Non-invasive detection and complementary diagnosis of liver metastases via chemokine receptor 4 imaging

Abstract

Noninvasive detection of early-stage liver metastases from different primary cancers is a pressing unmet medical need. The lack of both molecular biomarkers and the sensitive imaging methodology makes the detection challenging. In this study, we observed the elevated expression of chemokine receptor 4 (CXCR4) in uveal melanoma (UM) patient liver tissues, and high CXCR4 expression in liver metastases of UM murine models, regardless of the expression levels in the primary tumors. Based on these findings, we identified CXCR4 as an imaging biomarker and exploited a CXCR4-targeted MRI contrast agent ProCA32.CXCR4 for molecular MRI imaging. ProCA32.CXCR4 has strong CXCR4 binding affinity, high metal selectivity, and r1 and r2 relaxivities, which enables the sensitive detection of liver micrometastases. The MRI imaging capacity for detecting liver metastases was demonstrated in three UM models and one ovarian cancer model. The imaging results were validated by histological and immunohistochemical analysis. ProCA32.CXCR4 has strong potential clinical application for non-invasive diagnosis of liver metastases.

Pathological and Molecular Diagnosis of Uveal Melanoma

“…However, this seed and soil for uveal melanoma is not anatomic; it is genetic. Primary tumor uveal melanoma cells express CXC Motif Chemokine Receptor 4 (CXCR4) and C-C Chemokine Receptor 7 (CCR7) [88,89]. The work of Li H. et al found that CXCR4 and CCR7, which are both G-Protein-Coupled chemokine receptors, provided directional migration of uveal melanoma cells toward liver tissues [90].…”

“…The CXCR4-CXCL12 connection provides an attractive explanation for the selective metastasis of uveal melanoma to the liver [88]. CXCR4 could provide early migration of uveal melanoma cells toward the liver [89]. Chemokine Receptor 7 (CCR7) has immunological functions in migrating naïve lymphocytes and mature dendritic cells to secondary lymphoid organs [88] and toward chemokines CCL19 and CCL21 [88].…”

“…Uveal melanoma exhibits metastatic pleomorphism; the metastasis can be cytogenetically different from the original primary tumor Primary tumor uveal melanoma cells express CXC Motif Chemokine Receptor 4 (CXCR4) and C-C Chemokine Receptor 7 (CCR7) [88,89]. According to Li H. et al's study, the chemokine receptor composition in uveal melanoma liver metastases suffers downregulation after the metastasis of both CXCR4 and CCR7 [90].…”

“…DNA methylation can be used to trace the tissue of origin of various tumors [6,93,94] such as central nervous system neoplasms [88] and melanoma [89]. Jurmeister P. et al reported a uniquely characteristic methylation profile for uveal melanoma with distinct epigenetic signatures [6,95].…”

Magnetic Resonance Features of Liver Mucinous Colorectal Metastases: What the Radiologist Should Know

“…Consequentially, the radiologist plays a crucial role in the multidisciplinary team of CRCLM patients [23][24][25][26][27][28][29]. Although computed tomography (CT) is usually the imaging tool utilized for staging and surveillance [30][31][32][33], Magnetic Resonance Imaging (MRI) is the main appreciated imaging method in liver assessment thanks to its capacity to offer conventional and functional data that improve lesion characterizations [34][35][36][37][38][39][40][41][42].…”