Gastric carcinoma (GC) is the 4<sup>th</sup> most prevalent cancer and has the 2<sup>nd</sup> highest cancer-related mortality rate worldwide. Despite the incidence of GC has decreased over the...Gastric carcinoma (GC) is the 4<sup>th</sup> most prevalent cancer and has the 2<sup>nd</sup> highest cancer-related mortality rate worldwide. Despite the incidence of GC has decreased over the past few decades, it is still a serious health problem. Chronic inflammatory status of the stomach, caused by the infection of Helicobacter pylori (H. pylori) and through the production of inflammatory mediators within the parenchyma is suspected to play an important role in the initiation and progression of GC. In this review, the correlation between chronic inflammation and H. pylori infection as an important factor for the development of GC will be discussed. Major components, including tumor-associated macrophages, lymphocytes, cancer-associated fibroblasts, angiogenic factors, cytokines, and chemokines of GC microenvironment and their mechanism of action on signaling pathways will also be discussed. Increasing our understanding of how the components of the tumor microenviroment interact with GC cells and the signaling pathways involved could help identify new therapeutic and chemopreventive targets.展开更多
Macrophages are one of the most abundant leukocyte populations infiltrating tumor tissues and can exhibit both tumoricidal and tumor-promoting activities.In 1989,we reported the purification of monocyte chemoattractan...Macrophages are one of the most abundant leukocyte populations infiltrating tumor tissues and can exhibit both tumoricidal and tumor-promoting activities.In 1989,we reported the purification of monocyte chemoattractant protein-1(MCP-1)from culture supernatants of mitogen-activated peripheral blood mononuclear cells and tumor cells.MCP-1 is a potent monocyte-attracting chemokine,identical to the previously described lymphocyte-derived chemotactic factor or tumor-derived chemotactic factor,and greatly contributes to the recruitment of blood monocytes into sites of inflammatory responses and tumors.Because in vitro-cultured tumor cells often produce significant amounts of MCP-1,tumor cells are considered to be the main source of MCP-1.However,various nontumor cells in the tumor stroma also produce MCP-1 in response to stimuli.Studies performed in vitro and in vivo have provided evidence that MCP-1 production in tumors is a consequence of complex interactions between tumor cells and non-tumor cells and that both tumor cells and non-tumor cells contribute to the production of MCP-1.Although MCP-1 production was once considered to be a part of host defense against tumors,it is now believed to regulate the vicious cycle between tumor cells and macrophages that promotes the progression of tumors.展开更多
Cancer immunoediting consists of three sequential phases： elimination, equilibdum, and escape. For colorectal adenoma-carcinoma sequence, the adenoma dysplastic progression may represent an equilibdum phase and the c...Cancer immunoediting consists of three sequential phases： elimination, equilibdum, and escape. For colorectal adenoma-carcinoma sequence, the adenoma dysplastic progression may represent an equilibdum phase and the cancer stage as escape phase. Immune system eliminates transformed enterocytes by destroying them at first, sculpts them at the same time and selects the variants subsequently that are no longer recognized and insensitive to immune effectors, and finally induces immunosuppressive state within the tumor microenvironment that facilitates immune escape and tumor outgrowth. Immunosuppression and inflammation are the two crucial features of Pi （Spteen）-deficiency. Ctassic quotations, immune evidence and ctinicat observations suggest that Spleen （but not other organs） deficiency is the key pathogenesis of colorectal cancer （CRC） microenvironment. Weakness of old age, immunosuppressive cytokines from chronic inflammation, tumor-dedved immunosuppressive factors and surrendered immune cells--regulatory T cells, myeloid-derived suppressor cells and tumor associated macrophages （TAMs） constitutes CRC microenvironment of Pi-deficiency. Furthermore, excess in superficiality, such as phlegm stagnation, blood stasis and toxin accumulation are induced by chronic inflammation on the basis of asthenia in origin, an immunosuppressive state. Great masters of Chinese medicine emphasize that strengthen Pi is the chief therapeutic principle for CRC which receives good therapeutic effects. So, Pi-deficiency based syndrome is the pivotal pathogenesis of tumor microenvironment. The immunosuppressive microenvironment facilitates immune escape which play an important role in the transition from adenoma to adenocarcinoma. There are some signs that strengthen Pi based treatment has potential capacity to ameliorate tumor environment. It might be a novel starting point to explore the mechanism of strengthen Pi based therapy in the prevention and treatment of CRC through regulation of tumor environment and immunoedit展开更多
