Cholangiocarcinoma(CCA) is a highly aggressive epithelial malignancy still carrying a dismal prognosis, owing to early lymph node metastatic dissemination and striking resistance to conventional chemotherapy. Although...Cholangiocarcinoma(CCA) is a highly aggressive epithelial malignancy still carrying a dismal prognosis, owing to early lymph node metastatic dissemination and striking resistance to conventional chemotherapy. Although mechanisms underpinning CCA progression are still a conundrum, it is now increasingly recognized that the desmoplastic microenvironment developing in conjunction with biliary carcinogenesis, recently renamed tumor reactive stroma(TRS), behaves as a paramount tumor-promoting driver. Indeed, once being recruited, activated and dangerously co-opted by neoplastic cells, the cellular components of the TRS(myofibroblasts, macrophages, endothelial cells and mesenchymal stem cells) continuously rekindle malignancy by secreting a huge variety of soluble factors(cyto/chemokines, growth factors, morphogens and proteinases). Furthermore, these factors are long-term stored within an abnormally remodeled extracellular matrix(ECM), which in turn can deleteriously mold cancer cell behavior. In this review, we will highlight evidence for the active role played by reactive stromal cells(as well as by the TRS-associated ECM) in CCA progression, including an overview of the most relevant TRS-derived signals possibly fueling CCA cell aggressiveness. Hopefully, a deeper knowledge of the paracrine communications reciprocally exchanged between cancer and stromal cells will steer the development of innovative, combinatorial therapies, which can finally hinder the progression of CCA, as well as of other cancer types with abundant TRS, such as pancreatic and breast carcinomas.展开更多
Progression of cancer is often associated with interactions between cancer cells and extracellular matrix(ECM) surrounding them. Increasing evidence has suggested that accumulation of hyaluronan(HA), a major component...Progression of cancer is often associated with interactions between cancer cells and extracellular matrix(ECM) surrounding them. Increasing evidence has suggested that accumulation of hyaluronan(HA), a major component of ECM, provides a favorable microenvironment for cancer progression. Pancreatic ductal adenocarcinoma(PDAC) is characterized typically by a dense desmoplastic stroma with a large amount of HA, making this molecule as an attractive target for therapy. Several studies have shown efficacy of inhibitors of HA synthesis or signaling for the treatment of PDAC. Recent studies have also demonstrated substantial improvements in the effects of chemotherapy by a targeted depletion of stromal HA in PDAC using an enzymatic agent. Thus, targeting HA has been recognized as a promising therapeutic strategy to treat this highly aggressive neoplasm. In this review article, we summarize our current understanding of the role of HA in the progression of PDAC and discuss possible therapeutic approaches targeting HA.展开更多
The tumor microenvironment consists of diverse,complex etiological factors.The matrix component of pancreatic ductal adenocarcinoma(PDAC)plays an important role not only in physical properties such as tissue rigidity ...The tumor microenvironment consists of diverse,complex etiological factors.The matrix component of pancreatic ductal adenocarcinoma(PDAC)plays an important role not only in physical properties such as tissue rigidity but also in cancer progression and therapeutic responsiveness.Although significant efforts have been made to model desmoplastic PDAC,existing models could not fully recapitulate the etiology to mimic and understand the progression of PDAC.Here,two major components in desmoplastic pancreatic matrices,hyaluronic acid-and gelatin-based hydrogels,are engineered to provide matrices for tumor spheroids composed of PDAC and cancer-associated fibroblasts(CAF).Shape analysis profiles reveals that incorporating CAF contributes to a more compact tissue formation.Higher expression levels of markers associated with proliferation,epithelial to mesenchymal transition,mechanotransduction,and progression are observed for cancer-CAF spheroids cultured in hyper desmoplastic matrix-mimicking hydrogels,while the trend can be observed when those are cultured in desmoplastic matrix-mimicking hydrogels with the presence of transforming growth factor-β1(TGF-β1).The proposed multicellular pancreatic tumor model,in combination with proper mechanical properties and TGF-β1 supplement,makes strides in developing advanced pancreatic models for resembling and monitoring the progression of pancreatic tumors,which could be potentially applicable for realizing personalized medicine and drug testing applications.展开更多
