351 results on '"Rofstad EK"'
Search Results
2. Fraction of radiobiologically hypoxic cells in human melanoma xenografts measured by using single-cell survival, tumour growth delay and local tumour control as end points
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Rofstad, EK, primary and Måseide, K, additional
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- 1998
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3. Tumour hypoxia and vascular density as predictors of metastasis in squamous cell carcinoma of the uterine cervix
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Sundfør, K, primary, Lyng, H, additional, and Rofstad, EK, additional
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- 1998
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4. Hypoxia-induced angiogenesis and vascular endothelial growth factor secretion in human melanoma
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Rofstad, EK, primary and Danielsen, T, additional
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- 1998
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5. Energy metabolism in human melanoma cells under hypoxic and acidic conditions in vitro
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Skøyum, R, primary, Eide, K, additional, Berg, K, additional, and Rofstad, EK, additional
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- 1997
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6. Proton relaxation times and interstitial fluid pressure in human melanoma xenografts
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Lyng, H, primary, Tufto, I, additional, Skretting, A, additional, and Rofstad, EK, additional
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- 1997
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7. Oxygen tension and vascular density in human cervix carcinoma
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Lyng, H, primary, Sundfør, K, additional, Tropé, C, additional, and Rofstad, EK, additional
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- 1996
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8. Growth rates or radiobiological hypoxia are not correlated with local metabolite content in human melanoma xenografts with similar vascular network
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Kroeger, M, primary, Walenta, S, additional, Rofstad, EK, additional, and Mueller-Klieser, W, additional
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- 1995
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9. Transient perfusion in human melanoma xenografts
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Tufto, I, primary and Rofstad, EK, additional
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- 1995
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10. Detection of necrosis in human tumour xenografts by proton magnetic resonance imaging
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Jakobsen, I, primary, Kaalhus, O, additional, Lyng, H, additional, and Rofstad, EK, additional
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- 1995
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11. Orthotopic human melanoma xenograft model systems for studies of tumour angiogenesis, pathophysiology, treatment sensitivity and metastatic pattern
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Rofstad, EK, primary
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- 1994
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12. Step-down heating of human melanoma xenografts: effects of the tumour microenvironment
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Rofstad, EK, primary
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- 1994
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13. Analysis of the therapeutic gain in the treatment of human osteosarcoma microcolonies in vitro with 211At-labelled monoclonal antibody
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Larsen, RH, primary, Bruland, ØS, additional, Hoff, P, additional, Alstad, J, additional, and Rofstad, EK, additional
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- 1994
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14. 31P-nuclear magnetic resonance spectroscopy in vivo of six human melanoma xenograft lines: tumour bioenergetic status and blood supply
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Lyng, H, primary, Olsen, DR, additional, Southon, TE, additional, and Rofstad, EK, additional
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- 1993
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15. Tumour necrotisation in nude mice xenografts by the reversible protein synthesis inhibitor zilascorb(2H)
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Pettersen, EO, primary, Larsen, RO, additional, Dornish, JM, additional, Børretzen, B, additional, Juul, MEH, additional, Aastveit, TE, additional, Nesland, JM, additional, Rofstad, EK, additional, and Oftebro, R, additional
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- 1993
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16. PLD-repair in human melanoma xenografts following single dose and fractionated irradiation
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Rofstad, EK, primary
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- 1990
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17. Heat sensitivity and thermotolerance in vitro of human breast carcinoma, malignant melanoma and squamous cell carcinoma of the head and neck
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Rofstad, EK, primary
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- 1990
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18. Intracapillary HbO2 saturations in murine tumours and human tumour xenografts measured by cryospectrophotometry: relationship to tumour volume, tumour pH and fraction of radiobiologically hypoxic cells.
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Rofstad, EK, Fenton, BM, Sutherland, RM, Rofstad, E K, Fenton, B M, and Sutherland, R M
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- 1988
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19. Analysis of the therapeutic gain in the treatment of human osteosarcoma microcolonies in vitro with 211At-labelled monoclonal antibody.
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Larsen, RH, Bruland, ØS, Hoff, P, Alstad, J, and Rofstad, EK
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- 1994
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- View/download PDF
20. 31P-nuclear magnetic resonance spectroscopy in vivo of six human melanoma xenograft lines: tumour bioenergetic status and blood supply.
- Author
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Lyng, H, Olsen, DR, Southon, TE, and Rofstad, EK
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- 1993
- Full Text
- View/download PDF
21. Tumour necrotisation in nude mice xenografts by the reversible protein synthesis inhibitor zilascorb(2H).
- Author
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Pettersen, EO, Larsen, RO, Dornish, JM, Børretzen, B, Juul, MEH, Aastveit, TE, Nesland, JM, Rofstad, EK, and Oftebro, R
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- 1993
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22. Growth and radiation sensitivity of the MLS human ovarian carcinoma cell line grown as multicellular spheroids and xenografted tumours.
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Rofstad, EK, Sutherland, RM, Rofstad, E K, and Sutherland, R M
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- 1989
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23. Relationship between changes in antigen expression and protein synthesis in human melanoma cells after hyperthermia and photodynamic treatment.
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Davies, C de L, Ranheim, T, Malik, Z, Rofstad, EK, Moan, J, Lindmo, T, Davies, C L, and Rofstad, E K
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- 1988
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24. Intracapillary HbO2saturations in murine tumours and human tumour xenografts measured by cryospectrophotometry: relationship to tumour volume, tumour pH and fraction of radiobiologically hypoxic cells
- Author
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Rofstad, EK, Fenton, BM, and Sutherland, RM
- Abstract
Frequency distributions for intracapillary HbO2 saturation were determined for two murine tumour lines (KHT, RIF-1) and two human ovarian carcinoma xenograft lines (MLS, OWI) using a cryospectrophotometric method. The aim was to search for possible relationships between HbO2 saturation status and tumour volume, tumour pH and fraction of radiobiologically hypoxic cells. Tumour pH was measured by 31P NMR spectroscopy. Hypoxic fractions were determined from cell survival curves for tumours irradiated in vivo and assayed in vitro. Tumours in the volume range 100-4000 mm3 were studied and the majority of the vessels were found to have HbO2 saturations below 10%. The volume-dependence of the HbO2 frequency distributions differed significantly among the four tumour lines; HbO2 saturation status decreased with increasing tumour volume for the KHT, RIF-1 and MLS lines and was independent of tumour volume for the OWI line. The data indicated that the rate of decrease in HbO2 saturation status during tumour growth was related to the rate of development of necrosis. The volume-dependence of tumour pH was very similar to that of the HbO2 saturation status for all tumour lines. Significant correlations were therefore found between HbO2 saturation status and tumour pH, both within tumour lines and across the four tumour lines, reflecting that the volume-dependence of both parameters probably was a compulsory consequence of reduced oxygen supply conditions during tumour growth. Hypoxic fraction increased during tumour growth for the KHT, RIF-1 and MLS lines and was volume-independent for the OWI line, suggesting a relationship between HbO2 saturation status and hypoxic fraction within tumour lines. However, there was no correlation between these two parameters across the four tumour lines, indicating that the hypoxic fraction of a tumour is not determined only by the oxygen supply conditions; other parameters may also be important, e.g. oxygen diffusivity, rate of oxygen consumption and cell survival time under hypoxic stress.
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- 1988
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25. pO(2) Fluctuation Pattern and Cycling Hypoxia in Human Cervical Carcinoma and Melanoma Xenografts.
