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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.
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Objective To investigate the effect of Valsartan on Disintegrin metalloproteinases (ADAMs10,17) expressions in the process of heart failure (HF) after myocardial infarction (MI).MethodsAdult male Wistar rats weighing (200 ± 30) g were given humane care in compliance with the rules of the Animal Experimentation Committee of the first hospital of Harbin Medical University.And then the left anterior descending coronary artery was ligated.Based on UCG (LVEF ＜ 45％) Results The successfully MI-operated Wistar rats were divided randomly (random number) into three groups:HF group (HF group),placebo group (Pla group) and valsartan group (Val group).The rats in the Pla group and Val group were given the same volume of normal saline and valsartan 50 mg/ (kg · d),provided by Novartis company) by gavage.After 16 weeks,heart function was assessed by hemodynamic evaluation and serum TNF-α from LV cavity was measured by ELISA (R&D,USA).Muscle samples were extracted from the ischemic zone,and then the ADAMs 10,17 expressions were measured by immunoblotting.All the data were expressed by mean ± standard and evaluated by Student' s t test.Results After 16 weeks,the data of LV function including LVdp/dt LVdp/dtmin and LVSP were significantly improved in Val group than the others (P =0.006,P =0.015,P =0.003),and the LVEDP level was decreased (P =0.002).At the same time,the TNF-o level in the Val group was lower than that in the HF group (P =0.023).The ADAM17 and TNF-R1 expressions in the Val group was reduced compared with those in the HF group (P =0.01 1,P =0.022).However,ADAM10 expression is unchangeable in the four groups.Conclusions Valsartan may reduce the ADAM17 and TNF-R1 expressions in the ischemic zone,decrease the TNF-αconcentration and function in LV cavity so as to inhibit cardiac remodeling and improve heart function after MI.
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Objective To investigate the effects of erythropoietin(EPO) on extracellular matrix remodeling and the expressions of matrix metalloproteinase(MMPs) and tissue inhibitor of metalloproteinase-4(TIMP-4) after myocardial infarction in rats.Methods Eighty male SD rats were randomly divided into four groups:sham operation(SH) group,sham operation and drug(SHE) group,myocardial infarction(MI) group,and myocardial inferct and erythropoietin(MIE) group.Myocardial infarction in MI group and MIE group was reproduced by ligation of a branch of left anterior descending coronary artery.Hematocrit,echocardiography,capillary density,infarct area,fibrosis and collagen volume fraction were tested,and MMP-2,MMP-9 and TIMP-4 were measured by immunohistochemistry at 1-week and 6-week after myocardial infraction.Results One week after myocardial infraction,the protein expressions of MMP-2 and MMP-9 in MI and MIE groups were significantly higher than that in SH and SHE group(P0.05).Six weeks after myocardial infraction,echocardiography revealed that the left ventricular end-diastolic dimension(LVDd),left ventricular end-systolic dimension(LVDs),left ventricular end-diastolic volume(LVEDV) and left ventricular end-systolic volume(LVESV) were significantly increased,and left ventricular ejection fraction(LVEF) and left ventricular fractional shortening(LVFS) were significantly decreased in MI and MIE groups compared with those in SH and SHE groups(P