• DCLK1
• cancer progression
• gastrointestinal cancer
• metastasis

• Humans
• Doublecortin-Like Kinases
• Gastrointestinal Neoplasms/pathology
• Gastrointestinal Neoplasms/drug therapy
• Gastrointestinal Neoplasms/metabolism
• Gastrointestinal Neoplasms/genetics
• Protein Serine-Threonine Kinases/metabolism
• Protein Serine-Threonine Kinases/genetics
• Protein Serine-Threonine Kinases/antagonists & inhibitors
• Disease Progression
• Intracellular Signaling Peptides and Proteins/metabolism
• Intracellular Signaling Peptides and Proteins/genetics
• Intracellular Signaling Peptides and Proteins/antagonists & inhibitors
• Epithelial-Mesenchymal Transition
• Signal Transduction
• Animals
• Molecular Targeted Therapy
• Neoplastic Stem Cells/pathology
• Neoplastic Stem Cells/metabolism

• Doublecortin-like kinase 1
• HNSCC
• Invadopodia
• Loco-regional invasion
• Tumor microenvironment

• Humans
• Doublecortin-Like Kinases
• Podosomes/metabolism
• Protein Serine-Threonine Kinases/metabolism
• Protein Serine-Threonine Kinases/genetics
• Intracellular Signaling Peptides and Proteins/metabolism
• Intracellular Signaling Peptides and Proteins/genetics
• Cell Line, Tumor
• Neoplasm Invasiveness
• Squamous Cell Carcinoma of Head and Neck/pathology
• Squamous Cell Carcinoma of Head and Neck/metabolism
• Squamous Cell Carcinoma of Head and Neck/genetics
• Head and Neck Neoplasms/pathology
• Head and Neck Neoplasms/metabolism
• Head and Neck Neoplasms/genetics
• Protein Transport
• Proteomics/methods
• Matrix Metalloproteinases/metabolism
• Disease Progression
• Gene Expression Regulation, Neoplastic
• Cell Movement
• Matrix Metalloproteinase 9/metabolism

• Lkb1
• fibroblast
• gastrointestinal polyp
• lineage tracing
• mesenchymal cell
• polyposis
• scRNA‐seq
• vascular smooth muscle cell

• Animals
• Mice
• AMP-Activated Protein Kinases
• Peutz-Jeghers Syndrome/genetics
• Peutz-Jeghers Syndrome/pathology
• Protein Serine-Threonine Kinases/genetics
• Receptor, Platelet-Derived Growth Factor alpha/genetics
• Sequence Analysis, RNA
• Serine
• Tamoxifen/pharmacology

• 81830010 National Natural Science Foundation of China
• 82300489 National Natural Science Foundation of China
• 82130012 National Natural Science Foundation of China
• 23PJD084 Shanghai Pujiang Program
• 2022YNJCQ03 Shanghai Chest Hospital
• SHSMU-ZLCX20212302 Innovative Research Team of High-level Local Universities in Shanghai

• Doublecortin-like kinase 1
• HNSCC
• invadopodia
• loco-regional invasion
• tumor microenvironment

• P30 CA168524 NCI NIH HHS
• R24 GM137786 NIGMS NIH HHS
• S10 OD023625 NIH HHS

• Acute lung injury
• Anti-inflammatory
• Doublecortin-like kinase 1
• Drug design

• Humans
• Doublecortin-Like Kinases
• Intracellular Signaling Peptides and Proteins
• Lipopolysaccharides/pharmacology
• Protein Serine-Threonine Kinases
• Inflammation/drug therapy
• Acute Lung Injury/chemically induced
• Acute Lung Injury/drug therapy

• gastric cancer
• innate lymphoid cells
• tumour immunology

• Humans
• Mice
• Animals
• Immunity, Innate
• Interleukin-13/metabolism
• Stomach Neoplasms/pathology
• Lymphocytes/metabolism
• Hyperplasia/metabolism
• Metaplasia/metabolism

• R01 AI026918 NIAID NIH HHS
• R37 AI026918 NIAID NIH HHS
• Department of Health | National Health and Medical Research Council (NHMRC)
• La Trobe University
• State Government of Victoria (Victorian Government)

• Bacteria
• Host-pathogen interactions
• Immunity
• Intestinal epithelium
• Parasite
• Tuft cells
• Viruses