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Ellingsen C, Ovrebø KM, Galappathi K, Mathiesen B, and Rofstad EK
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- 2012
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26. Fluid-sensitive migration mechanisms predict association between metastasis and high interstitial fluid pressure in pancreatic cancer.
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Nævdal G, Rofstad EK, Søreide K, and Evje S
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- Humans, Tumor Microenvironment, Extracellular Fluid, Pancreatic Neoplasms
- Abstract
A remarkable feature in pancreatic cancer is the propensity to metastasize early, even for small, early stage cancers. We use a computer-based pancreatic model to simulate tumor progression behavior where fluid-sensitive migration mechanisms are accounted for as a plausible driver for metastasis. The model has been trained to comply with in vitro results to determine input parameters that characterize the migration mechanisms. To mimic previously studied preclinical xenografts we run the computer model informed with an ensemble of stochastic-generated realizations of unknown parameters related to tumor microenvironment only constrained such that pathological realistic values for interstitial fluid pressure (IFP) are obtained. The in silico model suggests the occurrence of a steady production of small clusters of cancer cells that detach from the primary tumor and form isolated islands and thereby creates a natural prerequisite for a strong invasion into the lymph nodes and venous system. The model predicts that this behavior is associated with high interstitial fluid pressure (IFP), consistent with published experimental findings. The continuum-based model is the first to explain published results for preclinical models which have reported associations between high IFP and high metastatic propensity and thereby serves to shed light on possible mechanisms behind the clinical aggressiveness of pancreatic cancer., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)
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- 2022
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27. In silico investigations of intratumoral heterogeneous interstitial fluid pressure.
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Waldeland JO, Gaustad JV, Rofstad EK, and Evje S
- Subjects
- Computer Simulation, Extracellular Matrix, Humans, Pressure, Extracellular Fluid, Neoplasms
- Abstract
Recent preclinical studies have shown that interstitial fluid pressure (IFP) within tumors can be heterogeneous Andersen et al. (2019). In that study tumors of two xenograft models, respectively, HL-16 cervical carcinoma and Panc-1 pancreatic carcinoma, were investigated. Significant heterogeneity in IFP was reported and it was proposed that this was associated with division of tissue into compartments separated by thick connective tissue bands for the HL-16 tumors and with dense collagen-rich extracellular matrix for the Panc-1 tumors. The purpose of the current work is to explore these experimental observations by using in silico generated tumor models. We consider a mathematical multiphase model which accounts for tumor cells, fibroblasts and interstitial fluid. The model has been trained to comply with experimental in vitro results reported in Shieh et al. (2011) which has identified autologous chemotaxis, ECM remodeling, and cell-fibroblast interaction as drivers for invasive tumor cell behavior. The in silico model is informed with parameters that characterize the leaky intratumoral vascular network, the peritumoral lymphatics which collect the fluid, and the density of ECM as represented through the hydraulic conductivity of the interstitial space. Heterogeneous distribution of solid stress may result in heterogeneous compression of blood vessels and, thus, heterogeneous vascular density inside the tumor. To mimic this we expose the in silico tumor to an intratumoral vasculature whose net effect of density of blood vesssels and vessel wall conductivity is varied through a 2D Gaussian variogram constrained such that the resulting IFPs lie within the range as reported from the preclinical study. The in silico cervical carcinoma model illustrates that sparse ECM was associated with uniform intratumoral IFP in spite of heterogeneous microvascular network, whereas compartment structures resulted in more heterogeneous IFP. Similarly, the in silico pancreatic model shows that heterogeneity in the microvascular network combined with dense ECM structure prevents IFP to even out and gives rise to heterogeneous IFP. The computer model illustrates how a heterogeneous invasive front might form where groups of tumor cells detach from the primary tumor and form isolated islands, a behavior which is natural to associate with metastatic propensity. However, unlike experimental studies, the current version of the in silico model does not show an association between metastatic propensity and elevated IFP., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2021
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28. Assessment of Intratumor Heterogeneity in Parametric Dynamic Contrast-Enhanced MR Images: A Comparative Study of Novel and Established Methods.
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Gaustad JV and Rofstad EK
- Abstract
Intratumor heterogeneity is associated with aggressive disease and poor survival rates in several types of cancer. A novel method for assessing intratumor heterogeneity in medical images, named the spatial gradient method, has been developed in our laboratory. In this study, we measure intratumor heterogeneity in K
trans maps derived by dynamic contrast-enhanced magnetic resonance imaging using the spatial gradient method, and we compare the performance of the novel method with that of histogram analyses and texture analyses using the Haralick method. Ktrans maps of 58 untreated and sunitinib-treated pancreatic ductal adenocaricoma (PDAC) xenografts from two PDAC models were investigated. Intratumor heterogeneity parameters derived by the spatial gradient method were sensitive to tumor line differences as well as sunitinib-induced changes in intratumor heterogeneity. Furthermore, the parameters provided additional information to the median value and were not severely affected by imaging noise. The parameters derived by histogram analyses were insensitive to spatial heterogeneity and were strongly correlated to the median value, and the Haralick features were severely influenced by imaging noise and did not differentiate between untreated and sunitinib-treated tumors. The spatial gradient method was superior to histogram analyses and Haralick features for assessing intratumor heterogeneity in Ktrans maps of untreated and sunitinib-treated PDAC xenografts, and can possibly be used to assess intratumor heterogeneity in other medical images and to evaluate effects of other treatments as well., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Gaustad and Rofstad.)- Published
- 2021
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29. Intravital microscopy of tumor vessel morphology and function using a standard fluorescence microscope.
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Gaustad JV, Simonsen TG, Hansem LMK, and Rofstad EK
- Subjects
- Angiogenesis Inhibitors therapeutic use, Cell Line, Tumor, Humans, Intravital Microscopy, Melanoma drug therapy, Neovascularization, Pathologic diagnostic imaging, Neovascularization, Pathologic drug therapy
- Abstract
Purpose: The purpose of the study was to demonstrate the performance and possible applications of an intravital microscopy assay using a standard fluorescence microscope., Methods: Melanoma and pancreatic ductal adenocarcinoma xenografts were initiated in dorsal window chambers and subjected to repeated intravital microscopy. The entire tumor vasculature as well as the normal tissue surrounding the tumor was imaged simultaneously with high spatial and temporal resolution. Vascular morphology images were recorded by using transillumination, and vascular masks were produced to quantify vessel density, vessel diameter, vessel segment length, and vessel tortuosity. First-pass imaging movies were recorded after an intervenous injection of a fluorescent marker and were used to investigate vascular function. Lymphatics were visualized by intradermal injections of a fluorescent marker., Results: The intravital microscopy assay was used to study tumor growth and vascularization, tumor vessel morphology and function, tumor-associated lymphatics, and vascular effects of acute cyclic hypoxia and antiangiogenic treatment. The assay was sensitive to tumor-line differences in vascular morphology and function and detected tumor-induced lymphatic dilation. Acute cyclic hypoxia induced angiogenesis and increased the density of small diameter vessels and blood supply times, whereas antiangiogenic treatment selectively removed small-diameter vessels, reduced blood supply times, and induced hypoxia. Moreover, the window chamber was compatible with magnetic resonance imaging (MRI), and parametric images derived by dynamic contrast-enhanced MRI were shown to reflect vascular morphology and function., Conclusions: The presented assay represents a useful and affordable alternative to intravital microscopy assays using confocal and multi-photon microscopes., (© 2021. The Author(s).)
