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§
§
From the Departments of Medical Biophysics,*
Microbiology and Immunology,
and
Oncology,§
University of Western Ontario,
London Regional Cancer Centre,
London,
Ontario, Canada
In cancer metastasis, only a small percentage of cells released from a primary tumor successfully form distant lesions, but it is uncertain at which steps in the process cells are lost. Our goal was to determine what proportions of B16F1 melanoma cells injected intraportally to target mouse liver 1) survive and extravasate, 2) form micrometastases (4 to 16 cells) by day 3, 3) develop into macroscopic tumors by day 13, and 4) remain as solitary dormant cells. Using in vivo videomicroscopy, a novel cell accounting assay, and immunohistochemical markers for proliferation (Ki-67) and apoptosis (TUNEL), we found that 1) 80% of injected cells survived in the liver microcirculation and extravasated by day 3, 2) only a small subset of extravasated cells began to grow, with 1 in 40 forming micrometastases by day 3, 3) only a small subset of micrometastases continued to grow, with 1 in 100 progressing to form macroscopic tumors by day 13 (in fact, most micrometastases disappeared), and 4) 36% of injected cells remained by day 13 as solitary cancer cells, most of which were dormant (proliferation, 2%; apoptosis, 3%; in contrast to cells within macroscopic tumors: proliferation, 91%; apoptosis/necrosis, 6%). Thus, in this model, metastatic inefficiency is principally determined by two distinct aspects of cell growth after extravasation: failure of solitary cells to initiate growth and failure of early micrometastases to continue growth into macroscopic tumors.
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J. E. Testa, P. C. Brooks, J.-M. Lin, and J. P. Quigley Eukaryotic Expression Cloning with an Antimetastatic Monoclonal Antibody Identifies a Tetraspanin (PETA-3/CD151) as an Effector of Human TumorCell Migration and Metastasis Cancer Res., August 1, 1999; 59(15): 3812 - 3820. [Abstract] [Full Text] [PDF]
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J. M. Jessup, P. Battle, H. Waller, K. H. Edmiston, D. B. Stolz, S. C. Watkins, J. Locker, and K. Skena Reactive Nitrogen and Oxygen Radicals Formed during Hepatic Ischemia-Reperfusion Kill Weakly Metastatic Colorectal Cancer Cells Cancer Res., April 1, 1999; 59(8): 1825 - 1829. [Abstract] [Full Text] [PDF]
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A.-M. Khatib, M. Kontogiannea, L. Fallavollita, B. Jamison, S. Meterissian, and P. Brodt Rapid Induction of Cytokine and E-Selectin Expression in the Liver in Response to Metastatic Tumor Cells Cancer Res., March 1, 1999; 59(6): 1356 - 1361. [Abstract] [Full Text] [PDF]
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G. Naumov, S. Wilson, I. MacDonald, E. Schmidt, V. Morris, A. Groom, R. Hoffman, and A. Chambers Cellular expression of green fluorescent protein, coupled with high-resolution in vivo videomicroscopy, to monitor steps in tumor metastasis J. Cell Sci., January 6, 1999; 112(12): 1835 - 1842. [Abstract] [PDF]
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