• helminth infection
• intestinal epithelial cell
• tuft cell
• tumor
• type 2 immune response

• Colorectal Carcinoma
• DCLK1
• Immune Escape
• MDSCs
• Tumor Microenvironment

• Biased signal
• CXCR7
• Colorectal cancer
• Epithelial-to-mesenchymal transition
• YAP1
• miRNAs

Doublecortin-like kinase 1 (DCLK1), a protein molecule, has been identified as a tumor stem cell marker in the cancer cells of gastrointestinal, pancreas, and human colon. DCLK1 expression in cancers, such as breast carcinoma, lung carcinoma, hepatic cell carcinoma, tuft cells, and human cholangiocarcinoma, has shown a way to target the DCLK1 gene and downregulate its expression. Several studies have discussed the inhibition of tumor cell proliferation along with neoplastic cell arrest when the DCLK1 gene, which is expressed in both cancer and normal cells, was targeted successfully. In addition, previous studies have shown that DCLK1 plays a vital role in various cancer metastases. The correlation of DCLK1 with numerous stem cell receptors, signaling pathways, and genes suggests its direct or an indirect role in promoting tumorigenesis. Moreover, the impact of DCLK1 was found to be related to the functioning of an oncogene. The downregulation of DCLK1 expression by using targeted strategies, such as embracing the use of siRNA, miRNA, CRISPR/Cas9 technology, nanomolecules, specific monoclonal antibodies, and silencing the pathways regulated by DCLK1, has shown promising results in both in vitro and in vivo studies on gastrointestinal (GI) cancers. In this review, we will discuss about the present understanding of DCLK1 and its role in the progression of GI cancer and metastasis.

• COVID-19
• alveolar regeneration
• basal cells
• cell biology
• lung regeneration
• mouse
• regenerative medicine
• stem cells
• tuft cells
• viral infection

• Animals
• Biomarkers
• COVID-19
• Cell Differentiation
• Cell Lineage
• Epithelial Cells
• Mice
• Tamoxifen/pharmacology
• Trans-Activators

• R01 DK100342 NIDDK NIH HHS
• P30 DK132710 NIDDK NIH HHS
• K08 HL132203 NHLBI NIH HHS
• R35 CA210088 NCI NIH HHS
• S10 OD032447 NIH HHS
• S10 OD020056 NIH HHS
• P30 CA013696 NCI NIH HHS
• R01 DK120650 NIDDK NIH HHS
• R01 HL159675 NHLBI NIH HHS
• R21 AI163753 NIAID NIH HHS
• R01 HL145302 NHLBI NIH HHS
• R01 HL152293 NHLBI NIH HHS
• National Heart, Lung, and Blood Institute
• National Institute of Diabetes and Digestive and Kidney Diseases
• Cystic Fibrosis Foundation
• Harvard Stem Cell Institute
• Charles H. Hood Foundation
• U.S. Department of Defense
• National Institute of Allergy and Infectious Diseases

The oncogenic role of doublecortin-like kinase 1 (DCLK1) as a putative cancer stem cell (CSC) marker has been clarified in colorectal cancer (CRC). Isoform-specific functions of DCLK1 have shed new light on different functions of DCLK1 short (DCLK1-S) and DCLK1 long (DCLK1-L) isoforms in tumor initiation, growth, and metastasis. Therefore, the current systematic review and meta-analysis aimed to review the available in vitro, in vivo, and clinical evidence on the oncogenic roles and clinical significance of DCLK1 isoforms in colorectal cancer.

The literature databases of PubMed, Scopus, ISI Web of Science, and Embase were searched to identify eligible articles. The description characteristics of in vitro and pre-clinical studies were extracted from identified reports. In addition, hazard ratios (HRs) or odds ratios (ORs) with 95% confidence intervals (CIs) were recorded to determine the relationships between DCLK1-L and DCLK1-S expression and prognostic outcomes in patients with CRC.