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- 2021
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30. Assessment of Hypoxic Tissue Fraction and Prediction of Survival in Cervical Carcinoma by Dynamic Contrast-Enhanced MRI.
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Gaustad JV and Rofstad EK
- Abstract
Tumor hypoxia is a major cause of treatment resistance and poor survival in locally-advanced cervical carcinoma (LACC). It has been suggested that K
trans and ve maps derived by dynamic contrast-enhanced magnetic resonance imaging can provide information on the oxygen supply and oxygen consumption of tumors, but it is not clear whether and how these maps can be combined to identify tumor hypoxia. The aim of the current study was to find the optimal strategy for calculating hypoxic fraction and predicting survival from Ktrans and ve maps in cervical carcinoma. Ktrans and ve maps of 98 tumors of four patient-derived xenograft models of cervical carcinoma as well as 80 patients with LACC were investigated. Hypoxic fraction calculated by using Ktrans maps correlated strongly ( P < 0.0001) to hypoxic fraction assessed with immunohistochemistry using pimonidazole as a hypoxia marker and was associated with disease-free and overall survival in LACC patients. Maps of ve did not provide information on hypoxic fraction and patient outcome, and combinations of Ktrans and ve were not superior to Ktrans alone for calculating hypoxic fraction. These observations imply that Ktrans maps reflect oxygen supply and may be used to identify hypoxia and predict outcome in cervical carcinoma, whereas ve is a poor parameter of oxygen consumption and does not provide information on tumor oxygenation status., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Gaustad and Rofstad.)- Published
- 2021
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31. DCE-MRI of Tumor Hypoxia and Hypoxia-Associated Aggressiveness.
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Gaustad JV, Hauge A, Wegner CS, Simonsen TG, Lund KV, Hansem LMK, and Rofstad EK
- Abstract
Tumor hypoxia is associated with resistance to treatment, aggressive growth, metastatic dissemination, and poor clinical outcome in many cancer types. The potential of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to assess the extent of hypoxia in tumors has been investigated in several studies in our laboratory. Cervical carcinoma, melanoma, and pancreatic ductal adenocarcinoma (PDAC) xenografts have been used as models of human cancer, and the transfer rate constant ( K
trans ) and the extravascular extracellular volume fraction ( ve ) have been derived from DCE-MRI data by using Tofts standard pharmacokinetic model and a population-based arterial input function. Ktrans was found to reflect naturally occurring and treatment-induced hypoxia when hypoxia was caused by low blood perfusion, radiation responsiveness when radiation resistance was due to hypoxia, and metastatic potential when metastasis was hypoxia-induced. Ktrans was also associated with outcome for patients with locally-advanced cervical carcinoma treated with cisplatin-based chemoradiotherapy. Together, the studies imply that DCE-MRI can provide valuable information on the hypoxic status of cervical carcinoma, melanoma, and PDAC. In this communication, we review and discuss the studies and provide some recommendations as to how DCE-MRI data can be analyzed and interpreted to assess tumor hypoxia.- Published
- 2020
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32. Antifibrotic therapy to normalize the tumor microenvironment.
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Hauge A and Rofstad EK
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- Extracellular Matrix pathology, Fibroblasts pathology, Fibrosis, Humans, Transforming Growth Factor beta, Tumor Microenvironment
- Abstract
Most tumors develop abnormal fibrotic regions consisting of fibroblasts, immune cells, and a dense extracellular matrix (ECM) immersed in a viscous interstitial fluid, and an abundant fibrotic tumor microenvironment (TME) is associated with poor outcome of treatment. It has been hypothesized that the treatment of cancer may be improved by interventions aiming to normalize this TME. The approaches used in attempts to normalize the fibrotic TME can be categorized into three strategies of targeted antifibrotic therapy: targeting of components of the ECM, targeting of the producers of the ECM components-the activated cancer-associated fibroblasts (CAFs), and targeting of the signaling pathways activating CAFs. To target the ECM, enzymes against components of the ECM have been used, including collagenase, relaxin, hyaluronidase, and lyxyl oxidase. Targeting of CAFs have been investigated by using agents aiming to eliminate or reprogram CAFs. CAFs are activated primarily by transforming growth factor-β (TGF-β), hedgehog, or focal adhesion kinase signaling, and several agents have been used to target these signaling pathways, including angiotensin II receptor I blockers (e.g., losartan) to inhibit the TGF-β pathway. Taken together, these studies have revealed that antifibrotic therapy is a two-edged sword: while some studies suggest enhanced response to treatment after antifibrotic therapy, others suggest that antifibrotic therapy may lead to increased tumor growth, metastasis, and impaired outcome of treatment. There are several possible explanations of these conflicting observations. Most importantly, tumors contain different subpopulations of CAFs, and while some subpopulations may promote tumor growth and metastasis, others may inhibit malignant progression. Furthermore, the outcome of antifibrotic therapy may depend on stage of disease, duration of treatment, treatment-induced activation of alternative profibrotic signaling pathways, and treatment-induced recruitment of tumor-supporting immune cells. Nevertheless, losartan-induced suppression of TGF-β signaling appears to be a particularly promising strategy. Losartan is a widely prescribed antihypertensive drug and highly advantageous therapeutic effects have been observed after losartan treatment of pancreatic cancer. However, improved understanding of the mechanisms governing the development of fibrosis in tumors is needed before safe antifibrotic treatments can be established.
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- 2020
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33. DCE-MRI of locally-advanced carcinoma of the uterine cervix: Tofts analysis versus non-model-based analyses.
- Author
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Lund KV, Simonsen TG, Kristensen GB, and Rofstad EK
- Subjects
- Biomarkers metabolism, Carcinoma metabolism, Carcinoma pathology, Carcinoma therapy, Chemoradiotherapy, Contrast Media pharmacokinetics, Disease-Free Survival, Female, Gadolinium DTPA pharmacokinetics, Humans, Models, Biological, Prognosis, Survival Rate, Tumor Burden, Uterine Cervical Neoplasms metabolism, Uterine Cervical Neoplasms pathology, Uterine Cervical Neoplasms therapy, Carcinoma diagnostic imaging, Magnetic Resonance Imaging methods, Uterine Cervical Neoplasms diagnostic imaging
- Abstract
Background: Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) may provide biomarkers of the outcome of locally-advanced cervical carcinoma (LACC). There is, however, no agreement on how DCE-MR recordings should be analyzed. Previously, we have analyzed DCE-MRI data of LACC using non-model-based strategies. In the current study, we analyzed DCE-MRI data of LACC using the Tofts pharmacokinetic model, and the biomarkers derived from this analysis were compared with those derived from the non-model-based analyses., Methods: Eighty LACC patients given cisplatin-based chemoradiotherapy with curative intent were included in the study. Treatment outcome was recorded as disease-free survival (DFS) and overall survival (OS). DCE-MRI series were analyzed voxelwise to produce K
trans and ve frequency distributions, and ROC analysis was used to identify the parameters of the frequency distributions having the greatest potential as biomarkers. The prognostic power of these parameters was compared with that of the non-model-based parameters LETV (low-enhancing tumor volume) and TVIS (tumor volume with increasing signal)., Results: Poor DFS and OS were associated with low values of Ktrans , whereas there was no association between treatment outcome and ve . The Ktrans parameters having the greatest prognostic value were p35-Ktrans (the Ktrans value at the 35 percentile of a frequency distribution) and RV-Ktrans (the tumor subvolume with Ktrans values below 0.13 min- 1 ). Multivariate analysis including clinical parameters and p35-Ktrans or RV-Ktrans revealed that RV-Ktrans was the only independent prognostic factor of DFS and OS. There were significant correlations between RV-Ktrans and LETV and between RV-Ktrans and TVIS, and the prognostic power of RV-Ktrans was similar to that of LETV and TVIS., Conclusions: Biomarkers of the outcome of LACC can be provided by analyzing DCE-MRI series using the Tofts pharmacokinetic model. However, these biomarkers do not appear to have greater prognostic value than biomarkers determined by non-model-based analyses.- Published
- 2020
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34. Bevacizumab treatment of meningeal melanoma metastases.
