CXCL1 from tumor-associated lymphatic endothelial cells drives gastric cancer cell into lymphatic system via activating integrin β1/FAK/AKT signaling.
Crosstalk between lymphatic endothelial cells (LECs) and tumor cells in the tumor microenvironment plays a crucial role in tumor metastasis. Our previous study indicated chemokine (C-X-C motif) ligand 1 (CXCL1) from LECs stimulates the metastasis of gastric cancer. However, the mechanism is still unclear. Here, we successfully isolated tumor-associated LECs (T-LECs) and normal LECs (N-LECs) from clinical samples by magnetic-activated cell sorting system (MACS) and proved that CXCL1 expression was elevated in T-LECs compared with N-LECs in situ and vitro. Besides, we demonstrated that CXCL1 secreted by T-LECs promoted the migration, invasion, and adhesion of gastric cancer cells by upregulating integrin β1, MMP2, and MMP9. Furthermore, CXCL1 induced MMP2/9 expression by activating integrin β1-FAK-AKT signaling. In the animal model, CXCL1 overexpressed in LECs increased the lymph node metastasis of gastric cancer. In conclusion, CXCL1 expression in T-LECs was upregulated, and CXCL1 secreted by T-LECs promoted the lymph node metastasis of gastric cancer through integrin β1/FAK/AKT signaling, leading to MMP2 and MMP9 expression. Therefore, CXCL1 produced in T-LECs represents a potentially promising target for treating gastric cancer.
Department of Gastrointestinal Surgery, First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China; Gastric Cancer Center of Sun Yat-Sen University, Guangzhou, China.
Zhixiong
Z
Wang
Department of Gastrointestinal Surgery, First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China; Gastric Cancer Center of Sun Yat-Sen University, Guangzhou, China.
Zhao
Z
Wang
Department of Gastrointestinal Surgery, First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China; Gastric Cancer Center of Sun Yat-Sen University, Guangzhou, China.
Guanghua
G
Li
Department of Gastrointestinal Surgery, First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China; Gastric Cancer Center of Sun Yat-Sen University, Guangzhou, China.
Hui
H
Wu
Department of Gastrointestinal Surgery, First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China; Gastric Cancer Center of Sun Yat-Sen University, Guangzhou, China.
Kaiyu
K
Sun
Department of Gastrointestinal Surgery, First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China; Gastric Cancer Center of Sun Yat-Sen University, Guangzhou, China.
Jianhui
J
Chen
Department of Gastrointestinal Surgery, First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China; Gastric Cancer Center of Sun Yat-Sen University, Guangzhou, China.
Yun
Y
Feng
Department of Gastrointestinal Surgery, First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China; Gastric Cancer Center of Sun Yat-Sen University, Guangzhou, China.
Chuangqi
C
Chen
Department of Gastrointestinal Surgery, First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China; Gastric Cancer Center of Sun Yat-Sen University, Guangzhou, China.
Shirong
S
Cai
Department of Gastrointestinal Surgery, First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China; Gastric Cancer Center of Sun Yat-Sen University, Guangzhou, China. Electronic address: xjianb@mail.sysu.edu.cn.
Jianbo
J
Xu
Department of Gastrointestinal Surgery, First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China; Gastric Cancer Center of Sun Yat-Sen University, Guangzhou, China. Electronic address: ylh@medmail.com.cn.
Yulong
Y
He
D000818:Animals; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D054360:Chemokine CXCL1 / Q000235:genetics / Q000378:metabolism*; D018920:Coculture Techniques; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D004729:Endothelium, Lymphatic / Q000378:metabolism* / Q000473:pathology; D005260:Female; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism*; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism*; D053208:Kaplan-Meier Estimate; D008207:Lymphatic Metastasis; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D019899:Paracrine Communication; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D013997:Time Factors; D014162:Transfection; D015854:Up-Regulation
C475829:CXCL1 protein, human; D054360:Chemokine CXCL1; D019012:Integrin beta1; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D051057:Proto-Oncogene Proteins c-akt; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9
CXCL1; Gastric cancer; Integrin β1; Lymphatic endothelial cells