• Wnt pathway
• cancer stem cells
• tumor biology

• Animals
• Humans
• Carcinogenesis/genetics
• Drug Resistance, Neoplasm/genetics
• Neoplasms/metabolism
• Neoplasms/pathology
• Neoplasms/genetics
• Neoplasms/drug therapy
• Neoplastic Stem Cells/metabolism
• Neoplastic Stem Cells/pathology
• Wnt Signaling Pathway

• Lenvatinib
• combination therapy
• drug resistance
• prognostic factors

• BCL-XL
• Elastic net
• Ovarian cancer
• Random Forest
• WNT/β-catenin
• XGBoost

• combination therapy
• hepatic arterial infusion chemotherapy
• hepatocellular carcinoma
• sorafenib

• Thiosemicarbazones/chemistry
• Thiosemicarbazones/pharmacology
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/chemistry
• Antineoplastic Agents/chemical synthesis
• Humans
• Pyridines/chemistry
• Pyridines/pharmacology
• Coordination Complexes/chemistry
• Coordination Complexes/pharmacology
• Coordination Complexes/chemical synthesis
• Structure-Activity Relationship
• Animals
• Apoptosis/drug effects
• Cell Line, Tumor
• Cell Proliferation/drug effects
• Mice
• Drug Screening Assays, Antitumor
• Molecular Structure

Our previous study showed that hepatic arterial infusion chemotherapy (HAIC) using oxaliplatin, fluorouracil, and leucovorin (FOLFOX) plus sorafenib provided a significant survival benefit over sorafenib for advanced hepatocellular carcinoma. However, it is unclear whether the survival benefit should be attributed to the synergism between HAIC and sorafenib or just HAIC alone. We aim to compare HAIC using FOLFOX plus sorafenib with HAIC alone in patients with advanced hepatocellular carcinoma.

This was a retrospective study including 225 eligible patients treated with HAIC using FOLFOX (HAIC alone group, n=126, oxaliplatin 85 mg/m², leucovorin 400 mg/m², fluorouracil bolus 400 mg/m² and 2400 mg/m² for 46 hours, every 3 weeks) alone or HAIC plus sorafenib (soraHAIC group, n=99, sorafenib 400 mg twice daily). Survival curves were calculated by the Kaplan-Meier method, and propensity-score matching was used to reduce bias.

The soraHAIC group showed a longer overall survival (12.9 [95% CI, 10.4-15.4] vs. 10.5 [95% CI, 9.5-11.5] months, HR=0.71 [95% CI, 0.53-0.96]; P=0.025), a better progression free survival (7.0 [95% CI, 5.3-8.8] vs. 5.3 [95% CI, 3.5-7.1] months, HR=0.76 [95% CI, 0.58-0.99]; P=0.046), and a higher disease control rate (RECIST 1.1: 74.8% vs. 61.1%, P=0.030) than the HAIC alone group. In multivariate analysis, soraHAIC was an independent favor factor for survival. In terms of the grade 3/4 adverse event, hand–foot skin reaction was more frequent in the soraHAIC group than the HAIC alone group. In the propensity-score matched cohorts (93 pairs), the overall survival, the progression free survival and disease control rates in the soraHAIC group were also better than those in the HAIC group (P<0.05).

HAIC plus sorafenib may improve overall survival and progression free survival compared with HAIC alone as initial treatment for advanced hepatocellular carcinoma.

• FOLFOX
• hepatic arterial infusion chemotherapy
• hepatocellular carcinoma
• sorafenib
• treatment

• Chemo-resistance
• Ovarian cancer
• PARP inhibitors
• miR-506-3p

Matrine, an alkaloid isolated from Sophora flavescens, promotes tumor cell apoptosis and strengthens the anticancer capacity of chemotherapeutic drugs. The present study aimed to investigate the inhibitory effect and underlying mechanism of matrine in combination with cisplatin on liver cancer progression. Tumor progression was studied in nude mice. The human liver cancer cell line HepG2 was injected into BALB/c nude mice subcutaneously to establish a tumor model. Mice were subsequently treated with matrine, cisplatin, matrine + cisplatin or normal saline. Nude mice and tumor growth were monitored. Tumors were excised and the expression of survivin, caspase-3, caspase-7 and caspase-9 was detected by immunohistochemistry. Western blotting was used to determine the expression of survivin, caspase-3, caspase-7, caspase-9 and X-linked inhibitor of apoptosis protein (XIAP) in tumor tissues. The results demonstrated that matrine exerted anticancer effects in liver cancer-transplanted tumors, as evidenced by decrease in tumor weight and volume. Furthermore, the tumor inhibition rate in mice treated with matrine + cisplatin was 83.3%, whereas it was of 37.5 and 75% in mice treated with matrine or cisplatin alone, respectively. In addition, the expression of survivin and XIAP was significantly downregulated, whereas the expression of caspase-3, caspase-7 and caspase-9 was significantly upregulated in tumor tissues from nude mice treated with matrine + cisplatin, compared with those treated with cisplatin, matrine or normal saline. These findings suggested that the combination of matrine and cisplatin may promote tumor cell apoptosis in liver cancer by activating the caspase apoptosis pathway and suppressing the survivin-associated inhibition of caspase-9.

