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GDF15 promotes prostate cancer bone metastasis and colonization through osteoblastic CCL2 and RANKL activation

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Bone Research 2022年第1期10卷 150-164页

作者： Jawed Akhtar Siddiqui Parthasarathy Seshacharyulu Sakthivel Muniyan Ramesh Pothuraju Parvez Khan Raghupathy Vengoji Sanjib Chaudhary Shailendra Kumar Maurya Subodh Mukund Lele Maneesh Jain Kaustubh Datta Mohd Wasim Nasser Surinder Kumar Batra Department of Biochemistry and Molecular Biology University of Nebraska Medical CenterOmahaNEUSA Department of Pathology and Microbiology University of Nebraska Medical CenterOmahaNEUSA fred&pamela buffett cancer center University of Nebraska Medical CenterOmahaNE 68198-5870USA Eppley Institute for Research in cancer and Allied Diseases University of Nebraska Medical CenterOmahaNEUSA

Bone metastases occur in patients with advanced-stage prostate cancer(PCa). The cell-cell interaction between PCa and the bone microenvironment forms a vicious cycle that modulates the bone microenvironment, increases bone deformities, and drives tumor growth in the bone. However, the molecular mechanisms of PCa-mediated modulation of the bone microenvironment are complex and remain poorly defined. Here, we evaluated growth differentiation factor-15(GDF15) function using in vivo preclinical PCa-bone metastasis mouse models and an in vitro bone cell coculture system. Our results suggest that PCa-secreted GDF15 promotes bone metastases and induces bone microarchitectural alterations in a preclinical xenograft model. Mechanistic studies revealed that GDF15 increases osteoblast function and facilitates the growth of PCa in bone by activating osteoclastogenesis through osteoblastic production of CCL2 and RANKL and recruitment of osteomacs. Altogether, our findings demonstrate the critical role of GDF15 in the modulation of the bone microenvironment and subsequent development of PCa bone metastasis.

关键词： GDF15 metastasis RANKL

Current updates in management of relapsed/refractory small cell lung cancer

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Journal of cancer Metastasis and Treatment 2020年第1期6卷 647-659页

作者： Omar Abughanimeh Vinicius Ernani Alissa Marr Apar Kishor Ganti Division of Oncology and Hematology Department of Internal MedicineUniversity of Nebraska Medical Center-Fred&Pamela Buffett Cancer CenterOmahaNE 68198-6840USA Division of Oncology and Hematology VA Nebraska Western Iowa Health Care SystemOmahaNE 68198-6840USA

Small cell lung cancer(SCLC)is an aggressive subtype of neuroendocrine *** is characterized by a rapid doubling time and early development of metastatic *** being responsive to initial chemotherapy,most of the patients will have relapse of the disease within a few *** prognosis of SCLC is dismal with a 5-year survival rate of less than 5%.For that reason,management of SCLC has been an active area of *** utilization of immunotherapy has provided promising results in treatment of SCLC in the front-line ***,utilization of immunotherapy and targeted therapy is being studied in the setting of relapsed/refractory disease,and currently,different clinical trials are exploring new drugs and further *** this review,we will explore the latest updates in management of relapsed/refractory SCLC.

关键词： Small cell lung cancer relapsed small cell lung cancer chemotherapy immunotherapy targeted therapy

Inflammatory bowel disease:Therapeutic limitations and prospective of the stem cell therapy

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World Journal of Stem Cells 2020年第10期12卷 1050-1066页

作者： Rangnath Mishra Punita Dhawan Anand S Srivastava Amar B Singh Institute of Stem Cell Therapy and Research San DiegoCA 92122United States Department of Biochemistry and Molecular Biology University of Nebraska Medical CenterOmahaNE 68118United States fred and pamela buffett cancer center OmahaNE 68118United States VA Nebraska-Western Iowa Health Care System OmahaNE 68118United States

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 ***,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 *** 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 ***,despite the increasing clinical realization of the significance of the concept of mucosal healing,its regulation and means of therapeutic targeting remain largely ***,stemcell therapy,which uses hematopoietic stem cells or mesenchymal stem cells,remains a promising *** cells are the pluripotent cells with ability to differentiate into the epithelial and/or immune-modulatory *** overreaching concept is that the stem cells can migrate to the damaged areas of the intestine to provide curative help in the mucosal healing ***,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 *** 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.

