© 2001 by Oxford University Press
Journal of the National Cancer Institute, Vol. 93, No. 14, 1075-1081,
July 18, 2001
© 2001 Oxford University Press
REPORT |
Heterogeneity of Angiogenic Activity in a Human Liposarcoma: a Proposed Mechanism for "No Take" of Human Tumors in Mice
Affiliations of authors: E.-G. Achilles, Department of Surgery, Division of Surgical Research, Children's Hospital, Harvard Medical School, Boston, MA, and Department of Hepato-Biliary Surgery, University of Hamburg, University Hospital Hamburg, Germany; A. Fernandez, T. Udagawa, E. Flynn, J. Folkman, Department of Surgery, Division of Surgical Research, Children's Hospital, Harvard Medical School; E. N. Allred, Department of Surgery, Division of Surgical Research, Children's Hospital, and Neuroepidemiology Unit, Harvard Medical School; O. Kisker, Department of Surgery, Division of Surgical Research, Children's Hospital, Harvard Medical School, and Department of General Surgery, University Hospital Marburg, Philipps University Marburg, Germany; W.-D. Beecken, Department of Surgery, Division of Surgical Research, Children's Hospital, Harvard Medical School, and Clinic for Urology and Pediatric Urology, J. W. Goethe University, University Hospital Frankfurt, Germany.
Correspondence to: Judah Folkman, M.D., Department of Surgery, Division of Surgical Research, Children's Hospital, Harvard Medical School, 300 Longwood Ave., Boston, MA 02115.
Background: Tumor cells are known to be heterogeneous with respect to their metastatic activity, proliferation rate, and activity of several enzymes. However, little is known about the heterogeneity of tumor angiogenic activity. We investigated whether heterogeneity of angiogenic activity could be responsible for the well-known observation of "no take" of human tumors transplanted into immunodeficient mice. Methods: Severe combined immunodeficient (SCID) mice were xenotransplanted subcutaneously with tumor tissue (n = 55) or cell suspension of a human liposarcoma cell line (SW-872) or subclones (n = 28), with varying cell proliferation rates. Xenograft tumor growth was recorded for up to 6 months. Tumor tissues were then removed and analyzed for tumor cell apoptosis, microvessel density, and cell proliferation. All statistical tests were two-sided. Results: Pieces of tumor derived from the parental cell line or its clones gave rise to three kinds of tumors: 1) highly angiogenic and fast-growing (aggressive) tumors, 2) weakly angiogenic and slow-growing tumors, and 3) nonangiogenic and stable tumors. Most tumors retained the original phenotype of their parental tumor. Tumor volume correlated positively with microvessel density (Spearman correlation coefficient [r] = .89; P
.0001) and inversely with tumor cell apoptosis (Spearman r = -.68; P = .002). Tumor volume was less strongly but still positively correlated with tumor cell proliferation in vivo (Spearman r = .55; P = .02). Conclusions: Human liposarcoma cells appear to be heterogeneous in their angiogenic activity. When tumor cells with little or no angiogenic activity are transplanted into SCID mice, a microscopic, dormant tumor results that may not grow further. Because such tiny tumors are neither grossly visible nor palpable, they have previously been called "no take." The finding that an angiogenic tumor can contain subpopulations of tumor cells with little or no angiogenic activity may provide a novel mechanism for dormant micrometastases, late recurrence, and changes in rate of tumor progression.
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