Dynamic Remodeling of the Vascular Bed Precedes Tumor Growth: MLS Ovarian Carcinoma Spheroids Implanted in Nude Mice

Abstract

The goal of this study was to monitor the vascular bed during the lag phase in growth of implanted spheroids as a model of tumor dormancy. Vascular development and tumor growth were followed up by magnetic resonance imaging in a model system of MLS ovarian carcinoma spheroids implanted subcutaneously in female nude mice. Apparent vessel density in a 1-mm rim surrounding the spheroid was evaluated by gradient echo imaging as a measure of the angiogenic potential of the tumor. Vascular functionality and maturation were assessed by signal intensity changes in response to hyperoxia (elevated oxygen) and hypercapnia (elevated carbon dioxide), respectively. Tumor growth was delayed by 12 to 57 days after implantation. During this long period in which tumor volume did not change, up to 6 cycles of vascular development and regression were observed. We propose here that dynamic remodeling of the vascular bed may precede exit of tumors from dormancy. The sustained oscillations in the angiogenic response to the implanted spheroid are consistent with hypoxic regulation of vascular endothelial growth factor (VEGF), combined with the role of VEGF as an essential survival factor for newly formed blood vessels. Vascular maturation, manifested by physiological vasodilatory response to carbon dioxide, may be important for conferring vascular stability and exit from dormancy.

Hopf point analysis for angiogenesis models

“…This problem was studied by analyzing experiments, where magnetic resonance imaging (MRI) was used for measuring tumor growth and blood vessel density in human epithelial ovarian carcinoma spheroid xenografts [13]. In the analysis of these experiments tumor size was measured as a function of various vessel density parameters evaluated at different preceding time points.…”

European Journal of Cancer

“…Apparent VD (AVD); this was done by acquiring averaged signal intensity maps during inhalation of air and carbogen and air and air-CO 2 (see Gilead and colleagues [21] for further details); note that the experimental estimation units rely on the measurement instrument, i.e., MRI, rather than on biological dimensions. In order to normalise these data, we calculated the ratio between the signal intensity in a ring of 1 mm surrounding the implanted spheroid (Rim), and the signal intensity in a control region (d) as follows: AVD = 1 À ln S Rim /S d , where S is the signal intensity [20][21][22][23] normalised around 1 by the 1Àln term in order to rule out negative values. Note that ''AVD'' is an experimental parameter, not to be confused with the model units of average vessel density, which reflect the ratio between vessel number and tumour volume.…”

Utilidad clínica del lactato en el paciente oncológico

“…Aunque no están claros todos los mecanismos por los cuales las células tumorales utilizan la glucólisis aeróbica, para producir energía, se ha propuesto, algunos: alteraciones vasculares, que incrementan la secreción de factor de crecimiento vascular endotelial (VEGF), para formar nuevos vasos sanguíneos, (condiciones de hipoxia, anemia, remodelación vascular) (Gilead and Neeman, 1999), estas condiciones de hipoxia regulan la glucólisis aeróbica, generando un medió acido, en el cual las células normales sufren de necrosis y apoptosis, a través de mecanismos de p53 y caspasas 3 (Park et al, 1999).…”