- Author
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Simonsen TG, Gaustad JV, and Rofstad EK
- Subjects
- Adult, Angiogenesis Inhibitors pharmacology, Angiogenesis Inhibitors therapeutic use, Animals, Female, Humans, Mice, Mice, Inbred BALB C, Neovascularization, Pathologic drug therapy, Vascular Endothelial Growth Factor A, Bevacizumab pharmacology, Bevacizumab therapeutic use, Melanoma drug therapy, Meningeal Neoplasms drug therapy, Meningeal Neoplasms secondary
- Abstract
Background: Melanoma patients with metastatic growth in the meninges have poor prognosis and few treatment options. Although treatment with BRAF inhibitors or immune checkpoint inhibitors has provided promising results, most patients with advanced melanoma are resistant to these treatments and develop severe side effects. Novel treatment strategies are needed for patients with meningeal melanoma metastases, and the potential of antiangiogenic therapy was investigated in this preclinical study., Methods: Two GFP-transfected melanoma models (A-07 and D-12) differing substantially in VEGF-A expression were included in the study, and the anti-VEGF-A antibody bevacizumab was used as therapeutic agent. Meningeal metastases were initiated in BALB/c nu/nu mice by intracranial inoculation of melanoma cells, and bevacizumab treatment was given twice a week in i.p. doses of 10 mg/kg until the mice became moribund. Therapeutic effects were evaluated by determining tumor host survival time, assessing tumor growth and angiogenic activity by quantitative analyses of histological preparations, and measuring the expression of angiogenesis-related genes by quantitative PCR., Results: Meningeal A-07 melanomas showed higher expression of VEGF-A than meningeal D-12 melanomas, whereas the expression of ANGPT2 and IL8, two important angiogenesis drivers in melanoma, was much higher in D-12 than in A-07 tumors. Bevacizumab treatment inhibited tumor angiogenesis and prolonged host survival in mice with A-07 tumors but not in mice with D-12 tumors. Meningeal A-07 tumors in bevacizumab-treated mice compensated for the reduced VEGF-A activity by up-regulating a large number of angiogenesis-related genes, including ANGPT2 and its receptors TIE1 and TIE2. Melanoma cells migrated from meningeal tumors into the cerebrum, where they initiated metastatic growth by vessel co-option. In the A-07 model, the density of cerebral micrometastases was higher in bevacizumab-treated than in untreated mice, either because bevacizumab treatment increased mouse survival or induced increased tumor gene expression., Conclusions: The development of antiangiogenic strategies for the treatment of meningeal melanoma metastases is a challenging task because the outcome of treatment will depend on the angiogenic signature of the tumor tissue, treatment-induced alterations of the angiogenic signature, and the treatment sensitivity of metastatic lesions in other intracranial sites.
- Published
- 2020
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35. Vascularization, Oxygenation, and the Effect of Sunitinib Treatment in Pancreatic Ductal Adenocarcinoma Xenografts.
- Author
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Gaustad JV, Simonsen TG, Wegner CS, and Rofstad EK
- Abstract
The purpose of the study was to investigate vascularization, oxygenation, and the effect of sunitinib treatment in pancreatic ductal adenocarcinoma (PDAC). BxPC-3 and Capan-2 xenografts grown in dorsal window chambers were used as preclinical models of human PDAC. Tumor angiogenesis and the morphology and function of tumor vascular networks were studied by intravital microscopy, and tumor hypoxia was assessed by immunohistochemistry. The PDAC models differed in vessel distribution and oxygenation, and the differences were induced by the initial tumor angiogenesis. In both models, sunitinib treatment reduced intratumor and peritumor vessel densities by selectively removing small-diameter vessels. Sunitinb treatment resulted in a general decrease in vessel density and scattered hypoxia in BxPC-3 tumors, and depleted most vessels and induced massive hypoxia in central parts of Capan-2 tumors. The study demonstrates that PDAC xenografts can differ in vascularization, and the differences can impact oxygenation and effects of treatment. Neoadjuvant sunitinib treatment is inappropriate in combination with conventional therapy for human PDACs resembling the PDAC xenografts used here, because sunitinib-induced hypoxia can impair the effect of most conventional therapies.
- Published
- 2019
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36. Intratumor Heterogeneity in Interstitial Fluid Pressure in Cervical and Pancreatic Carcinoma Xenografts.
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Hansem LMK, Huang R, Wegner CS, Simonsen TG, Gaustad JV, Hauge A, and Rofstad EK
- Abstract
Preclinical studies have suggested that interstitial fluid pressure (IFP) is uniformly elevated in the central region of tumors, whereas clinical studies have revealed that IFP may vary among different measurement sites in the tumor center. IFP measurements are technically difficult, and it has been claimed that the intratumor heterogeneity in IFP reported for human tumors is due to technical problems. The main purpose of this study was to determine conclusively whether IFP may be heterogeneously elevated in the central tumor region, and if so, to reveal possible mechanisms and possible consequences. Tumors of two xenograft models were included in the study: HL-16 cervical carcinoma and Panc-1 pancreatic carcinoma. IFP was measured with Millar SPC 320 catheters in two positions in each tumor and related to tumor histology or the metastatic status of the host mouse. Some tumors of both models showed significant intratumor heterogeneity in IFP, and this heterogeneity was associated with a compartmentalized histological appearance (i.e., the tissue was divided into compartments separated by thick connective tissue bands) in HL-16 tumors and with a dense collagen-I-rich extracellular matrix in Panc-1 tumors, suggesting that these connective tissue structures prevented efficient interstitial convection. Furthermore, some tumors of both models developed lymph node metastases, and of the two IFP values measured in each tumor, only the higher value was significantly higher in metastatic than in non-metastatic tumors, suggesting that metastatic propensity was determined by the tumor region having the highest IFP., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2019
- Full Text
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37. DCE-MRI and Quantitative Histology Reveal Enhanced Vessel Maturation but Impaired Perfusion and Increased Hypoxia in Bevacizumab-Treated Cervical Carcinoma.
