Vascular abnormalities associated with acute hypoxia in human melanoma xenografts.

BACKGROUND AND PURPOSE The fraction of hypoxic cells has been shown to differ substantially among human tumors of the same histological type. In this study, a window chamber model was used to identify possible mechanisms leading to the development of highly different hypoxic fractions in A-07 and R-18 human melanoma xenografts. MATERIALS AND METHODS Chronic and acute hypoxia was assessed in intradermal tumors using an immunohistochemical and a radiobiological assay. Functional and morphological parameters of the vascular networks of tumors growing in dorsal window chambers were assessed with intravital microscopy. RESULTS R-18 tumors showed significantly higher hypoxic fractions than A-07 tumors, and the difference was mostly due to acute hypoxia. Compared to A-07 tumors, R-18 tumors showed low vascular densities, low vessel diameters, long vessel segments, low blood flow velocities, frequent fluctuations in blood flow, and a high fraction of narrow vessels with absent or very low and varying flux of red blood cells. CONCLUSION The high fraction of acute hypoxia in R-18 tumors was a consequence of frequent fluctuations in blood flow and red blood cell flux combined with low vascular density. The fluctuations were most likely caused by high geometric resistance to blood flow in the tumor microvasculature.

[1]  P Lambin,et al.  Hypoxia as a target for combined modality treatments. , 2002, European journal of cancer.

[2]  A. Giaccia,et al.  The unique physiology of solid tumors: opportunities (and problems) for cancer therapy. , 1998, Cancer research.

[3]  A. Fyles,et al.  Oxygenation predicts radiation response and survival in patients with cervix cancer. , 1998, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[4]  D. Brizel,et al.  Prognostic value of tumor oxygenation in 397 head and neck tumors after primary radiation therapy. An international multi-center study. , 2005, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[5]  R K Jain,et al.  Determinants of tumor blood flow: a review. , 1988, Cancer research.

[6]  M. Varia,et al.  Proliferation and hypoxia in human squamous cell carcinoma of the cervix: first report of combined immunohistochemical assays. , 1997, International journal of radiation oncology, biology, physics.

[7]  Adrian L. Harris,et al.  Hypoxia — a key regulatory factor in tumour growth , 2002, Nature Reviews Cancer.

[8]  R. Hill,et al.  Acute (cyclic) hypoxia enhances spontaneous metastasis of KHT murine tumors. , 2001, Cancer research.

[9]  M. Dewhirst,et al.  Fluctuations in red cell flux in tumor microvessels can lead to transient hypoxia and reoxygenation in tumor parenchyma. , 1996, Cancer research.

[10]  E. Rofstad,et al.  Tumor vascularity assessed by magnetic resonance imaging and intravital microscopy imaging. , 2008, Neoplasia.

[11]  Timothy W Secomb,et al.  Effect of longitudinal oxygen gradients on effectiveness of manipulation of tumor oxygenation. , 2003, Cancer research.

[12]  E. Rofstad,et al.  pO₂ fluctuation pattern and cycling hypoxia in human cervical carcinoma and melanoma xenografts. , 2012, International journal of radiation oncology, biology, physics.

[13]  P. Vaupel,et al.  Hypoxia in cancer: significance and impact on clinical outcome , 2007, Cancer and Metastasis Reviews.

[14]  E. Rofstad,et al.  Assessment of hypoxia and radiation response in intramuscular experimental tumors by dynamic contrast-enhanced magnetic resonance imaging. , 2012, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[15]  D. Thrall,et al.  Longevity of pimonidazole adducts in spontaneous canine tumors as an estimate of hypoxic cell lifetime. , 1997, Radiation research.

[16]  E. Rofstad,et al.  Differentiation between hypoxic and non-hypoxic experimental tumors by dynamic contrast-enhanced magnetic resonance imaging. , 2011, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[17]  E. Rofstad,et al.  Growth Characteristics of Human Melanoma Multicellular Spheroids In Liquid‐Overlay Culture: Comparisons With the Parent Tumour Xenografts , 1986, Cell and tissue kinetics.

[18]  E. Rofstad,et al.  Radiobiological and immunohistochemical assessment of hypoxia in human melanoma xenografts: acute and chronic hypoxia in individual tumours. , 1999, International journal of radiation biology.

[19]  M. Dewhirst,et al.  Microvascular studies on the origins of perfusion-limited hypoxia. , 1996, The British journal of cancer. Supplement.

[20]  Jens Overgaard,et al.  Measurements of hypoxia using pimonidazole and polarographic oxygen-sensitive electrodes in human cervix carcinomas. , 2003, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[21]  E. Rofstad,et al.  Blood supply in melanoma xenografts is governed by the morphology of the supplying arteries. , 2009, Neoplasia.

[22]  K. Bennewith,et al.  Orally administered pimonidazole to label hypoxic tumor cells. , 2002, Cancer research.

[23]  Janice M. Y. Brown,et al.  The hypoxic cell: a target for selective cancer therapy--eighteenth Bruce F. Cain Memorial Award lecture. , 1999, Cancer research.

[24]  E. Rofstad,et al.  Fluctuating and Diffusion-Limited Hypoxia in Hypoxia-Induced Metastasis , 2007, Clinical Cancer Research.

[25]  S M Evans,et al.  Quantification of longitudinal tissue pO2 gradients in window chamber tumours: impact on tumour hypoxia , 1999, British Journal of Cancer.

[26]  Johan Bussink,et al.  Dynamics of Tumor Hypoxia Measured with Bioreductive Hypoxic Cell Markers , 2007, Radiation research.

[27]  E. Rofstad,et al.  Orthotopic human melanoma xenograft model systems for studies of tumour angiogenesis, pathophysiology, treatment sensitivity and metastatic pattern. , 1994, British Journal of Cancer.

[28]  K. Bennewith,et al.  Quantifying Transient Hypoxia in Human Tumor Xenografts by Flow Cytometry , 2004, Cancer Research.

[29]  M. Dewhirst.  Relationships between Cycling Hypoxia, HIF-1, Angiogenesis and Oxidative Stress , 2009, Radiation research.

[30]  E. Rofstad,et al.  Radiocurability is associated with interstitial fluid pressure in human tumor xenografts. , 2009, Neoplasia.

[31]  E. Rofstad,et al.  Dynamic contrast‐enhanced‐MRI of tumor hypoxia , 2012, Magnetic resonance in medicine.

[32]  E. Rofstad,et al.  Tumor-line specific pO(2) fluctuations in human melanoma xenografts. , 2004, International journal of radiation oncology, biology, physics.

[33]  M. Dewhirst,et al.  Concepts of oxygen transport at the microcirculatory level. , 1998, Seminars in radiation oncology.

[34]  G. Arteel,et al.  Comparisons among pimonidazole binding, oxygen electrode measurements, and radiation response in C3H mouse tumors. , 1999, Radiation research.

[35]  E. Rofstad,et al.  Assessment of tumor hypoxia and interstitial fluid pressure by gadomelitol-based dynamic contrast-enhanced magnetic resonance imaging. , 2011, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[36]  S. Rockwell,et al.  Hypoxic fractions of solid tumors: experimental techniques, methods of analysis, and a survey of existing data. , 1984, International journal of radiation oncology, biology, physics.