Inhibition of PFKFB3 in HER2-positive gastric cancer improves sensitivity to trastuzumab by inducing tumour vessel normalisation.

BACKGROUND: Multiple mechanisms have been proposed that lead to reduced effectiveness of trastuzumab in HER2-positive gastric cancer (GC), yet resistance to trastuzumab remains a challenge in clinics. METHODS: We established trastuzumab-resistant cells and patient-derived xenografts models to measure metabolic levels and vascular density and shape. The HER2-positive GC patient samples were used to determine clinical significance. We also measured protein expression and phosphorylation modifications to determine those alterations related to resistance. In vivo studies combining inhibitor of PFKFB3 with trastuzumab corroborated the in vitro findings. RESULTS: The 6-phosphofructo-2-kinase (PFKFB3)-mediated trastuzumab resistance pathways in HER2-positive GC by activating the glycolytic pathway. We also found vessels are chaotic and destabilised in the tumour during the trastuzumab resistance process. Inhibition of PFKFB3 significantly diminished tumour proliferation and promoted vessel normalisation in the patient-derived xenograft model. Mechanistically, PFKFB3 promoted the secretion of CXCL8 into the tumour microenvironment, and phosphorylated Ser1151 of ERBB2, enhancing the transcription of CXCL8 by activating the PI3K/AKT/NFκB p65 pathway. CONCLUSIONS: Our current findings discover that PFKFB3 inhibitors might be effective tools to overcome adjuvant therapy resistance in HER2-positive GC and reshaping the microenvironment by normalising tumour vessels is a novel strategy to overcome trastuzumab resistance.

Yes associated protein 1 promotes resistance to 5-fluorouracil in gastric cancer by regulating GLUT3-dependent glycometabolism reprogramming of tumor-associated macrophages.

The antimetabolite 5-fluorouracil (5-FU) is a widely used chemotherapy regimen for the treatment of gastric cancer (GC). However, resistance to 5-FU remains a major drawback in the clinical use. The treatments of anti-tumor chemo-agents recruit tumor associated macrophages (TAMs) which are highly implicated in the chemoresistance development, but the underlying molecular mechanism is unclear. Here, we demonstrate that YAP1 is overexpressed in resistant GC tissues compared to sensitive GC tissues. Further, IL-3 secreted by YAP1-overexpressed GC could skew macrophage polarization to M2-like phenotype and inducing GLUT3-depended glycolysis program. Meanwhile, polarized M2 macrophages enhance 5-FU resistance in tumor cells by secreting CCL8 and activating phosphorylation of JAK1/STAT3 signaling pathway.

SLC2A3 promotes macrophage infiltration by glycolysis reprogramming in gastric cancer.

BACKGROUND: Tumors display a high rate of glucose metabolism and the SLC2A (also known as GLUT) gene family may be central regulators of cellular glucose uptake. However, roles of SLC2A family in mechanism of metabolite communication with immunity in gastric cancer remains unknown. METHODS: Bioinformatics analysis and IHC staining were used to reveal the expression of SLC2A3 in gastric cancer and the correlation with survival prognosis. Real-time PCR, western blots, OCR, ECAR, lactate production and glucose uptake assays were applied to determine the effect of SLC2A3 on glycolysis reprogramming. We then investigated the consequences of SLC2A3 upregulation or inhibition on aerobic glycolysis, also explored the underlying mechanism. Bioinformatics analysis and in vitro and in vivo research were used to reveal the role of SLC2A3 in macrophage infiltration and transition. RESULTS: Here, we show that SLC2A3 acts as a tumor promoter and accelerates aerobic glycolysis in GC cells. Mechanistically, the SLC2A3-STAT3-SLC2A3 feedback loop could promote phosphorylation of the STAT3 signaling pathway and downstream glycolytic targeting genes. Moreover, SLC2A3 potentially contributes to M2 subtype transition of macrophage infiltration in the GC microenvironment. CONCLUSIONS: SLC2A3 could be used as a prognostic biomarker to determine prognosis and immune infiltration in GC and may provide an intervention strategy for GC therapy.

Circulating tumor cell-associated white blood cell cluster is associated with poor survival of patients with gastric cancer following radical gastrectomy.

INTRODUCTION: The prognostic implication of circulating tumor cell (CTC) -associated white blood cell clusters (CTC-WBC clusters) in patients with gastric cancer (GC) after radical gastrectomy is not well defined. METHODS: The prognostic value of the CTC-WBC clusters was evaluated retrospectively in an independent cohort of GC patients with radical gastrectomy from Nanfang Hospital, Southern Medical University, China, between March 1, 2018, and September 31, 2019. The cohort was grouped into two groups: CTC-WBC group and CTC group. The CTC-WBC clusters and CTCs in blood were detected by technology of Canapatrol™ CTC filtration system. The Kaplan-Meier method was used to generate survival curve and compare the disease-free survival and OS. Cox regression model was used for multivariate analyses. RESULTS: Two hundred and seventeen patients were included for analyses, 29 patients presenting CTC-WBC clusters positive (CTC-WBC group) and 188 patients presenting exclusively CTCs (CTC group). Depth of tumor invasion was statistically different between two groups (P = 0.043), and the other clinicopathological features between the two groups were similar. Kaplan-Meier analysis showed that positive CTC-WBC cluster patients had significantly shorter OS than patients with exclusively CTC (P = 0.037). Cox regression analysis revealed that CTC-WBC cluster was an independent factor (Hazard Ratio = 2.553, 95% Confidence Interval: 1.008-6.465, P = 0.048) for OS after adjustment of age, gender, number of CTCs, type of CTCs, and tumor stage. CONCLUSION: The presence of CTC-WBC clusters is associated with poor OS in the GC patients after radical surgery regardless of tumor stage. Our data suggest alternative prognostic model needs to be further investigated.

Comparison of quality of life and cosmetic result between open and transaxillary endoscopic thyroid lobectomy for papillary thyroid microcarcinoma survivors: A single-center prospective cohort study.

BACKGROUND: Transaxillary endoscopic thyroidectomy has been introduced to achieve better cosmetic outcomes. However, the benefits of this technology on the patients' health-related quality of life (HRQoL) remain unclear. We aimed to investigate whether transaxillary endoscopic lobectomy is comparable to conventional open lobectomy in terms of QOL and cosmetic results in order to provide more evidence for establishing appropriate clinical decisions. METHODS: Between August 2019 and May 2020, transaxillary endoscopic lobectomy and conventional open lobectomy were performed in 73 and 99 patients with papillary thyroid microcarcinoma, respectively. HRQoL was assessed at 1, 3, 6, and 12 months after surgery using the Thyroid Cancer-Specific Quality of Life Questionnaire. The cosmetic outcomes were assessed 12 months after surgery using the Patient and Observer Scar Assessment Scale (POSAS). RESULTS: No significant difference was observed in the surgical results between the two groups. However, the data showed that the average operative time and postoperative hospital stay of the transaxillary group were longer than those of the open group (p < 0.001). Both groups showed similar changes in the QOL scores over time. However, the transaxillary group had fewer complaints of the throat or oral problems at 1 month postoperatively than the open group (p < 0.001). During the follow-up, the cosmetic results of scars in the transaxillary group were significantly better than those in the open group (p < 0.05). Patients who underwent transaxillary endoscopic lobectomy had higher overall satisfaction with their scar appearance, determined using POSAS, at 12 months postoperatively. CONCLUSIONS: The current findings suggest that transaxillary endoscopic lobectomy may offer better cosmetic and HRQoL outcomes.