- Author
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Hauge A, Gaustad JV, Huang R, Simonsen TG, Wegner CS, Andersen LMK, and Rofstad EK
- Subjects
- Actins, Animals, Capillary Permeability drug effects, Contrast Media, Female, Heterografts, Humans, Magnetic Resonance Imaging methods, Mice, Mice, Inbred BALB C, Mice, Nude, Microvessels pathology, Nitroimidazoles, Oxygen Consumption drug effects, Pericytes drug effects, Tumor Microenvironment drug effects, Angiogenesis Inhibitors pharmacology, Bevacizumab pharmacology, Microvessels drug effects, Tumor Hypoxia drug effects, Uterine Cervical Neoplasms blood supply, Uterine Cervical Neoplasms metabolism
- Abstract
Purpose: This study had a dual purpose: to investigate (1) whether bevacizumab can change the microvasculature and oxygenation of cervical carcinomas and (2) whether any changes can be detected with dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI)., Methods and Materials: Two patient-derived xenograft models of cervical cancer (BK-12 and HL-16) were included in the study. Immunostained histologic preparations from untreated and bevacizumab-treated tumors were analyzed with respect to microvascular density, vessel pericyte coverage, and tumor hypoxia using CD31, α-SMA, and pimonidazole as markers, respectively. DCE-MRI was performed at 7.05 T, and parametric images of K
trans and ve were derived from the data using the Tofts pharmacokinetic model., Results: The tumors of both models showed decreased microvascular density, increased vessel pericyte coverage, and increased vessel maturation after bevacizumab treatment. Bevacizumab-treated tumors were more hypoxic and had lower Ktrans values than untreated tumors in the BK-12 model, whereas bevacizumab-treated and untreated HL-16 tumors had similar hypoxic fractions and similar Ktrans values. Significant correlations were found between median Ktrans and hypoxic fraction, and the data for untreated and bevacizumab-treated tumors were well fitted by the same curve in both tumor models., Conclusions: Bevacizumab-treated tumors show less abnormal microvessels than untreated tumors do, but because of treatment-induced vessel pruning, the overall function of the microvasculature might be impaired after bevacizumab treatment, resulting in increased tumor hypoxia. DCE-MRI has great potential for monitoring bevacizumab-induced changes in tumor hypoxia in cervical carcinoma., (Copyright © 2019 Elsevier Inc. All rights reserved.)- Published
- 2019
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38. Pharmacokinetic analysis of DCE-MRI data of locally advanced cervical carcinoma with the Brix model.
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Lund KV, Simonsen TG, Kristensen GB, and Rofstad EK
- Subjects
- Adenocarcinoma metabolism, Adenocarcinoma therapy, Adult, Aged, Aged, 80 and over, Carcinoma, Squamous Cell metabolism, Carcinoma, Squamous Cell therapy, Chemoradiotherapy mortality, Female, Follow-Up Studies, Humans, Image Processing, Computer-Assisted methods, Middle Aged, Neoplasm Recurrence, Local metabolism, Neoplasm Recurrence, Local therapy, Prognosis, Survival Rate, Tissue Distribution, Uterine Cervical Neoplasms metabolism, Uterine Cervical Neoplasms therapy, Young Adult, Adenocarcinoma pathology, Carcinoma, Squamous Cell pathology, Contrast Media pharmacokinetics, Magnetic Resonance Imaging methods, Models, Statistical, Neoplasm Recurrence, Local pathology, Uterine Cervical Neoplasms pathology
- Abstract
Background: There is significant evidence that DCE-MRI may have the potential to provide clinically useful biomarkers of the outcome of locally advanced cervical carcinoma. However, there is no consensus on how to analyze DCE-MRI data to arrive at the most powerful biomarkers. The purpose of this study was to analyze DCE-MRI data of cervical cancer patients by using the Brix pharmacokinetic model and to compare the biomarkers derived from the Brix analysis with biomarkers determined by non-model-based analysis [i.e., low-enhancing tumor volume (LETV) and tumor volume with increasing signal (TVIS)] of the same patient cohort. Material and methods: DCE-MRI recordings of 80 patients (FIGO stage IB-IVA) treated with concurrent cisplatin-based chemoradiotherapy were analyzed voxel-by-voxel, and frequency distributions of the three parameters of the Brix model ( A
Brix , kep , and kel ) were determined. Moreover, risk volumes were calculated from the Brix parameters and termed RV- ABrix , RV- kep , and RV- kel , where the RVs represent the tumor volume with voxel values below a threshold value determined by ROC analysis. Disease-free survival (DFS) and overall survival (OS) were used as measures of treatment outcome. Results: Significant associations between the median value or any other percentile value of ABrix , kep , or kel and treatment outcome were not found. However, RV- ABrix , RV- kep , and RV- kel correlated with DFS and OS. Multivariate analysis revealed that the prognostic power of RV- ABrix , RV- kep , and RV- kel was independent of well-established clinical prognostic factors. RV- ABrix , RV- kep , and RV- kel correlated with each other as well as with LETV and TVIS. Conclusion: Strong biomarkers of the outcome of locally advanced cervical carcinoma can be provided by subjecting DCE-MRI series to pharmacokinetic analysis using the Brix model. The prognostic power of these biomarkers is not necessarily superior to that of biomarkers identified by non-model-based analyses.- Published
- 2019
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39. DCE-MRI-Derived Measures of Tumor Hypoxia and Interstitial Fluid Pressure Predict Outcomes in Cervical Carcinoma.
- Author
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Simonsen TG, Lund KV, Hompland T, Kristensen GB, and Rofstad EK
- Subjects
- Chemoradiotherapy, Contrast Media, Disease-Free Survival, Female, Humans, Image Enhancement, Pressure, Tumor Burden, Tumor Hypoxia, Uterine Cervical Neoplasms diagnostic imaging, Uterine Cervical Neoplasms metabolism, Uterine Cervical Neoplasms therapy, Extracellular Fluid physiology, Magnetic Resonance Imaging methods, Uterine Cervical Neoplasms mortality
- Abstract
Purpose: The poor outcome of locally advanced cervical cancer has been associated with extensive hypoxia and high interstitial fluid pressure (IFP) in the primary tumor. In the present study, measures of tumor hypoxia and IFP were provided using dynamic contrast-enhanced (DCE)-magnetic resonance imaging (MRI) and related to the treatment outcomes., Methods and Materials: The data from 54 cervical cancer patients treated with concurrent cisplatin-based chemoradiotherapy were studied. A low-enhancing tumor volume (LETV) and peritumoral fluid flow velocity (v
0 ) were used as measures of tumor hypoxia and IFP, respectively., Results: Poor disease-free survival and overall survival were associated with large LETV and high v0 . The multivariate analysis results suggested that the prognostic power of v0 and LETV is independent of established clinical prognostic factors and that the prognostic power of v0 is strong compared with that of LETV. The outcomes was especially poor for patients with a high v0 combined with a large LETV and especially good for those with a low v0 combined with a small LETV, with 5-year disease-free survival and overall survival of 13% versus 100%, respectively., Conclusions: The outcome of locally advanced cervical carcinoma seems to be influenced strongly by the tumor IFP and to a lesser extent by tumor hypoxia. DCE-MRI might have the power to provide important biomarkers for the outcome of cervical cancer., (Copyright © 2018 Elsevier Inc. All rights reserved.)- Published
- 2018
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40. Diffusion-Weighted MRI Is Insensitive to Changes in the Tumor Microenvironment Induced by Antiangiogenic Therapy.
