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Tunable hybrid hydrogels with multicellular spheroids for modeling desmoplastic pancreatic cancer

Bioactive Materials 2023年第7期25卷 360-373页

作者： Menekse Ermis Natashya Falcone Natan Roberto de Barros Marvin Mecwan Reihaneh Haghniaz Auveen Choroomi Mahsa Monirizad Yeji Lee Jihyeon Song Hyun-Jong Cho Yangzhi Zhu Heemin Kang Mehmet R.Dokmeci Ali Khademhosseini Junmin Lee Han-Jun Kim Terasaki Institute for Biomedical Innovation(TIBI) Los AngelesCA90024USA Department of Materials Science and Engineering Pohang University of Science and Technology(POSTECH)PohangGyeongbuk37673Republic of Korea College of Pharmacy Kangwon National UniversityChuncheonGangwon24341Republic of Korea Department of Materials Science and Engineering Korea UniversitySeoul02841Republic of Korea Institute for Convergence Research and Education in Advanced Technology Yonsei UniversityIncheon 21983Republic of Korea College of Pharmacy Korea UniversitySejong30019Republic of Korea

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.

关键词： Pancreatic cancer desmoplasia Fibrosis Extracellular matrix Tumor microenvironment

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Targeting hyaluronan for the treatment of pancreatic ductal adenocarcinoma

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Acta Pharmaceutica Sinica B 2016年第2期6卷 101-105页

作者： Norihiro Sato Xiao-Bo Cheng Shiro Kohi Atsuhiro Koga Keiji Hirata Department of Surgery 1 School of Medicine University of Occupational and Environmental Health

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.

关键词： Pancreatic ductal adenocarcinoma Hyaluronan Tumor stroma desmoplasia Tumor–stromal interaction Therapeutic target 4-Methylumbelliferone PEGPH20

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Pancreatic cancer: genetics, disease progression, therapeutic resistance and treatment strategies

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Journal of Cancer Metastasis and Treatment 2021年第1期7卷 794-808页

作者： Karnika Singh Gauri Shishodia Hari K.Koul Department of Radiation Oncology The Ohio State University Comprehensive Cancer CenterColumbusOH 43210USA Department of Otolaryngology/Head&Neck Cancer Surgery LSU Health Sciences CenterShreveportLA 71103USA Department of Biochemistry&Molecular Biology Urology and Stanley S Scott Cancer Center School of Medicine LSU Health Sciences CenterNew OrleansLA 70112USA.

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.

关键词： Pancreatic cancer signature mutations gemcitabine desmoplasia therapeutic resistance immunotherapy

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Recent advances in immunotherapy for pancreatic cancer

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Journal of Cancer Metastasis and Treatment 2020年第1期6卷 531-547页

作者： Jeffrey Chi Rajvi Patel Hasan Rehman Shreya Goyal Muhammad Wasif Saif Department of Medical Oncology/Hematology Donald&Barbara Zucker School of Medicine at Hofstra/NorthwellNew YorkNY 11042USA

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.

关键词： Pancreatic ductal adenocarcinoma chemoresistance desmoplasia tumor microenvironment extracellular matrix immunogenicity immunotherapy vaccines immune checkpoint inhibitors immunomodulation

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Tumor reactive stroma in cholangiocarcinoma:The fuel behind cancer aggressiveness

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World Journal of Hepatology 2017年第9期9卷 455-468页

作者： Simone Brivio Massimiliano Cadamuro Mario Strazzabosco Luca Fabris School of Medicine and Surgery University of Milan-Bicocca International Center for Digestive Health University of MilanBicocca Digestive Disease Section Yale University School of Medicine Department of Molecular Medicine University of Padua School of Medicine

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.

关键词： Tumor microenvironment desmoplasia Cancer-associated fibroblast Inflammation Tumor-associated macrophage Lymphatic endothelial cell Mesenchymal stem cell Extracellular matrix

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