Optical tomography of MMP activity allows a sensitive noninvasive characterization of the invasiveness and angiogenesis of SCC xenografts.
For improved tumor staging and therapy control, imaging biomarkers are of great interest allowing a noninvasive characterization of invasiveness. In squamous epithelial skin and cervix lesions, transition to invasive stages is associated with enhanced matrix metalloproteinase (MMP) activity, increased angiogenesis, and worsened prognosis. Thus, we investigated MMP activity as imaging biomarker of invasiveness and the potential of optical tomography in characterizing the angiogenic and invasive behavior of skin squamous cell carcinoma (SCC) xenografts. MMP activity was measured in vivo in HaCaT-ras A-5RT3 tumors at different angiogenic and invasive stages (onset of angiogenesis, intermediate and highly angiogenic, invasive stage) and after 1 week of sunitinib treatment by fluorescence molecular tomography-microcomputed tomography imaging using an activatable probe. Treatment response was additionally assessed morphologically by optical coherence tomography (OCT). In vivo MMP activity significantly differed between the groups, revealing highest levels in the highly angiogenic, invasive tumors that were confirmed by immunohistochemistry. At the onset of angiogenesis with lowest MMP activity, fibroblasts were detected in the MMP-positive areas, whereas macrophages were absent. Accumulation of both cell types occurred in both invasive groups, again to a significantly higher degree at the most invasive and angiogenic stage. Sunitinib treatment significantly reduced the MMP activity and accumulation of fibroblasts and macrophages and blocked tumor invasion that was additionally visualized by OCT. Human cervical SCCs also showed high MMP activity and a similar stromal composition as the HaCaT xenografts, whereas normal tissue was negative. This study strongly suggests MMP activity as imaging biomarker and demonstrates the high sensitivity of optical tomography in determining tumor invasiveness that can morphologically be supported by OCT.
Department of Experimental Molecular Imaging, Rheinisch-Westfaelische Technische Hochschule Aachen University, Aachen, Germany.
Wa'el
W
Al Rawashdeh
Department of Experimental Molecular Imaging, Rheinisch-Westfaelische Technische Hochschule Aachen University, Aachen, Germany.
Susanne
S
Arns
Department of Experimental Molecular Imaging, Rheinisch-Westfaelische Technische Hochschule Aachen University, Aachen, Germany.
Felix
F
Gremse
Department of Experimental Molecular Imaging, Rheinisch-Westfaelische Technische Hochschule Aachen University, Aachen, Germany; Institute of Pathology, University Hospital Aachen, RWTH Aachen University, Aachen, Germany.
Josef
J
Ehling
Institute of Pathology, University Hospital Aachen, RWTH Aachen University, Aachen, Germany.
Ruth
R
Knüchel-Clarke
Institute for Semiconductor Electronics, RWTH Aachen University, Aachen, Germany.
Stefan
S
Kray
Institute for Semiconductor Electronics, RWTH Aachen University, Aachen, Germany.
Felix
F
Spöler
Department of Experimental Molecular Imaging, Rheinisch-Westfaelische Technische Hochschule Aachen University, Aachen, Germany.
Fabian
F
Kiessling
Department of Experimental Molecular Imaging, Rheinisch-Westfaelische Technische Hochschule Aachen University, Aachen, Germany. Electronic address: wlederle@ukaachen.de.
Wiltrud
W
Lederle
D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D014408:Biomarkers, Tumor / Q000032:analysis* / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000098:blood supply / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology*; D005260:Female; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D020782:Matrix Metalloproteinases / Q000032:analysis* / Q000378:metabolism; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D011758:Pyrroles / Q000494:pharmacology; D012878:Skin Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology*; D017154:Stromal Cells / Q000201:enzymology / Q000473:pathology; D000077210:Sunitinib; D041623:Tomography, Optical Coherence / Q000379:methods*; D002583:Uterine Cervical Neoplasms / Q000201:enzymology / Q000473:pathology; D055114:X-Ray Microtomography / Q000379:methods; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D014408:Biomarkers, Tumor; D007211:Indoles; D011758:Pyrroles; D020782:Matrix Metalloproteinases; D000077210:Sunitinib