Dataset Information

The Effect of Sunitinib Treatment in Human Melanoma Xenografts: Associations with Angiogenic Profiles.

ABSTRACT: The effect of antiangiogenic agents targeting the vascular endothelial growth factor A (VEGF-A) pathway has been reported to vary substantially in preclinical studies. The purpose of this study was to investigate the effect of sunitinib treatment on tumor vasculature and oxygenation in melanoma xenografts with different angiogenic profiles. A-07, U-25, D-12, or R-18 melanoma xenografts were grown in dorsal window chambers and given daily treatments of sunitinib (40 mg/kg) or vehicle. Morphologic parameters of tumor vascular networks were assessed from high-resolution transillumination images, and tumor blood supply times (BSTs) were assessed from first-pass imaging movies. Tumor hypoxia was assessed with immunohistochemistry by using pimonidazole as hypoxia marker, and the gene expression and the protein secretion rate of angiogenic factors were assessed by quantitative polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. The melanoma lines differed substantially in the expression of VEGF-A, VEGF-C, and platelet-derived growth factor A. Sunitinib treatment reduced vessel densities and induced hypoxia in all melanoma lines, and the magnitude of the effect was associated with the gene expression and protein secretion rate of VEGF-A. Sunitinib treatment also increased vessel segment lengths, reduced the number of small-diameter vessels, and inhibited growth-induced increases in the diameter of surviving vessels but did not change BST. In conclusion, sunitinib treatment did not improve vascular function but reduced vessel density and induced hypoxia in human melanoma xenografts. The magnitude of the treatment-induced effect was associated with the VEGF-A expression of the melanoma lines.

SUBMITTER: Gaustad JV

PROVIDER: S-EPMC5293738 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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The Effect of Sunitinib Treatment in Human Melanoma Xenografts: Associations with Angiogenic Profiles.

Gaustad Jon-Vidar JV Simonsen Trude G TG Andersen Lise Mari K LM Rofstad Einar K EK

Translational oncology 20170203 2

The effect of antiangiogenic agents targeting the vascular endothelial growth factor A (VEGF-A) pathway has been reported to vary substantially in preclinical studies. The purpose of this study was to investigate the effect of sunitinib treatment on tumor vasculature and oxygenation in melanoma xenografts with different angiogenic profiles. A-07, U-25, D-12, or R-18 melanoma xenografts were grown in dorsal window chambers and given daily treatments of sunitinib (40 mg/kg) or vehicle. Morphologic ...[more]

PMID: 28167241

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Project description:The spatial heterogeneity of the oxygen tension (pO(2)) in human and experimental tumours has been studied extensively, whereas studies of the temporal heterogeneity in pO(2) are sparse. In the work reported here, pO(2) was measured continuously over periods of at least 60 min in A-07 human melanoma xenografts by using the OxyLite fibre-optic oxygen-sensing device. The main purpose of the work was to establish the usefulness of the OxyLite system in measuring the temporal heterogeneity in pO(2) in tissues and to characterise the fluctuations in tissue pO(2) in A-07 tumours. The OxyLite device was found to be suitable for studies of the temporal heterogeneity in pO(2) in tumours. However, potential pitfalls were identified, and reliable pO(2) measurements require that precautions are taken to avoid these pitfalls, that is, erroneous pO(2) readings caused by tissue trauma induced by the probe, probe movements induced by reflex actions of the host mouse and occasional probe drift. Significant fluctuations in pO(2) were detected in the majority of the 70 tumour regions subjected to measurement. The fluctuations in different regions of the same tumour were in general temporally independent, implying that they were caused primarily by redistribution of the tumour perfusion rather than fluctuations in global perfusion. Fourier analysis of the pO(2) traces showed that the pO(2) usually fluctuated at frequencies lower than 1.5-2.0 mHz, corresponding to less than 0.1 cycle min(-1). Haemodynamic effects may cause pO(2) fluctuations in this frequency range, and hence, the redistribution of the perfusion could have been caused by morphological abnormalities of the tumour microvasculature. Moreover, acute hypoxia, that is, pO(2) fluctuations around 10 or 5 mmHg, was detected in 20 of 70 regions, that is, 29% (10 mmHg), or 27 of 70 regions, that is, 39% (5 mmHg). The median fraction of the time these regions were acutely hypoxic was 73% (10 mmHg) or 53% (5 mmHg). Consequently, if A-07 tumours are adequate models of tumours in man, acute hypoxia may be a commonly occurring phenomenon in neoplastic tissues, and hence, acute hypoxia is likely to cause resistance to radiation therapy and promote tumour aggressiveness.

Project description:BackgroundMalignant 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.MethodsTwo 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 mm3, 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.ResultsC-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.ConclusionThe 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.

Dataset Information

The Effect of Sunitinib Treatment in Human Melanoma Xenografts: Associations with Angiogenic Profiles.

Publications

The Effect of Sunitinib Treatment in Human Melanoma Xenografts: Associations with Angiogenic Profiles.

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