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Bone loss from Wnt inhibition mitigated by concurrent alendronate therapy

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Bone Research 2018年第2期6卷 167-176页

作者： Babita Madan Mitchell J.McDonald Gabrielle E.Foxa Cassandra R.Diegel Bart O.Williams David M.Virshup Program in Cancer and Stem Cell Biology Duke-NUS Medical School Center for cancer and cell biology and Program for Skeletal Disease and Tumor Microenvironment Van Andel Research Institute Department of Pediatrics Duke University

Dysregulated Wnt signaling is associated with the pathogenesis of cancers, fibrosis, and vascular diseases. Inhibition of Wnt signaling has shown efficacy in various pre-clinical models of these disorders. One of the key challenges in developing targeted anti-cancer drugs is to balance efficacy with on-target toxicity. Given the crucial role Wnts play in the differentiation of osteoblasts and osteoclasts, acute inhibition of Wnt signaling is likely to affect bone homeostasis. In this study, we evaluated the skeletal effect of small molecule inhibitor of an o-acyl transferase porcupine（PORCN） that prevents Wnt signaling by blocking the secretion of all Wnts. Micro-computed tomography and histomorphometric evaluation revealed that the bones of mice treated with two structurally distinct PORCN inhibitors LGK974 and ETC-1922159（ETC-159） had loss-of-bone volume and density within 4 weeks of exposure. This decreased bone mass was associated with a significant increase in adipocytes within the bone marrow. Notably,simultaneous administration of a clinically approved anti-resorptive, alendronate, a member of the bisphosphonate family,mitigated loss-of-bone mass seen upon ETC-159 treatment by regulating activity of osteoclasts and blocking accumulation of bone marrow adipocytes. Our results support the addition of bone protective agents when treating patients with PORCN inhibitors.Mitigation of bone toxicity can extend the therapeutic utility of Wnt pathway inhibitors.

关键词： Wnt ETC Bone loss Wnt inhibition mitigated concurrent alendronate therapy

Targeting cancer stem cells in squamous cell carcinoma

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Precision Clinical Medicine 2019年第3期2卷 152-165页

作者： Demeng Chen Cun-Yu Wang Laboratory of Molecular Signaling Division of Oral Biology and MedicineSchool of DentistryUCLALos AngelesCA 90095USA Department of Bioengineering Henry Samueli School of Engineering and Applied ScienceUCLALos AngelesCA 90095USA Jonsson Comprehensive cancer Center and Broad stem cell Research Center UCLALos AngelesCA 90095USA

Head and neck squamous cell carcinoma(HNSCC)is a highly aggressive tumor and the sixth most common cancer worldwide.Current treatment strategies for HNSCC are surgery,radiotherapy,chemotherapy,immunotherapy or combinatorial therapies.However,the overall 5-year survival rate of HNSCC patients remains at about 50%.cancer stem cells(CSCs),a small population among tumor cells,are able to self-renew and differentiate into different tumor cell types in a hierarchical manner,similar to normal tissue.In HNSCC,CSCs are proposed to be responsible for tumor initiation,progression,metastasis,drug resistance,and recurrence.In this review,we discuss the molecular and cellular characteristics of CSCs in HNSCC.We summarize current approaches used in the literature for identification of HNSCC CSCs,and mechanisms required for CSC regulation.We also highlight the role of CSCs in treatment failure and therapeutic targeting options for eliminating CSCs in HNSCC.

关键词： cancer stem cells head and neck squamous cell carcinoma lymph node metastasis resistance

Next-generation sequencing traces human induced pluripotent stem cell lines clonally generated from heterogeneous cancer tissue

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World Journal of stem cells 2017年第5期9卷 77-88页

作者： Tetsuya Ishikawa cell biology Core Facilities for Research and Innovative MedicineNational Cancer Center Research InstituteTokyo 104-0045Japan Central Animal Division Fundamental Innovative Oncology Core CenterNational Cancer Center Research InstituteTokyo 104-0045Japan

AIM To investigate genotype variation among induced pluripotent stem cell(iPSC) lines that were clonally generated from heterogeneous colon cancer tissues using next-generation sequencing. METHODS Human iPSC lines were clonally established by selecting independent single colonies expanded from heterogeneous primary cells of S-shaped colon cancer tissues by retroviral gene transfer(OCT3/4, SOX2, and KLF4). The ten iPSC lines, their starting cancer tissues, and the matched adjacent non-cancerous tissues were analyzed using nextgeneration sequencing and bioinformatics analysis using the human reference genome hg19. Non-synonymous single-nucleotide variants(SNVs)(missense, nonsense,and read-through) were identified within the target region of 612 genes related to cancer and the human kinome. All SNVs were annotated using dbS NP135, CCDS, RefSeq, GENCODE, and 1000 Genomes. The SNVs of the iPSC lines were compared with the genotypes of the cancerous and non-cancerous tissues. The putative genotypes were validated using allelic depth and genotype quality. For final confirmation, mutated genotypes were manually curated using the Integrative Genomics Viewer. RESULTS In eight of the ten iPSC lines, one or two non-synonymous SNVs in EIF2AK2, TTN, ULK4, TSSK1 B, FLT4, STK19, STK31, TRRAP, WNK1, PLK1 or PIK3R5 were identified as novel SNVs and were not identical to the genotypes found in the cancer and non-cancerous tissues. This result suggests that the SNVs were de novo or pre-existing mutations that originated from minor populations, such as multifocal pre-cancer(stem) cells or pre-metastatic cancer cells from multiple, different clonal evolutions, present within the heterogeneous cancer tissue. The genotypes of all ten iPSC lines were different from the mutated ERBB2 and MKNK2 genotypes of the cancer tissues and were identical to those of the noncancerous tissues and that found in the human reference genome hg19. Furthermore, two of the ten iPSC lines did not have any confirmed mutated genotypes, despite being derived fro

