Pancreatic ductal adenocarcinoma(PDAC) is an almost uniformly lethal disease with less than 5% survival at five years. This is largely due to metastatic disease, which is already present in the majority of patients wh...Pancreatic ductal adenocarcinoma(PDAC) is an almost uniformly lethal disease with less than 5% survival at five years. This is largely due to metastatic disease, which is already present in the majority of patients when diagnosed. Even when the primary cancer can be removed by radical surgery, local recurrence occurs within one year in 50%-80% of cases. Therefore, it is imperative to develop new approaches for the treatment of advanced cancer and the prevention of recurrence after surgery. Tumour-targeted oncolytic viruses(TOVs) have become an attractive therapeutic agent as TOVs can kill cancer cells through multiple mechanisms of action, especially via virus-induced engagement of the immune response specifically against tumour cells. To attack tumour cells effectively, tumour-specific T cells need to overcome negative regulatory signals that suppress their activation or that induce tolerance programmes such as anergy or exhaustion in the tumour microenvironment. In this regard, the recent breakthrough in immunotherapy achieved with immune checkpoint blockade agents, such as anti-cytotoxic T-lymphocyte-associate protein 4, programmed death 1(PD-1) or PD-L1 antibodies, has demonstrated the possibility of relieving immune suppression in PDAC. Therefore, the combination of oncolytic virotherapy and immune checkpoint blockade agents may synergistically function to enhance the antitumour response, lending the opportunity to be the future for treatment of pancreatic cancer.展开更多
BACKGROUND Multiple sites of metastasis and desmoplastic reactions in the stroma are key features of human pancreatic cancer(PC).There are currently no simple and reliable animal models that can mimic these features f...BACKGROUND Multiple sites of metastasis and desmoplastic reactions in the stroma are key features of human pancreatic cancer(PC).There are currently no simple and reliable animal models that can mimic these features for accurate disease modeling.AIM To create a new xenograft animal model that can faithfully recapitulate the features of human PC.METHODS Interleukin 2 receptor subunit gamma(IL2RG)gene knockout Syrian hamster was created and characterized.A panel of human PC cell lines were transplanted into IL2RG knockout Syrian hamsters and severe immune-deficient mice subcutaneously or orthotopically.Tumor growth,local invasion,remote organ metastasis,histopathology,and molecular alterations of tumor cells and stroma were compared over time.RESULTS The Syrian hamster with IL2RG gene knockout(named ZZU001)demonstrated an immune-deficient phenotype and function.ZZU001 hamsters faithfully recapitulated most features of human PC,in particular,they developed metastasis at multiple sites.PC tissues derived from ZZU001 hamsters displayed desmoplastic reactions in the stroma and epithelial to mesenchymal transition phenotypes,whereas PC tissues derived from immune-deficient mice did not present such features.CONCLUSION ZZU001 hamsters engrafted with human PC cells are a superior animal model compared to immune-deficient mice.ZZU001 hamsters can be a valuable animal model for better understanding the molecular mechanism of tumorigenesis and metastasis and the evaluation of new drugs targeting human PC.展开更多
基金Supported by The United Kingdom Charity pancreatic Cancer Research Fundpancreatic Cancer Research United Kingdom+1 种基金Ministry of Sciences and Technology of ChinaNo.2013DFG32080
文摘Pancreatic ductal adenocarcinoma(PDAC) is an almost uniformly lethal disease with less than 5% survival at five years. This is largely due to metastatic disease, which is already present in the majority of patients when diagnosed. Even when the primary cancer can be removed by radical surgery, local recurrence occurs within one year in 50%-80% of cases. Therefore, it is imperative to develop new approaches for the treatment of advanced cancer and the prevention of recurrence after surgery. Tumour-targeted oncolytic viruses(TOVs) have become an attractive therapeutic agent as TOVs can kill cancer cells through multiple mechanisms of action, especially via virus-induced engagement of the immune response specifically against tumour cells. To attack tumour cells effectively, tumour-specific T cells need to overcome negative regulatory signals that suppress their activation or that induce tolerance programmes such as anergy or exhaustion in the tumour microenvironment. In this regard, the recent breakthrough in immunotherapy achieved with immune checkpoint blockade agents, such as anti-cytotoxic T-lymphocyte-associate protein 4, programmed death 1(PD-1) or PD-L1 antibodies, has demonstrated the possibility of relieving immune suppression in PDAC. Therefore, the combination of oncolytic virotherapy and immune checkpoint blockade agents may synergistically function to enhance the antitumour response, lending the opportunity to be the future for treatment of pancreatic cancer.
基金Supported by the National Key R and D Program of China,No.2016YFE0200800Nature Sciences Foundation of China,No.81771776+1 种基金Nature Sciences Foundation of China,No.U1704282Medical Research of Council,No.MR/M015696/1.
文摘BACKGROUND Multiple sites of metastasis and desmoplastic reactions in the stroma are key features of human pancreatic cancer(PC).There are currently no simple and reliable animal models that can mimic these features for accurate disease modeling.AIM To create a new xenograft animal model that can faithfully recapitulate the features of human PC.METHODS Interleukin 2 receptor subunit gamma(IL2RG)gene knockout Syrian hamster was created and characterized.A panel of human PC cell lines were transplanted into IL2RG knockout Syrian hamsters and severe immune-deficient mice subcutaneously or orthotopically.Tumor growth,local invasion,remote organ metastasis,histopathology,and molecular alterations of tumor cells and stroma were compared over time.RESULTS The Syrian hamster with IL2RG gene knockout(named ZZU001)demonstrated an immune-deficient phenotype and function.ZZU001 hamsters faithfully recapitulated most features of human PC,in particular,they developed metastasis at multiple sites.PC tissues derived from ZZU001 hamsters displayed desmoplastic reactions in the stroma and epithelial to mesenchymal transition phenotypes,whereas PC tissues derived from immune-deficient mice did not present such features.CONCLUSION ZZU001 hamsters engrafted with human PC cells are a superior animal model compared to immune-deficient mice.ZZU001 hamsters can be a valuable animal model for better understanding the molecular mechanism of tumorigenesis and metastasis and the evaluation of new drugs targeting human PC.
