Sunitinib treatment does not improve blood supply but induces hypoxia in human melanoma xenografts

BMC Cancer

Einar K Rofstad¹  Marit N Leinaas¹  Trude G Simonsen¹  Jon-Vidar Gaustad¹ 

[1]Group of Radiation Biology and Tumor Physiology, Department of Radiation Biology, Institute for Cancer Research, Oslo University Hospital, Montebello, Oslo, N-0310, Norway

关键词: Tumor hypoxia;    Vascular normalization;    Intravital microscopy;    Sunitinib;    Antiangiogenic treatment;   

Others  :  1080220
DOI  :  10.1186/1471-2407-12-388

 received in 2012-06-07, accepted in 2012-08-31,  发布年份 2012

【 摘 要 】

Background

Antiangiogenic agents that disrupt the vascular endothelial growth factor pathway have been demonstrated to normalize tumor vasculature and improve tumor oxygenation in some studies and to induce hypoxia in others. The aim of this preclinical study was to investigate the effect of sunitinib treatment on the morphology and function of tumor vasculature and on tumor oxygenation.

Methods

A-07-GFP and R-18-GFP human melanoma xenografts grown in dorsal window chambers were used as preclinical tumor models. Morphologic parameters of tumor vascular networks were assessed from high-resolution transillumination images, and tumor blood supply time was assessed from first-pass imaging movies recorded after a bolus of 155 kDa tetramethylrhodamine isothiocyanate-labeled dextran had been administered intravenously. Tumor hypoxia was assessed from immunohistochemical preparations of the imaged tissue by use of pimonidazole as a hypoxia marker.

Results

Sunitinib treatment reduced vessel densities, increased vessel segment lengths, did not affect blood supply times, and increased hypoxic area fractions.

Conclusion

Sunitinib treatment did not improve vascular function but induced hypoxia in A-07-GFP and R-18-GFP tumors.

【 授权许可】

   
2012 Gaustad et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 1.

Figure 6.

Figure 7.

Figure 8.

Figure 9.