Both in vitro and in vivo evidence have emphasized the potential oncogenic functions of DCLK1 in tumor initiation, self-renewal ability, tumor invasion, epithelial-mesenchymal transition (EMT), and metastasis. However, the anti-DCLK1 antibodies generally utilized in these studies could detect sequence homology epitopes of both isoforms. Recent limited isoform-specific evidence has strongly supported the significant positive expression and rather oncogenic efficacy of DCLK1-S in tumorigenesis, EMT, and invasion compared with DCLK1-L in human CRC cell lines. Our meta-analysis findings of limited clinical studies indicated that only overexpression of DCLK1-S is associated with worse overall survival (OS) (HR = 7.930, 95% CI 2.252–27.924, p = 0.001). Increased expression of both DCLK1-S (HR = 1.610, 95% CI 1.020–2.541, p = 0.041) and DCLK1-L (HR = 5.890, 95% CI 1.219–28.453, p = 0.027) isoforms was closely associated with worse DSS/CSS in CRC patients. Furthermore, the high expression of DCLK1-S was found to be associated with poor DFS/RFS/PFS (HR = 1.913, 95% CI 1.230–2.973, p = 0.004).

The current findings strongly supported that the DCLK1-S isoform may play a crucial role in the invasion, aggressive tumor behavior, and worsened survival outcomes of CRC patients. However, further critical investigations related to the potential preclinical and clinical utilities of DCLK1-S as a specific CRC-CSC marker are warranted.

The online version contains supplementary material available at 10.1186/s12935-022-02632-9.

• Colorectal cancer
• DCLK1-L
• DCLK1-S
• Meta-analysis
• Oncogenic functions

Although tuft cells were discovered over 60 years ago, their functions have long been enigmatic, especially in human health. Nonetheless, tuft cells have recently emerged as key orchestrators of the host response to diverse microbial infections in the gut and airway. While tuft cells are epithelial in origin, they exhibit functions akin to immune cells and mediate important interkingdom interactions between the host and helminths, protists, viruses, and bacteria. With broad intra- and intertissue heterogeneity, tuft cells sense and respond to microbes with exquisite specificity. Tuft cells can recognize helminth and protist infection, driving a type 2 immune response to promote parasite expulsion. Tuft cells also serve as the primary physiologic target of persistent murine norovirus (MNV) and promote immune evasion. Recently, tuft cells were also shown to be infected by rotavirus. Other viral infections, such as influenza A virus, can induce tuft cell–dependent tissue repair. In the context of coinfection, tuft cells promote neurotropic flavivirus replication by dampening antiviral adaptive immune responses. Commensal and pathogenic bacteria can regulate tuft cell abundance and function and, in turn, tuft cells are implicated in modulating bacterial infiltration and mucosal barrier integrity. However, the contribution of tuft cells to microbial sensing in humans and their resulting effector responses are poorly characterized. Herein, we aim to provide a comprehensive overview of microbial activation of tuft cells with an emphasis on tuft cell heterogeneity and differences between mouse and human tuft cell biology as it pertains to human health and disease.

• Animals
• Intestinal Mucosa
• Mice
• Norovirus
• Parasites

• K08 AI128043 NIAID NIH HHS
• R01 AI148467 NIAID NIH HHS
• National Institutes of Health
• Burroughs Wellcome Fund
• Robert E. Leet and Clara Guthrie Patterson Trust
• National Science Foundation

Given the functional attributes of Doublecortin-like kinase 1 (DCLK1) in tumor growth, invasion, metastasis, cell motility, and tumor stemness, it is emerging as a therapeutic target in gastrointestinal cancers. Although a series of specific or nonspecific ATP-competitive inhibitors were identified against DCLK1, different types of scaffolds that can be utilized for the development of highly selective inhibitors or structural understanding of binding specificities of the compounds remain limited. Here, we present our work to repurpose a Janus kinase 1 inhibitor, ruxolitinib as a DCLK1 inhibitor, showing micromolar binding affinity and inhibitory activity. Furthermore, to gain an insight into its interaction mode with DCLK1, a crystal structure of the ruxolitinib-complexed DCLK1 has been determined and analyzed. Ruxolitinib as a nonspecific DCLK1 inhibitor characterized in this work is anticipated to provide a starting point for the structure-guided discovery of selective DCLK1 inhibitors.

