TY - JOUR
T1 - Interaction with CD68 and regulation of GAS6 expression by endosialin in fibroblasts drives recruitment and polarization of macrophages in hepatocellular carcinoma
AU - Yang, Fa
AU - Wei, Yan
AU - Han, Donghui
AU - Li, Yu
AU - Shi, Shengjia
AU - Jiao, Dian
AU - Wu, Jieheng
AU - Zhang, Qiang
AU - Shi, Changhong
AU - Yang, Lijun
AU - Song, Wei
AU - Zhang, Jingliang
AU - Han, Yueheng
AU - Zhang, Rui
AU - Yang, An Gang
AU - Dimitrov, Dimiter S.
AU - Zhao, Aizhi
AU - Qin, Weijun
AU - Wen, Weihong
N1 - Funding Information:
We thank Letpub for helping us draw the graphical conclusion. We thank Mrs. Yunxin Cao and Mr. Jintao Hu (Department of Immunology, Fourth Military Medical University) for assistance with flow cytometry analysis and Dr. Dengxu Tan (Laboratory Animal Center) for assistance with the animal study. This work was partly supported by grants from the National Natural Science Foundation of China (Nos. 81772734, 81372225, and 81372771) and the Open Project Program of the State Key Laboratory of Cancer Biology (Fourth Military Medical University; No. CBSKL201723).
Publisher Copyright:
© 2020 American Association for Cancer Research.
PY - 2020/9/15
Y1 - 2020/9/15
N2 - Fibroblasts and macrophages play key roles in the development of hepatocellular carcinoma (HCC). However, cross-talk between these two kinds of cells has not been well studied. Endosialin (CD248/TEM1) is a transmembrane glycoprotein that is expressed in certain cancer cells, tumor stromal cells, and pericytes. In this study, we found that endosialin is mainly expressed in cancer-associated fibroblasts (CAF) in HCC and its expression inversely correlates with patient prognosis. Endosialin interacted with CD68 to recruit macrophages and regulated expression of GAS6 in CAFs to mediate M2 polarization of macrophages. The fully human antibody IgG78 bound glycosylated endosialin and induced its internalization in CAFs, thus weakening the cross-talk between CAFs and macrophages. In subcutaneous and orthotopic xenograft models of HCC in nude mice, treatment with IgG78 significantly inhibited tumor growth. These results indicate that endosialin-positive CAFs promote HCC progression and highlight IgG78 as a promising therapeutic candidate for HCC treatment.
AB - Fibroblasts and macrophages play key roles in the development of hepatocellular carcinoma (HCC). However, cross-talk between these two kinds of cells has not been well studied. Endosialin (CD248/TEM1) is a transmembrane glycoprotein that is expressed in certain cancer cells, tumor stromal cells, and pericytes. In this study, we found that endosialin is mainly expressed in cancer-associated fibroblasts (CAF) in HCC and its expression inversely correlates with patient prognosis. Endosialin interacted with CD68 to recruit macrophages and regulated expression of GAS6 in CAFs to mediate M2 polarization of macrophages. The fully human antibody IgG78 bound glycosylated endosialin and induced its internalization in CAFs, thus weakening the cross-talk between CAFs and macrophages. In subcutaneous and orthotopic xenograft models of HCC in nude mice, treatment with IgG78 significantly inhibited tumor growth. These results indicate that endosialin-positive CAFs promote HCC progression and highlight IgG78 as a promising therapeutic candidate for HCC treatment.
UR - http://www.scopus.com/inward/record.url?scp=85090117473&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85090117473&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-19-2691
DO - 10.1158/0008-5472.CAN-19-2691
M3 - Article
C2 - 32591411
AN - SCOPUS:85090117473
SN - 0008-5472
VL - 80
SP - 3892
EP - 3905
JO - Cancer Research
JF - Cancer Research
IS - 18
ER -
