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

Purpose: 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.

Methods: 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.

Results: 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.

Conclusion: 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.