关键词： Crohn′s disease Ulcerative colitis Mesenchymal stem cells Hematopoietic stem cells Mucosal healing

Tumor microenvironment in pancreatic ductal adenocarcinoma:Implications in immunotherapy

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World Journal of Gastroenterology 2022年第27期28卷 3297-3313页

作者： Caitlyn Smith Wei Zheng Jixin Dong Yaohong Wang Jinping Lai Xiuli Liu Feng Yin Department of Pathology and Anatomical Sciences University of Missouri School of MedicineColumbiaMO 65212United States Department of Pathology Emory University School of MedicineAtlantaGA 30322United State Eppley Institute for Research in cancer and Allied Diseases Fred and Pamela Buffett Cancer CenterUniversity of Nebraska Medical CenterOmahaNE 68198United States Department of Pathology Microbiology and ImmunologyVanderbilt University Medical CenterNashvilleTN 37232United States Department of Pathology and Laboratory Medicine Kaiser Permanente Sacramento Medical CenterSacramentoCA 95825United States Department of Pathology and Immunology Washington UniversitySt.LouisMO 63110United States Department of Pathology and Anatomical Sciences University of MissouriColumbiaMO 65212United States

Pancreatic ductal adenocarcinoma is one of the most aggressive and lethal *** resection is the only curable treatment option,but it is available for only a small fraction of patients at the time of *** current therapeutic regimens,the average 5-year survival rate is less than 10%in pancreatic cancer *** has emerged as one of the most promising treatment options for multiple solid tumors of advanced ***,its clinical efficacy is suboptimal in most clinical trials on pancreatic *** studies have suggested that the tumor microenvironment is likely the underlying barrier affecting immunotherapy drug efficacy in pancreatic *** this review,we discuss the role of the tumor microenvironment in pancreatic cancer and the latest advances in immunotherapy on pancreatic cancer.

关键词： Pancreatic ductal adenocarcinoma Tumor microenvironment Immunotherapy Clinical trial Chemotherapy Treatment

Novel fibrin-fibronectin matrix accelerates mice skin wound healing

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Bioactive Materials 2020年第4期5卷 949-962页

作者： Carlos Poblete Jara Ou Wang Thais Paulino do Prado Ayman Ismail Frank Marco Fabian Han Li Licio A.Velloso Mark A.Carlson William Burgess Yuguo Lei William H.Velander Eliana P.Araújo Nursing School University of CampinasCampinasSPBrazil Laboratory of Cell Signaling University of CampinasCampinasSPBrazil Department of Chemical and Biomolecular Engineering University of NebraskaLincolnNEUSA Biomedical Engineering Program University of NebraskaLincolnNEUSA School of Biological Science University of NebraskaLincolnNEUSA Department of Surgery University of Nebraska Medical Center and the VA Nebraska-Western Iowa Health Care SystemUSA Mary and Dick Holland Regenerative Medicine Program University of Nebraska Medical CenterOmahaNEUSA fred&pamela buffett cancer center University of Nebraska Medical CenterOmahaNEUSA

Plasma fibrinogen(F1)and fibronectin(pFN)polymerize to form a fibrin clot that is both a hemostatic and provisional matrix for wound *** 90%of plasma F1 has a homodimeric pair ofγchains(γγF1),and 10%has a heterodimeric pair ofγand more acidicγ′chains(γγ′F1).We have synthesized a novel fibrin matrix exclusively from a 1:1(molar ratio)complex ofγγ′F1 and pFN in the presence of highly active thrombin and recombinant Factor XIII(rFXIIIa).In this matrix,the fibrin nanofibers were decorated with pFN nanoclusters(termedγγ′F1:pFN fibrin).In contrast,fibrin made from 1:1 mixture ofγγF1 and pFN formed a sporadic distribution of“pFN droplets”(termedγγF1+pFN fibrin).Theγγ′F1:pFN fibrin enhanced the adhesion of primary human umbilical vein endothelium cells(HUVECs)relative to theγγF1+FN *** dimensional(3D)culturing showed that theγγ′F1:pFN complex fibrin matrix enhanced the proliferation of both HUVECs and primary human *** in the 3Dγγ′F1:pFN fibrin exhibited a starkly enhanced vascular morphogenesis while an apoptotic growth profile was observed in theγγF1+pFN *** toγγF1+pFN fibrin,mouse dermal wounds that were sealed byγγ′F1:pFN fibrin exhibited accelerated and enhanced *** study suggests that a 3D pFN presentation on a fibrin matrix promotes wound healing.