- Author
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Hauge A, Wegner CS, Gaustad JV, Simonsen TG, Andersen LMK, and Rofstad EK
- Abstract
Antiangiogenic treatment (AAT) used in combination with radiation therapy or chemotherapy is a promising strategy for the treatment of several cancer diseases. The vascularity and oxygenation of tumors may be changed significantly by AAT, and consequently, a noninvasive method for monitoring AAT-induced changes in these microenvironmental parameters is needed. The purpose of this study was to evaluate the potential usefulness of diffusion-weighted magnetic resonance imaging (DW-MRI). DW-MRI was conducted with a Bruker Biospec 7.05-T scanner using four diffusion weightings and diffusion sensitization gradients in three orthogonal directions. Maps of the apparent diffusion coefficient (ADC) were calculated by using a monoexponential diffusion model. Two cervical carcinoma xenograft models (BK-12, HL-16) were treated with bevacizumab, and two pancreatic carcinoma xenograft models (BxPC-3, Panc-1) were treated with sunitinib. Pimonidazole and CD31 were used as markers of hypoxia and blood vessels, respectively, and fraction of hypoxic tissue (HF
Pim ) and microvascular density (MVD) were quantified by analyzing immunohistochemical preparations. MVD decreased significantly after AAT in BK-12, HL-16, and BxPC-3 tumors, and this decrease was sufficiently large to cause a significant increase in HFPim in BK-12 and BxPC-3 tumors. The ADC maps of treated tumors and untreated control tumors were not significantly different in any of these three tumor models, suggesting that the AAT-induced microenvironmental changes were not detectable by DW-MRI. DW-MRI is insensitive to changes in tumor vascularity and oxygenation induced by bevacizumab or sunitinib treatment., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2018
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41. DCE-MRI of Sunitinib-Induced Changes in Tumor Microvasculature and Hypoxia: A Study of Pancreatic Ductal Adenocarcinoma Xenografts.
- Author
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Wegner CS, Hauge A, Simonsen TG, Gaustad JV, Andersen LMK, and Rofstad EK
- Subjects
- Animals, Biomarkers, Cell Line, Tumor, Contrast Media, Disease Models, Animal, Female, Humans, Image Enhancement, Immunohistochemistry, Male, Mice, Sunitinib, Tumor Microenvironment, Xenograft Model Antitumor Assays, Pancreatic Neoplasms, Carcinoma, Pancreatic Ductal diagnosis, Carcinoma, Pancreatic Ductal metabolism, Hypoxia metabolism, Indoles pharmacology, Magnetic Resonance Imaging methods, Neovascularization, Pathologic metabolism, Pancreatic Neoplasms diagnosis, Pancreatic Neoplasms metabolism, Pyrroles pharmacology
- Abstract
The purpose of this study was dual: to investigate (a) whether sunitinib may induce changes in tumor microvasculature and hypoxia in pancreatic ductal adenocarcinoma (PDAC) and (b) whether any changes can be detected by DCE-MRI. Sunitinib-treated and untreated control tumors of two PDAC xenograft models (BxPC-3 and Panc-1) were subjected to DCE-MRI before the imaged tumors were prepared for quantitative analysis of immunohistochemical preparations. Pimonidazole was used as a hypoxia marker, and fraction of hypoxic tissue (HF
Pim ), density of CD31-positive microvessels (MVDCD31 ), and density of αSMA-positive microvessels (MVDαSMA ) were measured. Parametric images of Ktrans and ve were derived from the DCE-MRI data by using the Tofts pharmacokinetic model. BxPC-3 tumors showed increased HFPim , decreased MVDCD31 , unchanged MVDαSMA , and increased vessel maturation index (VMI = MVDαSMA /MVDCD31 ) after sunitinib treatment. The increase in VMI was seen because sunitinib induced selective pruning rather than maturation of αSMA-negative microvessels. Even though the microvessels in sunitinib-treated tumors were less abnormal than those in untreated tumors, this microvessel normalization did not improve the function of the microvascular network or normalize the tumor microenvironment. In Panc-1 tumors, HFPim , MVDCD31 , MVDαSMA , and VMI were unchanged after sunitinib treatment. Median Ktrans increased with increasing MVDCD31 and decreased with increasing HFPim , and the correlations were similar for treated and untreated BXPC-3 and Panc-1 tumors. These observations suggest that sunitinib may induce significant changes in the microenvironment of PDACs, and furthermore, that Ktrans may be an adequate measure of tumor vascular density and hypoxia in untreated as well as sunitinib-treated PDACs., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2018
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42. Integrins as therapeutic targets in the organ-specific metastasis of human malignant melanoma.
- Author
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Huang R and Rofstad EK
- Subjects
- Humans, Neoplasm Metastasis, Integrins therapeutic use, Melanoma therapy
- Abstract
Integrins are a large family of adhesion molecules that mediate cell-cell and cell-extracellular matrix interactions. Among the 24 integrin isoforms, many have been found to be associated with tumor angiogenesis, tumor cell migration and proliferation, and metastasis. Integrins, especially αvβ3, αvβ5 and α5β1, participate in mediating tumor angiogenesis by interacting with the vascular endothelial growth factor and angiopoietin-Tie signaling pathways. Melanoma patients have a poor prognosis when the primary tumor has generated distant metastases, and the melanoma metastatic site is an independent predictor of the survival of these patients. Different integrins on the melanoma cell surface preferentially direct circulating melanoma cells to different organs and promote the development of metastases at specific organ sites. For instance, melanoma cells expressing integrin β3 tend to metastasize to the lungs, whereas those expressing integrin β1 preferentially generate lymph node metastases. Moreover, tumor cell-derived exosomes which contain different integrins may prepare a pre-metastatic niche in specific organs and promote organ-specific metastases. Because of the important role that integrins play in tumor angiogenesis and metastasis, they have become promising targets for the treatment of advanced cancer. In this paper, we review the integrin isoforms responsible for angiogenesis and organ-specific metastasis in malignant melanoma and the inhibitors that have been considered for the future treatment of metastatic disease.
- Published
- 2018
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43. Increasing aggressiveness of patient-derived xenograft models of cervix carcinoma during serial transplantation.
- Author
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Wegner CS, Hauge A, Andersen LMK, Huang R, Simonsen TG, Gaustad JV, and Rofstad EK
- Abstract
Four patient-derived xenograft (PDX) models (BK-12, ED-15, HL-16, LA-19) of carcinoma of the uterine cervix have been developed in our laboratory, and their stability during serial transplantation in vivo was investigated in this study. Two frozen cell stocks were established, one from xenografted tumors in passage 2 (early generation) and the other from xenografted tumors transplanted serially in mice for approximately two years (late generation), and the biology of late generation tumors was compared with that of early generation tumors. Late generation tumors showed higher incidence of lymph node metastases than early generation tumors in three models (ED-15, HL-16, LA-19), and the increased metastatic propensity was associated with increased tumor growth rate, increased microvascular density, and increased expression of angiogenesis-related and cancer stem cell-related genes. Furthermore, late generation tumors showed decreased fraction of pimonidazole-positive tissue ( i.e. , decreased fraction of hypoxic tissue) in two models (HL-16, LA-19) and decreased fraction of collagen-I-positive tissue (i.e., less extensive extracellular matrix) in two models (ED-15, HL-16). This study showed that serially transplanted PDXs may not necessarily mirror the donor patients' diseases, and consequently, proper use of serially transplanted PDX models in translational cancer research requires careful molecular monitoring of the models., Competing Interests: CONFLICTS OF INTEREST The authors have no potential conflicts of interest to disclose.
- Published
- 2018
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44. Dynamic contrast-enhanced MRI of the microenvironment of pancreatic adenocarcinoma xenografts.