Colorectal cancer(CRC)is a predominant life-threatening cancer,with liver and peritoneal metastases as the primary causes of death.Intestinal inflammation,a known CRC risk factor,nurtures a local inflammatory environ...Colorectal cancer(CRC)is a predominant life-threatening cancer,with liver and peritoneal metastases as the primary causes of death.Intestinal inflammation,a known CRC risk factor,nurtures a local inflammatory environment enriched with tumor cells,endothelial cells,immune cells,cancer-associated fibroblasts,immunosuppressive cells,and secretory growth factors.The complex interactions of aberrantly expressed cytokines,chemokines,growth factors,and matrix-remodeling enzymes promote CRC pathogenesis and evoke systemic responses that affect disease outcomes.Mounting evidence suggests that these cytokines and chemokines play a role in the progression of CRC through immunosuppression and modulation of the tumor microenvironment,which is partly achieved by the recruitment of immunosuppressive cells.These cells impart features such as cancer stem cell-like properties,drug resistance,invasion,and formation of the premetastatic niche in distant organs,promoting metastasis and aggressive CRC growth.A deeper understanding of the cytokineand chemokine-mediated signaling networks that link tumor progression and metastasis will provide insights into the mechanistic details of disease aggressiveness and facilitate the development of novel therapeutics for CRC.Here,we summarized the current knowledge of cytokine-and chemokine-mediated crosstalk in the inflammatory tumor microenvironment,which drives immunosuppression,resistance to therapeutics,and metastasis during CRC progression.We also outlined the potential of this crosstalk as a novel therapeutic target for CRC.The major cytokine/chemokine pathways involved in cancer immunotherapy are also discussed in this review.展开更多
Gastric cancer(GC) is the fifth most common malignancy in the world. The major cause of GC is chronic infection with Helicobacter pylori(H. pylori). Infection with H. pylori leads to an active inflammatory microenviro...Gastric cancer(GC) is the fifth most common malignancy in the world. The major cause of GC is chronic infection with Helicobacter pylori(H. pylori). Infection with H. pylori leads to an active inflammatory microenvironment that is maintained by immune cells such as T cells, macrophages, natural killer cells, among other cells. Immune cell dysfunction allows the initiation and accumulation of mutations in GC cells, inducing aberrant proliferation and protection from apoptosis. Meanwhile, immune cells can secrete certain signals, including cytokines, and chemokines, to alter intracellular signaling pathways in GC cells. Thus, GC cells obtain the ability to metastasize to lymph nodes by undergoing the epithelial-mesenchymal transition(EMT), whereby epithelial cells lose their epithelial attributes and acquire a mesenchymal cell phenotype. Metastasis is a leading cause of death for GC patients, and the involved mechanisms are still under investigation. In this review, we summarize the current research on how the inflammatory environment affects GC initiation and metastasis via EMT.展开更多
Pancreatic ductal adenocarcinoma(PDAC)is one of the deadliest cancers,mostly due to its resistance to treatment.Of these,checkpoint inhibitors(CPI)are inefficient when used as monotherapy,except in the case of a rare ...Pancreatic ductal adenocarcinoma(PDAC)is one of the deadliest cancers,mostly due to its resistance to treatment.Of these,checkpoint inhibitors(CPI)are inefficient when used as monotherapy,except in the case of a rare subset of tumors harboring microsatellite instability(<2%).This inefficacy mainly resides in the low immunogenicity and non-inflamed phenotype of PDAC.The abundant stroma generates a hypoxic microenvironment and drives the recruitment of immunosuppressive cells through cancerassociated-fibroblast activation and transforming growth factorβsecretion.Several strategies have recently been developed to overcome this immunosuppressive microenvironment.Combination therapies involving CPI aim at increasing tumor immunogenicity and promoting the recruitment and activation of effector T cells.Ongoing studies are therefore exploring the association of CPI with vaccines,oncolytic viruses,MEK inhibitors,cytokine inhibitors,and hypoxia-and stroma-targeting agents.Adoptive T-cell transfer is also under investigation.Moreover,translational studies on tumor tissue and blood,prior to and during treatment may lead to the identification of biomarkers with predictive value for both clinical outcome and response to immunotherapy.展开更多
