OPTICAL IMAGING OF INTEGRIN ΑVSS3 DETECTS PANCREATIC CANCER IN ENDOGENOUS MOUSE MODELS
Manila Tralkovic-Arsic; Athanasios Sarantopoulos; George Themelis; Evdokia Kalideris; Rickmer Braren; Vasilis Ntziachristos; Jens Siveke. (01-05-2011).
Research Area C
Pancreatic ductal adenocarcinoma remains one of the most lethal malignacies in the Western World with a 5-year survival rate Iower then 4%. Late diagnosis and poor response to all available chemotherapies are main causes for the devastating clinical course. Development of methods for early detection and evaluation of new therapies is of great importance. Here, we used optical imaging for detection of αVß3 integrin in pancreatic cancer in endogenous mouse models. To model stages of PDAC development in humans, following genetically engineered animal models (GEMM) were used: mice with pancreas specific activation of oncogenic Kras (p48+/Cre Kras +/LSL-G12D , CK) that develop preneoplastic lesions preceding the cancer and mice with concomitant deletion of p53 (p48+/Cre Kras+/LSL-Gi2Dp53Lox/Lox^c/cp) that develop PDAC already at 6-8 weeks of age. Pancreatic aVß3 integrin expression was analysed by immunohistochemistry and Western blot. For optical imaging, animals were injected with Integrisense680, Near Infrared fluorochrome labelled agent that specifically binds to aVß3. After 24h, animals were subjected to intraoperative epi-illumination optical imaging procedure. Sacrificed animals were whole-mount frozen for analysis of Integrisense intratissue distribution via muitispectral cryoslicing optical imaging. For comparison, T2 weighted (T2w) images of the abdomen were generated with 1,5T clinical MRI Scanner and a dedicated surface coil. ß3 protein expression was dramatically increased in CKP pancreatic tumors compared to CK pancreata. ß3 positive cells were found among malignant cells and in the reactive stroma. In CK animals, ß3 expression was specifically limited to ductal and preneoplastic lesions and surrounding stroma with no expression in normal tissue. Intraoperative optical imaging of Integrisense correlated well with the high ß3 expression in the tumor and demonstrated very strong and specific fluorescence Signals at the tumor surface with excellent demarcation of tumor borders and good contrast to surrounding tissues. CK pancreas was well visualized and spotty fluorescence pattern of Integrisense was observed. Cryoslicing imaging of the animals confirmed that Integrisense680 penetrated well into all parts of the tumor and accumulated very specifically in cancer tissue in CKPanimals. In CK pancreata, spots of fluorescence were also observed throughout the tissue confirming intraoperative imaging. Spots of fluorescence correlated well with the foci of ductal and preneoplastic lesions embedded in healthy tissue äs confirmed by histopathological analysis. In contrast, preneoplastic lesions were difficult to differentiate on T2w-MRI images due to low spatial resolution. Tumors appeared relative homogenously hyperintense on T2w images and tumor borders were in certain cases difficult to identify, when adjacent structures, i.e. gut, were of similar Signal intensity.