br Chemotherapy br metastatic recurrences even after
metastatic recurrences even after these postoperative adjuvant che-motherapies, especially in those with pathological stage III disease . NAC, or perioperative chemotherapy (POC), consisting of three courses of ECF (epirubicin/cisplatin/infusional 5-FU) combined with surgery and three postoperative courses of ECF, has been the standard treat-ment for resectable gastric cancer in Europe . Recently, the German FLOT4 trial established the perioperative FLOT regimen (docetaxel/ oxaliplatin/5-fluorouracil) as the new treatment standard for resectable adenocarcinoma of the gastroesophageal junction (GEJ) and the sto-mach . In a large series of patients with stage II/III resectable gas-tric/GEJ adenocarcinomas, patients receiving POC were shown to sur-vive longer than those receiving postoperative chemoradiotherapy . An updated meta-analysis also indicated that NAC is associated with significant improvement in the outcomes of survival and disease progression for gastric cancer patients . However, resistance to chemotherapy remains the major obstacle to achieve optimal results in gastric cancer patients.
Chemotherapeutic resistance, whether intrinsic or acquired, is a complex and multifactorial phenomenon that is associated with tumor Dehydroergosterol as well as with the tumor microenvironment (TME) [12,13]. A variety of factors have been demonstrated to be involved in chemore-sistance, including a reduction in drug uptake, enhanced drug eﬄux , a reduced prodrug activation, alterations in drug targets , the dysregulation of cell survival and death signaling pathways , and interactions between cancer cells and TME.
Increasing evidence has demonstrated that TME plays a major role in the pathogenesis of multiple cancer types. Cancer-associated fibro-blasts (CAFs) are the predominant cell type in the tumor-associated stroma and contribute to tumorigenesis by secreting growth factors, modifying the extracellular matrix, supporting angiogenesis, and sup-pressing antitumor immune responses, and fostering resistance to therapy . CAFs have also been reported to predict poor outcome of many cancer types, including gastric cancer . Currently, CAFs has gained attention as a promising target for cancer therapy.
Of note, CAFs contribute to chemoresistance via multiple mechan-isms. The dense extracellular matrix synthesized by CAFs can act as a physical barrier to drug delivery , and CAFs create a micro-environmental niche that accelerates cancer cell proliferation [20,21], resists apoptosis , and promotes cancer stem cell maintenance . However, the underlying molecular mechanisms of CAFs in gastric cancer chemoresistance remain poorly understood .
In this present study, we investigated the clinicopathological sig-nificance of the pretherapeutic serum proinflammatiory cytokine levels, including IL-6 and IL-8, in patients with advanced primary gastric cancer, and found that the high IL-8 level was associated with the poor response to neoadjuvant chemotherapy. The high serum IL-8 was de-termined to be highly expressed in CAFs in the tumor microenviron-ment gastric cancer. Functional studies revealed that IL-8 mediated gastric cancer resistance to cisplatin via NF-κB activation and ABCB1 up-regulation. Our study highlights the importance and its underlying
Fig. 1. The serum IL-8 level was associated with chemoresistance of gastric cancer patients. A. The pretherapeutic serum IL-8 level in chemoresistant gastric cancer patients (282.00 ± 65.18 pg/ml) was higher than that in chemosensitive patients (85.77 ± 30.67 pg/ml, P = 0.011). B. During NAC, the serum IL-8 levels in the chemoresistant patients increased gradually (P = 0.023), and it decreased dramatically post radical surgery (P = 0.037); however, it decreased slightly in chemosistantive patients (P = 0.070). C. The serum IL-6 level remained nearly unchanged in the chemosensitive patients (P = 0.901) and the chemoresistant patients (P = 0.918).
Fig. 2. IL-8 was highly expressed in CAFs in gastric cancer tissues. In the tissue of chemoresistant patient, IL-8 was highly expressed in CAFs, which expressed α-SMA, in the stroma of gastric tumor tissues. In the chemosensitive patient who obtained CR after NAC, α-SMA was expressed in the stroma, but there was no IL-8 immunoactivity found.
mechanisms of CAFs in gastric cancer chemoresistance, and provides a new indicator for evaluating the response to chemotherapy in gastric cancer, as well as a novel strategy to improve the chemotherapeutical eﬃcacy and the prognosis in gastric cancer patients.
2. Materials and methods
2.1. Human serum and tissue specimens
A total of 111 patients, diagnosed with primary advanced gastric adenocarcinoma by endoscopy and pathological examination, were enrolled in this retrospective study. All these patients were evaluated as cT2∼3N1∼2M0 stage by abdominal computed tomography scan (CT) or endoscopic ultrasonography (EUS). After systemic evaluation, these patients underwent two cycles NAC containing platinum-based drugs, and they were performed radical surgery after the chemotherapy. Tumor response rate was determined by tumor size as described by Response Evaluation Criteria in Solid Tumors (RECIST) . There were no severe complications associated with chemotherapy and sur-gery in these patients. The serum specimens were collected at pre-therapy, pre-second chemotherapy, preoperation and one month post-operation respectively. The gastric cancer tissues and the corresponding non-cancerous mucosal tissues were collected from all patients im-mediately after resection, and were snap frozen in liquid nitrogen, and were transferred to laboratories anonymously. All patients provided written informed consent. The study protocol was approved by the Institutional Review Board of Nanjing University of Chinese Medicine, and complied with the Helsinki Declaration.