【 参考文献 】

• [1]Folkman J: What is the evidence that tumors are angiogenesis dependent? J Natl Cancer Inst 1990, 82:4-6.
• [2]Carmeliet P, Jain RK: Angiogenesis in cancer and other diseases. Nature 2000, 407:249-257.
• [3]Vaupel P, Kallinowski F, Okunieff P: Blood flow, oxygen and nutrient supply, and metabolic microenvironment of human tumors: a review. Cancer Res 1989, 49:6449-6465.
• [4]Brown JM, Giaccia AJ: The unique physiology of solid tumors: opportunities (and problems) for cancer therapy. Cancer Res 1998, 58:1408-1416.
• [5]Dewhirst MW, Ong ET, Braun RD, Smith B, Klitzman B, Evans SM, Wilson D: Quantification of longitudinal tissue pO2 gradients in window chamber tumours: impact on tumour hypoxia. Br J Cancer 1999, 79:1717-1722.
• [6]Baish JW, Gazit Y, Berk DA, Nozue M, Baxter LT, Jain RK: Role of tumor vascular architecture in nutrient and drug delivery: an invasion percolation-based network model. Microvasc Res 1996, 51:327-346.
• [7]Jain RK: Determinants of tumor blood flow: a review. Cancer Res 1988, 48:2641-2658.
• [8]Vaupel P: Tumor microenvironmental physiology and its implications for radiation oncology. Semin Radiat Oncol 2004, 14:198-206.
• [9]Rofstad EK: Microenvironment-induced cancer metastasis. Int J Radiat Biol 2000, 76:589-605.
• [10]Jia Y, Liu M, Huang W, Wang Z, He Y, Wu J, Ren S, Ju Y, Geng R, Li Z: Recombinant human endostatin endostar inhibits tumor growth and metastasis in a mouse xenograft model of colon cancer. Pathol Oncol Res 2012, 18:315-323.
• [11]Albini A, Brigati C, Ventura A, Lorusso G, Pinter M, Morini M, Mancino A, Sica A, Noonan DM: Angiostatin anti-angiogenesis requires IL-12: the innate immune system as a key target. J Transl Med 2009, 7:5. BioMed Central Full Text
• [12]Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, Baron A, Griffing S, Holmgren E, et al.: Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004, 350:2335-2342.
• [13]Winkler F, Kozin SV, Tong RT, Chae SS, Booth MF, Garkavtsev I, Xu L, Hicklin DJ, Fukumura D, di Tomaso E, et al.: Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: role of oxygenation, angiopoietin-1, and matrix metalloproteinases. Cancer Cell 2004, 6:553-563.
• [14]Czabanka M, Vinci M, Heppner F, Ullrich A, Vajkoczy P: Effects of sunitinib on tumor hemodynamics and delivery of chemotherapy. Int J Cancer 2009, 124:1293-1300.
• [15]Liu L, Cao Y, Chen C, Zhang X, McNabola A, Wilkie D, Wilhelm S, Lynch M, Carter C: Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5. Cancer Res 2006, 66:11851-11858.
• [16]Horsman MR, Siemann DW: Pathophysiologic effects of vascular-targeting agents and the implications for combination with conventional therapies. Cancer Res 2006, 66:11520-11539.
• [17]Jain RK: Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 2005, 307:58-62.
• [18]Tong RT, Boucher Y, Kozin SV, Winkler F, Hicklin DJ, Jain RK: Vascular normalization by vascular endothelial growth factor receptor 2 blockade induces a pressure gradient across the vasculature and improves drug penetration in tumors. Cancer Res 2004, 64:3731-3736.
• [19]Lee CG, Heijn M, di Tomaso E, Griffon-Etienne G, Ancukiewicz M, Koike C, Park KR, Ferrara N, Jain RK, Suit HD, et al.: Anti-Vascular endothelial growth factor treatment augments tumor radiation response under normoxic or hypoxic conditions. Cancer Res 2000, 60:5565-5570.
• [20]Eichhorn ME, Strieth S, Luedemann S, Kleespies A, Noth U, Passon A, Brix G, Jauch KW, Bruns CJ, Dellian M: Contrast enhanced MRI and intravital fluorescence microscopy indicate improved tumor microcirculation in highly vascularized melanomas upon short-term anti-VEGFR treatment. Cancer Biol Ther 2008, 7:1006-1013.
• [21]Cao Y, Sonveaux P, Liu S, Zhao Y, Mi J, Clary BM, Li CY, Kontos CD, Dewhirst MW: Systemic overexpression of angiopoietin-2 promotes tumor microvessel regression and inhibits angiogenesis and tumor growth. Cancer Res 2007, 67:3835-3844.
• [22]Dickson PV, Hamner JB, Sims TL, Fraga CH, Ng CY, Rajasekeran S, Hagedorn NL, McCarville MB, Stewart CF, Davidoff AM: Bevacizumab-induced transient remodeling of the vasculature in neuroblastoma xenografts results in improved delivery and efficacy of systemically administered chemotherapy. Clin Cancer Res 2007, 13:3942-3950.