• caspase
• cisplatin
• liver cancer
• matrine
• surviving

• 4-Acetylantrocamol LT3
• Autophagy
• Hepatocellular Carcinoma Cells
• Wnt/[Formula: see text]-Catenin, mTOR
• YAP/TAZ

• Biomarker
• Hepatocellular carcinoma
• Specific diagnosis
• Target therapy
• Wnt3a

• Cardamonin
• Gastric cancer
• Multidrug resistance
• Wnt/β-catenin

• Wnt signaling
• apoptosis
• cell fusion
• mesenchymal stem cells
• tumor

The clinical benefit of adjuvant chemotherapy for stage II colorectal cancer (CRC) is controversial. This study aimed to explore novel gene signature to predict outcome benefit of postoperative 5-Fu-based therapy in stage II CRC.

Gene-expression profiles of stage II CRCs from two datasets with 5-Fu-based adjuvant chemotherapy (training dataset, n = 212; validation dataset, n = 85) were analyzed to identify the indicator. A systemic approach by integrating gene-expression and protein-protein interaction (PPI) network was implemented to develop the predictive signature. Kaplan-Meier curves and Cox proportional hazards model were used to determine the survival benefit of adjuvant chemotherapy. Experiments with shRNA knock-down were carried out to confirm the signature identified in this study.

In the training dataset, we identified 44 PPI sub-modules, by which we separate patients into two clusters (1 and 2) having different chemotherapeutic benefit. A predictor of 11 PPI sub-modules (11-PPI-Mod) was established to discriminate the two sub-groups, with an overall accuracy of 90.1%. This signature was independently validated in an external validation dataset. Kaplan-Meier curves showed an improved outcome for patients who received adjuvant chemotherapy in Cluster 1 sub-group, but even worse survival for those in Cluster 2 sub-group. Similar results were found in both the training and the validation dataset. Multivariate Cox regression revealed an interaction effect between 11-PPI-Mod signature and adjuvant therapy treatment in the training dataset (RFS, p = 0.007; OS, p = 0.006) and the validation dataset (RFS, p = 0.002). From the signature, we found that PTGES gene was up-regulated in CRC cells which were more resistant to 5-Fu. Knock-down of PTGES indicated a growth inhibition and up-regulation of apoptotic markers induced by 5-Fu in CRC cells.

Only a small proportion of stage II CRC patients could benefit from adjuvant therapy. The 11-PPI-Mod as a potential predictor could be helpful to distinguish this sub-group with favorable outcome.

The online version of this article (10.1186/s12885-017-3821-4) contains supplementary material, which is available to authorized users.

• 11-PPI-Mod
• Adjuvant chemotherapy
• Biomarkers
• Colorectal cancer

Colorectal cancer (CRC) is the fourth most frequent type of malignancy in the world. Metastasis accounts for >90% mortalities in patients with CRC. The metastasis-associated in colon cancer 1 (MACC1) gene has been identified as a novel biomarker for the prediction of metastasis and disease prognosis, particularly for patients with early-stage disease. Previous clinical studies demonstrated that MACC1 expression and polymorphisms in CRC tissues were indicators of metastasis, and that circulating transcripts in plasma were also significantly associated with the survival of patients. The present review describes the use of MACC1 beyond its utility in the clinic. By elucidating the upstream and downstream signal pathways of MACC1, the well-known mechanisms of MACC1-mediated cell proliferation, invasion, migration and epithelial-mesenchymal transition (EMT) are summarized, as well as the potential signaling pathways. Furthermore, the underlying mechanisms by which the overexpression of MACC1 causes cisplatin resistance are emphasized.

• biomarker
• colorectal cancer
• mechanism
• metastasis
• metastasis-associated in colon cancer 1

• CARF
• HCC
• RasV12
• beta-catenin/TCF signaling

In a randomized phase II study of sorafenib plus hepatic arterial infusion chemotherapy with cisplatin in comparison with sorafenib alone in patients with advanced hepatocellular carcinoma, it yielded favorable overall survival when compared with sorafenib alone. This is the first report of its effectiveness in relation to the overall survival in comparison with that of sorafenib alone in patients with advanced hepatocellular carcinoma.

