Cancer-associated fibroblast-derived CXCL12 causes tumor progression in adenocarcinoma of the esophagogastric junction.
Although cancer-associated fibroblasts (CAFs) mainly produce CXCL12 and stimulate CXCL12/CXCR4 signaling in cancer cells, the significance of this interaction in adenocarcinoma of the esophagogastric junction (AEG) was unclear. This study investigated the functional characteristics of CAF-derived CXCL12 in AEG. Immunohistochemical staining for CXCL12 was performed on sections from 123 AEG patients and analyzed against clinicopathological data. Newly isolated CAFs and normal fibroblasts were examined for phenotype. An invasion assay was performed with AEG cells co-cultured with CAFs isolated from AEG. CXCL12 expression was significantly associated with age, depth of invasion, lymphatic invasion, and lymph node metastases. High CXCL12 expression significantly correlated with poor prognosis. Isolated CAFs had abundant α-smooth muscle actin expression and showed various CXCL12 expression patterns. Notably, AEG cells co-cultured with CXCL(high)-expressing CAFs invaded more than when co-cultured with CXCL(low)-expressing CAFs; these invasive properties were impeded by CXCR4 antagonist AMD3100. We demonstrated that AEG cells co-cultured with CXCL12(high) CAFs were significantly more invasive than those co-cultured with CXCL12(low) CAFs and that high CXCL12 expression correlates with poor prognosis in AEG patients. CXCL12 derived from CAFs in tumor microenvironment stimulates CXCL12/CXCR4 signaling in AEG cells and promotes their invasive ability, resulting in tumor progression.
Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan.
Hidetaka
H
Sugihara
Takatsugu
T
Ishimoto
Tadahito
T
Yasuda
Daisuke
D
Izumi
Kojiro
K
Eto
Hiroshi
H
Sawayama
Keisuke
K
Miyake
Junji
J
Kurashige
Yu
Y
Imamura
Yukiharu
Y
Hiyoshi
Masaaki
M
Iwatsuki
Shiro
S
Iwagami
Yoshifumi
Y
Baba
Yasuo
Y
Sakamoto
Yuji
Y
Miyamoto
Naoya
N
Yoshida
Masayuki
M
Watanabe
Hiroshi
H
Takamori
Hideo
H
Baba
D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology*; D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D054377:Chemokine CXCL12 / Q000378:metabolism*; D018450:Disease Progression; D004943:Esophagogastric Junction / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D008207:Lymphatic Metastasis; D008297:Male; D009361:Neoplasm Invasiveness / Q000473:pathology; D011379:Prognosis; D019718:Receptors, CXCR4 / Q000378:metabolism; D059016:Tumor Microenvironment / Q000502:physiology
D014408:Biomarkers, Tumor; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019718:Receptors, CXCR4