Colorectal carcinoma(CRC) is one of the most common types of cancer worldwide and the prognosis for CRC patients with recurrence or metastasis is extremely poor. Although chemotherapy and radiation therapy can improve...Colorectal carcinoma(CRC) is one of the most common types of cancer worldwide and the prognosis for CRC patients with recurrence or metastasis is extremely poor. Although chemotherapy and radiation therapy can improve survival, there are still numerous efforts to be performed. Immunotherapy is frequently used, either alone or in combination with other therapies, for the treatment of CRC and is a safe and feasible way to improve CRC treatment. Furthermore, the significance of the immune system in the biology of CRC has been demonstrated by retrospective assessments of immune infiltrates in resected CRC tumors. Micro RNAs(mi RNAs) are short, non-coding RNAs that can regulate multiple target genes at the post-transcriptional level and play critical roles in cell proliferation, differentiation and apoptosis. Mi RNAs are required for normal immune system development and function. Nevertheless, aberrant expression of mi RNAs is often observed in various tumor types and leads to immune disorders or immune evasion. The immunomodulatory function of mi RNAs indicates that mi RNAs may ultimately be part of the portfolio of anti-cancer targets. Herein, we will review the potential roles of mi RNAs in the regulation of the immune response in CRC and then move on to discuss how to utilize different mi RNA targets to treat CRC. We also provide an overview of the major limitations and challenges of using mi RNAs as immunotherapeutic targets.展开更多
文摘Gastric carcinoma (GC) is the 4<sup>th</sup> most prevalent cancer and has the 2<sup>nd</sup> highest cancer-related mortality rate worldwide. Despite the incidence of GC has decreased over the past few decades, it is still a serious health problem. Chronic inflammatory status of the stomach, caused by the infection of Helicobacter pylori (H. pylori) and through the production of inflammatory mediators within the parenchyma is suspected to play an important role in the initiation and progression of GC. In this review, the correlation between chronic inflammation and H. pylori infection as an important factor for the development of GC will be discussed. Major components, including tumor-associated macrophages, lymphocytes, cancer-associated fibroblasts, angiogenic factors, cytokines, and chemokines of GC microenvironment and their mechanism of action on signaling pathways will also be discussed. Increasing our understanding of how the components of the tumor microenviroment interact with GC cells and the signaling pathways involved could help identify new therapeutic and chemopreventive targets.
文摘Macrophages are one of the most abundant leukocyte populations infiltrating tumor tissues and can exhibit both tumoricidal and tumor-promoting activities.In 1989,we reported the purification of monocyte chemoattractant protein-1(MCP-1)from culture supernatants of mitogen-activated peripheral blood mononuclear cells and tumor cells.MCP-1 is a potent monocyte-attracting chemokine,identical to the previously described lymphocyte-derived chemotactic factor or tumor-derived chemotactic factor,and greatly contributes to the recruitment of blood monocytes into sites of inflammatory responses and tumors.Because in vitro-cultured tumor cells often produce significant amounts of MCP-1,tumor cells are considered to be the main source of MCP-1.However,various nontumor cells in the tumor stroma also produce MCP-1 in response to stimuli.Studies performed in vitro and in vivo have provided evidence that MCP-1 production in tumors is a consequence of complex interactions between tumor cells and non-tumor cells and that both tumor cells and non-tumor cells contribute to the production of MCP-1.Although MCP-1 production was once considered to be a part of host defense against tumors,it is now believed to regulate the vicious cycle between tumor cells and macrophages that promotes the progression of tumors.