Sorafenib (Sor) is acknowledged as a standard therapy for advanced hepatocellular carcinoma (HCC). This trial was conducted to evaluate the effect of addition of hepatic arterial infusion chemotherapy with cisplatin (SorCDDP) to Sor for the treatment of advanced HCC.

We conducted a multicenter open-labeled randomized phase II trial in chemo-naïve patients with advanced HCC with Child-Pugh scores of 5–7. Eligible patients were randomly assigned 2:1 to receive SorCDDP (sorafenib: 400 mg bid; cisplatin: 65 mg/m², day 1, every 4–6 weeks) or Sor (400 mg bid). The primary end point was overall survival.

A total of 108 patients were randomized (Sor, n = 42; SorCDDP, n = 66). The median survival in the Sor and SorCDDP arms were 8.7 and 10.6 months, respectively [stratified hazard ratio (95% confidence interval), 0.60 (0.38–0.96), P = 0.031]. The median time to progression and the response rate were, respectively, 2.8 months and 7.3% in the Sor arm and 3.1 months and 21.7% in the SorCDDP arm. The adverse events were more frequent in the SorCDDP arm than in the Sor arm, but well-tolerated.

SorCDDP yielded favorable overall survival when compared with Sor in patients with advanced HCC.

UMIN-CTR (http://www.umin.ac.jp/ctr/index-j.htm), identification number: UMIN000005703.

• cisplatin
• hepatic arterial infusion chemotherapy
• hepatocellular carcinoma
• randomized phase II trial
• sorafenib

• GSK-3β
• NDRG1
• Nur77
• liver cancer
• β-catenin

• Krüppel-like factor 8 chemoresistance
• hepatocellular carcinoma
• liver cancer stem cells
• prognosis

• Hepatocellular carcinoma
• Immunohistochemistry
• Prognosis
• Tissue microarrays
• Wnt/β-catenin signal
• Wnt3a

• Adult
• Aged
• Biomarkers, Tumor/analysis
• Carcinoma, Hepatocellular/chemistry
• Carcinoma, Hepatocellular/mortality
• Carcinoma, Hepatocellular/pathology
• Carcinoma, Hepatocellular/therapy
• Chi-Square Distribution
• Disease-Free Survival
• Female
• Humans
• Immunohistochemistry
• Kaplan-Meier Estimate
• Liver Neoplasms/chemistry
• Liver Neoplasms/mortality
• Liver Neoplasms/pathology
• Liver Neoplasms/therapy
• Male
• Middle Aged
• Multivariate Analysis
• Neoplasm Staging
• Proportional Hazards Models
• Risk Factors
• Time Factors
• Tissue Array Analysis
• Treatment Outcome
• Up-Regulation
• Wnt3A Protein/analysis

• ELISA
• Hepatocellular carcinoma
• Immunohistochemistry
• Wnt3a

• Adult
• Aged
• Biomarkers, Tumor/blood
• Biomarkers, Tumor/genetics
• Carcinoma, Hepatocellular/blood
• Carcinoma, Hepatocellular/genetics
• Carcinoma, Hepatocellular/pathology
• Diagnosis, Differential
• Female
• Gene Expression Regulation, Neoplastic
• Hepatitis B/blood
• Hepatitis B/pathology
• Hepatitis B/virology
• Humans
• Liver Cirrhosis/blood
• Liver Cirrhosis/genetics
• Liver Cirrhosis/pathology
• Liver Neoplasms/blood
• Liver Neoplasms/genetics
• Liver Neoplasms/pathology
• Male
• Middle Aged
• Neoplasm Metastasis
• Wnt3A Protein/blood
• Wnt3A Protein/genetics
• alpha-Fetoproteins/biosynthesis
• alpha-Fetoproteins/genetics

Wnt signaling transduces evolutionarily conserved pathways which play important roles in initiating and regulating a diverse range of cellular activities, including cell proliferation, calcium homeostasis, and cell polarity. The role of Wnt signaling in controlling cell proliferation and stem cell self-renewal is primarily carried out through the canonical pathway, which is the best-characterized the multiple Wnt signaling branches. The past 10 years has seen a rapid expansion in our understanding of the complexity of this pathway, as many new components of Wnt signaling have been identified and linked to signaling regulation, stem cell functions, and adult tissue homeostasis. Additionally, a substantial body of evidence links Wnt signaling to tumorigenesis of cancer types and implicates it in the development of cancer drug resistance. Thus, a better understanding of the mechanisms by which dysregulation of Wnt signaling precedes the development and progression of human cancer may hasten the development of pathway inhibitors to augment current therapy. This review summarizes and synthesizes our current knowledge of the canonical Wnt pathway in development and disease. We begin with an overview of the components of the canonical Wnt signaling pathway and delve into the role this pathway has been shown to play in stemness, tumorigenesis, and cancer drug resistance. Ultimately, we hope to present an organized collection of evidence implicating Wnt signaling in tumorigenesis and chemoresistance to facilitate the pursuit of Wnt pathway modulators that may improve outcomes of cancers in which Wnt signaling contributes to aggressive disease and/or treatment resistance.

