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Validation of Heat Shock Protein 70 as a Tumor-Specific Biomarker for Monitoring the Outcome of Radiation Therapy in Tumor Mouse Models  Christine Bayer,

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Presentation on theme: "Validation of Heat Shock Protein 70 as a Tumor-Specific Biomarker for Monitoring the Outcome of Radiation Therapy in Tumor Mouse Models  Christine Bayer,"— Presentation transcript:

1 Validation of Heat Shock Protein 70 as a Tumor-Specific Biomarker for Monitoring the Outcome of Radiation Therapy in Tumor Mouse Models  Christine Bayer, PhD, Michael E. Liebhardt, MD, Thomas E. Schmid, PhD, Marija Trajkovic-Arsic, PhD, Kathrin Hube, MD, Hanno M. Specht, MD, Daniela Schilling, PhD, Mathias Gehrmann, PhD, Stefan Stangl, Dipl Ing, Jens T. Siveke, MD, Jan J. Wilkens, DSc, Gabriele Multhoff, PhD  International Journal of Radiation Oncology • Biology • Physics  Volume 88, Issue 3, Pages (March 2014) DOI: /j.ijrobp Copyright © 2014 Elsevier Inc. Terms and Conditions

2 Fig. 1 (A) Representative flow cytometric analysis is shown of mHsp70 expression in viable FaDu cells from cell culture (FaDu cells, left panel), single-cell suspensions of FaDu xenograft tumors (middle panel), and primary cells of cultivated spontaneous PDAC mouse tumors (right panel). The cells stained with the FITC-labeled IgG1 isotype-matched control antibody are shown in the gray histogram, and the cells stained with cmHsp70.1 monoclonal antibody (16) are shown in the white histogram. (B) Cell culture medium from FaDu tumor spheroids was analyzed for their Hsp70 secretion by ELISA during growth for 2 weeks. Linear regression analysis and Pearson coefficient of correlation (r) were used to examine the relationship between variables. Abbreviations: cmHsp = cell membrane Hsp70; ELISA = enzyme-linked immunosorbent assay; FITC = fluorescein isothiocyanate; PDAC = pancreatic ductal adenocarcinoma; mHsp70 = membrane Hsp70. International Journal of Radiation Oncology • Biology • Physics  , DOI: ( /j.ijrobp ) Copyright © 2014 Elsevier Inc. Terms and Conditions

3 Fig. 2 (A) sHsp70 levels were significantly higher in FaDu xenograft tumor-bearing than in non-tumor-bearing NMRI nu/nu mice. (B) sHsp70 levels were significantly higher in spontaneous PDAC tumor-bearing mice (Ptf1a+/Cre;Kras+/LSL-G12D;p53LoxP/LoxP) than in their corresponding wt littermates. Mean values ± SEM are presented. *P<.05, **P<.01 as compared to non-tumor-bearing control animals. Abbreviations: PDAC = pancreatic ductal adenocarcinoma; sHsp, soluble Hsp; wt = wild type. International Journal of Radiation Oncology • Biology • Physics  , DOI: ( /j.ijrobp ) Copyright © 2014 Elsevier Inc. Terms and Conditions

4 Fig. 3 sHsp70 was assessed in non-tumor-bearing (gray bars) and FaDu xenograft tumor-bearing (black bars) NMRI nu/nu mice. Blood was collected from healthy mice 24 h after sham (0 Gy) or 30-Gy irradiation of the hind leg (gray bars) or from tumor-bearing mice 24 h after sham (0 Gy) or 30-Gy irradiation of the tumor (black bars). The tumor volumes of sham and 30-Gy-irradiated mice was 0.32 cm3. Blood was also collected from mice after waiting for the tumors to be locally controlled (after 30 Gy) by 50% (tumor volume = 0.16 cm3) or 100% (tumor volume = 0 cm3). Values are means ± SEM. ***P<.001. Abbreviation: sHsp, soluble Hsp. International Journal of Radiation Oncology • Biology • Physics  , DOI: ( /j.ijrobp ) Copyright © 2014 Elsevier Inc. Terms and Conditions

5 Fig. 4 (A) Representative images of pimonidazole staining of FaDu tumors are shown. Hoechst fluorescence of cells in perfused areas is shown in blue, pimonidazole staining of hypoxic cells in green, and CD31 staining for microvascular endothelial cells in red. The white areas represent necrotic contours based on H&E staining. (B) Gray circles represent nonirradiated tumors at different sizes, and red-rimmed gray circles indicate tumors that were previously irradiated with a single dose of 30 Gy. The volume of the tumor is reflected by sHsp70 levels (purple) but not by the pimonidazole-stained (pHF) hypoxic fraction (green). The pHF fraction remains unchanged, with increasing tumor volumes, and decreases only after 50% local tumor control. The fraction of necrotic tumor cells (gray) gradually increases with the tumor volume and further increases after irradiation. Necrosis also does not correlate with the tumor volume. Abbreviations: H&E = hematoxylin and eosin; sHsp = soluble Hsp; t after IR = time after irradiation. International Journal of Radiation Oncology • Biology • Physics  , DOI: ( /j.ijrobp ) Copyright © 2014 Elsevier Inc. Terms and Conditions

6 Fig. 5 Blood was extracted from nonirradiated (A) or previously irradiated (B) mice bearing FaDu tumors of increasing volumes (0-0.64 cm3). Linear regression analysis and Pearson coefficient of correlation (r) were used to examine the relationship between variables. International Journal of Radiation Oncology • Biology • Physics  , DOI: ( /j.ijrobp ) Copyright © 2014 Elsevier Inc. Terms and Conditions

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