Gemcitabine impairs tumor perfusion in stroma rich murine endogenous PDAC

• Published in: European journal of cancer (1990) 2016-12, Vol.69, p.S67-S68
• Main Authors: Heid, I, Trajkovic-Arsic, M, Steiger, K, Settles, M, Steingötter, A, Gupta, A, Lubeseder-Martellato, C, Schmid, R.M, Rummeny, E, Siveke, J, Braren, R
• Format: Article
• Language: English
• Subjects: Adenocarcinoma; Animal models; Chemotherapy; Correlation analysis; Drugs; Gadolinium; Gadopentetate dimeglumine; Gemcitabine; Genetic engineering; Genotypes; Hematology, Oncology and Palliative Medicine; Histopathology; Lesions; Magnetic resonance imaging; Mice; Microscopy; Muscles; p53 Protein; Pancreas; Pancreatic cancer; Perfusion; Stroma; Therapy; Tumor cells; Tumors
• ISSN: 0959-8049; 1879-0852
• DOI: 10.1016/S0959-8049(16)32790-3

Background: Prominent fibroinflammatory response and reduced perfusion are hallmarks of pancreatic ductal adenocarcinoma (PDAC). Ineffective delivery of therapy agents to the tumor side is one of the reasons for therapeutic resistance of PDAC. Here we investigate vascular function in PDAC with different cellularity and stroma content developed in genetically engineered mouse models (GEM). In addition, we use GEM to assess perfusion changes under the standard palliative treatment with gemcitabine. Material and Methods: A cohort of mice (N = 48) with genotypes Ptf1awt/cre(C)Kraswt/G12D(K)Ela-Tgfa(T), CK;p53(P)wt/fl, CKPfl/fl, CKTPwt/R172H and CKTPwt/flwas subjected to final Dynamic Contrast Enhanced (DCE)-MRI employing a 1.5T Achieva, Philips with a 47-mm microscopy surface coil. Tumor perfusion was measured by single-shot Look-Locker based radial T1 mapping technique using the golden cut principle with a bolus of 0.04mmol/kg of Gd-DTPA (Magnevist®). In a subset of CKPfl/fl mice therapy response to gemcitabine (Gem, twice per week, 120mg/kg by intraperitoneal injection, NNaCl = 10, Ngem = 12) was monitored pre and 2 weeks post treatment. Imaging data were validated by histopathology using H&E, Movat and CD31 staining. Results: Relative area under the curve of the first 60s (AUC60. tumor/muscle ratio) derived from measured Gadolinium concentration curves correlated positively with open vascular spaces (r = 0.68, CI: 0.28,0.88) and stroma content (r = 0.46, CI: 0.2,0.66) and negatively with the amount of tumor cell (r = -0.42, CI: -0.63.-0.17) in murine PDAC. Significant differences were noted in AUC60 between stroma rich, low cellular (PDAClow, 2.06±0.1, n = 27) and stroma poor, moderately cellular lesions (PDACmed, 1.21 ±0.1. n = 25) albeit an overlap in individual tumors. PDACmed tumors reveal significantly reduced perfusion after 14 days independent of the treatment and analysis method. PDAClow tumors showed impaired perfusion under gemcitabine treatment (AUC60pre = 2.7±0.6, AUC60post = 2.0±0.2, P = 0.012), whereas no significant changes were noted in the vehicle group. Conclusions: Murine PDAC lesions with low amount of tumor cells reveal higher perfusion compared to tumors with intermediate cellularity and reduce their vascular function under gemcitabine treatment.