Combined in vivo molecular and anatomic imaging for detection of ovarian carcinoma-associated protease activity and integrin expression in mice.
Most patients with epithelial ovarian cancer (EOC) experience drug-resistant disease recurrence. Identification of new treatments is a high priority, and preclinical studies in mouse models of EOC may expedite this goal. We previously developed methods for magnetic resonance imaging (MRI) for tumor detection and quantification in a transgenic mouse model of EOC. The goal of this study was to determine whether three-dimensional (3D) fluorescence molecular tomography (FMT) and fluorescent molecular imaging probes could be effectively used for in vivo detection of ovarian tumors and response to therapy. Ovarian tumor-bearing TgMISIIR-TAg mice injected with fluorescent probes were subjected to MRI and FMT. Tumor-specific probe retention was identified in vivo by alignment of the 3D data sets, confirmed by ex vivo fluorescent imaging and correlated with histopathologic findings. Mice were treated with standard chemotherapy, and changes in fluorescent probe binding were detected by MRI and FMT. Ovarian tumors were detected using probes specific for cathepsin proteases, matrix metalloproteinases (MMPs), and integrin α(v)β(3). Cathepsin and integrin α(v)β(3) probe activation and retention correlated strongly with tumor volume. MMP probe activation was readily detected in tumors but correlated less strongly with tumor volume. Tumor regression associated with response to therapy was detected and quantified by serial MRI and FMT. These results demonstrate the feasibility and sensitivity of FMT for detection and quantification of tumor-associated biologic targets in ovarian tumors and support the translational utility of molecular imaging to assess functional response to therapy in mouse models of EOC.
Biological Imaging Facility, Fox Chase Cancer Center, Philadelphia, PA 19111, USA. Harvey.Hensley@fccc.edu
Harvey H
HH
Hensley
Navid A
NA
Roder
Shane W
SW
O'Brien
Laura E
LE
Bickel
Fang
F
Xiao
Sam
S
Litwin
Denise C
DC
Connolly
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology; D002277:Carcinoma / Q000175:diagnosis* / Q000378:metabolism* / Q000473:pathology; D002403:Cathepsins / Q000378:metabolism; D045744:Cell Line, Tumor; D018450:Disease Progression; D005260:Female; D005456:Fluorescent Dyes / Q000737:chemistry / Q000378:metabolism; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D016023:Integrins / Q000235:genetics / Q000378:metabolism*; D008279:Magnetic Resonance Imaging; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D057054:Molecular Imaging; D010051:Ovarian Neoplasms / Q000175:diagnosis* / Q000188:drug therapy / Q000378:metabolism*; D010447:Peptide Hydrolases / Q000378:metabolism*; D011485:Protein Binding; D047368:Tumor Burden / Q000187:drug effects
D000970:Antineoplastic Agents; D005456:Fluorescent Dyes; D039302:Integrin alphaVbeta3; D016023:Integrins; D002403:Cathepsins; D010447:Peptide Hydrolases; D020782:Matrix Metalloproteinases