Pancreatic ductal adenocarcinoma(PDAC)remains a disease with a dismal prognosis.Since 1996 there have only been two upfront regimens found to be superior to gemcitabine:FOLFIRINOX(5-fluorouracil,leucovorin,irinotecan ...Pancreatic ductal adenocarcinoma(PDAC)remains a disease with a dismal prognosis.Since 1996 there have only been two upfront regimens found to be superior to gemcitabine:FOLFIRINOX(5-fluorouracil,leucovorin,irinotecan and oxaliplatin),and gemcitabine plus nab-paclitaxel.Despite the improvement noted in these trials,PDAC is highly chemo-resistant and patients who respond will inevitably develop resistance.The unique immunosuppressive tumor microenvironment with extensive desmoplasia has posed challenges to developing new and effective treatments.Therapeutic vaccines,combination treatments,adoptive T cell transfer,as well as immunomodulators are being explored.With the emerging use of immunotherapy and immunomodulators,the scope of this review is to present the current data on these agents as well as focus on the advancements in the treatment of PDAC.Overall,results in this realm have been disappointing to date reflecting the non-immunogenic and complex tumor microenvironment of PDAC.展开更多
Pancreatic cancer is a deadly disease and the third-highest cause of cancer-related deaths in the United States.It has a very low five-year survival rate(<5%)in the United States as well as in the world(about 9%).T...Pancreatic cancer is a deadly disease and the third-highest cause of cancer-related deaths in the United States.It has a very low five-year survival rate(<5%)in the United States as well as in the world(about 9%).The current gemcitabine-based therapy soon becomes ineffective because treatment resistance and surgical resection also provides only selective benefit.Signature mutations in pancreatic cancer confer chemoresistance by deregulating the cell cycle and promoting anti-apoptotic mechanisms.The stroma-rich tumor microenvironment impairs drug delivery and promotes tumor-specific immune escape.All these factors render the current treatment incompetent and prompt an urgent need for new,improved therapy.In this review,we have discussed the genetics of pancreatic cancer and its role in tumor evolution and treatment resistance.We have also evaluated new treatment strategies for pancreatic cancer,like targeted therapy and immunotherapy.展开更多
The application of extracellular vesicles,particularly exosomes(EXs),is rapidly expanding in the field of medicine,owing to their remarkable properties as natural carriers of biological cargo.This study investigates u...The application of extracellular vesicles,particularly exosomes(EXs),is rapidly expanding in the field of medicine,owing to their remarkable properties as natural carriers of biological cargo.This study investigates utilization of exosomes derived from stromal cells of tumor adjacent normal tissues(NAF-EXs)for personalized medicine,which can be derived at the time of diagnosis by endoscopic ultrasound.Herein,we show that exosomes(EXs)derived from NAFs demonstrate differential bio-physical characteristics,efficient cellular internalization,drug loading efficiency,pancreatic tumor targeting and delivery of payloads.NAF-derived EXs(NAF-EXs)were used for loading ormeloxifene(ORM),a potent anti-cancer and desmoplasia inhibitor as a model drug.We found that ORM maintains normal fibroblast cell phenotype and renders them incompatible to be triggered for a CAF-like phenotype,which may be due to regulation of Ca^(2+) influx in fibroblast cells.NAF-EXs-ORM effectively blocked oncogenic signaling pathways involved in desmoplasia and epithelial mesenchymal transition(EMT)and repressed tumor growth in xenograft mouse model.In conclusion,our data suggests preferential tropism of NAF-EXs for PDAC tumors,thus imply feasibility of developing a novel personalized medicine for PDAC patients using autologous NAF-EXs for improved therapeutic outcome of anti-cancer drugs.Additionally,it provides the opportunity of utilizing this biological scaffold for effective therapeutics in combination with standard therapeutic regimen.展开更多
