Mucosal healing(MH)is vital in maintaining homeostasis within the gut and protecting against injury and infections.Multiple factors and signaling pathways contribute in a dynamic and coordinated manner to maintain int...Mucosal healing(MH)is vital in maintaining homeostasis within the gut and protecting against injury and infections.Multiple factors and signaling pathways contribute in a dynamic and coordinated manner to maintain intestinal homeostasis and mucosal regeneration/repair.However,when intestinal homeostasis becomes chronically disturbed and an inflammatory immune response is constitutively active due to impairment of the intestinal epithelial barrier autoimmune disease results,particularly inflammatory bowel disease(IBD).Many proteins and signaling pathways become dysregulated or impaired during these pathological conditions,with the mechanisms of regulation just beginning to be understood.Consequently,there remains a relative lack of broadly effective therapeutics that can restore MH due to the complexity of both the disease and healing processes,so tissue damage in the gastrointestinal tract of patients,even those in clinical remission,persists.With increased understanding of the molecular mechanisms of IBD and MH,tissue damage from autoimmune disease may in the future be ameliorated by developing therapeutics that enhance the body’s own healing response.In this review,we introduce the concept of mucosal healing and its relevance in IBD as well as discuss the mechanisms of IBD and potential strategies for altering these processes and inducing MH.展开更多
Inflammatory bowel disease(IBD),consisting primarily of ulcerative colitis and Crohn’s disease,is a group of debilitating auto-immune disorders,which also increases the risk of colitis-associated cancer.However,due t...Inflammatory bowel disease(IBD),consisting primarily of ulcerative colitis and Crohn’s disease,is a group of debilitating auto-immune disorders,which also increases the risk of colitis-associated cancer.However,due to the chronic nature of the disease and inconsistent treatment outcomes of current anti-IBD drugs(e.g.,approximately 30%non-responders to anti-TNFαagents),and related serious side effects,about half of all IBD patients(in millions)turn to alternative treatment options.In this regard,mucosal healing is gaining acceptance as a measure of disease activity in IBD patients as recent studies have correlated the success of mucosal healing with improved prognosis.However,despite the increasing clinical realization of the significance of the concept of mucosal healing,its regulation and means of therapeutic targeting remain largely unclear.Here,stemcell therapy,which uses hematopoietic stem cells or mesenchymal stem cells,remains a promising option.Stem cells are the pluripotent cells with ability to differentiate into the epithelial and/or immune-modulatory cells.The overreaching concept is that the stem cells can migrate to the damaged areas of the intestine to provide curative help in the mucosal healing process.Moreover,by differentiating into the mature intestinal epithelial cells,the stem cells also help in restoring the barrier integrity of the intestinal lining and hence prevent the immunomodulatory induction,the root cause of the IBD.In this article,we elaborate upon the current status of the clinical management of IBD and potential role of the stem cell therapy in improving IBD therapy and patient’s quality of life.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 environm...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
文摘Mucosal healing(MH)is vital in maintaining homeostasis within the gut and protecting against injury and infections.Multiple factors and signaling pathways contribute in a dynamic and coordinated manner to maintain intestinal homeostasis and mucosal regeneration/repair.However,when intestinal homeostasis becomes chronically disturbed and an inflammatory immune response is constitutively active due to impairment of the intestinal epithelial barrier autoimmune disease results,particularly inflammatory bowel disease(IBD).Many proteins and signaling pathways become dysregulated or impaired during these pathological conditions,with the mechanisms of regulation just beginning to be understood.Consequently,there remains a relative lack of broadly effective therapeutics that can restore MH due to the complexity of both the disease and healing processes,so tissue damage in the gastrointestinal tract of patients,even those in clinical remission,persists.With increased understanding of the molecular mechanisms of IBD and MH,tissue damage from autoimmune disease may in the future be ameliorated by developing therapeutics that enhance the body’s own healing response.In this review,we introduce the concept of mucosal healing and its relevance in IBD as well as discuss the mechanisms of IBD and potential strategies for altering these processes and inducing MH.
基金Department of Veterans Affairs,No.2I01BX002761-05 and No.2I01BX002086-06A1The National Institutes of Health,No.1R01DK124095-01A1 and No.1R21CA216746-01A1.
文摘Inflammatory bowel disease(IBD),consisting primarily of ulcerative colitis and Crohn’s disease,is a group of debilitating auto-immune disorders,which also increases the risk of colitis-associated cancer.However,due to the chronic nature of the disease and inconsistent treatment outcomes of current anti-IBD drugs(e.g.,approximately 30%non-responders to anti-TNFαagents),and related serious side effects,about half of all IBD patients(in millions)turn to alternative treatment options.In this regard,mucosal healing is gaining acceptance as a measure of disease activity in IBD patients as recent studies have correlated the success of mucosal healing with improved prognosis.However,despite the increasing clinical realization of the significance of the concept of mucosal healing,its regulation and means of therapeutic targeting remain largely unclear.Here,stemcell therapy,which uses hematopoietic stem cells or mesenchymal stem cells,remains a promising option.Stem cells are the pluripotent cells with ability to differentiate into the epithelial and/or immune-modulatory cells.The overreaching concept is that the stem cells can migrate to the damaged areas of the intestine to provide curative help in the mucosal healing process.Moreover,by differentiating into the mature intestinal epithelial cells,the stem cells also help in restoring the barrier integrity of the intestinal lining and hence prevent the immunomodulatory induction,the root cause of the IBD.In this article,we elaborate upon the current status of the clinical management of IBD and potential role of the stem cell therapy in improving IBD therapy and patient’s quality of life.
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.