• [23]Myers AL, Williams RF, Ng CY, Hartwich JE, Davidoff AM: Bevacizumab-induced tumor vessel remodeling in rhabdomyosarcoma xenografts increases the effectiveness of adjuvant ionizing radiation. J Pediatr Surg 2010, 45:1080-1085.
• [24]Carmeliet P, Jain RK: Principles and mechanisms of vessel normalization for cancer and other angiogenic diseases. Nat Rev Drug Discov 2011, 10:417-427.
• [25]Franco M, Man S, Chen L, Emmenegger U, Shaked Y, Cheung AM, Brown AS, Hicklin DJ, Foster FS, Kerbel RS: Targeted anti-vascular endothelial growth factor receptor-2 therapy leads to short-term and long-term impairment of vascular function and increase in tumor hypoxia. Cancer Res 2006, 66:3639-3648.
• [26]Fenton BM, Paoni SF: The addition of AG-013736 to fractionated radiation improves tumor response without functionally normalizing the tumor vasculature. Cancer Res 2007, 67:9921-9928.
• [27]Tailor TD, Hanna G, Yarmolenko PS, Dreher MR, Betof AS, Nixon AB, Spasojevic I, Dewhirst MW: Effect of pazopanib on tumor microenvironment and liposome delivery. Mol Cancer Ther 2010, 9:1798-1808.
• [28]Roskoski R: Sunitinib: a VEGF and PDGF receptor protein kinase and angiogenesis inhibitor. Biochem Biophys Res Commun 2007, 356:323-328.
• [29]Demetri GD, van Oosterom AT, Garrett CR, Blackstein ME, Shah MH, Verweij J, McArthur G, Judson IR, Heinrich MC, Morgan JA, et al.: Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet 2006, 368:1329-1338.
• [30]Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Oudard S, Negrier S, Szczylik C, Pili R, Bjarnason GA, et al.: Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol 2009, 27:3584-3590.
• [31]Rofstad EK: Orthotopic human melanoma xenograft model systems for studies of tumour angiogenesis, pathophysiology, treatment sensitivity and metastatic pattern. Br J Cancer 1994, 70:804-812.
• [32]Rofstad EK, Wahl A, Davies CL, Brustad T: Growth characteristics of human melanoma multicellular spheroids in liquid-overlay culture: comparisons with the parent tumour xenografts. Cell Tissue Kinet 1986, 19:205-216.
• [33]Brurberg KG, Gaustad JV, Mollatt CS, Rofstad EK: Temporal heterogeneity in blood supply in human tumor xenografts. Neoplasia 2008, 10:727-735.
• [34]Gaustad JV, Brurberg KG, Simonsen TG, Mollatt CS, Rofstad EK: Tumor vascularity assessed by magnetic resonance imaging and intravital microscopy imaging. Neoplasia 2008, 10:354-362.
• [35]Øye KS, Gulati G, Graff BA, Gaustad JV, Brurberg KG, Rofstad EK: A novel method for mapping the heterogeneity in blood supply to normal and malignant tissues in the mouse dorsal window chamber. Microvasc Res 2008, 75:179-187.
• [36]Rofstad EK, Måseide K: Radiobiological and immunohistochemical assessment of hypoxia in human melanoma xenografts: acute and chronic hypoxia in individual tumours. Int J Radiat Biol 1999, 75:1377-1393.
• [37]Vestvik IK, Egeland TA, Gaustad JV, Mathiesen B, Rofstad EK: Assessment of microvascular density, extracellular volume fraction, and radiobiological hypoxia in human melanoma xenografts by dynamic contrast-enhanced MRI. J Magn Reson Imaging 2007, 26:1033-1042.
• [38]Mendel DB, Laird AD, Xin X, Louie SG, Christensen JG, Li G, Schreck RE, Abrams TJ, Ngai TJ, Lee LB, et al.: In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship. Clin Cancer Res 2003, 9:327-337.
• [39]Gaustad JV, Simonsen TG, Brurberg KG, Huuse EM, Rofstad EK: Blood supply in melanoma xenografts is governed by the morphology of the supplying arteries. Neoplasia 2009, 11:277-285.
• [40]Rofstad EK, Halsør EF: Vascular endothelial growth factor, interleukin 8, platelet-derived endothelial cell growth factor, and basic fibroblast growth factor promote angiogenesis and metastasis in human melanoma xenografts. Cancer Res 2000, 60:4932-4938.
• [41]Morgan B, Horsfield MA, Steward WP: The role of imaging in the clinical development of antiangiogenic agents. Hematol Oncol Clin North Am 2004, 18:1183-1206. x
• [42]Sulkes A: Novel multitargeted anticancer oral therapies: sunitinib and sorafenib as a paradigm. Isr Med Assoc J 2010, 12:628-632.