Manganese-enhanced MRI (MEMRI) in breast and prostate cancers: exploring the potential role of calcium receptors

Abstract

26Procedures: To assess the relationship between Manganese Enhanced Magnetic Resonance 27 Imaging (MEMRI) and the expression of calcium receptors in human prostate and breast cancer 28 animal models. 29Methods: NOD/SCID mice were inoculated with MDA-MB-231 breast cancer cells and 30 prostate PC3 cancer cells to develop orthotopic or pseudometastatic cancer animal models. 31 Mice were studied on a clinical 3T scanner by using a prototype birdcage coil before and after 32 intravenous injection of MnCl 2 . Assessment of receptor's status was carried out after the MR 33 images acquisition by immunohistochemistry on excised tumours. 34 Results: Manganese contrast enhancement in breast or prostate cancer animal models well 35 correlated with CaSR expression (p<0.01), whereas TRPV6 expression levels appeared not 36 relevant to the Mn uptake.37 Conclusion: MEMRI appears an efficient tool to characterize human breast and prostate cancer 38 animal models in the presence of different expression level of CaSR. 39 40 Introduction 45Regulation of calcium metabolism is crucial for cellular activities such as proliferation, 46 gene transcription and cell death (1, 2). To maintain a balanced condition between the intra-47 and extra-cellular compartments, cells employ specialized calcium pumps, channels and 48 calcium binding proteins (the so called "molecular toolkit") (3, 4). Changes in calcium 49 metabolism are reported on the upsurge of certain pathological states, including cancer (5-7). 50To better detect the occurrence of an altered calcium metabolism in vivo, a non-invasive 51 method such as imaging could be extremely valuable. On the basis of the close analogy between 52 calcium and manganese, an imaging technique such as Manganese Enhanced Magnetic 53Resonance Imaging (MEMRI) has received increased attention in preclinical cancer imaging 54 studies (8-10). 55 MEMRI is a well-established method that, by combining the peculiar physical and 56 biological properties of Mn 2+ , allows to extract relevant anatomical and functional imaging 57 information in a variety of systems (11-14). 58 Previously we tested MEMRI as imaging tool to report on the high expression levels of 59 Calcium Sensing Receptor (CaSR) in a human breast cancer animal model (15). CaSR is a G 60 protein coupled receptor, which plays an important role in tumour development (16-19). Breast 61 tumours displaying high CaSR expression, as assessed by immunohistochemistry, correlated 62 well with manganese uptake assessed by Magnetic Resonance Imaging (MRI). However, CaSR 63 is not the only receptor involved in the presence of the altered calcium metabolism in cancer 64 cells, as other calcium receptors or channels can interfere with Ca 2+ homeostasis. Calcium-65 permeable ion channels, such as Transient Receptor Potential (TRP) have been recently 66 associated with tumour progression (20). An altered expression level of TRP channels is 67 associated with changes in intracellular Ca 2+ and in the proliferative pathways, promoting or 68 inhibiting apoptos...