Brevilin A is a potent anti-metastatic CRC agent that targets the VEGF-IL6-STAT3 axis in the HSCs-CRC interplay.

BACKGROUND: More than half of the colorectal cancer (CRC) patients will develop liver metastasis that underlies the cancer mortality. In the hepatic tumor microenvironment, the interplay between CRC cells and hepatic stellate cells (HSCs), and the activation of HSCs to become carcinoma-associated fibroblasts (CAFs) will further promote the cancer development. Nevertheless, the critical signaling molecule that involved in these processes remains unknown, which hinders the development of effective therapeutic agents for the treatment of metastatic CRC (mCRC). METHODS: Conditioned medium system and co-cultured system were used to examine the interplay between CRC cells and HSCs. Luminex liquid suspension chip detection and enzyme-linked immunosorbent assay were used to screen for the mediators in the conditioned medium that facilitated the CRC-HSCs interplay and HSCs-to-CAFs differentiation. Cell and animal models were used to examine whether brevilin A inhibited CRC liver metastasis via the VEGF-IL6-STAT3 axis. RESULTS: In the CRC-HSCs interplay, CRC promoted HSCs-to-CAFs differentiation by releasing vascular endothelial growth factor (VEGF); and HSCs released interleukin 6 (IL6) that activated signal transducer and activator of transcription 3 (STAT3) in the CRC and hence increased the cancer metastatic potential. The functions of the VEGF-IL6-STAT3 axis in the HSCs-CRC interplay were further validated by VEGF recombinant protein and IL6 neutralizing antibody. More importantly, brevilin A, an active compound isolated from Centipeda minima (L.) A. Br. et Aschers, targeted the VEGF-IL6-STAT3 axis in the CRC-HSCs interplay, hence significantly inhibited colorectal liver metastasis and cancer growth both in vitro and in vivo. CONCLUSIONS: We are the first to demonstrate brevilin A possesses potent anti-mCRC effect by targeting the VEGF-IL6-STAT3 axis in the CRC-HSCs interplay. Our findings not only support the development of brevilin A as a novel therapeutic agent for mCRC treatment, but also pave the path for the development of other VEGF-IL6-STAT3 targeting therapeutic strategies.

DEBIRI plus capecitabine: a treatment option for refractory liver-dominant metastases from colorectal cancer.

Aim: This single institution Phase II study evaluated drug-eluting beads loaded with irinotecan (DEBIRI) plus capecitabine in pretreated patients with colorectal cancer liver metastases. Patients & methods: Forty patients with liver-limited or liver-dominant disease, who have failed at least two previous lines of chemotherapy, underwent either four DEBIRI at 2-week interval or two DEBIRI every 4 weeks for bilobar or single-lobe metastases, respectively. Capecitabine was given at 1000 mg/m2 twice-daily on days 1-14 every 3 weeks. Results: Seven partial responses and 12 stable diseases were observed, achieving a disease control rate of 47.5%. Median progression-free survival and overall survival resulted 4 and 8 months, respectively. Grade 3 adverse events occurred in 6/40 points (15%) of patients. Conclusion: DEBIRI plus capecitabine is a valid treatment option for heavily pretreated patients with colorectal cancer liver metastases.

Effect of hematopoietic progenitor cells on the biological characteristics of colon cancer tumor stem cells.

BACKGROUND: Cancer stem cells (CSCs) are a type of tumor cell that are self-sustaining and can differentiate into several different types of cells. The present study aims to investigate the effect of hematopoietic progenitor cells (HPCs) on the biological behavior of colon CSCs (CCSCs) and to determine the underlying molecular mechanisms of liver metastasis in colorectal cancer. METHODS: Subsets of CCSCs were isolated from stem-like HCT116 cells and cocultured with CD133+ HPCs in vitro. Colony formation assay, and CCK-8 were used to assess the effects of HPCs on CCSC subsets. Invasive and migration assay were done to study the effects of HPCs mediated metastatic capacity of CCSC subsets. Expression of MMP-9, VEGF, E-cadherin and ß-catenin was analyzed by qPCR and Western blotting. RESULTS: CCK-8 and colony formation assays showed that HPCs significantly promoted proliferation and colony formation of the CCSC subsets (P=0.031). HPCs also significantly enhanced the migration (P=0.011) and invasive capacity (P=0.001) of the CCSC subsets. Quantitative PCR showed that MMP-9 and VEGF expression in CCSC subsets were significantly upregulated (P=0.000 and P=0.005). Western blotting showed that MMP-9, VEGF and ß-catenin expression in CCSC subsets were significantly upregulated (P=0.000, P=0.005, P=0.000). The protein expression levels of E-cadherin in the CCSC subsets was significantly downregulated (P=0.002). CONCLUSIONS: CD133+ HPCs enhanced migration, invasion and proliferation of CCSC subsets in vitro.

Analysis of the feasibility of microwave ablation for colorectal liver metastases: a preliminary report.

INTRODUCTION: Colorectal liver metastasis is a challenge in the treatment of colorectal cancer and an important factor affecting the prognosis of patients. Currently, microwave ablation has gradually been applied for the treatment of liver cancers as a type of thermal ablation. However, there are no large-scale studies on the effectiveness of microwave ablation for colorectal liver metastases. AIM: To investigate the efficacy of microwave ablation and liver resection for liver metastases from colorectal cancer, and to compare the prognosis between patients treated with microwave ablation and those in the SEER (Surveillance, Epidemiology, and End Results, National Cancer Institute) database. MATERIAL AND METHODS: We retrospectively analyzed the clinical data of 24 patients with colorectal liver metastasis who underwent radical colorectal cancer resection and liver microwave ablation (the MWA group) and 12 patients who received radical colorectal cancer resection and liver resection (the LR group). The complete ablation rate and complications after microwave ablation were observed. Survival analysis was performed for cases treated with liver resection and cases from the SEER database. RESULTS: A total of 53 tumors were ablated in the 24 patients who underwent radical colorectal cancer resection and liver microwave ablation; 52 tumors achieved complete ablation after the first ablation (98.1%). No serious complications occurred in the MWA group, and long-term survival was not significantly different between the MWA and other groups. CONCLUSIONS: Microwave ablation for colorectal liver metastases avoids extensive liver resection while ensuring therapeutic efficacy; the operation is safe, feasible, and reproducible.

Bevacizumab and postoperative wound complications in patients with liver metastases of colorectal cancer.

AIM: The present study investigated whether bevacizumab (BV) is associated with postoperative wound complications (PWCs). PATIENTS AND METHODS: We retrospectively analyzed patients undergoing surgery for liver metastases of colorectal cancer at our Institution. Patients were divided into 3 groups according to the preoperative treatment: che mo therapy with BV (group A), chemotherapy without BV (group B) and no chemotherapy (group C). RESULTS: Between February 2003 and September 2012, 297 patients underwent 373 surgeries. Groups A, B and C consisted of 23, 62 and 288 patients, respectively. PWCs occurred in 29 patients (7.8%). In multivariate analysis, there were no differences in PWCs among the groups (C vs. B:P=0.739; C vs. A: P=0.110). Conversely, lower serum albumin levels (<3.5 g/dl vs. ≥ 3.5 g/dl: p=0.030) and synchronous colorectal resection (no vs. yes; p<0.001) remained significant risk factors of developing PWCs. CONCLUSION: Chemotherapy with or without BV did not influence the risk of PWCs.