Vascular Morphogenesis and Remodeling in a Human Tumor Xenograft

Abstract

Abstract-To determine mechanisms of blood vessel formation and growth in solid tumors, we used a model in which LS174T human colon adenocarcinomas are grown in the isolated ovarian pedicle of nude mice. Reconstruction of 3500 histological serial sections demonstrated that a new vascular network composed of venous-venous loops of varying sizes grows inside the tumor from the wall of the adjacent main vein. Loops elongate and remodel to establish complex loop systems. The mechanisms of loop formation and remodeling correspond to intussusceptive microvascular growth (IMG). In the tissue surrounding the tumor segmentation, another mechanism of IMG is prevalent in venous vessels.Comparison to vascular morphogenesis in the ovariectomized pedicle not only confirms the existence of corresponding mechanisms in both systems, but also reveals numerous sprouts that are superimposed onto loop systems and pathological deviations of loop formation, remodeling, and segmentation in the tumor. These pathological mechanisms interfere with vessel patency that likely cause heterogenous perfusion and hypoxia thus perpetuating angiogenesis. Blood vessel formation based on IMG was also detected in a large thrombus that completely occluded a part of an ovarian artery branch. Key Words: angiogenesis Ⅲ colon adenocarcinoma (LS174T) Ⅲ endothelial cell Ⅲ intussusceptive microvascular growth Ⅲ restenosis T he formation of sprouts in angiogenesis 1,2 has been widely accepted as a basic mechanism of angiogenesis in wound healing 3-5 and tumors. 6 Another mechanism of vascular morphogenesis termed intussusceptive microvascular growth (IMG) has been identified in many organs and different species. [7][8][9][10][11][12][13][14][15][16][17] Intussusception involves growth and remodeling of the vascular system based on partitioning of the vessel lumen by columns of tissue, called tissue pillars or posts (diameter Ͻ2.5 m) and interstitial or intervascular tissue structures (ITSs, diameter Ͼ2.5 m). Evidence for IMG in pathological states comes from findings that intussusception is induced by tumor ascites fluid in peritoneal lining tissues. 18 It has also been suggested that the remodeling of vascular branching points during tumor angiogenesis be implemented by IMG. 19 In the first in vivo documentation of IMG in solid tumors, we demonstrated basic mechanisms of its implementation and its coexistence with sprout-like structures. Our data showed that the network architecture in tumors changes on a time scale of minutes based on frequent remodeling by IMG. This might explain intermittent blood flow. 14 In the present study, we analyzed histological serial sections to reconstruct the architecture of the vascular network of human colon adenocarcinomas (LS174T) transplanted onto the isolated ovarian pedicle of nude mice. 20,21 Two new mechanisms of blood vessel formation based on IMG were identified: in situ loop formation and remodeling, which give rise to a new vascular network inside the tumor and segmentation that expands and remodels the preexisting ...

Nonlinear Modeling and Simulation of Tumor Growth

“…16 are shown to be strongly dependent on diffusion gradients of oxygen/nutrient in the microenvironment and agree with previous experiments [94,74]. Chaotic angiogenesis leads to heterogeneous perfusion in the tumor that then might be responsi-ble for regression of parts of the vascular network and necrosis of tumor cells [45,158], further enhancing variable tumor cell proliferation. By taking vessel maturation into account, the simulations correctly predict that as tumor size increases, inner vessels may regress or shut down, leading to nutrient depletion and resulting in the formation of a large necrotic core (data not shown), as observed in patients.…”

“…[191,140]). Although tumor angiogenesis may occur via the formation of sprouts or intussuception [158], for simplicity here only the former process is incorporated in the model. Input parameter values to the model, e.g., cell proliferation and apoptosis, are estimated from in vitro cell lines and ex-vivo patient data.…”

Intussusceptive angiogenesis: Its emergence, its characteristics, and its significance

“…Patan and coworkers have proposed a further mode of capillarization found in tumors. They described vascular network growth by loop formation in the vascular pedicles after ovariectomy (Patan et al, 2001a) and in grafts of LS174T human colon adenocarcinomas (Patan et al, 2001b). They propose the loops to be formed by luminal extensions, somehow like sprouts, but without their classic characteristics, in particular without endothelial cell proliferation.…”

Variation of Breast Vascular Maps on Dynamic Contrast-Enhanced MRI After Primary Chemotherapy of Locally Advanced Breast Cancer

“…As a consequence, mixed arterial and venous vessels are also enhanced as a result of contrast material administration, which may be a study limitation. However, we should also consider the evidence that tumor blood supply also derives from the venous circulation side [31].…”