- Author
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Wegner CS, Hauge A, Gaustad JV, Andersen LMK, Simonsen TG, Galappathi K, and Rofstad EK
- Subjects
- Animals, Carcinoma, Pancreatic Ductal blood supply, Carcinoma, Pancreatic Ductal metabolism, Carcinoma, Pancreatic Ductal pathology, Contrast Media, Extracellular Fluid, Female, Heterocyclic Compounds, Heterografts blood supply, Heterografts metabolism, Heterografts pathology, Humans, Magnetic Resonance Imaging, Mice, Mice, Inbred BALB C, Mice, Nude, Neoplasm Transplantation, Nitroimidazoles metabolism, Organometallic Compounds, Pancreatic Neoplasms blood supply, Pancreatic Neoplasms metabolism, Pancreatic Neoplasms pathology, Platelet Endothelial Cell Adhesion Molecule-1 metabolism, Pressure, Carcinoma, Pancreatic Ductal diagnostic imaging, Heterografts diagnostic imaging, Hypoxia metabolism, Microvessels pathology, Pancreatic Neoplasms diagnostic imaging, Tumor Microenvironment
- Abstract
Background: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with poor outcome. Resistance to treatment is associated with impaired vascularity, extensive hypoxia, and interstitial hypertension. In this study, the potential of dynamic contrast-enhanced (DCE)-MRI as a method for assessing the microvascular density (MVD), the fraction of hypoxic tissue, and the interstitial fluid pressure (IFP) of PDACs was investigated., Material and Methods: Intramuscular BxPC-3, Capan-2, MIAPaCa-2, and Panc-1 PDAC xenografts were used as preclinical models of human PDACs. DCE-MRI with Gd-DOTA as contrast agent was conducted with a 7.05-T scanner, and the DCE-MRI series were analyzed voxelwise by using the Tofts pharmacokinetic model. Tumor MVD and hypoxia were measured in histological preparations by using pimonidazole as a hypoxia marker and CD31 as a marker of endothelial cells. IFP was measured with a Millar catheter., Results: K
trans (the volume transfer constant of Gd-DOTA) increased with increasing MVD and decreased with increasing hypoxic fraction, but was not associated with IFP. Any association between ve (the fractional distribution volume of Gd-DOTA) and MVD, hypoxic fraction, or IFP could not be detected., Conclusions: This study shows that DCE-MRI is a useful modality for assessing important features of the microenvironment of PDAC xenografts and thus provides the basis for future preclinical and clinical DCE-MRI investigations of PDAC.- Published
- 2017
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45. Vascular abnormalities and development of hypoxia in microscopic melanoma xenografts.
- Author
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Gaustad JV, Simonsen TG, Andersen LMK, and Rofstad EK
- Subjects
- Animals, Cell Hypoxia, Cell Line, Tumor, Female, Humans, Melanoma blood supply, Mice, Mice, Inbred BALB C, Mice, Nude, Neovascularization, Pathologic metabolism, Melanoma metabolism, Melanoma pathology, Neoplasm Transplantation, Neovascularization, Pathologic pathology, Oxygen metabolism, Transplantation, Heterologous
- Abstract
Background: Studies investigating the oxygenation status and the development of hypoxia in microscopic tumors are sparse. The purpose of this study was to measure the extent of hypoxia in microscopic melanoma xenografts and to search for possible mechanisms leading to the development of hypoxia in these tumors., Methods: A-07, D-12, R-18, and U-25 human melanoma xenografts grown in dorsal window chambers or as flank tumors were used as preclinical tumor models. Morphologic and functional parameters of vascular networks were assessed with intravital microscopy, and the expression of angiogenesis-related genes was assessed with quantitative PCR. Microvessels, pericytes, and the extent of hypoxia were assessed by immunohistochemistry in microscopic tumors by using CD31, αSMA, and pimonidazole as markers, and the extent of radiobiological hypoxia was assessed in macroscopic flank tumors., Results: Macroscopic R-18 and U-25 tumors showed extensive hypoxia, whereas macroscopic A-07 and D-12 tumors were less hypoxic. R-18 and U-25 tumors developed hypoxic regions before they reached a size of 2-3 mm in diameter, whereas A-07 and D-12 tumors of similar size did not show hypoxic regions. The development of hypoxic regions was not caused by low vessel density, but was rather a result of inadequate vascular function. Inadequate vascular function was not caused by low vessel diameters or long vessel segments, but was associated with poor vascular pericyte coverage. Poor pericyte coverage was associated with the expression of eight angiogenesis-related genes., Conclusions: Two of the four investigated melanoma models developed hypoxic regions in microscopic tumors, and the development of hypoxia was associated with poor vascular pericyte coverage and inadequate vascular function.
- Published
- 2017
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46. Diffusion-weighted MRI-derived ADC values reflect collagen I content in PDX models of uterine cervical cancer.
- Author
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Hauge A, Wegner CS, Gaustad JV, Simonsen TG, Andersen LMK, and Rofstad EK
- Abstract
Apparent diffusion coefficient (ADC) values derived from diffusion-weighted magnetic resonance imaging (DW-MRI) are known to reflect the cellular environment of biological tissues. However, emerging evidence accentuates the influence of stromal elements on ADC values. The current study sought to elucidate whether a correlation exists between ADC and the fraction of collagen I-positive tissue across different tumor models of uterine cervical cancer. Early and late generation tumors of four patient-derived xenograft (PDX) models of squamous cell carcinoma (BK-12, ED-15, HL-16, and LA-19) were included. DW-MRI was performed with diffusion encoding constants ( b ) of 200, 400, 700, and 1000 s/mm
2 and diffusion gradient sensitization in three orthogonal directions. The fraction of collagen I-positive connective tissue was determined by immunohistochemistry. Mono-exponential decay curves, from which the ADC value of tumor voxels was calculated, yielded good fits to the diffusion data. A significant inverse correlation was detected between median tumor ADC and collagen I fraction across the four PDX models, indicating that collagen fibers in the extracellular space have the ability to inhibit the movement of water molecules in these xenografts. The results encourage further exploration of DW-MRI as a non-invasive imaging method for characterizing the stromal microenvironment of tumors., Competing Interests: CONFLICTS OF INTEREST The authors have no conflicts of interest to declare.- Published
- 2017
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47. DCE-MRI of patient-derived xenograft models of uterine cervix carcinoma: associations with parameters of the tumor microenvironment.
- Author
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Hauge A, Wegner CS, Gaustad JV, Simonsen TG, Andersen LMK, and Rofstad EK
- Subjects
- Animals, Female, Heterocyclic Compounds chemistry, Humans, Mice, Inbred BALB C, Mice, Nude, Microvessels diagnostic imaging, Microvessels pathology, Organometallic Compounds chemistry, Uterine Cervical Neoplasms blood supply, Contrast Media chemistry, Magnetic Resonance Imaging, Tumor Microenvironment, Uterine Cervical Neoplasms diagnostic imaging, Uterine Cervical Neoplasms pathology
- Abstract
Background: Abnormalities in the tumor microenvironment are associated with resistance to treatment, aggressive growth, and poor clinical outcome in patients with advanced cervical cancer. The potential of dynamic contrast-enhanced (DCE) MRI to assess the microvascular density (MVD), interstitial fluid pressure (IFP), and hypoxic fraction of patient-derived cervical cancer xenografts was investigated in the present study., Methods: Four patient-derived xenograft (PDX) models of squamous cell carcinoma of the uterine cervix (BK-12, ED-15, HL-16, and LA-19) were subjected to Gd-DOTA-based DCE-MRI using a 7.05 T preclinical scanner. Parametric images of the volume transfer constant (K
trans ) and the fractional distribution volume (ve ) of the contrast agent were produced by pharmacokinetic analyses utilizing the standard Tofts model. Whole tumor median values of the DCE-MRI parameters were compared with MVD and the fraction of hypoxic tumor tissue, as determined histologically, and IFP, as measured with a Millar catheter., Results: Both on the PDX model level and the single tumor level, a significant inverse correlation was found between Ktrans and hypoxic fraction. The extent of hypoxia was also associated with the fraction of voxels with unphysiological ve values (ve > 1.0). None of the DCE-MRI parameters were related to MVD or IFP., Conclusions: DCE-MRI may provide valuable information on the hypoxic fraction of squamous cell carcinoma of the uterine cervix, and thereby facilitate individualized patient management.- Published
- 2017
- Full Text
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48. Metastatic pathway and the microvascular and physicochemical microenvironments of human melanoma xenografts.
