Angiogenesis, microvascular architecture, microhemodynamics, and interstitial fluid pressure during early growth of human adenocarcinoma LS174T in SCID mice

Abstract

To date, most quantitative information on tumor angiogenesis, microcirculation, and transport has been derived from rodent tumors grown in transparent chamber preparations. In this paper we present a chamber technique adapted to immunodeficient mice for the study of human tumor xenografts. Microcirculatory parameters in severe combined immunodeficient mice bearing a dorsal skin fold chamber preparation were quantified using intravital microscopy and image analysis. The take rate of the human colon adenocarcinoma LS174T in the chamber preparation was 100%, and the tumor area doubling time was 6.5 days. Three days following implantation of 2 x 10(5) tumor cells onto the striated skin muscle, capillary sprouts were noted in the tumor cell mass. Microvasculature in the tumors was established after 10 days. Capillary density, vessel diameter, red blood cell velocity, and blood flow rates in individual microvessels measured on days 10, 14, 18, and 22 showed no statistical difference in the striated muscle (capillaries) and subcutaneous tissue (arterioles and venules) of the skin of tumor-free animals (N = 6), whereas these parameters increased slightly, but not significantly, in the LS174T tumors (N = 7). Mean interstitial fluid pressure (+/- SD) in these small tumors was 4.6 +/- 1.7 mmHg (N = 4) on day 10 and 5.1 +/- 0.9 mmHg (N = 4) on day 22 and significantly elevated compared to that in the subcutaneous and skin tissue (-0.9 +/- 0.8 mmHg) (N = 4) (P < 0.001). To our knowledge, this is the first model enabling intravital microscopic studies of human tumor xenografts in a transparent chamber preparation in severe combined immunodeficient mice. Studies on angiogenesis, microcirculation, and transport using such a preparation should provide new insights into microcirculation-mediated mechanisms for cancer treatment.