• Wnt
• cancer
• cancer drug resistance
• cancer stem cells
• canonical Wnt
• cell differentiation
• cell proliferation
• fate determination
• self-renewal
• signal transduction
• stem cells
• tumorigenesis
• β-catenin

Wnt3a, one of Wnt family members, plays key roles in regulating pleiotropic cellular functions, including self-renewal, proliferation, differentiation, and motility. Accumulating evidence has suggested that Wnt3a promotes or suppresses tumor progression via the canonical Wnt signaling pathway depending on cancer type. In addition, the roles of Wnt3a signaling can be inhibited by multiple proteins or chemicals. Herein, we summarize the latest findings on Wnt3a as an important therapeutic target in cancer.

Sorafenib is a recommended treatment for advanced hepatocellular carcinoma. The study is to evaluate the efficacy of sorafenib plus cyproheptadine compared with sorafenib alone in patients with advanced hepatocellular carcinoma.

A retrospective cohort study reviewed all consecutive advanced hepatocellular carcinoma cases with Child-Pugh Class A disease starting sorafenib treatment at our hospital from August 2012 to March 2013. They were followed up until 31 December 2013. A total of 52 patients were enrolled: 32 patients in the combination (sorafenib–cyproheptadine) group and 20 patients in the control (sorafenib alone) group. The response to treatment, overall survival and progression-free survival were compared.

The median overall survival was 11.0 months (95% confidence interval: 6.8–15.1 months) in the combination group compared with 4.8 months (95% confidence interval: 3.1–6.6 months) in the control group (crude hazard ratio = 0.45, 95% confidence interval: 0.22–0.82). The median progression-free survival time was 7.5 months (95% confidence interval: 5.1–10.0 months) in the combination group compared with 1.7 months (95% confidence interval: 1.4–2.1 months) in the control group (crude hazard ratio = 0.43, 95% confidence interval: 0.22–0.86). Kaplan–Meier survival analysis revealed that both overall survival and progression-free survival in the combination group were significantly longer than that in the control group. The multivariate model found patients in the combination group were 76% less likely to die (adjusted hazard ratio = 0.24, 95% confidence interval: 0.10–0.58) and 82% less likely to have progression (adjusted hazard ratio = 0.18, 95% confidence interval: 0.08–0.44) during the 17 months of follow-up.

Cyproheptadine may significantly improve survival outcomes of sorafenib-treated advanced hepatocellular carcinoma patients.

• cyproheptadine
• hepatocellular carcinoma
• sorafenib
• survival

• DKK
• beta-catenin
• biomarker
• hepatoma
• morphogen

The aims of this study were to evaluate the frequency of dose-limiting toxicities and to find the recommended dose of combination chemotherapy with sorafenib and transcatheter arterial infusion (TAI) using cisplatin for patients with advanced hepatocellular carcinoma (HCC), for whom surgical resection, local ablation therapy, or transcatheter arterial chemoembolization were not indicated. Patients received 800 mg sorafenib daily. Cisplatin was given at one of three dosages (level 1, 35 mg/m²/cycle; level 2, 50 mg/m²/cycle; and level 3, 65 mg/m²/cycle) from feeding arteries to the HCC. The treatment was repeated every 4–6 weeks up to a maximum of six cycles, until there were signs of tumor progression or unacceptable toxicity. The dose-limiting toxicities experienced by the 20 enrolled patients were grade 4 increased aspartate aminotransferase at level 1, grade 3 gastrointestinal hemorrhaging at level 1, and grade 3 hypertension at level 3. The common drug-related adverse events that were of severity grade 3 or 4 included the elevation of aspartate aminotransferase (30%), alanine aminotransferase (20%), amylase (30%), and lipase (30%). Partial response was seen in four patients (20%), and 13 patients (65%) had stable disease. The median overall survival and progression-free survival were 9.1 and 3.3 months, respectively. The combination of sorafenib at 800 mg/day with TAI of cisplatin at 65 mg/m²/cycle was determined to be the recommended regimen. A randomized phase II trial of sorafenib alone versus sorafenib plus TAI of cisplatin is currently underway. This study was registered at UMIN as trial number UMIN000001496.

• Arterial infusion
• chemotherapy
• cisplatin
• hepatocellular carcinoma
• sorafenib