文摘Cholangiocarcinoma(CCA) is a highly aggressive epithelial malignancy still carrying a dismal prognosis, owing to early lymph node metastatic dissemination and striking resistance to conventional chemotherapy. Although mechanisms underpinning CCA progression are still a conundrum, it is now increasingly recognized that the desmoplastic microenvironment developing in conjunction with biliary carcinogenesis, recently renamed tumor reactive stroma(TRS), behaves as a paramount tumor-promoting driver. Indeed, once being recruited, activated and dangerously co-opted by neoplastic cells, the cellular components of the TRS(myofibroblasts, macrophages, endothelial cells and mesenchymal stem cells) continuously rekindle malignancy by secreting a huge variety of soluble factors(cyto/chemokines, growth factors, morphogens and proteinases). Furthermore, these factors are long-term stored within an abnormally remodeled extracellular matrix(ECM), which in turn can deleteriously mold cancer cell behavior. In this review, we will highlight evidence for the active role played by reactive stromal cells(as well as by the TRS-associated ECM) in CCA progression, including an overview of the most relevant TRS-derived signals possibly fueling CCA cell aggressiveness. Hopefully, a deeper knowledge of the paracrine communications reciprocally exchanged between cancer and stromal cells will steer the development of innovative, combinatorial therapies, which can finally hinder the progression of CCA, as well as of other cancer types with abundant TRS, such as pancreatic and breast carcinomas.
基金supported in part by a grant-in-aid from the Ministry of Education, Culture, Sports, Science and Technologies of Japan (26462076)
文摘Progression of cancer is often associated with interactions between cancer cells and extracellular matrix(ECM) surrounding them. Increasing evidence has suggested that accumulation of hyaluronan(HA), a major component of ECM, provides a favorable microenvironment for cancer progression. Pancreatic ductal adenocarcinoma(PDAC) is characterized typically by a dense desmoplastic stroma with a large amount of HA, making this molecule as an attractive target for therapy. Several studies have shown efficacy of inhibitors of HA synthesis or signaling for the treatment of PDAC. Recent studies have also demonstrated substantial improvements in the effects of chemotherapy by a targeted depletion of stromal HA in PDAC using an enzymatic agent. Thus, targeting HA has been recognized as a promising therapeutic strategy to treat this highly aggressive neoplasm. In this review article, we summarize our current understanding of the role of HA in the progression of PDAC and discuss possible therapeutic approaches targeting HA.
基金Dr.M.Ermis and Dr.N.Falcone contributed equally to this work.The authors gratefully acknowledge the funding by the National Institutes of Health(HL140951,HL137193,CA257558,DK130566)Dr.M.Ermis acknowledges The Scientific and Technological Research Council of Turkiye for 2219-International Postdoctoral Research Fellowship Program.
文摘The tumor microenvironment consists of diverse,complex etiological factors.The matrix component of pancreatic ductal adenocarcinoma(PDAC)plays an important role not only in physical properties such as tissue rigidity but also in cancer progression and therapeutic responsiveness.Although significant efforts have been made to model desmoplastic PDAC,existing models could not fully recapitulate the etiology to mimic and understand the progression of PDAC.Here,two major components in desmoplastic pancreatic matrices,hyaluronic acid-and gelatin-based hydrogels,are engineered to provide matrices for tumor spheroids composed of PDAC and cancer-associated fibroblasts(CAF).Shape analysis profiles reveals that incorporating CAF contributes to a more compact tissue formation.Higher expression levels of markers associated with proliferation,epithelial to mesenchymal transition,mechanotransduction,and progression are observed for cancer-CAF spheroids cultured in hyper desmoplastic matrix-mimicking hydrogels,while the trend can be observed when those are cultured in desmoplastic matrix-mimicking hydrogels with the presence of transforming growth factor-β1(TGF-β1).The proposed multicellular pancreatic tumor model,in combination with proper mechanical properties and TGF-β1 supplement,makes strides in developing advanced pancreatic models for resembling and monitoring the progression of pancreatic tumors,which could be potentially applicable for realizing personalized medicine and drug testing applications.