• ATP-competitive inhibitor
• DCLK1
• anticancer
• doublecortin-like kinase 1
• kinase inhibitor
• structure-based drug discovery

• Antineoplastic Agents/chemistry
• Antineoplastic Agents/pharmacology
• Doublecortin-Like Kinases
• Humans
• Intracellular Signaling Peptides and Proteins/antagonists & inhibitors
• Intracellular Signaling Peptides and Proteins/chemistry
• Intracellular Signaling Peptides and Proteins/metabolism
• Molecular Docking Simulation
• Nitriles
• Protein Conformation/drug effects
• Protein Kinase Inhibitors/chemistry
• Protein Kinase Inhibitors/pharmacology
• Protein Serine-Threonine Kinases/antagonists & inhibitors
• Protein Serine-Threonine Kinases/chemistry
• Protein Serine-Threonine Kinases/metabolism
• Pyrazoles/chemistry
• Pyrazoles/pharmacology
• Pyrimidines

• DCLK1
• cancer stem cell marker
• kinase inhibitor
• structural biology

• apoptosis
• cancer stem cells
• colitis associated cancer
• colonospheres
• doublecortin-like kinase 1
• hippo signaling
• leucine-rich repeat-containing G-protein coupled receptor 5
• spheroids

• Adaptor Proteins, Signal Transducing/metabolism
• Animals
• Apoptosis/drug effects
• Apoptosis Regulatory Proteins/metabolism
• Biomarkers, Tumor/metabolism
• Biphenyl Compounds/pharmacology
• Carcinogenesis/drug effects
• Carcinogenesis/pathology
• Cell Line, Tumor
• Cell Proliferation/drug effects
• Cell Survival/drug effects
• Colitis/complications
• Colonic Neoplasms/pathology
• Doublecortin-Like Kinases
• Down-Regulation/drug effects
• Hippo Signaling Pathway
• Humans
• Intracellular Signaling Peptides and Proteins/metabolism
• Lignans/pharmacology
• Male
• Mice, Inbred ICR
• Models, Biological
• Neoplastic Stem Cells/drug effects
• Neoplastic Stem Cells/pathology
• Protein Binding/drug effects
• Protein Serine-Threonine Kinases/metabolism
• Proto-Oncogene Proteins/metabolism
• Signal Transduction/drug effects
• Transcription Factors/metabolism
• Tumor Stem Cell Assay
• YAP-Signaling Proteins
• Mice

• P20 RR016443 NCRR NIH HHS
• P30 CA168524 NCI NIH HHS

• DCLK1
• cell migration
• extracellular vesicles
• gastric cancer
• proteome

Doublecortin-like kinase 1 (DCLK1) is a tumor stem cell marker in colon, pancreatic, and potentially other cancers that has received wide attention recently. Aside from its role as a tuft cell marker in normal tissue and as a tumor stem cell marker in cancer, previous studies have demonstrated that silencing DCLK1 functionally reduces stemness, epithelial mesenchymal transition (EMT), and tumorigenesis in cancers. More recently, DCLK1′s role in regulating the inflammatory, pre-cancer, and tumor microenvironment including its ability to modulate immune cell mechanisms has started to come into focus. Importantly, clinically viable therapeutic means of targeting DCLK1 have finally become available in the form of kinase inhibitors, monoclonal antibodies, and chimeric antigen receptor T cells (CAR-T). Herein, we comprehensively review the mechanistic role of DCLK1 in the tumor microenvironment, assess the potential for targeting DCLK1 in colon, pancreatic and renal cancer.

Microtubule-associated doublecortin-like kinase 1 (DCLK1) is an accepted marker of tuft cells (TCs) and several kinds of cancer stem cells (CSCs), and emerging evidence suggests that DCLK1-positive TCs participate in the initiation and formation of inflammation-associated cancer. DCLK1-expressing CSCs regulate multiple biological processes in cancer, promote resistance to therapy, and are associated with metastasis. In solid tumor cancers, tumor epithelia, immune cells, cancer-associated fibroblasts, endothelial cells and blood vessels, extracellular matrix, and hypoxia all support a CSC phenotype characterized by drug resistance, recurrence, and metastasis. Recently, studies have shown that DCLK1-positive CSCs are associated with epithelial-mesenchymal transition, angiogenesis, and immune checkpoint. Emerging data concerning targeting DCLK1 with small molecular inhibitors, monoclonal antibodies, and chimeric antigen receptor T-cells shows promising effects on inhibiting tumor growth and regulating the tumor immune microenvironment. Overall, DCLK1 is reaching maturity as an anti-cancer target and therapies directed against it may have potential against CSCs directly, in remodeling the tumor microenvironment, and as immunotherapies.

