Ultrasound Molecular Imaging as a Potential Non-invasive Diagnosis to Detect the Margin of Hepatocarcinoma via CSF-1R Targeting.

Qiongchao Jiang,Xiaoyun Xiao,Boyang Zhou,Baoming Luo,Hejun Liu,Phei Er Saw,Yao Kong,Yunting Zeng,Yanni Xu

doi:10.3389/fbioe.2020.00783

Abstract

Though radiofrequency ablation (RFA) is considered to be an effective treatment for hepatocellular carcinoma (HCC), but more than 30% of patients may suffer insufficient RFA (IRFA), which can promote more aggressive of the residual tumor. One possible method to counter this is to accurately identify the margin of the HCC. Colony-stimulating factor 1 receptor (CSF-1R) has been found to be restrictively expressed by tumor associated macrophages (TAMs) and monocytes which more prefer to locate at the boundary of HCC. Using biotinylation method, we developed a CSF-1R-conjugated nanobubble CSF-1R (NBCSF–1R) using a thin-film hydration method for margin detection of HCC. CSF-1R expression was higher in macrophages than in HCC cell lines. Furthermore, immunofluorescence showed that CSF-1R were largely located in the margin of xenograft tumor and IFRA models. In vitro, NBCSF–1R was stable and provided a clear ultrasound image even after being stored for 6 months. In co-culture, NBCSF–1R adhered to macrophages significantly better than HCC cells (p = 0.05). In in vivo contrast-enhanced ultrasound imaging, the washout half-time of the NBCSF–1R was significantly greater than that of NBCTRL and Sonovue® (p = 0.05). The signal intensity of the tumor periphery was higher than the tumor center or non-tumor region after NBCSF–1R injection. Taken together, NBCSF–1R may potentially be used as a non-invasive diagnostic modality in the margin detection of HCC, thereby improving the efficiency of RFA. This platform may also serve as a complement method to detect residual HCC after RFA; and may also be used for targeted delivery of therapeutic drugs or genes.

Highlights

Hepatocellular carcinoma (HCC), is the third leading cause of cancer death in China (Chen et al, 2016)
Some researchers found that colony-stimulating factor 1 receptor (CSF-1R) expression and tumor associated macrophage (TAM) density (CSF-1 receptor, CSF-1R or CD68) in the adjacent liver tissues are associated with patient survival after resection of HCC (Zhu et al, 2008; Jia et al, 2010; Kong et al, 2013)
We investigated the specificity and efficacy of the nanobubbles (NBCTRL and NBCSF−1R) against HCC xenograft tumors and insufficient RFA (IRFA) models to evaluate the feasibility of using NBCSF−1R in the clinical diagnosis of HCC margin (Scheme 1)

Summary

Introduction

Hepatocellular carcinoma (HCC), is the third leading cause of cancer death in China (Chen et al, 2016). Radiofrequency ablation (RFA) which considered to be a valid local treatment method with curative intent and shows a comparable overall outcome to that of liver resection when patients with HCCs smaller than 3 cm in diameter (N’Kontchou et al, 2009; Kang et al, 2015). Some researchers found that colony-stimulating factor 1 receptor (CSF-1R) expression and tumor associated macrophage (TAM) density (CSF-1 receptor, CSF-1R or CD68) in the adjacent liver tissues are associated with patient survival after resection of HCC (Zhu et al, 2008; Jia et al, 2010; Kong et al, 2013). A high density of CSF-1R in peritumoral liver tissue, but not in tumor tissue, was associated with poor survival and a high incidence of metastasis after resection of the primary tumor (Zhu et al, 2008; Nandi et al, 2013). CSF-1R might be a feasible target for molecular imaging of HCC

Methods

Results

Discussion

Conclusion