关键词： Fibrin Fibronectin Nanoclusters Wound healing

Alcoholic pancreatitis:New insights into the pathogenesisand treatment

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World Journal of Gastrointestinal Pathophysiology 2016年第1期7卷 48-58页

作者： Dahn L Clemens Katrina J Schneider Christopher K Arkfeld Jaclyn R Grode Mark A Wells Shailender Singh fred and pamela buffett cancer center University of Nebraska Medical CenterOmahaNE 68198-8098United States Nebraska-Western Iowa VA Heath Care System University of Nebraska Medical CenterOmahaNE 68198-8098United States Department of Internal Medicine Section of Gastroenterology and HepatologyUniversity of Nebraska Medical CenterOmahaNE 68198-8098United States

Acute pancreatitis is a necro-inflammatory disease of the exocrine pancreas that is characterized by inappropriate activation of zymogens, infiltration of the pancreas by inflammatory cells, and destruction of the pancreatic exocrine cells. Acute pancreatitis can progress to a severe life-threatening disease. Currently there is no pharmacotherapy to prevent or treat acute pancreatitis. One of the more common factors associated with acute pancreatitis is alcohol abuse. Although commonly associated with pancreatitis alcohol alone is unable to cause pancreatitis. Instead, it appears that alcohol and its metabolic by-products predispose the pancreas to damage from agents that normally do not cause pancreatitis, or to more severe disease from agents that normally cause mild pancreatic damage. Over the last 10 to 20 years, a tremendous amount of work has defined a number of alcohol-mediated biochemical changes in pancreatic cells. Among these changes are: Sustained levels of intracellular calcium, activation of the mitochondrial permeability transition pore, endoplasmic reticulum stress, impairment in autophagy, alteration in the activity of transcriptional activators, and colocalization of lysosomal and pancreatic digestive enzymes. Elucidation of these changes has led to a deeper understanding of the mechanisms by which ethanol predisposes acinar cells to damage. This greater understanding has revealed a number of promising targets for therapeutic intervention. It is hoped that further investigation of these targets will lead to the development of pharmacotherapy that is effective in treating and preventing the progression of acute pancreatitis.

关键词： Alcohol Pancreatitis Alcoholic pancreatitis Ethanol metabolism Acute pancreatitis Fatty acid ethylesters

Molecular mechanisms of alcohol associated pancreatitis

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World Journal of Gastrointestinal Pathophysiology 2014年第3期5卷 147-157页

作者： Dahn L Clemens Mark A Wells Katrina J Schneider Shailender Singh Nebraska-Western Iowa Veterans Administration Medical center Department of Internal Medicine University of Nebraska Medical Center fred and pamela buffett cancer University of Nebraska Medical Center

Alcohol abuse is commonly associated with the development of both acute and chronic pancreatitis. Despite this close association, the fact that only a small percentage of human beings who abuse alcohol develop pancreatitis indicates that alcohol abuse alone is not sufficient to initiate clinical pancreatitis. This contention is further supported by the fact that administration of ethanol to experimental animals does not cause pancreatitis. Because of these findings, it is widely believed that ethanol sensitizes the pancreas to injury and additional factors trigger the development of overt pancreatitis. How ethanol sensitizes the pancreas to pancreatitis is not entirely known. Numerous studies have demonstrated that ethanol and its metabolites have a number of deleterious effects on acinar cells. Important acinar cells properties that are affected by ethanol include: calcium signaling, secretion of zymogens, autophagy, cellular regeneration, the unfolded protein response, and mitochondrial membrane integrity. In addition to the actions of ethanol on acinar cells, it is apparent that ethanol also affects pancreatic stellatecells. Pancreatic stellate cells have a critical role in normal tissue repair and the pathologic fibrotic response. Given that ethanol and its metabolites affect so many pancreatic functions, and that all of these effects occur simultaneously, it is likely that none of these effects is "THE" effect. Instead, it is most likely that the cumulative effect of ethanol on the pancreas predisposes the organ to pancreatitis. The focus of this article is to highlight some of the important mechanisms by which ethanol alters pancreatic functions and may predispose the pancreas to disease.

关键词： Pancreatitis Alcoholic pancreatitis Alcoholic acute pancreatitis Alcoholic chronic pancreatitis

Reprogramming of ovarian granulosa cells by YAP1 leads to development of high-grade cancer with mesenchymal lineage and serous features

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Science Bulletin 2020年第15期65卷 1281-1296,M0004页

