DW-MRI in assessment of the hypoxic fraction, interstitial fluid pressure, and metastatic propensity of melanoma xenografts

BMC Cancer

Tord Hompland¹  Christine Ellingsen¹  Kanthi Galappathi¹  Einar K Rofstad¹ 

[1] Group of Radiation Biology and Tumor Physiology, Department of Radiation Biology, Institute for Cancer Research, Oslo University Hospital, Nydalen, Box 4953, Oslo N-0424, Norway

关键词: Cell density;    Metastasis;    Interstitial fluid pressure;    Hypoxia;    DW-MRI;   

Others  :  859065
DOI  :  10.1186/1471-2407-14-92

 received in 2013-09-30, accepted in 2014-02-12,  发布年份 2014

【 摘 要 】

Background

Cancer patients with primary tumors showing extensive hypoxia and highly elevated interstitial fluid pressure (IFP) have poor prognosis. The potential of diffusion-weighted magnetic resonance imaging (DW-MRI) in assessing the hypoxic fraction, IFP, and metastatic propensity of tumors was investigated in this study.

Methods

A-07 and R-18 melanoma xenografts were used as general models of human cancer. DW-MRI was performed at 1.5 T, and maps of the apparent diffusion coefficient (ADC) were produced with in-house-made software developed in Matlab. Pimonidazole was used as a hypoxia marker. Tumor cell density and hypoxic fraction were assessed by quantitative analysis of histological sections. IFP was measured with a Millar catheter. Metastatic propensity was determined by examining tumor-bearing mice for pulmonary micrometastases post mortem.

Results

ADC decreased with increasing tumor cell density, independent of whether the A-07 and R-18 data were analyzed separately or together. In the A-07 line, ADC decreased with increasing hypoxic fraction and increasing IFP and was lower in metastatic than in nonmetastatic tumors, and in the R-18 line, ADC decreased with increasing hypoxic fraction. There was a strong inverse correlation between ADC and hypoxic fraction as well as between ADC and IFP across the two tumor lines, primarily because low ADC as well as high hypoxic fraction and high IFP were associated with high cell density.

Conclusion

Low ADC is a potentially useful biomarker of poor prognosis in cancer, since low ADC is mainly a consequence of high cell density, and high cell density may lead to increased hypoxia and interstitial hypertension and, therefore, increased microenvironment-associated metastasis.