关键词： Colon cancer Next-generation sequencing Single-nucleotide variant Genotype Heterogeneous cancer tissue cancer associated fibroblast Pre-cancer cell Induced pluripotent stem cell Single cell Clonal evolution

Pancreatic cancer stem cell markers and exosomes-the incentive push

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World Journal of Gastroenterology 2016年第26期22卷 5971-6007页

作者： Sarah Heiler Zhe Wang Margot Zoller Tumor cell biology University Hospital of SurgeryD 69120 HeidelbergGermany

Pancreatic cancer(Pa Ca) has the highest death rate and incidence is increasing. Poor prognosis is due to late diagnosis and early metastatic spread, which is ascribed to a minor population of so called cancer stem cells(CSC) within the mass of the primary tumor. CSC are defined by biological features, which they share with adult stem cells like longevity, rare cell division, the capacity for self renewal, differentiation, drug resistance and the requirement for a niche. CSC can also be identified by sets of markers, which for pancreatic CSC(Pa-CSC) include CD44v6, c-Met, Tspan8, alpha6beta4, CXCR4, CD133, Ep CAM and claudin7. The functional relevance of CSC markers is still disputed. We hypothesize that Pa-CSC markers play a decisive role in tumor progression. This is fostered by the location in glycolipid-enriched membrane domains, which function as signaling platform and support connectivity of the individual Pa-CSC markers. Outsidein signaling supports apoptosis resistance, stem cell gene expression and tumor suppressor gene repression as well as mi RNA transcription and silencing. Pa-CSC markers also contribute to motility and invasiveness. By ligand binding host cells are triggered towards creating a milieu supporting Pa-CSC maintenance. Furthermore, CSC markers contribute to the generation, loading and delivery of exosomes, whereby CSC gain the capacity for a cell-cell contact independent crosstalk with the host and neighboring non-CSC. This allows PaCSC exosomes(TEX) to reprogram neighboring nonCSC towards epithelial mesenchymal transition and to stimulate host cells towards preparing a niche for metastasizing tumor cells. Finally, TEX communicate with the matrix to support tumor cell motility, invasion and homing. We will discuss the possibility that CSC markers are the initial trigger for these processes and what is the special contribution of CSC-TEX.

关键词： Pancreatic cancer cancer stem cells stem cell markers Exosomes Crosstalk

Role of Lef1 in sustaining self-renewal in mouse embryonic stem cells

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Journal of Genetics and Genomics 2010年第7期37卷 441-449页

作者： Chen Huang Dajiang Qin stem cell and cancer biology Group Key Laboratory of Regenerative Biology South China Institute for Stem Cell Biology and Regenerative Medicine Guangzhou Institute of Biomedicine and Health Chinese Academy of Sciences Guangzhou 510530 China

Embryonic stem cells （ESCs） can self-renew indefinitely while maintaining the ability to generate all three germ-layer derivatives.Despite the importance of ESCs in developmental biology and their potential impact on regenerative medicine,the molecular mechanisms controlling ESC behavior are incompletely understood.Previously,activation of the canonical Wnt signaling pathway has been shown to contribute to mouse ESC self-renewal.Here we report that ectopic expression of Lef1,a component of the Wnt signaling pathway,has a positive effect on the self-renewal of mouse ESCs.Lef1 up-regulates Oct4 promoter activity and physically interacts with Nanog,two key components of the ESC pluripotency machinery.Moreover,siRNA for Lef1 induced mouse ESC differentiation.Our results thus suggest that in response to Wnt signaling Lef1 binds to stabilized β-catenin and helps maintain the undifferentiated status of ESCs through modulation of Oct4 and Nanog.

关键词： embryonic stem cells Wnt signaling 13-catenin Lefl Oct4 Nanog

Molecular insights into colorectal cancer stem cell regulation by environmental factors

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Journal of cancer Metastasis and Treatment 2015年第1期1卷 156-162页

作者： Daisuke Izumi Takatsugu Ishimoto Yasuo Sakamoto Yuji Miyamoto Hideo Baba Department of Gastroenterological Surgery Graduate School of Medical ScienceKumamoto University1-1-1 HonjoKumamoto 860-8556Japan Cancer and Stem Cell Biology Duke-NUS Graduate Medical School Singapore169857 Singapore.