- Author
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Huang R, Andersen LMK, and Rofstad EK
- Subjects
- Animals, Female, Gene Expression Regulation, Neoplastic, Humans, Melanoma genetics, Mice, Inbred BALB C, Neovascularization, Pathologic genetics, Pressure, Skin Neoplasms genetics, Melanoma, Cutaneous Malignant, Lymphatic Metastasis pathology, Melanoma blood supply, Melanoma pathology, Microvessels pathology, Skin Neoplasms blood supply, Skin Neoplasms pathology, Tumor Microenvironment, Xenograft Model Antitumor Assays
- Abstract
Background: Malignant melanoma of the skin can metastasize through blood vessels and lymphatics. The primary tumor develops a vascular microenvironment characterized by abnormal blood vessels and lymphatics and a physicochemical microenvironment characterized by low oxygen tension, regions with hypoxic tissue, and high interstitial fluid pressure (IFP). This study aimed at identifying relationships between the metastatic route of melanomas and characteristic features of the microvascular and physicochemical microenvironments of the primary tumor., Methods: Two patient-derived xenograft (PDX) models (E-13, N-15) and four cell line-derived xenografts (CDX) models (C-10, D-12, R-18, T-22) of human melanoma were included in the study. Tumors were transplanted to an orthotopic site in BALB/c-nu/nu mice, and when the tumors had grown to a volume of 500-600 mm
3 , the IFP of the primary tumor was measured and the hypoxia marker pimonidazole was administered before the host mouse was euthanized. The primary tumor, lungs, and six pairs of lymph nodes were evaluated by examining hematoxylin/eosin-stained and immunostained histological preparations. The expression of angiogenesis-related genes was assessed by quantitative PCR., Results: C-10, D-12, and E-13 tumors disseminated primarily by the hematogenous route and developed pulmonary metastases. These tumors showed high angiogenic activity and high expression of the F3 gene as well as ANGPT2 and TIE1, genes encoding proteins of the angiopoietin-tie system. N-15, R-18, and T-22 tumors disseminated mainly by the lymphogenous route and developed metastases in draining lymph nodes. These tumors had highly elevated IFP and showed high expression of NRP2, a gene encoding neuropilin-2., Conclusion: The primary metastatic route of orthotopic human melanoma xenografts and the development of lung and lymph node metastases are influenced significantly by the microvascular and physicochemical microenvironments of the primary tumor.- Published
- 2017
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49. Lymph node metastasis and the physicochemical micro-environment of pancreatic ductal adenocarcinoma xenografts.
- Author
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Andersen LMK, Wegner CS, Simonsen TG, Huang R, Gaustad JV, Hauge A, Galappathi K, and Rofstad EK
- Subjects
- Animals, Biopsy, Cell Line, Tumor, Disease Models, Animal, Female, Heterografts, Humans, Hypoxia metabolism, Lymphatic Metastasis, Mice, Neovascularization, Pathologic metabolism, Pancreatic Neoplasms, Carcinoma, Pancreatic Ductal metabolism, Carcinoma, Pancreatic Ductal pathology, Pancreatic Neoplasms metabolism, Pancreatic Neoplasms pathology, Tumor Microenvironment
- Abstract
Pancreatic ductal adenocarcinoma (PDAC) patients develop lymph node metastases early and have a particularly poor prognosis. The poor prognosis has been shown to be associated with the physicochemical microenvironment of the tumor tissue, which is characterized by desmoplasia, abnormal microvasculature, extensive hypoxia, and highly elevated interstitial fluid pressure (IFP). In this study, we searched for associations between lymph node metastasis and features of the physicochemical microenvironment in an attempt to identify mechanisms leading to metastatic dissemination and growth. BxPC-3 and Capan-2 PDAC xenografts were used as preclinical models of human PDAC. In both models, lymph node metastasis was associated with high IFP rather than high fraction of hypoxic tissue or high microvascular density. Seven angiogenesis-related genes associated with high IFP-associated lymph node metastasis were detected by quantitative PCR in each of the models, and these genes were all up-regulated in high IFP/highly metastatic tumors. Three genes were mutual for the BxPC-3 and Capan-2 models: transforming growth factor beta, angiogenin, and insulin-like growth factor 1. Further comprehensive studies are needed to determine whether there is a causal relationship between the up-regulation of these genes and high IFP and/or high propensity for lymph node metastasis in PDAC.
- Published
- 2017
- Full Text
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50. Antiangiogenic agents targeting different angiogenic pathways have opposite effects on tumor hypoxia in R-18 human melanoma xenografts.
- Author
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Gaustad JV, Simonsen TG, Andersen LMK, and Rofstad EK
- Subjects
- Angiogenesis Inhibitors therapeutic use, Animals, Cell Line, Tumor, Female, Humans, Indoles pharmacology, Indoles therapeutic use, Melanoma blood supply, Melanoma metabolism, Mice, Neovascularization, Pathologic metabolism, Peptide Fragments pharmacology, Peptide Fragments therapeutic use, Properdin pharmacology, Properdin therapeutic use, Pyrroles pharmacology, Pyrroles therapeutic use, Receptors, Vascular Endothelial Growth Factor agonists, Sunitinib, Xenograft Model Antitumor Assays, Angiogenesis Inhibitors pharmacology, Melanoma drug therapy, Neovascularization, Pathologic drug therapy, Receptors, Vascular Endothelial Growth Factor antagonists & inhibitors, Tumor Hypoxia drug effects
- Abstract
Background: Studies comparing the effect of antiangiogenic agents targeting different angiogenic pathways are sparse. The purpose of this study was to compare the effect of properdistatin and sunitinib treatment in a preclinical model of malignant melanoma. Properdistatin is a small peptide derived from the thrombospondin-1 domain of the plasma protein properdin, and sunitinib is a tyrosine kinase inhibitor targeting several receptors including the vascular endothelial growth factor receptors., Methods: R-18 human melanoma xenografts growing in dorsal window chambers were treated with properdistatin, sunitinib, or vehicle. Parameters describing the morphology of tumor vasculature were assessed from high-resolution transillumination images, and BST (blood supply time; the time needed for arterial blood to flow from the main supplying artery to downstream microvessels) was assessed from first-pass imaging movies recorded after a bolus of fluorescence-labeled dextran had been administered intravenously. Tumor hypoxia was assessed from immunohistochemical preparations of the imaged tissue by using pimonidazole as a hypoxia marker., Results: Properdistatin treatment selectively removed small-diameter vessels and reduced BST, whereas sunitinib treatment reduced the density of small- and large-diameter vessel similarly and did not change BST. These observations imply that properdistatin treatment reduced geometric resistance to blood flow and improved vascular function, whereas sunitinib treatment did not affect vascular function. Accordingly, sunitinib-treated tumors showed higher hypoxic fractions than properdistatin-treated tumors., Conclusions: Properdistatin and sunitinib both inhibited angiogenesis, but had distinctly different effects on vascular morphology, vascular function, and extent of hypoxia in R-18 human melanoma xenografts.
- Published
- 2017
- Full Text
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