Theranostics 2018; 8(5):1376-1388. doi:10.7150/thno.22717

Research Paper

Cancer-associated fibroblasts enhance tumor 18F-FDG uptake and contribute to the intratumor heterogeneity of PET-CT

Chengfang Shangguan1,#, Guifang Gan2,#, Jieying Zhang2,#, Jinliang Wu2, Ying Miao1, Miao Zhang1, Biao Li1,✉, Jun Mi2,✉

1. Department of Nuclear Medicine & Department of Oncology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine
2. Department of Biochemistry and Molecular Cell Biology; Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine
# these authors equally contribute to this paper

Abstract

Purpose: Elevated glucose uptake is a hallmark of cancer. Fluorodeoxyglucose (FDG) uptake was believed to indicate the aggressiveness of tumors and the standardized uptake value (SUV) is a well-known measurement for FDG uptake in positron emission tomography-computed tomography (PET/CT). However, the SUV is variable due to the heterogeneity of tumors. Methods: 126 patients with colorectal cancer underwent 18F-FDG PET/CT scanning before surgery between Jan 2011 and April 2016. Cancer-associated fibroblast (CAF) densities were calculated with the inForm Advanced image analysis software and were comparatively analyzed between patients with high and low maximum SUV (SUVmax-high and SUVmax-low). Glucose uptake was evaluated in induced and isolated CAFs and CAF-cocultured colon cancer HCT116 cells. Moreover, micro-PET/CT was performed on xenografted tumors and autoradiography was performed in the AOM/DSS induced colon cancer model. Results: CAFs were glycolytic, evidenced by glucose uptake and upregulated HK2 expression. Compared to non-activated fibroblasts (NAFs), CAFs were more dependent on glucose and sensitive to a glycolysis inhibitor. CAFs increased the SUVmax in xenograft tumors and spontaneous colon cancers. Moreover, multivariate analysis revealed that the SUVmax was only associated with tumor size among conventional parameters in colon cancer patients (126 cases, p = 0.009). Besides tumor size, the CAF density was the critical factor associated with SUVmax and outcome, which was 2.27 ± 0.74 and 1.68 ± 0.45 in the SUVmax-high and the SUVmax-low groups, respectively (p = 0.014). Conclusion: CAFs promote tumor progression and increase SUVmax of 18F-FDG, suggesting CAFs lead to the intratumor heterogeneity of the SUV and the SUVmax is a prognostic marker for cancer patients.

Keywords: Cancer associated fibroblast, PET/CT, SUVmax, intratumor heterogeneity

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How to cite this article:
Shangguan C, Gan G, Zhang J, Wu J, Miao Y, Zhang M, Li B, Mi J. Cancer-associated fibroblasts enhance tumor 18F-FDG uptake and contribute to the intratumor heterogeneity of PET-CT. Theranostics 2018; 8(5):1376-1388. doi:10.7150/thno.22717. Available from http://www.thno.org/v08p1376.htm