• DCLK1
• cancer stem cells
• immunotherapies
• microenvironment
• tuft cells

The intestinal epithelium possesses a great capacity of self-renewal under normal homeostatic conditions and of regeneration upon damages. The renewal and regenerative processes are driven by intestinal stem cells (ISCs), which reside at the base of crypts and are marked by Lgr5. As Lgr5⁺ ISCs undergo fast cycling and are vulnerable to damages, there must be other types of cells that can replenish the lost Lgr5⁺ ISCs and then regenerate the damage epithelium. In addition to Lgr5⁺ ISCs, quiescent ISCs at the + 4 position in the crypt have been proposed to convert to Lgr5⁺ ISCs during regeneration. However, this “reserve stem cell” model still remains controversial. Different from the traditional view of a hierarchical organization of the intestinal epithelium, recent works support the dynamic “dedifferentiation” model, in which various cell types within the epithelium can de-differentiate to revert to the stem cell state and then regenerate the epithelium upon tissue injury. Here, we provide an overview of the cell identity and features of two distinct models and discuss the possible mechanisms underlying the intestinal epithelial plasticity.

• Dedifferentiation
• Intestine
• Plasticity
• Quiescence
• Regeneration
• Stem cells

• Chemosensitivity
• Doublecortin-like kinase 1
• Esophageal squamous cell carcinoma
• Invasion
• Migration
• β-Catenin

• DCAMKL1
• Doublecortin Linked Kinase-1
• Wistar Kyoto
• brush cells
• chronic stress
• helminths
• interleukin-25
• irritable bowel syndrome

• autophagy
• cancer stem cell
• chemoresistance
• natural products
• stemness

Osteosarcoma (OS) is the most common primary bone tumor that primarily affects children and adolescents. Studies suggested that dysregulation JAK/STAT signaling promotes the development of OS. Cells treated with pimozide, a STAT5 inhibitor suppressed proliferation and colony formation and induced sub G0/G1 cell cycle arrest and apoptosis. There was a reduction in cyclin D1 and CDK2 expression and Rb phosphorylation, and activation of Caspase-3 and PARP cleavage. In addition, pimozide suppressed the formation of 3-dimensional osteospheres and growth of the cells in the Tumor in a Dish lung organoid system. Furthermore, there was a reduction in expression of cancer stem cell marker proteins DCLK1, CD44, CD133, Oct-4, and ABCG2. More importantly, it was the short form of DCLK1 that was upregulated in osteospheres, which was suppressed in response to pimozide. We further confirmed by flow cytometry a reduction in DCLK1+ cells. Moreover, pimozide inhibits the phosphorylation of STAT5, STAT3, and ERK in OS cells. Molecular docking studies suggest that pimozide interacts with STAT5A and STAT5B with binding energies of −8.4 and −6.4 Kcal/mol, respectively. Binding was confirmed by cellular thermal shift assay. To further understand the role of STAT5, we knocked down the two isoforms using specific siRNAs. While knockdown of the proteins did not affect the cells, knockdown of STAT5B reduced pimozide-induced necrosis and further enhanced late apoptosis. To determine the effect of pimozide on tumor growth in vivo, we administered pimozide intraperitoneally at a dose of 10 mg/kg BW every day for 21 days in mice carrying KHOS/NP tumor xenografts. Pimozide treatment significantly suppressed xenograft growth. Western blot and immunohistochemistry analyses also demonstrated significant inhibition of stem cell marker proteins. Together, these data suggest that pimozide treatment suppresses OS growth by targeting both proliferating cells and stem cells at least in part by inhibiting the STAT5 signaling pathway.

Immunotherapy that has proven efficacy in several solid cancers plays a partial role in improving clinical outcomes of advanced gastrointestinal (GI) cancers. There is an unmet need to find new immune-related therapeutic targets. Doublecortin-like kinase 1 (DCLK1) marks tuft cells which are recognized as cancer-initiating cells and regulators of the type II immune response, and has been studied for its role in many cancers including colon and gastric cancers, but its role in tumor immunity remains unexplored. In the current study, we analyzed colon and gastric cancer RNA sequencing data from 283 and 415 patients, respectively, from The Cancer Genome Atlas (TCGA). High DCLK1 expression predicted the worse clinical outcomes in colon and gastric cancer patients and correlated with increased immune and stromal components. Further analysis indicated that DCLK1 was strongly linked to infiltration of multiple immune cell types, especially TAMs and Treg, and strongly correlated with increased CD8+ T cell inhibitors TGFB1 and CXCL12 and their receptors, suggesting it may contribute to TAM-mediated inhibition of CD8+ T cells. Interestingly, we found that DCLK1 was a prognostic biomarker in left-sided colon cancer, which has worse outcomes and demonstrates a reduced response to existing immunotherapies. In conclusion, our results demonstrate that DCLK1 is linked with functional regulation of the tumor microenvironment and may have potential as a prognostic biomarker and adjuvant target to promote immunotherapy sensitivity in colon and gastric cancer patients.

