Hepatocellular carcinoma(HCC) is the fifth most common cancer and is the second leading cause of cancer death. Since the diagnosis of HCC is difficult, in many cases patients with HCC are diagnosed advanced stage of d...Hepatocellular carcinoma(HCC) is the fifth most common cancer and is the second leading cause of cancer death. Since the diagnosis of HCC is difficult, in many cases patients with HCC are diagnosed advanced stage of development. Hepatocyte growth factor(HGF)/c-mesenchymal-epithelial transition receptor(c-Met) axis is a key signaling pathway in HCC, either via canonical or non-canonical pathways. Available treatments against HCC based upon HGF/c-Met inhibition can increase patient lifespan, but do not reach the expected therapeutic benefits. In HCC, c-Met monomers can bind other receptor monomers, activating several noncanonical signaling pathways, leading to increased cell proliferation, invasion, motility, and drug resistance. All of these processes are enhanced by the tumor microenvironment, with stromal cells contributing to boost tumor progression through oxidative stress, angiogenesis, lymphangiogenesis, inflammation, and fibrosis. Novel treatments against HCC are being explored to modulate other targets such as microR NAs, methyltransferases, and acetyltransferases, which are all involved in the regulation of gene expression in cancer. This review compiles basic knowledge regarding signaling pathways in HCC, and compounds already used or showing potential to be used in clinical trials.展开更多
Verticillin A is a diketopiperazine compound which was previously isolated from Amanita flavorubescens Aik(containing parasitic fungi Hypomyces hyalines(Schw.)Tul.).Here,we initially found,by wound healing assay and T...Verticillin A is a diketopiperazine compound which was previously isolated from Amanita flavorubescens Aik(containing parasitic fungi Hypomyces hyalines(Schw.)Tul.).Here,we initially found,by wound healing assay and Tran swell assay in vitro,that verticilli n A possesses an inhibitory effect agai nst the migrati on and in vasion of the human colon cancer cell.Subsequently,c-mesenchymal,epithelial transition factor(c-Met)was identified as a molecular target of verticillin A by screening key genes related to cell migration.Verticillin A-mediated c-Met suppress!on is at the transcriptio nal level.Further study dem on strated that verticilli n A suppressed c-MET phosphorylation and decreased c-MET protein level.In addition,verticillin A inhibited the phosphorylation of c-MET downstream molecules including rat sarcoma(Ras)-associated factor(Raf),extracellular signal-regulated kinase(ERK),and protein kinase B(AKT).Overexpression of Erk partially reversed the verticillin A-mediated anti-metastasis action in the human colon cancer cell.More importantly,verticillin A also inhibited cancer cell metastasis in vivo.Thus,verticillin A can significantly inhibit the migration and invasion of colon cancer cells by targeting c-Met and inhibiting Ras/Raf/mitogen-activated extracellular signal-regulated kinase(MEK)/ERK signaling pathways.Therefore,we determined that verticillin A is a natural compound that can be further developed as an anti-metastatic drug in human cancers.展开更多
Pancreatic cancer is ranked as the fourth leading cause of cancer-related mortality and is predicted to become the second leading cause of cancer-related death by 2030.The cause of this high mortality rate is due to p...Pancreatic cancer is ranked as the fourth leading cause of cancer-related mortality and is predicted to become the second leading cause of cancer-related death by 2030.The cause of this high mortality rate is due to pancreatic ductal adenocarcinoma’s rapid progression and metastasis,and development of drug resistance.Today,cancer immunotherapy is becoming a strong candidate to not only treat various cancers but also to combat against chemoresistance.Studies have suggested that complement system pathways play an important role in cancer progression and chemoresistance,especially in pancreatic cancer.A recent report also suggested that several signaling pathways play an important role in causing chemoresistance in pancreatic cancer,major ones including nuclear factor kappa B,signal transducer and activator of transcription 3,c-mesenchymal-epithelial transition factor,and phosphoinositide-3-kinase/protein kinase B.In addition,it has also been proven that the complement system has a very active role in establishing the tumor microenvironment,which would aid in promoting tumorigenesis,progression,metastasis,and recurrence.Interestingly,it has been shown that the downstream products of the complement system directly upregulate inflammatory mediators,which in turn activate these chemo-resistant pathways.Therefore,targeting complement pathways could be an innovative approach to combat against pancreatic cancer drugs resistance.In this review,we have discussed the role of complement system pathways in pancreatic cancer drug resistance and a special focus on the complement as a therapeutic target in pancreatic cancer.展开更多