基金Supported by the National Natural Science Foundation of China(No.81273621)Guangdong Natural Science Foundation of China(No.2014A030313323)
文摘Cancer immunoediting consists of three sequential phases： elimination, equilibdum, and escape. For colorectal adenoma-carcinoma sequence, the adenoma dysplastic progression may represent an equilibdum phase and the cancer stage as escape phase. Immune system eliminates transformed enterocytes by destroying them at first, sculpts them at the same time and selects the variants subsequently that are no longer recognized and insensitive to immune effectors, and finally induces immunosuppressive state within the tumor microenvironment that facilitates immune escape and tumor outgrowth. Immunosuppression and inflammation are the two crucial features of Pi （Spteen）-deficiency. Ctassic quotations, immune evidence and ctinicat observations suggest that Spleen （but not other organs） deficiency is the key pathogenesis of colorectal cancer （CRC） microenvironment. Weakness of old age, immunosuppressive cytokines from chronic inflammation, tumor-dedved immunosuppressive factors and surrendered immune cells--regulatory T cells, myeloid-derived suppressor cells and tumor associated macrophages （TAMs） constitutes CRC microenvironment of Pi-deficiency. Furthermore, excess in superficiality, such as phlegm stagnation, blood stasis and toxin accumulation are induced by chronic inflammation on the basis of asthenia in origin, an immunosuppressive state. Great masters of Chinese medicine emphasize that strengthen Pi is the chief therapeutic principle for CRC which receives good therapeutic effects. So, Pi-deficiency based syndrome is the pivotal pathogenesis of tumor microenvironment. The immunosuppressive microenvironment facilitates immune escape which play an important role in the transition from adenoma to adenocarcinoma. There are some signs that strengthen Pi based treatment has potential capacity to ameliorate tumor environment. It might be a novel starting point to explore the mechanism of strengthen Pi based therapy in the prevention and treatment of CRC through regulation of tumor environment and immunoedit
基金Ramalingaswami Fellowship,Grant/Award Number:D.O.NO.BT/HRD/35/02/2006the Department of Biotechnology,&Core Research grant,Grant/Award Number:CRG/2021/003805+1 种基金Science and Engineering Research Board(SERB),Govt.of India,New DelhiSidra Medicine Precision Program,Grant/Award Numbers:5081012003,5081012002。
文摘Colorectal cancer(CRC)is a predominant life-threatening cancer,with liver and peritoneal metastases as the primary causes of death.Intestinal inflammation,a known CRC risk factor,nurtures a local inflammatory environment enriched with tumor cells,endothelial cells,immune cells,cancer-associated fibroblasts,immunosuppressive cells,and secretory growth factors.The complex interactions of aberrantly expressed cytokines,chemokines,growth factors,and matrix-remodeling enzymes promote CRC pathogenesis and evoke systemic responses that affect disease outcomes.Mounting evidence suggests that these cytokines and chemokines play a role in the progression of CRC through immunosuppression and modulation of the tumor microenvironment,which is partly achieved by the recruitment of immunosuppressive cells.These cells impart features such as cancer stem cell-like properties,drug resistance,invasion,and formation of the premetastatic niche in distant organs,promoting metastasis and aggressive CRC growth.A deeper understanding of the cytokineand chemokine-mediated signaling networks that link tumor progression and metastasis will provide insights into the mechanistic details of disease aggressiveness and facilitate the development of novel therapeutics for CRC.Here,we summarized the current knowledge of cytokine-and chemokine-mediated crosstalk in the inflammatory tumor microenvironment,which drives immunosuppression,resistance to therapeutics,and metastasis during CRC progression.We also outlined the potential of this crosstalk as a novel therapeutic target for CRC.The major cytokine/chemokine pathways involved in cancer immunotherapy are also discussed in this review.