Colorectal cancer remains a signifi cant cause of cancer-related mortality worldwide,mainly because of tumor relapse and metastases.cancer stem cells(CSCs)are considered to be the main cause of resistance to chemotherapeutic agents,as well as being responsible for distant metastases.Although CSCs themselves possess innate abilities for self-renewal and differentiation,the environment surrounding CSCs provides oxygen,nutrients and secreted factors,and also supports angiogenesis,thus it's responsible for maintaining their CSC properties.Furthermore,extensive investigations have revealed that obesity,accompanied by excess visceral adipose tissue,induces chronic infl ammation,and is linked to the risk and progression of several gastrointestinal cancers,through modulating the capacities of the CSCs.This review presents the evidence linking colorectal CSCs and their environment and summarizes our current understanding of the molecular mechanisms underlying this relationship.

关键词： cancer stem cells markers colorectal cancer stem cell nutrient obesity tumor microenvironment

Pathological features of tissues and cell populations during cancer cachexia

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cell Regeneration 2022年第1期11卷 146-162页

作者： Daniela Di Girolamo Shahragim Tajbakhsh stem cells&Development Department of Developmental&Stem Cell BiologyInstitut Pasteur75015 ParisFrance UMR 3738 CNRSInstitut Pasteur75015 ParisFrance

cancers remain among the most devastating diseases in the human population in spite of considerable advances in limiting their impact on lifespan and healthspan.The multifactorial nature of cancers,as well as the number of tissues and organs that are affected,have exposed a considerable diversity in mechanistic features that are reflected in the wide array of therapeutic strategies that have been adopted.Cachexia is manifested in a number of diseases ranging from cancers to diabetes and ageing.In the context of cancers,a majority of patients experience cachexia and succumb to death due to the indirect effects of tumorigenesis that drain the energy reserves of different organs.Considerable information is available on the pathophysiological features of cancer cachexia,however limited knowledge has been acquired on the resident stem cell populations,and their function in the context of these diseases.Here we review current knowledge on cancer cachexia and focus on how tissues and their resident stem and progenitor cell populations are individually affected.

关键词： cancer cachexia stem cells Tissue wasting

Retinoblastoma tumor suppressor functions shared by stem cell and cancer cell strategies

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World Journal of stem cells 2016年第4期8卷 170-184页

作者： Susumu Kohno Shunsuke Kitajima Nobunari Sasaki Chiaki Takahashi Division of Oncology and Molecular biology Cancer Research InstituteKanazawa University Department of Medical Oncology Dana-Farber Cancer Institute Department of Pharmacy Graduate School of MedicineKeio University

Carcinogenic transformation of somatic cells resembles nuclear reprogramming toward the generation of pluripotent stem cells.These events share eternal escape from cellular senescence,continuous self-renewal in limited but certain population of cells,and refractoriness to terminal differentiation while maintaining the potential to differentiate into cells of one or multiple lineages.As represented by several oncogenes those appeared to be first keys to pluripotency,carcinogenesis and nuclear reprogramming seem to share a number of core mechanisms.The retinoblastoma tumor suppressor product retinoblastoma(RB)seems to be critically involved in both events in highly complicated manners.However,disentangling such complicated interactions has enabled us to better understand how stem cell strategies are shared by cancer cells.This review covers recent findings on RB functions related to stem cells and stem cell-like behaviors of cancer cells.

关键词： stem cells cancer Retinoblastoma cancer stem cells

Review of the potential of mesenchymal stem cells for the treatment of infectious diseases

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World Journal of stem cells 2021年第6期13卷 568-593页

作者： Amit Sharma Anuja Chakraborty Bithiah Grace Jaganathan stem cell and cancer biology Group Department of Biosciences and BioengineeringIndian Institute of Technology GuwahatiGuwahati 781039India

The therapeutic value of mesenchymal stem cells (MSCs) for the treatment of infectious diseases and the repair of disease-induced tissue damage has been explored extensively. MSCs inhibit inflammation, reduce pathogen load and tissue damage encountered during infectious diseases through the secretion of antimicrobial factors for pathogen clearance and they phagocytose certain bacteria themselves. MSCs dampen tissue damage during infection by downregulating thelevels of pro-inflammatory cytokines, and inhibiting the excessive recruitment ofneutrophils and proliferation of T cells at the site of injury. MSCs aid in theregeneration of damaged tissue by differentiating into the damaged cell types orby releasing paracrine factors that direct tissue regeneration, differentiation, andwound healing. In this review, we discuss in detail the various mechanisms bywhich MSCs help combat pathogens, tissue damage associated with infectiousdiseases, and challenges in utilizing MSCs for therapy.

关键词： Infectious diseases Mesenchymal stem cells Antimicrobial effect Immunomodulation Tissue repair COVID-19