Heterogeneity of angiogenic activity in a human liposarcoma: A proposed mechanism for "no take" of human tumors in mice

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 activi ty. We investigated whether heterogeneity of angiogenic activity could be r esponsible for the well-known observation of "no take" of human tumors tran splanted into immunodeficient mice. Methods: Severe combined immunodeficient (SCID) mice were xenotransplanted subcutaneously with tumor tissue (n = 55) or cell suspension of a human lip osarcoma cell line (SW-872) or subclones (n = 28), with varying cell prolif eration rates. Xenograft tumor growth was recorded for up to 6 months. Tumo r tissues were then removed and analyzed for tumor cell apoptosis, microves sel 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) no nangiogenic and stable tumors. Most tumors retained the original phenotype of their parental tumor. Tumor volume correlated positively with microvesse l density (Spearman correlation coefficient [r] = .89; P less than or equal to .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 an giogenic activity. When tumor cells with little or no angiogenic activity a re transplanted into SCID mice, a microscopic, dormant tumor results that m ay not grow further. Because such tiny tumors are neither grossly visible n or palpable, they have previously been called "no take." The finding that a n angiogenic tumor can contain subpopulations of tumor cells with little or no angiogenic activity may provide a novel mechanism for dormant micrometa stases, late recurrence, and changes in rate of tumor progression.