基金Supported by National Science Foundation of China,No.31471147
文摘Gastric cancer(GC) is the fifth most common malignancy in the world. The major cause of GC is chronic infection with Helicobacter pylori(H. pylori). Infection with H. pylori leads to an active inflammatory microenvironment that is maintained by immune cells such as T cells, macrophages, natural killer cells, among other cells. Immune cell dysfunction allows the initiation and accumulation of mutations in GC cells, inducing aberrant proliferation and protection from apoptosis. Meanwhile, immune cells can secrete certain signals, including cytokines, and chemokines, to alter intracellular signaling pathways in GC cells. Thus, GC cells obtain the ability to metastasize to lymph nodes by undergoing the epithelial-mesenchymal transition(EMT), whereby epithelial cells lose their epithelial attributes and acquire a mesenchymal cell phenotype. Metastasis is a leading cause of death for GC patients, and the involved mechanisms are still under investigation. In this review, we summarize the current research on how the inflammatory environment affects GC initiation and metastasis via EMT.
文摘Pancreatic ductal adenocarcinoma(PDAC)is one of the deadliest cancers,mostly due to its resistance to treatment.Of these,checkpoint inhibitors(CPI)are inefficient when used as monotherapy,except in the case of a rare subset of tumors harboring microsatellite instability(<2%).This inefficacy mainly resides in the low immunogenicity and non-inflamed phenotype of PDAC.The abundant stroma generates a hypoxic microenvironment and drives the recruitment of immunosuppressive cells through cancerassociated-fibroblast activation and transforming growth factorβsecretion.Several strategies have recently been developed to overcome this immunosuppressive microenvironment.Combination therapies involving CPI aim at increasing tumor immunogenicity and promoting the recruitment and activation of effector T cells.Ongoing studies are therefore exploring the association of CPI with vaccines,oncolytic viruses,MEK inhibitors,cytokine inhibitors,and hypoxia-and stroma-targeting agents.Adoptive T-cell transfer is also under investigation.Moreover,translational studies on tumor tissue and blood,prior to and during treatment may lead to the identification of biomarkers with predictive value for both clinical outcome and response to immunotherapy.
基金Supported by National Natural Science Foundation of ChinaNo.81272867 and No.81572914+1 种基金Beijing Nova ProgramNo.Z131107000413103
文摘Colorectal carcinoma(CRC) is one of the most common types of cancer worldwide and the prognosis for CRC patients with recurrence or metastasis is extremely poor. Although chemotherapy and radiation therapy can improve survival, there are still numerous efforts to be performed. Immunotherapy is frequently used, either alone or in combination with other therapies, for the treatment of CRC and is a safe and feasible way to improve CRC treatment. Furthermore, the significance of the immune system in the biology of CRC has been demonstrated by retrospective assessments of immune infiltrates in resected CRC tumors. Micro RNAs(mi RNAs) are short, non-coding RNAs that can regulate multiple target genes at the post-transcriptional level and play critical roles in cell proliferation, differentiation and apoptosis. Mi RNAs are required for normal immune system development and function. Nevertheless, aberrant expression of mi RNAs is often observed in various tumor types and leads to immune disorders or immune evasion. The immunomodulatory function of mi RNAs indicates that mi RNAs may ultimately be part of the portfolio of anti-cancer targets. Herein, we will review the potential roles of mi RNAs in the regulation of the immune response in CRC and then move on to discuss how to utilize different mi RNA targets to treat CRC. We also provide an overview of the major limitations and challenges of using mi RNAs as immunotherapeutic targets.
