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Modeling metastasis in the mouse

Oncogene volume 18, pages 5334–5339 (1999)Cite this article

Cancer is a progressive disease that is often fatal even though removal and treatment of the primary tumor is often successful. The most insidious feature of cancer is its spread to and compromise of distant organs via the complex process of metastasis. It is now well established that cancer development usually follows a course of progression through increasingly aggressive and treatment-resistant stages that reflect the accumulation of molecular genetic changes. While tumor initiation reflects unscheduled cellular hyperproliferation, either through direct activation of cell cycle machinery or of signaling pathways that directly regulate the cell cycle, progression to malignancy and metastasis reflects changes in the intimate relationship between a tumor cell and its host environment. For this reason, the mouse as a model organism provides the most physiologically relevant setting in which to study and molecularly dissect the process of metastasis in vivo.

Metastasis is often thought of in terms of the hurdles that tumor cells must overcome in order to successfully metastasize (reviewed in Ruoslahti, 1999). Thus, tumor cells must invade their surrounding extracellular milieu; for epithelially-derived carcinomas this may include degradation and passage through a collagen-IV-rich basement membrane, while mesenchymally-derived sarcomas invade the loose fibrillar collagen matrix of connective tissue. The concomitant invasion of neovasculature into the tumor, solicited by the tumor cells themselves, facilitates the juxtaposition of tumor cell and blood vessel. Metastasizing cells must then cross the slightly different basement membrane surrounding a blood vessel and invade between the vascular endothelial cells into the circulation in a process known as intravasation. Here they must survive in the circulation in a state of suspension (no small feat for epithelial cells, which normally undergo apoptosis when deprived of adhesion in a process known as anoikis (Schwartz, 1997)). Colonization involves lodging in a distant capillary bed, extravasation back out of the blood vessel and subsequent survival, invasion and proliferation in what is now a foreign microenvironment for those cells. The process of extravasation is thought to model many aspects of normal lymphocyte trafficking; the study of lymphocyte:endothelial cell interactions has provided important clues toward understanding tumor cell behavior (reviewed in Buck, 1995). The events subsequent to entering the circulation are thought to be rate-limiting; of the large number of tumor cells that successfully enter the circulation, only a small percentage can actually successfully colonize a distant organ such as the liver or lung (Stetler-Stevenson et al., 1993). Some studies even suggest that most tumor cells successfully extravasate, but fail to subsequently colonize the target organ (Koop et al., 1995; Yu et al., 1997), suggesting that survival and proliferation in a foreign milieu is a particularly challenging hurdle to tumor cells.

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Acknowledgements

The field of metastasis is enormous and encompasses many areas of scientific inquiry; I apologize to my colleagues whose work was not cited due to space considerations. AIM is a recipient of a Career Award from the Burroughs Wellcome Fund.

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  1. Department of Pathology, MGH Cancer Center and Harvard Medical School, Building 149, 13th Street, Charlestown, MA 02129, Massachusetts, USA

    Andrea I McClatchey

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McClatchey, A. Modeling metastasis in the mouse. Oncogene 18, 5334–5339 (1999). https://doi.org/10.1038/sj.onc.1203086

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