• DCLK1
• GI cancer
• biomarker and adjuvant targets
• tumor immunity

• P30 CA225520 NCI NIH HHS
• R50 CA233186 NCI NIH HHS
• R50CA233186 NIH HHS
• 5R01CA21401-7 NIH HHS

• cancer metastasis
• cancer therapy
• epithelial‐mesenchymal transition
• nanomaterials
• nanomedicine

• SAF2017-87305-R Ministerio de Economía y Competitividad
• SEV-2016-0686 Ministerio de Economía y Competitividad
• IND2017/IND-7809 Consejería de Educación e Investigación

Doublecortin like kinase 1 (DCLK1) is a cancer stem cell marker for the colorectal cancer (CRC). It plays critical roles in the oncogenesis, progression and metastasis of CRC. DCLK1 can be an intriguing therapeutic target for CRC treatment. However, the molecular mechanism of how DCLK1 functions is unclear currently. In our research, we aim to apply RNA-Sequencing (RNA Seq) technology, a high throughput massively Next Generation Sequencing approach, to monitor transcriptome changes due to DCLK1 over-expression in the CRC cells. In order to achieve our goal, RNA from quadruplicate samples from two clones of isogenic DCLK1 stable over-expression cells and the parental wild type HCT116 cells was sent for RNA Seq on the Illumina NextSeq500 platform. Differentially expressed (DE) genes were evaluated by t-test (P <0.05 and fold-change ±1.5 or greater) using two methods: (1) FWER; and (2) Benjamani and Hochberg FDR (false discovery rate) which corrects for multiple comparisons. Gene networks and functional analysis were evaluated using Ingenuity Pathways Analysis (IPA). We identified 1463 DE genes common for both DCLK1 overexpression clone A and clone B cells. IPA results indicated that 72 canonical pathways were significantly modified by DCLK1 over-expression (P<0.05), among which 9 out of the top 10 pathways are involved in the cell cycle regulation, indicating that DCLK1 might play its tumorigenesis role via activation of pathways facilitating cell proliferation, repression of pathways inhibiting cells proliferation and function against pathways facilitating cell apoptosis. Cell cycle analysis results confirmed the IPA findings, which demonstrated that DCLK1 over-expression cells had much less G0/G1 cells but much more S and G2/M cells (P<0.05). In conclusion, DCLK1 over-expression significantly modified transcriptome profile of CRC cancer cells. Control of the cell cycle regulation might be one of the critical mechanism for DCLK1 function. Our findings provide more direct evidence for the development of DCLK1 as a therapeutic target for CRC treatment, and will be of great benefit for the discovery of novel therapeutic target within the DCLK1 molecular network for the treatment of colorectal cancer patients.

• Anti-apoptosis pathway
• Chemoresistance
• Colorectal cancer
• Doublecortin-like kinase 1

• Bladder cancer
• Cancer stem cell
• DCLK1

• DCLK1
• chemo-/radiotherapy
• colorectal cancer
• miR-15b

• Animals
• Base Sequence
• Carcinogenesis/genetics
• Carcinogenesis/pathology
• Cell Line, Tumor
• Cell Self Renewal
• Chemotherapy, Adjuvant
• Colorectal Neoplasms/drug therapy
• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/pathology
• Colorectal Neoplasms/radiotherapy
• Doublecortin-Like Kinases
• Drug Resistance, Neoplasm
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Intracellular Signaling Peptides and Proteins/genetics
• Intracellular Signaling Peptides and Proteins/metabolism
• Male
• Mice, Inbred NOD
• Mice, SCID
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Middle Aged
• Multivariate Analysis
• Neoplastic Stem Cells/metabolism
• Neoplastic Stem Cells/pathology
• Phenotype
• Polycomb Repressive Complex 1/metabolism
• Prognosis
• Proportional Hazards Models
• Protein Serine-Threonine Kinases/genetics
• Protein Serine-Threonine Kinases/metabolism
• Signal Transduction
• Treatment Outcome