【 授权许可】

   
2014 Hompland et al.; licensee BioMed Central Ltd.

【 图 表 】

【 参考文献 】

• [1]Padhani AR: Diffusion magnetic resonance imaging in cancer patient management. Semin Radiat Oncol 2011, 21:119-140.
• [2]Yankeelov TE, Arlinghaus LR, Li X, Gore JC: The role of magnetic resonance imaging biomarkers in clinical trials of treatment response in cancer. Semin Oncol 2011, 38:16-25.
• [3]Bonekamp S, Corona-Villalobos CP, Kamel IR: Oncologic applications of diffusion-weighted MRI in the body. J Magn Reson Imaging 2012, 35:257-279.
• [4]Li SP, Padhani AR: Tumor response assessments with diffusion and perfusion MRI. J Magn Reson Imaging 2012, 35:745-763.
• [5]Liu Y, Bai R, Sun H, Liu H, Zhao X, Li Y: Diffusion-weighted imaging in predicting and monitoring the response of uterine cervical cancer to combined chemoradiation. Clin Radiol 2009, 64:1067-1074.
• [6]Razek AA, Gaballa G, Denewer A, Nada N: Invasive ductal carcinoma: correlation of apparent diffusion coefficient value with pathological prognostic factors. NMR Biomed 2010, 23:619-623.
• [7]Turkbey B, Shah VP, Pang Y, Bernardo M, Xu S, Kruecker J, Locklin J, Baccala AA, Rastinehad AR, Merino MJ, Shih JH, Wood BJ, Pinto PA, Choyke PL: Is apparent diffusion coefficient associated with clinical risk scores for prostate cancers that are visible on 3-T MR images? Radiology 2011, 258:488-495.
• [8]Roth Y, Tichler T, Kostenig G, Ruiz-Cabello J, Maier SE, Cohen JS, Orenstein A, Mardor Y: High-b-value diffusion-weighted MR imaging for pretreatment prediction and early monitoring of tumor response to therapy in mice. Radiology 2004, 232:685-692.
• [9]Sun YS, Zhang XP, Tang L, Ji JF, Gu J, Cai Y, Zhang XY: Locally advanced rectal carcinoma treated with preoperative chemotherapy and radiation therapy: preliminary analysis of diffusion-weighted MR imaging for early detection of tumor histopathologic downstaging. Radiology 2010, 254:170-178.
• [10]Nordsmark M, Bentzen SM, Rudat V, Brizel D, Lartigau E, Stadler P, Becker A, Adam M, Molls M, Dunst J, Terris DJ, Overgaard J: Prognostic value of tumor oxygenation in 397 head and neck tumors after primary radiation therapy. An international multi-center study. Radiother Oncol 2005, 77:18-24.
• [11]Fyles A, Milosevic M, Pintilie M, Syed A, Levin W, Manchul L, Hill RP: Long-term performance of interstitial fluid pressure and hypoxia as prognostic factors in cervix cancer. Radiother Oncol 2006, 80:132-137.
• [12]Vaupel P, Mayer A: Hypoxia in cancer: significance and impact on clinical outcome. Cancer Metastasis Rev 2007, 26:225-239.
• [13]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.
• [14]Padhani AR, Liu G, Koh DM, Chenevert TL, Thoeny HC, Takahara T, Dzik-Jurasz A, Ross BD, Van Cauteren M, Collins D, Hammoud DA, Rustin GJ, Taouli B, Choyke PL: Diffusion-weighted magnetic resonance imaging as a cancer biomarker: consensus and recommendations. Neoplasia 2009, 2:102-125.
• [15]Brammer I, Jung H: Morphometry of irradiated tumors. In Rodent Tumor Models in Experimental Cancer Therapy. Edited by Kallman RF. Oxford: Pergamon Press; 1987:97-100.
• [16]Egeland TAM, Simonsen TG, Gaustad JV, Gulliksrud K, Ellingsen C, Rofstad EK: Dynamic contrast-enhanced magnetic resonance imaging of tumors: preclinical validation of parametric images. Radiat Res 2009, 172:339-347.
• [17]Rofstad EK, Måseide K: Radiobiological and immunohistochemical assessment of hypoxia in human melanoma xenografts: acute and chronic hypoxia in individual tumors. Int J Radiat Biol 1999, 75:1377-1393.
• [18]Ozerdem U, Hargens AR: A simple method for measuring interstitial fluid pressure in cancer tissues. Microvasc Res 2005, 70:116-120.
• [19]Padhani AR, Koh DM, Collins DJ: Whole-body diffusion-weighted MR imaging in cancer: current status and research directions. Radiology 2011, 261:700-718.
• [20]Gulledge CJ, Dewhirst MW: Tumor oxygenation: a matter of supply and demand. Anticancer Res 1996, 16:741-750.
• [21]Heldin CH, Rubin K, Pietras K, Östman A: High interstitial fluid pressure―an obstacle in cancer therapy. Nat Rev Cancer 2004, 4:806-813.
• [22]Lunt SJ, Fyles A, Hill RP, Milosevic M: Interstitial fluid pressure in tumors: therapeutic barrier and biomarker of angiogenesis. Future Oncol 2008, 4:793-802.
• [23]Milosevic M, Fyles A, Hill RP: The relationship between elevated interstitial fluid pressure and blood flow in tumors: a bioengineering analysis. Int J Radiat Oncol Biol Phys 1999, 43:1111-1123.
• [24]Padera TP, Stoll BR, Tooredman JB, Capen D, di Tomaso E, Jain RK: Pathology: cancer cells compress intratumour vessels. Nature 2004, 427:695.
• [25]Cairns RA, Kalliomäki T, Hill RP: Acute (cyclic) hypoxia enhances spontaneous metastasis of KHT murine tumors. Cancer Res 2001, 61:8903-8908.
• [26]Rofstad EK, Galappathi K, Mathiesen B, Ruud EBM: Fluctuating and diffusion-limited hypoxia in hypoxia-induced metastasis. Clin Cancer Res 2007, 13:1971-1978.
• [27]Hompland T, Ellingsen C, Øvrebø KM, Rofstad EK: Interstitial fluid pressure and associated lymph node metastasis revealed in tumors by dynamic contrast-enhanced MRI. Cancer Res 2012, 72:4899-4908.
• [28]Rofstad EK, Tunheim SH, Mathiesen B, Graff BA, Halsør EF, Nilsen K, Galappathi K: Pulmonary and lymph node metastasis is associated with primary tumor interstitial fluid pressure in human melanoma xenografts. Cancer Res 2002, 62:661-664.
• [29]Rofstad EK, Gaustad JV, Egeland TAM, Mathiesen B, Galappahi K: Tumors exposed to acute cyclic hypoxic stress show enhanced angiogenesis, perfusion and metastatic dissemination. Int J Cancer 2010, 127:1535-1546.
• [30]Razek AA, Fathy A, Gawad TA: Correlation of apparent diffusion coefficient value with prognostic parameters of lung cancer. J Comput Assist Tomogr 2011, 35:248-252.
• [31]Dietzel M, Baltzer PA, Vag T, Gröschel T, Gajda M, Camara O, Kaiser WA: Application of breast MRI for prediction of lymph node metastases – systematic approach using 17 individual descriptors and a dedicated decision tree. Acta Radiol 2010, 51:885-894.
• [32]de Souza NM, Riches SF, Vanas NJ, Morgan VA, Ashley SA, Fisher C, Payne GS, Parker C: Diffusion-weighted magnetic resonance imaging: a potential non-invasive marker of tumour aggressiveness in localized prostate cancer. Clin Radiol 2008, 63:774-782.
• [33]Rosenkrantz AB, Mussi TC, Spieler B, Melamed J, Taneja SS, Huang WC: High-grade bladder cancer: associations of the apparent diffusion coefficient with metastatic disease: preliminary results. J Magn Reson Imaging 2012, 35:1478-1483.
• [34]Egeland TAM, Gaustad JV, Galappathi K, Rofstad EK: Magnetic resonance imaging of tumor necrosis. Acta Oncol 2011, 50:427-434.
• [35]Øvrebø KM, Gulliksrud K, Mathiesen B, Rofstad EK: Assessment of tumor radioresponsiveness and metastatic potential by dynamic contrast-enhanced magnetic resonance imaging. Int J Radiat Oncol Biol Phys 2011, 81:255-261.
• [36]Rofstad EK, Rasmussen H, Galappathi K, Mathiesen B, Nilsen K, Graff BA: Hypoxia promotes lymph node metastasis in human melanoma xenografts by up-regulating the urokinase-type plasminogen activator receptor. Cancer Res 2002, 62:1847-1853.