Non-invasive imaging of glioma vessel size and densities in correlation with tumour cell proliferation by small animal PET and MRI

Angiogenesis is a key event in the progression of glioblastomas (GBM). Our goal was to measure different anatomical and physiological parameters of GBM vessels using steady-state contrast-enhanced magnetic resonance imaging (SSCE-MRI), together with the assessment of biochemical parameters on GBM proliferation and angiogenesis using [(11)C]methyl-L-methionine (MET) and 3'-deoxy-3'-[(18)F]fluorothymidine (FLT) and positron emission tomography (PET). We focused on how these anatomical and biochemical read-outs correlate with one another and with immunohistochemistry.SSCE-MRI together with (11)C-MET and (18)F-FLT PET were performed 3 weeks after intracranial implantation of human GBM spheroids in nude rats (n = 8). Total cerebral blood volume (tCBV), blood volume present in microvessels (μCBV), vessel density and size were calculated. Rats were treated with bevacizumab (n = 4) or vehicle (n = 4) for 3 weeks. Imaging was repeated at week 6, and thereafter immunohistochemistry was performed.Three weeks after implantation, MRI showed an increase of vessel density and μCBV in the tumour compared to the contralateral brain. At week 6, non-treated rats showed a pronounced increase of (11)C-MET and (18)F-FLT tumour uptake. Between weeks 3 and 6, tCBV and vessel size increased, whereas vessel density and μCBV decreased. In rats treated with bevacizumab μCBV values were significantly smaller at week 6 than in non-treated rats, whereas the mean vessel size was higher. Accumulation of both radiotracers was lower for the treated versus the non-treated group. Most importantly, non-invasive measurement of tumour vessel characteristics and tumour proliferation correlated to immunohistochemistry findings.Our study demonstrates that SSCE-MRI enables non-invasive assessment of the anatomy and physiology of the vasculature of experimental gliomas. Combined SSCE-MRI and (11)C-MET/(18)F-FLT PET for monitoring biochemical markers of angiogenesis and proliferation in addition to vessel anatomy could be useful to improve our understanding of therapy response of gliomas.