文摘Pancreatic ductal adenocarcinoma(PDAC)remains a disease with a dismal prognosis.Since 1996 there have only been two upfront regimens found to be superior to gemcitabine:FOLFIRINOX(5-fluorouracil,leucovorin,irinotecan and oxaliplatin),and gemcitabine plus nab-paclitaxel.Despite the improvement noted in these trials,PDAC is highly chemo-resistant and patients who respond will inevitably develop resistance.The unique immunosuppressive tumor microenvironment with extensive desmoplasia has posed challenges to developing new and effective treatments.Therapeutic vaccines,combination treatments,adoptive T cell transfer,as well as immunomodulators are being explored.With the emerging use of immunotherapy and immunomodulators,the scope of this review is to present the current data on these agents as well as focus on the advancements in the treatment of PDAC.Overall,results in this realm have been disappointing to date reflecting the non-immunogenic and complex tumor microenvironment of PDAC.
基金supported in part by funds from Carroll W.Feist Endowed Chair in Cancer(Koul HK)LSUHSC-graduate stipend to Singh K.Koul HK is supported in part by the NIH/NCI RO1 R01CA242839.
文摘Pancreatic cancer is a deadly disease and the third-highest cause of cancer-related deaths in the United States.It has a very low five-year survival rate(<5%)in the United States as well as in the world(about 9%).The current gemcitabine-based therapy soon becomes ineffective because treatment resistance and surgical resection also provides only selective benefit.Signature mutations in pancreatic cancer confer chemoresistance by deregulating the cell cycle and promoting anti-apoptotic mechanisms.The stroma-rich tumor microenvironment impairs drug delivery and promotes tumor-specific immune escape.All these factors render the current treatment incompetent and prompt an urgent need for new,improved therapy.In this review,we have discussed the genetics of pancreatic cancer and its role in tumor evolution and treatment resistance.We have also evaluated new treatment strategies for pancreatic cancer,like targeted therapy and immunotherapy.
基金UTRGV School of medicine start up,CPRIT TREC Award RP230419 and Integrated Cancer Research Core(ICRC)-RP210180Herb Kosten foundation for pancreatic cancer researchNational Institutes of Health grants R01CA206069,SC1GM139727,SC2GM139715,R01CA210192 and R01CA204552.
文摘The application of extracellular vesicles,particularly exosomes(EXs),is rapidly expanding in the field of medicine,owing to their remarkable properties as natural carriers of biological cargo.This study investigates utilization of exosomes derived from stromal cells of tumor adjacent normal tissues(NAF-EXs)for personalized medicine,which can be derived at the time of diagnosis by endoscopic ultrasound.Herein,we show that exosomes(EXs)derived from NAFs demonstrate differential bio-physical characteristics,efficient cellular internalization,drug loading efficiency,pancreatic tumor targeting and delivery of payloads.NAF-derived EXs(NAF-EXs)were used for loading ormeloxifene(ORM),a potent anti-cancer and desmoplasia inhibitor as a model drug.We found that ORM maintains normal fibroblast cell phenotype and renders them incompatible to be triggered for a CAF-like phenotype,which may be due to regulation of Ca^(2+) influx in fibroblast cells.NAF-EXs-ORM effectively blocked oncogenic signaling pathways involved in desmoplasia and epithelial mesenchymal transition(EMT)and repressed tumor growth in xenograft mouse model.In conclusion,our data suggests preferential tropism of NAF-EXs for PDAC tumors,thus imply feasibility of developing a novel personalized medicine for PDAC patients using autologous NAF-EXs for improved therapeutic outcome of anti-cancer drugs.Additionally,it provides the opportunity of utilizing this biological scaffold for effective therapeutics in combination with standard therapeutic regimen.
