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Lymphatic metastasis is the main metastatic route for colorectal cancer, which increases the risk of cancer recurrence and distant metastasis. The properties of the lymph node metastatic colorectal cancer (LNM-CRC) cells are poorly understood, and effective therapies are still lacking. Here, we found that hypoxia-induced fibroblast activation protein alpha (FAPα) expression in LNM-CRC cells. Gain- or loss-function experiments demonstrated that FAPα enhanced tumor cell migration, invasion, epithelial-mesenchymal transition, stemness, and lymphangiogenesis via activation of the STAT3 pathway. In addition, FAPα in tumor cells induced extracellular matrix remodeling and established an immunosuppressive environment via recruiting regulatory T cells, to promote colorectal cancer lymph node metastasis (CRCLNM). Z-GP-DAVLBH, a FAPα-activated prodrug, inhibited CRCLNM by targeting FAPα-positive LNM-CRC cells. Our study highlights the role of FAPα in tumor cells in CRCLNM and provides a potential therapeutic target and promising strategy for CRCLNM.
ABSTRACT
OBJECTIVE: To investigate the interventional effect of the Chinese herbal preparation Xi Fu Pai Chen(XFPC) on pulmonary inflammation and fibrosis in rats with silicosis. METHODS: A total of 144 adult specific pathogen free male SD rats were randomly divided into 6 groups: blank control group, silicosis model group, drug administration control group and groups of low-dose,medium-dose and high-dose XFPC, with 24 rats in each group. Lung silicosis model was established by single inhalation tracheal instillation method, which was treated with 50.0 g/L silica suspension, in groups except in the blank control group. On the 7 th day of modeling, the rats in the drug administration control group were orally given tetrandrine(5 mg/kg body weight), while those in the low-, medium-and high-dose groups were given 43, 86 and 192 g/L of XFPC by atomization inhalation once a day for 20 minutes, 5 days a week for 4 weeks. At the end of drug administration, the histopathological changes of the lung were observed. The number and classification of cells in bronchoalveolar lavage fluid(BALF)were examined, and the levels of malondialdehyde(MDA) and interferon-gamma(IFN-γ) in BALF were measured by enzyme-linked immunosorbent assay. RESULTS: On the 7 th day after modeling, the body weight in the drug administration control group and XFPC high-dose group decreased compared with the blank control group(P<0.05). On the 35 th day after modeling, the body weights of rats in the other 5 groups were lower than that in the blank control group(P<0.05). The pathological changes of lung tissue(infiltration of inflammatory cells, fibrosis and size of silicon nodule) in drug administration control group and XFPC low-dose group were better than those in silicosis model group by naked eyes and under light microscope. The lung coefficient, the proportion of neutrophils and the level of MDA and IFN-γ in BALF of the drug administration control group and XFPC low-dose group decreased(P<0.05), and the proportion of macrophages in BALF increased(P<0.05) compared with the silicosis model group. There was no significant difference in lung coefficients and the relevant indices of BALF between XFPC medium-, high-dose groups and silicosis model group(P>0.05). CONCLUSION: Low dosage XFPC can improve pulmonary fibrosis and inflammation in rats with silicosis, and its mechanism of action may be related to reducing the levels of IFN-γ and MDA in BALF.
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Objective@#To evaluate the feasibility of intravoxel incoherent motion diffusion-weighted magnetic resonance imaging (IVIM-DWI MRI) in the evaluation of tumor vascular normalization in a mouse model of colorectal cancer induced by recombinant human endostatin (rhES).@*Methods@#The CT26 colorectal cancer xenograft model of BALB/c mice were established and divided into rhES group and control group, with 20 mice in each group. The mice of rhES group were intravenously injected with rhES 5 mg·kg-1·d-1 once daily for 12 days, while the mice of the control group were intravenously injected with the same volume of 0.9% saline. 5 mice of rhES group and control group were randomly selected to perform IVIM-DWI MRI as following times: before treatment and four, eight, twelve days after treatment. The parameters of IVIM-DWI were recorded, including true diffusion coefficient(D), pseudo-diffusion coefficient (D*) and perfusion fraction (f). Meanwhile, microvessel density (MVD), pericyte coverage and tumor perfusion in tumor tissues were detected by immunofluorescence, respectively.@*Results@#The tumor volumes of control group and rhES group before treatment were (154.42±24.65) mm3 and (174.24±28.27)mm3, respectively, without statistically significant difference (P=0.440). From day 2 to day 12 after treatment, the tumor volume of rhES group was significantly smaller than that of control group (all P<0.05). There were no statistical significances of D value between the rhES group and control group before and after treatment (all P>0.05). The D* values of the rhES group were (10.940±2.834)×10-3mm2/s and (12.940±2.801)×10-3mm2/s in day 4 and 8 after treatment respectively, significantly higher than (6.980±1.554)×10-3mm2/s and (7.898±1.603)×10-3mm2/s of control group (P<0.05). Moreover, compared with control group, the D* value of rhES group was significantly lower in day 12 (6.848±1.460)×10-3mm2/s vs (9.950±2.596)×10-3mm2/s, (P<0.05). The f value of rhES group in day 8 was (0.226±0.021)%, significantly higher than (0.178±0.016)% of control group (P<0.01). The MVD of rhES group was significantly lower than that of control group (P<0.05), while the pericyte coverage and tumor perfusion of rhES group were significantly higher than those of control group in day 4 and 8 after treatment (all P<0.05). In addition, we found D* value of IVIM-DWI in rhES group was significantly related with MVD, pericyte coverage and tumor perfusion (r=-0.354, r=0.555, r=0.559, all P<0.05). Meanwhile, the f value in rhES group was also significantly related with MVD, pericyte coverage and tumor perfusion (r=-0.391, r=0.538, r=0.315, all P<0.05).@*Conclusions@#IVIM-DWI MRI can effectively evaluate the vascular normalization in rhES-induced CT26 colorectal tumor.The parameters D* and f are closely related to intratumorally microvessel density, pericyte coverage and perfusion, which can effectively monitor the occurrence of tumor vascular normalization time.
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BACKGROUND:Studies have shown that Wnt signaling pathways play an important role in the osteogenic differentiation of mesenchymal stem cells. OBJECTIVE:To review the mechanism and regulation of the Wnt signaling pathways, as wel as Wnt signaling pathway effects on osteogenic differentiation of mesenchymal stem cells. METHODS:A computer-based search of PuMed database and CNKI database from September 1998 to March 2013 was performed to search related articles. The key words of“Wnt, mesenchymal stem cells, Wnt signaling pathways, osteoblastic differentiation, canonical wnt signaling pathway, non-canonical signaling pathway”in English or Chinese were used to search the articles in the title and the abstract. A total of 31 articles were included to review. RESULTS AND CONCLUSION:Wnt signaling pathways play a critical role in the osteogenic differentiation of mesenchymal stem cells. Canonical Wnt signaling pathway, non-canonical Wnt signaling pathway, and their mutli-factors were involved in regulating the proliferation and differentiation of mesenchymal stem cells. The osteogenic differentiation of mesenchymal stem cells can be promoted effectively via specific induction of Wnt signaling pathways. Wnt11, FZD6, sFRP2, sFRP3 and Ror2 expressions increase, while Wnt9a and FZD7 decreases during the regulation. However, the relations of factors in Wnt signaling pathways and how to use the mechanism of Wnt signaling for promoting mesenchymal stem cells faster, more accurate differentiation need further studies.