作者： Xiangmin Lv Chunbo He Cong Huang Guohua Hua Xingcheng Chen Barbara K.Timm Victoria M.Maclin Abigail A.Haggerty Shelly K.Aust Denae M.Golden Bhavana J.Dave Yun-An Tseng Li Chen Hongbo Wang Peichao Chen David L.Klinkebiel Adam R.Karpf Jixin Dong Ronny I.Drapkin Bo R.Rueda John S.Davis Cheng Wang Vincent center for Reproductive Biology Department of Obstetrics and GynecologyMassachusetts General HospitalHarvard Medical SchoolBostonMA 02114USA Olson center for Women's Health Department of Obstetrics and GynecologyUniversity of Nebraska Medical CenterOmahaNE 68198USA College of Animal Sciences and Veterinary Medicine Huazhong Agricultural UniversityWuhan 470000China fred&pamela buffett cancer center University of Nebraska Medical CenterOmahaNE 68198USA Department of Pathology and Microbiology.University of Nebraska Medical center OmahaNE 68198USA Heartland center for Reproductive Medicine OmahaNE 68198USA Munroe-Meyer Institute University of Nebraska Medical CenterOmahaNE 68198USA Key Laboratory of Animal Ecology and Conservation Biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China College of Life and Environmental Science Wenzhou UniversityWenzhou 325035China Biochemistry and Molecular Biology University of Nebraska Medical CenterOmahaNE 68198USA Department of Obstetrics and Gynecology University of PennsylvaniaPhiladelphiaPA 19104USA

Understanding the cell-of-origin of ovarian high grade serous cancer(HGSC)is the prerequisite for efficient prevention and early diagnosis of this most lethal gynecological ***,a mesenchymal type of ovarian HGSC with the poorest prognosis among ovarian cancers was identified by both TCGA and AOCS *** cell-of-origin of this subtype of ovarian cancer is *** pursuing studies to understand the role of the Hippo pathway in ovarian granulosa cell physiology and pathology,we unexpectedly found that the Yes-associated protein 1(YAP1),the major effector of the Hippo signaling pathway,induced dedifferentiation and reprogramming of the ovarian granulosa cells,a unique type of ovarian follicular cells with mesenchymal lineage and high plasticity,leading to the development of high grade ovarian cancer with serous *** research results unveil a potential cell-of-origin for a subtype of HGSC with mesenchymal features.

关键词： Ovarian granulosa cells Cell reprogramming Cell dedifferentiation The Hippo pathway YAP1 oncogene Mesenchymal type of high grade serous cancer

Tumor-and osteoclast-derived NRP2 in prostate cancer bone metastases

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Bone Research 2021年第2期9卷 233-247页

作者： Navatha Shree Polavaram Samikshan Dutta Ridwan Islam Arup K.Bag Sohini Roy David Poitz Jeffrey Karnes Lorenz C.Hofbauer Manish Kohli Brian A.Costello Raffael Jimenez Surinder K.Batra Benjamin A.Teply Michael H.Muders Kaustubh Datta Department of Microbiology and Pathology University of Nebraska Medical CenterOmahaNEUSA Department of Biochemistry and Molecular Biology University of Nebraska Medical CenterOmahaNEUSA Institute for Clinical Chemistry University Hospital DresdenDresdenGermany Department of Urology Mayo ClinicRochesterMNUSA center for Healthy Aging and Bone Lab Dresden Department of Medicine IIITechnische Universität DresdenDresdenGermany School of Medicine Division of OncologyHuntsman Cancer InstituteSalt Lake CityUTUSA Division of Anatomic Pathology Department of Pathology and Laboratory MedicineMayo ClinicRochesterMNUSA Internal Medicine Division of Oncology&HematologyUniversity of Nebraska Medical CenterOmahaNEUSA Rudolf-Becker Laboratory for Prostate cancer Research Institute of PathologyUniversity of Bonn Medical CenterBonnGermany

Understanding the role of neuropilin 2(NRP2)in prostate cancer cells as well as in the bone microenvironment is pivotal in the development of an effective targeted therapy for the treatment of prostate cancer bone *** observed a significant upregulation of NRP2 in prostate cancer cells metastasized to ***,we report that targeting NRP2 in cancer cells can enhance taxane-based chemotherapy with a better therapeutic outcome in bone metastasis,implicating NRP2 as a promising therapeutic ***,osteoclasts present in the tumor microenvironment express NRP2,we have investigated the potential effect of targeting NRP2 in *** results revealed NRP2 negatively regulates osteoclast differentiation and function in the presence of prostate cancer cells that promotes mixed bone *** study further delineated the molecular mechanisms by which NRP2 regulates osteoclast ***,depletion of NRP2 in osteoclasts in vivo showed a decrease in the overall prostate tumor burden in the *** results therefore indicate that targeting NRP2 in prostate cancer cells as well as in the osteoclastic compartment can be beneficial in the treatment of prostate cancer bone metastasis.

关键词： metastasis chemotherapy treatment