• U24 AA020801 NIAAA NIH HHS

• Chromatin instability
• DCLK1
• DNA repair

• Intestine
• Regeneration
• Stem Cells

Recent studies have identified and begun to characterize the roles of regenerative cellular plasticity in many organs. In Part I of our two-part Review, we discussed how cells reprogram following injury to the stomach and pancreas. We introduced the concept of a conserved cellular program, much like those governing division and death, which may allow mature cells to become regenerative. This program, paligenosis, is likely necessary to help organs repair the numerous injuries they face over the lifetime of an organism; however, we also postulated that rounds of paligenosis and redifferentiation may allow long-lived cells to accumulate and store oncogenic mutations, and could thereby contribute to tumorigenesis. We have termed the model wherein differentiated cells can store mutations and then unmask them upon cell cycle re-entry the ‘cyclical hit’ model of tumorigenesis. In the present Review (Part II), we discuss these concepts, and cell plasticity as a whole, in the skin and intestine. Although differentiation and repair are arguably more thoroughly studied in skin and intestine than in stomach and pancreas, it is less clear how mature skin and intestinal cells contribute to tumorigenesis. Moreover, we conclude our Review by discussing plasticity in all four organs, and look for conserved mechanisms and concepts that might help advance our knowledge of tumor formation and advance the development of therapies for treating or preventing cancers that might be shared across multiple organs.

Summary: This final installment of a two-part Review discusses how cycles of dedifferentiation and redifferentiation can promote tumorigenesis in the skin and intestine, showing how plasticity in these continuously renewing tissues might contribute to tumorigenesis.

• Dedifferentiation
• Paligenosis
• Plasticity
• Regeneration
• Stem cells
• Tumorigenesis

• Cancer stem cell
• colorectal adenoma
• colorectal cancer
• colorectal polyp
• doublecortin-like kinase 1

• DCLK1 monoclonal antibodies
• colorectal cancer
• doublecortin-like kinase 1
• epitope
• prognosis

• Cancer
• Cancer stem cell
• Marker
• Stem cell
• Targeted cancer therapy

• Basic Science Research Program through the National Research Foundation of Korea (NRF)

Although small intestinal epithelial stem cells form crypts when using intestinal culture conditions, colon stem cells usually form colonospheres. Colon mesenchymal cell feeder layers can stimulate colon crypts to form organoids and produce crypts. We have investigated whether conditioned medium from colon mesenchymal cells can also stimulate colonosphere and organoid cryptogenesis. We prepared conditioned medium (CM) from WEHI-YH2 cells (mouse colon myofibroblasts); the CM stimulated both colonosphere formation and organoid cryptogenesis in vitro. The colon organoid-stimulating factors in WEHI-YH2 CM are inactivated by heating and trypsin digestion and proteins can be concentrated by ultrafiltration. Both the colonosphere- and organoid cryptogenesis- stimulatory effects of the CM are independent of canonical Wnt and Notch signaling. In contrast, bone morphogenetic protein 4 (BMP4) abolishes colonosphere formation and organoid cryptogenesis. The Transforming Growth Factor beta (TGFβ) Type I receptor kinase inhibitor (A83-01) stimulates colonosphere formation, whereas the Epidermal Growth Factor receptor (EGFR) kinase inhibitor (AG1478) reduces the formation of colonospheres, but in the presence of EGF, a “just-right” concentration of AG1478 increases colon organoid cryptogenesis.

• Animals
• Biomarkers/metabolism
• Cell Line
• Cell Survival/drug effects
• Colon/drug effects
• Colon/growth & development
• Culture Media, Conditioned/pharmacology
• Feeder Cells/cytology
• Intercellular Signaling Peptides and Proteins/pharmacology
• Mice, Inbred C57BL
• Microvilli/drug effects
• Microvilli/metabolism
• Myofibroblasts/drug effects
• Myofibroblasts/metabolism
• Organoids/drug effects
• Organoids/growth & development
• Receptors, Notch/metabolism
• Signal Transduction/drug effects
• Spheroids, Cellular/cytology
• Spheroids, Cellular/drug effects
• Spheroids, Cellular/metabolism
• Stem Cells/drug effects
• Stem Cells/metabolism
• Wnt Proteins/metabolism