Changqie Pan

Low expression of DLC1 is predictive of poor therapeutic efficiency of fluoropyrimidine and oxaliplatin as adjuvant chemotherapy in gastric cancer

The Rho-GTPase-activating protein, deleted in liver cancer-1 (DLC1), has been reported to be a tumor suppressor. However, the prognostic value of DLC1 in gastric cancer (GC) remains to be fully elucidated. Fluoropyrimidine-oxaliplatin (FP-LOHP) combination therapy has been widely used for the adjuvant chemotherapy of GC, however, no reliable marker has been identified to determine its efficiency. Thus, the present study performed a retrospective investigation involving 251 patients with stage IB-III GC, who received adjuvant chemotherapy following radical resection and 37 patients with stage IV GC, who underwent palliative resection. The expression of DLC1 was found to be reduced in the majority of GC samples (212/288 pairs of samples), compared with normal mucosa, in immunohistochemical analyses. Lower expression levels of DLC1 indicated a more advanced tumor-node-metastasis stage, increased lymph node metastasis, deeper tumor invasion, increased tumor size and a higher rate of distant metastasis. By contrast, relatively increased expression levels of DLC1 indicated a longer time to recurrence (TTR) [hazard ratio (HR), 2.232; P=0.004] and overall survival (OS) rate (HR, 2.910; P=0.001). Patients receiving FP-LOHP adjuvant chemotherapy were significantly less likely to suffer GC recurrence (P=0.001) and succumb to mortality (P=0.004), compared with those who received alternative chemotherapies. However, only the patients with DLC1-positive GC receiving FP-LOHP [DLC1 (+)/FP-LOHP (+)] exhibited a more favorable TTR and OS, compared with the patients with DLC1 (+)/FP-LOHP (−) (TTR, P=0.001; OS, P=0.020). No significant improvement in clinical outcome was observed in GC patients with low DLC1 receiving FP-LOHP treatment (TTR, P=0.270; OS, P=0.197). In conclusion, low expression of DLC1 correlated with GC progression and is predictive of higher rates of recurrence and mortality. Only patients with DLC1-positive GC may have an improved treatment outcome from the use of FP-LOHP as adjuvant chemotherapy.

Theranostic pH-sensitive nanoparticles for highly efficient targeted delivery of doxorubicin for breast tumor treatment

A multifunctional theranostic nanoplatform integrated with environmental responses has been developed rapidly over the past few years as a novel treatment strategy for several solid tumors. We synthesized pH-sensitive poly(β-thiopropionate) nanoparticles with a supermagnetic core and folic acid (FA) conjugation (FA-doxorubicin-iron oxide nanoparticles [FA-DOX@ IONPs]) to deliver an antineoplastic drug, DOX, for the treatment of folate receptor (FR)-overexpressed breast cancer. In addition to an imaging function, the nanoparticles can release their payloads in response to an environment of pH 5, such as the acidic environment found in tumors. After chemical (1H nuclear magnetic resonance) and physical (morphology and super-magnetic) characterization, FA-DOX@IONPs were shown to demonstrate pH-dependent drug release profiles. Western blotting analysis revealed the expression of FRs in three breast cancer cell lines, MCF-7, BT549, and MD-MBA-231. The cell counting kit-8 assay and transmission electron microscopy showed that FA-DOX@IONPs had the strongest cytotoxicity against breast cancer cells, compared with free DOX and non-FR targeted nanoparticles (DOX@IONPs), and caused cellular apoptosis. The FA-DOX@IONP-mediated cellular uptake and intracellular internalization were clarified by fluorescence microscopy. FA-DOX@IONPs plus magnetic field treatment suppressed in vivo tumor growth in mice to a greater extent than either treatment alone; furthermore, the nanoparticles exerted no toxicity against healthy organs. Magnetic resonance imaging was successfully applied to monitor the nanoparticle accumulation. Our results suggest that theranostic pH-sensitive nanoparticles with dual targeting could enhance the available therapies for cancer.

Mitochondrial topoisomerase I absence enhances aerobic glycolysis in cancer

Aerobic glycolysis plays an important role in cancer progression. New target genes regulating cancer aerobic glycolysis must be explored to improve patient prognosis. Mitochondrial topoisomerase I (TOP1MT) deficiency suppresses glucose oxidative metabolism but enhances glycolysis in normal cells. Here, we examined the role of TOP1MT in gastric cancer (GC) and attempted to determine the underlying mechanism. Using in vitro and in vivo experiments and analyzing the clinicopathological characteristics of patients with GC, we found that TOP1MT expression was lower in GC samples than in adjacent nonmalignant tissues. TOP1MT knockdown significantly promoted GC migration and invasion in vitro and in vivo. Importantly, TOP1MT silencing increased glucose consumption, lactate production, glucose transporter 1 expression and the epithelial-mesenchymal transition (EMT) in GC. Additionally, regulation of glucose metabolism induced by TOP1MT was significantly associated with lactate dehydrogenase A (LDHA) expression. A retrospective analysis of clinical data from 295 patients with GC demonstrated that low TOP1MT expression was associated with lymph node metastasis, recurrence and high mortality rates. TOP1MT deficiency enhanced glucose aerobic glycolysis by stimulating LDHA to promote GC progression.

