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Regulation of angiogenesis in ovarian carcinoma

Regulatory pathways of angiogenesis in ovarian cancer. MRI provided multiple views of angiogenesis in ovarian cancer and assisted in establishing the regulatory network presented here. Dormancy of tumors was maintained through dynamic instability of vessels, while stabilization of the vasculature was achieved by recruitment of supporting tumor myofibroblasts (Gilad 2005, Granot 2005). Metastatic spread of tumors is mediated in part by adhesion of cells on hyaluronan, while the antiangiogenic microenvironment of hyaluronan is modified by hyaluronidase

Fibroblast labeling for in vivo detection by MRI

Dorit Granot and Michal Neeman
Biological Regulation, Weizmann Institute

Motivation
Establishment and verification of a technique for fibroblasts labeling with a paramagnetic MR probe that would enable their non-invasive in vivo detection by MRI.

Ex Vivo labeling of fibroblasts with biotin-BSA-GdDTPA-FAM

a) Confocal microscopy of PFN2 fibroblasts double labeled with CM (48 hours; 10 mg/ml) and propidium iodide. Arrowheads indicate proliferating cells. b) Cell viability assessed by neutral red assay. C) Various primary fibroblasts were labeled with biotin-BSA-GdDTPA (48 hr, 10 mg/ml) in the presence (close bars) or absence (open bars) of the caveolae inhibitor nystatin. d) Intracellular relaxivity (RIC) of the contrast material was calculated according to the equation RIC  R1/[Gd] (where [Gd] is the intracellular concentration in pmol/cell as measured by ICP-AES). Daily concentrations of [Gd] were determined from average measurements of six individual labeling repetitions.

In Vivo MRI detection of fibroblast in subcutaneous ovarian tumors

In vivo detection of ex vivo labeled fibroblasts. T1-weighted 3D-GE images acquired on a horizontal 4.7 T Biospec spectrometer. Representative R1 maps of tumors initiatedfrom MLS cells co-inoculated with (a) unlabeled cos-7 cells and (b) cells labeled with biotin-BSA-GdDTPA contrast material (48 hr, 10 mg/ml). Arrows indicate tumor region. c: Average R1 values obtained from ROI analysis of the tumor regions initiated from MLS cells co-inoculated with cos-7 cells, untreated (N=4) or labeled with biotin-BSA-GdDTPA (N= 4). (*Significant change in R1 oflabeled vs. unlabeled tumors; P  0.01, t-test, unpaired, two-tailed).

In vivo quantitative assessment of hyaluronidase activity in ovarian carcinoma tumors

Liora Shiftan and Michal Neeman

HA-GdDTPA-beads administered s.c. to the hind limb in the vicinity of a ES-2 tumor, followed by dynamic R2 measurements. Analysis of enzymatic activity:
left- contrast material concentration map overlaid on the grayscale image.
Right- The percent of activated contrast material.
Most of the activation of the contrast material occurred at the rim of the tumor.

(Liora Shiftan, 2005, Liora Shiftan, 2006)