Purpose: MET signaling has been suggested a potential role in hepatocellular carcinoma (HCC) and associated with prometastasis during antiangiogenesis therapy. We investigated the potential association between MET expression and therapeutic response to sorafenib in patients with HCC. Antitumor effects of cabozantinib, a dual inhibitor of MET and VEGFR2, were examined in cultured HCC cells as well as in vivo models.Experimental Design: Total MET and phosphorylated MET (p-MET) were measured in 29 resected HCC specimens, and correlated with response to sorafenib as postoperative adjuvant therapy. In the second set of experiments using cultured HCC cells, and mouse xenograft and metastatic models, effects of cabozantinib were examined.Results: High level of p-MET in resected HCC specimens was associated with resistance to adjuvant sorafenib therapy. In cultured HCC cells that expressed p-MET, cabozantinib inhibited the activity of MET and its downstream effectors, leading to G 1 -phase arrest. Cabozantinib inhibited tumor growth in p-METpositive and p-MET-negative HCC by decreasing angiogenesis, inhibiting proliferation, and promoting apoptosis, but it exhibited more profound efficacy in p-MET-positive HCC xenografts. Cabozantinib blocked the hepatocyte growth factor (HGF)-stimulated MET pathway and inhibited the migration and invasion of the HCC cells. Notably, cabozantinib reduced the number of metastatic lesions in the lung and liver in the experimental metastatic mouse model.Conclusions: Patients with HCC with high level of p-MET are associated with resistance to adjuvant sorafenib treatment. The dual blockade of VEGFR2 and MET by cabozantinib has significant antitumor activities in HCC, and the activation of MET in HCC may be a promising efficacy-predicting biomarker.
Our findings indicate that transplantation of LINGO-1-RNA interference-treated neural stem cells facilitates functional recovery after spinal cord injury and represents a promising potential strategy for the repair of spinal cord injury.
Cabozantinib reverses P-gp-mediated MDR by directly inhibiting the efflux function of P-gp, indicating that cabozantinib may help to reverse P-gp-mediated MDR in HCC and other cancer chemotherapy.
BackgroundTivantinib has been described as a highly selective inhibitor of MET and is currently in a phase III clinical trial for the treatment of hepatocellular carcinoma (HCC). However, the mechanism of tivantinib anti-tumor effect has been questioned by recent studies.ResultsWe show that tivantinib indiscriminately inhibited MET dependent and independent HCC cells proliferation. In contrast, other MET inhibitors, JNJ-38877605 and PHA-665752, just specifically inhibited the growth of MET dependent HCC cells. Tivantinib neither inhibit constitutive MET phosphorylation nor HGF-induced MET phosphorylation in HCC cells. In the microtubule polymerization analysis, tivantinib affected microtubule dynamics by a mechanism as a microtubule depolymerizer. Interesting, unlike other microtubule-targeting agents, paclitaxel and vincristine, tivantinib showed similar anti-proliferative activity in parental and multidrug-resistant cells. Further studies demonstrated that tivantinib induced a G2/M arrest and promoted apoptosis by both intrinsic and extrinsic pathway. The in vivo efficacy evaluation showed that tivantinib exhibited a good anti-tumor growth activity with anti-proliferative and pro-apoptotic effects.ConclusionsThe potent anti-tumor activity of tivantinib in HCC was achieved by targeting microtubule. Tivantinib treatment for patients with HCC should not be selected based on MET status.
The transplantation of bone marrow mesenchymal stem cells (BMSCs) to repair spinal cord injury (SCI) has become a promising therapy. However, there is still a lack of visual evidence directly implicating the transplanted cells as the source of the improvement of spinal cord function. In this study, BMSCs were labeled with NF-200 promoter and lipase-activated gadolinium-containing nanoparticles (Gd-DTPA-FA). Double labeled BMSCs were implanted into spinal cord transaction injury in rat models in situ, the function recovery was evaluated on 1st, 7th, 14th, 28 th days by MRI, Diffusion Tensor Imaing, CT imaging and post-processing, and histological observations. BBB scores were used for assessing function recovery. After transplantation of BMSCs, the hypersignal emerged in spinal cord in T1WI starting at day 7 that was focused at the injection site, which then increased and extended until day 14. Subsequently, the increased signal intensity area rapidly spread from the injection site to entire injured segment lasting four weeks. The diffusion tensor tractography and histological analysis both showed the nerve fibre from dividing to connecting partly. Immunofluorescence showed higher expression of NF-200 in Repaired group than Injury group. Electron microscopy showed detachment and loose of myelin lamellar getting better in Repaired group compared with the Injury group. BBB scores in Repaired group were significantly higher than those of injury animals. Our study suggests that the migration and distribution of Gd-DTPA-FA labeled BMSCs can be tracked using MRI. Transplantation of BMSCs represents a promising potential strategy for the repair of SCI.
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