基金Supported by grants BIO2014-56092-R(MINECO and FEDER)No.P12-CTS-1507(Andalusian Government and FEDER)+1 种基金funds from group BIO-267(Andalusian Government)The“CIBER de Enfermedades Raras”is an initiative from the ISCIII(Spain)
文摘Hepatocellular carcinoma(HCC) is the fifth most common cancer and is the second leading cause of cancer death. Since the diagnosis of HCC is difficult, in many cases patients with HCC are diagnosed advanced stage of development. Hepatocyte growth factor(HGF)/c-mesenchymal-epithelial transition receptor(c-Met) axis is a key signaling pathway in HCC, either via canonical or non-canonical pathways. Available treatments against HCC based upon HGF/c-Met inhibition can increase patient lifespan, but do not reach the expected therapeutic benefits. In HCC, c-Met monomers can bind other receptor monomers, activating several noncanonical signaling pathways, leading to increased cell proliferation, invasion, motility, and drug resistance. All of these processes are enhanced by the tumor microenvironment, with stromal cells contributing to boost tumor progression through oxidative stress, angiogenesis, lymphangiogenesis, inflammation, and fibrosis. Novel treatments against HCC are being explored to modulate other targets such as microR NAs, methyltransferases, and acetyltransferases, which are all involved in the regulation of gene expression in cancer. This review compiles basic knowledge regarding signaling pathways in HCC, and compounds already used or showing potential to be used in clinical trials.
基金Zhejiang Provincial Natural Science Foundation of China(No.LY20H160039)the National Natural Science Foundation of China(No.31570811)Siyuan Foundation,Hongkong,China。
文摘Verticillin A is a diketopiperazine compound which was previously isolated from Amanita flavorubescens Aik(containing parasitic fungi Hypomyces hyalines(Schw.)Tul.).Here,we initially found,by wound healing assay and Tran swell assay in vitro,that verticilli n A possesses an inhibitory effect agai nst the migrati on and in vasion of the human colon cancer cell.Subsequently,c-mesenchymal,epithelial transition factor(c-Met)was identified as a molecular target of verticillin A by screening key genes related to cell migration.Verticillin A-mediated c-Met suppress!on is at the transcriptio nal level.Further study dem on strated that verticilli n A suppressed c-MET phosphorylation and decreased c-MET protein level.In addition,verticillin A inhibited the phosphorylation of c-MET downstream molecules including rat sarcoma(Ras)-associated factor(Raf),extracellular signal-regulated kinase(ERK),and protein kinase B(AKT).Overexpression of Erk partially reversed the verticillin A-mediated anti-metastasis action in the human colon cancer cell.More importantly,verticillin A also inhibited cancer cell metastasis in vivo.Thus,verticillin A can significantly inhibit the migration and invasion of colon cancer cells by targeting c-Met and inhibiting Ras/Raf/mitogen-activated extracellular signal-regulated kinase(MEK)/ERK signaling pathways.Therefore,we determined that verticillin A is a natural compound that can be further developed as an anti-metastatic drug in human cancers.
文摘Pancreatic cancer is ranked as the fourth leading cause of cancer-related mortality and is predicted to become the second leading cause of cancer-related death by 2030.The cause of this high mortality rate is due to pancreatic ductal adenocarcinoma’s rapid progression and metastasis,and development of drug resistance.Today,cancer immunotherapy is becoming a strong candidate to not only treat various cancers but also to combat against chemoresistance.Studies have suggested that complement system pathways play an important role in cancer progression and chemoresistance,especially in pancreatic cancer.A recent report also suggested that several signaling pathways play an important role in causing chemoresistance in pancreatic cancer,major ones including nuclear factor kappa B,signal transducer and activator of transcription 3,c-mesenchymal-epithelial transition factor,and phosphoinositide-3-kinase/protein kinase B.In addition,it has also been proven that the complement system has a very active role in establishing the tumor microenvironment,which would aid in promoting tumorigenesis,progression,metastasis,and recurrence.Interestingly,it has been shown that the downstream products of the complement system directly upregulate inflammatory mediators,which in turn activate these chemo-resistant pathways.Therefore,targeting complement pathways could be an innovative approach to combat against pancreatic cancer drugs resistance.In this review,we have discussed the role of complement system pathways in pancreatic cancer drug resistance and a special focus on the complement as a therapeutic target in pancreatic cancer.