Bapx1 mediates transforming growth factor-β- induced epithelial-mesenchymal transition and promotes a malignancy phenotype of gastric cancer cells

The homeoprotein Bapx1 is an important regulator of gastroduodenal tract morphogenesis. Here, we investigated how Bapx1 influences gastric cancer (GC) prognosis and elucidated the underlying mechanisms. Bapx1 expression was greater in GC tissues compared to adjacent non-tumor tissues and expression was positively correlated with mortality, lymph node and distance metastasis. Silencing Bapx1 diminished cell invasion/migration and decreased mesenchymal phenotypes. Transforming growth factor-β (TGF-β) induced Bapx1 expression and epithelial-mesenchymal transition (EMT) in GC cells. However, down-regulated Bapx1 reversed TGF-β induced invasion, migration, morphological changes, and EMT. In summary, Bapx1 indicates poor prognosis for GC by promoting tumor migration and invasion via TGF-β-induced EMT.

Combined neutrophil/platelet/lymphocyte/differentiation score predicts chemosensitivity in advanced gastric cancer

BackgroundGastric cancer is common in developing regions, and we hope to find out an economical but practical prognostic indicator. It was reported that pre-treatment peripheral neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR), as well as differentiation status, were associated with cancer progression. Hence, we introduced a novel combined Neutrophil/platelet/lymphocyte/differentiation Score (cNPLDS) to improve the prediction value of palliative chemotherapeutic response in advanced gastric cancer.MethodsAccording to statistical sample size estimation, 136 primary diagnosed unresectable advanced ptaients were included for a retrospective study. The follow-up end-point was progression free survival (PFS) during the first-line palliative chemotherapy. Differentiation stratified patients into well, medium and poor groups by score 1 to 3, while patients with neither elevated NLR and PLR, only one elevated, or both elevated were of the combined NLR-PLR score (cNPS) 1 to 3, respectively. The cNPLDS was calculated by multiplying the tumor differentiation score and cNPS.ResultsDetermined by the receiver operating characteristic (ROC) curve, the optimal cut-off points for NLR and PLR were 3.04 and 223. Through univariate analysis and survival analysis, poor differentiation, high NLR, high PLR, high cNPS, and high cNPLDS respectively indicated inferior PFS during the first-line palliative chemotherapy. Patients were furhter classified into low to high risk groups by cNPLDS. Groups of elevated NLR, PLR, cNPS, and cNPLDS showed lower disease control rate. Compared to other parameters, cNPLDS significantly improved the accuracy in predicing the first-progression.ConclusionsThis study indicates that the novel parameter cNPLDS is superior to NLR or PLR alone, or even cNPS, in predicting the first-line chemosensitivity in advanced gastric cancer.

686PDLC1 DETERMINES THE EFFICIENCY OF FLUOROPYRIMIDINE AND OXALIPLATIN REGIMEN IN GASTRIC CANCER ADJUVANT CHEMOTHERAPY

ABSTRACT Aim: The Rho-GTPase-activating protein Deleted in liver cancer (DLC1) is recently known as a tumor suppressor and deficient in gastric cancer (GC) cells. However, the prognostic value of DLC1 in GC is still unclear. On the other hand, fluoropyrimidine and oxaliplatin (FP-LOHP) regimen is wildly used for GC adjuvant chemotherapy, but no reliable marker has been found to determine the efficiency of this regimen. Methods: From 2004 to 2014, we retrospectively followed 251 Stage IB-III patients with radical resection. All patients received adjuvant chemotherapy with or without FP-LOHP. The DLC1 expression of in GC and their para-cancerous tissues was detected by immunohistochemical staining. The pathological factors, including time to recurrence (TTR) and overall survival time (OS), were analyzed. Results: DLC1 was lowly expressed in most (185/251) GC samples compared to normal mucosa. Lower expression of DLC1 indicated larger tumor size, more advanced TNM stage, deeper tumor invasion, and more lymph node metastasis. On the contrary, relatively higher DLC1 expression demonstrated longer TTR (HR 2.232; 95% CI 1.295-3.857; P = 0.004) and OS (HR 2.910; 95% CI 1.543-5.488; P = 0.001). Patients applying FP-LOHP as adjuvant chemotherapy are less likely to suffer GC recurrence than those used other therapies. However, only the DLC1 positive GC patients receiving FP-LOHP [DLC1(+)/FP-LOHP(+)] showed more favorable TTR and OS than DLC1(-)/FP-LOHP(+) (TTR, k2 = 26.364, P DCL1 FP-LOHP Total (%) TTR (month) Median (95% CI) 3-yr non-recurrence (%) OS (month) Median (95% CI) 5-yr survival (%) + + 13.9 / 89.6 / 74.5 + - 12.4 37 (25.8-48.2) 51.4 / 58.6 - + 27.5 27 (21.6-32.4) 32.9 51 (33.2-68.8) 16.7 - - 46.2 22 (14.3-29.7) 23.3 36 (32.4-39.6) 28.2 Conclusions: Low expression of DLC1 is correlated with GC progression and predicts high risk of recurrence and mortality. Only the DLC1 positive patients may benefit from FP-LOHP as adjuvant chemotherapy in GC. Disclosure: All authors have declared no conflicts of interest.