Fukushima Medical University, Fukushima City, Japan; and the University of California San Diego Cancer Center and the Department of Pathology,University of California San Diego, La Jolla, California

It is generally believed that active invasion by cancer cells is essential to the metastatic process. In this report, we describe a murine mammary tumor (MCH66) model of metastasis that does not require invasion into the vascular wall of both the primary tumor and the target organ, in this case, the lung. The process involves intravasation of tumor nests surrounded by sinusoidal blood vessels, followed by intravascular tumor growth in the lung, without penetration of the vascular wall during the process. Comparative studies using a nonmetastatic MCH66 clone (MCH66C8) and another highly invasive metastatic cell line (MCH416) suggested that high angiogenic activity and sinusoidal remodeling of tumor blood vessels were prerequisites for MCH66 metastasis. Differential cDNA analysis identified several genes that were overexpressed by MCH66, including genes for the angiogenesis factor pleiotrophin, and extracellular matrix-associated molecules that may modulate the microenvironment toward neovascularization. Our analyses suggest that tumor angiogenesis plays a role in the induction of invasion-independent metastasis. This model should prove useful in screening and development of new therapeutic agents for cancer metastasis.

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