br c Institute of Translational Medicine College of
c Institute of Translational Medicine, College of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University, Nanjing, 211800, China
d Department of Pathology, Jiangsu Province Hospital of Chinese Medicine, Aﬃliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, China
Chemoresistance Cancer-associated fibroblast
Chemoresistance remains the major obstacle to achieve optimal prognosis in gastric cancer patients, and the underlying molecular mechanisms of cancer-associated fibroblasts (CAFs) in gastric cancer chemoresistance remain poorly understood. We identified the high pretherapeutical serum IL-8 level in gastric cancer patients was associated with poor response to platinum-based therapy, and it increased gradually during neoadjuvant chemotherapy and it decreased after radical surgery. Immunohistochemistry assays showed that IL-8 was highly expressed in gastric cancer tissues in chemoresistant patients, and located in CAFs. Primary CAFs produced more IL-8 than the corresponding normal fibroblasts, and human stomach fibroblast line Hs738 secreted more IL-8 after co-cultured with conditioned media from AGS or MGC-803 cells. IL-8 increased the IC50 of cisplatin (CDDP) in AGS or MGC-803 in vitro. Simultaneously, IL-8 treatment enhanced the 4235-95-4 of PI3K, phos-phorylated-AKT (p-AKT), phosphorylated-IKb (p-IKb), phosphorylated-p65 (p-p65) and ABCB1, and ABCB1 and p-p65 were overexpressed in tumor tissues of chemoresistant patients. Collectively, CAFs derived IL-8 promotes chemoresistance in human gastric cancer via NF-κB activation and ABCB1 up-regulation. Our study provides a novel strategy to improve the chemotherapeutical eﬃcacy and the prognosis of gastric cancer.
Although the incidence has been declining in most parts of the world in the last decades, stomach carcinoma remains a prominent cancer worldwide and is responsible for over 1,000,000 new cases in 2018 and an estimated 783,000 deaths, making it the fifth most fre-quently diagnosed cancer and the third leading cause of cancer death . In 2014, 410,400 new stomach cancer cases and 293,800 cancer-associated deaths were estimated to have occurred in China, accounting for 10.79% and ranking third in incidence of all cancers combined, which indicates that stomach cancer remains a major contributor to the
cancer burden among the Chinese population . Gastrectomy with D2 lymph node dissection has become the global standard procedure for locally advanced gastric cancer to maximally reduce locoregional re-currence, particularly in East Asia . However, even after curative surgery and adequate lymphadenectomy the survival of advanced gastric cancer remains poor. Multimodality therapy including neoad-juvant chemotherapy (NAC) and postoperative adjuvant chemotherapy (POAC) has been studied and applied to improve survival . Based on the evidence of the ACTS-GC  and the CLASSIC trials , POAC after curative D2 gastrectomy is the current standard strategy. However, approximately 20%–30% of patients still develop locoregional or
Abbreviations: NAC, neoadjuvant chemotherapy; POAC, postoperative adjuvant chemotherapy; POC, perioperative chemotherapy; ECF, epirubicin/cisplatin/in-fusional 5-FU; FLOT, docetaxel/oxaliplatin/5-fluorouracil; GEJ, gastroesophageal junction; TME, tumor microenvironment; CAFs, Cancer-associated fibroblasts; CT, computed tomography; EUS, endoscopic ultrasonography; RECIST, response evaluation criteria in solid tumors; NFs, normal fibroblasts; ELISA, enzyme-linked immunosorbent assay; CCK-8, cell counting kit-8; α-SMA, α-smooth muscle actin; IHC, immunohistochemistry; CDDP, cisplatin; ABCB1, ATP-binding cassette subfamily B member 1; NF-κB, nuclear factor kappa B; ECM, extracellular matrix; MSCs, mesenchymal stem cells; FSP-1, fibroblast-specific protein-1; FAP, fibroblast-activated protein; TEM1, tumor endothelial marker 1
∗ Corresponding author. Department of Surgical Oncology, Jiangsu Province Hospital of Chinese Medicine, Aﬃliated Hospital of Nanjing University of Chinese Medicine, 155 Hanzhong Road, Nanjing, Jiangsu 210029, China.
E-mail address: [email protected] (L. Shen).
1 These authors contributed equally to this work.
Correlation between the pretherapeutic serum levels of IL-6 and IL-8 and clinicopathological features of gastric cancer patients.
Tumor size (cm)
Depth of tumor invasion
Lymph node metastasis