Matrix Stiffness Triggers Lipid Metabolic Cross-talk between Tumor and Stromal Cells to Mediate Bevacizumab Resistance in Colorectal Cancer Liver Metastases.

Bevacizumab is an anti-VEGF monoclonal antibody that plays an important role in the combination treatment of advanced colorectal cancer. However, resistance remains a major hurdle limiting bevacizumab efficacy, highlighting the importance of identifying a mechanism of antiangiogenic therapy resistance. Here, we investigated biophysical properties of the extracellular matrix (ECM) related to metabolic processes and acquired resistance to bevacizumab. Evaluation of paired pre- and posttreatment samples of liver metastases from 20 colorectal cancer patients treated with combination bevacizumab therapy, including 10 responders and 10 nonresponders, indicated that ECM deposition in liver metastases and a highly activated fatty acid oxidation (FAO) pathway were elevated in nonresponders after antiangiogenic therapy compared with responders. In mouse models of liver metastatic colorectal cancer (mCRC), anti-VEGF increased ECM deposition and FAO in colorectal cancer cells, and treatment with the FAO inhibitor etomoxir enhanced the efficacy of antiangiogenic therapy. Hepatic stellate cells (HSC) were essential for matrix stiffness-mediated FAO in colon cancer cells. Matrix stiffness activated lipolysis in HSCs via the focal adhesion kinase (FAK)/yes-associated protein (YAP) pathway, and free fatty acids secreted by HSCs were absorbed as metabolic substrates and activated FAO in colon cancer cells. Suppressing HSC lipolysis using FAK and YAP inhibition enhanced the efficacy of anti-VEGF therapy. Together, these results indicate that bevacizumab-induced ECM remodeling triggers lipid metabolic cross-talk between colon cancer cells and HSCs. This metabolic mechanism of bevacizumab resistance mediated by the physical tumor microenvironment represents a potential therapeutic target for reversing drug resistance. SIGNIFICANCE: Extracellular matrix stiffening drives bevacizumab resistance by stimulating hepatic stellate cells to provide fuel for mCRC cells in the liver, indicating a potential metabolism-based therapeutic strategy for overcoming resistance.

Design and Synthesis of Polysiloxane Based Side Chain Liquid Crystal Polymer for Improving the Processability and Toughness of Magnesium Hydrate/Linear Low-Density Polyethylene Composites.

In this study, a polysiloxane grafted by thermotropic liquid crystal polymer (PSCTLCP) is designed and synthesized to effectively improve the processability and toughness of magnesium hydroxide (MH)/linear low-density polyethylene (LLDPE) composites. The obtained PSCTLCP is a nematic liquid crystal polymer; the liquid crystal phase exists in a temperature range of 170 to 275 °C, and its initial thermal decomposition temperature is as high as 279.6 °C, which matches the processing temperature of MH/LLDPE composites. With the increase of PSCTLCP loading, the balance melt torque of MH/LLDPE/PSCTLCP composites is gradually decreased by 42% at 5 wt % PSCTLCP loading. Moreover, the power law index of MH/LLDPE/PSCTLCP composite melt is smaller than 1, but gradually increased with PSCTLCP, the flowing activation energy of PSCTLCP-1.0 is lower than that of MH/LLDPE at the same shear rate, indicating that the sensitivity of apparent melt viscosity of the composites to shear rate and to temperature is decreased with the increase of PSCTLCP, and the processing window is broadened by the addition of PSCTLCP. Besides, the elongation at break of MH/LLDPE/PSCTLCP composites increases from 6.85% of the baseline MH/LLDPE to 17.66% at 3 wt % PSCTLCP loading. All the results indicate that PSCTLCP can significantly improve the processability and toughness of MH/LLDPE composites.

Chain Extension and Synergistic Flame-Retardant Effect of Aromatic Schiff Base Diepoxide on Polyamide 6/Aluminum Diethylphosphinate Composites.

A way to suppress the deterioration in mechanical properties of polyamide 6 (PA6) is required, especially with high loading of flame retardants in the matrix. In this study, a novel aromatic Schiff base diepoxide (DES) was synthesized. It exhibited an efficient chain extension effect on PA6 and a synergistic flame-retardant effect with aluminum diethylphosphinate (AlPi) for PA6. The PA6 composite with 16 wt.% AlPi only passed UL-94 V-0 rating at 1.6 mm thickness, while the combination of 1.5 wt.% DES with 13 wt.% AlPi induced PA6 to achieve a UL-94 V-0 rating at 0.8 mm thickness. The tensile, flexural, and Izod notched impact strengths were increased by 16.2%, 16.5%, and 24.9%, respectively, compared with those of V-0 flame-retarded PA6 composites with 16 wt.% AlPi. The flame-retarded mechanism of PA6/AlPi/DES was investigated by cone calorimetry and infrared characterization of the char residues and pyrolysis products. These results showed that DES had a synergistic effect with AlPi in condensed-phase flame retardation by promoting the production of aluminum phosphorus oxides and polyphosphates in the char residues.