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• W2000936557 abstract "See “Disruption of Klf4 in villin-positive gastric progenitor cells promotes formation and progression of tumors of the antrum in mice,” by Li Q, Jia Z, Wang L, et al, on page 531. See “Disruption of Klf4 in villin-positive gastric progenitor cells promotes formation and progression of tumors of the antrum in mice,” by Li Q, Jia Z, Wang L, et al, on page 531. Although gastric cancer continues to rank as a frequent cause of cancer-related death in the world, the molecular and cellular etiologies underlying gastric tumor initiation and progression are poorly understood. The search for common molecular signatures in gastric cancer has implicated several factors, including reduced expression of the zinc finger transcriptional regulator KLF4,1Wei D. Gong W. Kanai M. et al.Drastic down-regulation of Krüppel-like factor 4 expression is critical in human gastric cancer development and progression.Cancer Res. 2005; 65: 2746-2754Crossref PubMed Scopus (259) Google Scholar In this issue of Gastroenterology, Li et al2Li Q. Jia Z. Wang L. et al.Disruption of Klf4 in villin-positive gastric progenitor cells promotes formation and progression of tumors of the antrum in mice.Gastroenterology. 2011; 142: 531-542Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar demonstrate that targeted deletion of Klf4 in a quiescent antral stem cell population known as villin-marked gastric progenitor cells (VGPC)3Qiao X.T. Ziel J.W. McKimpson W. et al.Prospective identification of a multilineage progenitor in murine stomach epithelium.Gastroenterology. 2007; 133: 1989-1998Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar results in gastric tumorigenesis. KLF4 is expressed in multiple tissues and has been implicated in processes as diverse as the establishment and maintenance of pluripotency, cell differentiation, inflammation, and carcinogenesis.4McConnell B.B. Ghaleb A.M. Nandan M.O. et al.The diverse functions of Kruppel-like factors 4 and 5 in epithelial biology and pathobiology.Bioessays. 2007; 29: 549-557Crossref PubMed Scopus (203) Google Scholar, 5Liao X. Sharma N. Kapadia F. et al.Krüppel-like factor 4 regulates macrophage polarization.J Clin Invest. 2011; 121: 2736-2749Crossref PubMed Scopus (451) Google Scholar, 6Tetreault M.P. Wang M.L. Yang Y. et al.Klf4 overexpression activates epithelial cytokines and inflammation-mediated esophageal squamous cell cancer in mice.Gastroenterology. 2010; 139: 2124-2134Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar, 7Okita K. Yamanaka S. Induction of pluripotency by defined factors.Exp Cell Res. 2010; 316: 2565-2570Crossref PubMed Scopus (74) Google Scholar KLF4 is down-regulated in several human cancers, and this decrease is generally mediated by loss of heterozygosity or promoter hypermethylation.1Wei D. Gong W. Kanai M. et al.Drastic down-regulation of Krüppel-like factor 4 expression is critical in human gastric cancer development and progression.Cancer Res. 2005; 65: 2746-2754Crossref PubMed Scopus (259) Google Scholar, 8Zhao W. Hisamuddin I.M. Nandan M.O. et al.Identification of Krüppel-like factor 4 as a potential tumor suppressor gene in colorectal cancer.Oncogene. 2004; 23: 395-402Crossref PubMed Scopus (260) Google Scholar, 9Zammarchi F. Morelli M. Menicagli M. et al.KLF4 is a novel candidate tumor suppressor gene in pancreatic ductal carcinoma.Am J Pathol. 2011; 178: 361-372Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar In the stomach, KLF4 is expressed primarily in postmitotic epithelial cells in the upper regions of the glands, where it is predicted to act as a gastric tumor suppressor.1Wei D. Gong W. Kanai M. et al.Drastic down-regulation of Krüppel-like factor 4 expression is critical in human gastric cancer development and progression.Cancer Res. 2005; 65: 2746-2754Crossref PubMed Scopus (259) Google Scholar, 10Katz J.P. Perreault N. Goldstein B.G. et al.Loss of Klf4 in mice causes altered proliferation and differentiation and precancerous changes in the adult stomach.Gastroenterology. 2005; 128: 935-945Abstract Full Text Full Text PDF PubMed Scopus (192) Google Scholar In the mouse, panepithelial deletion of Klf4 in the stomach, using a Foxa3Cre transgene, produces widespread hypertrophy and premalignant changes known as spasmolytic polypeptide-expressing metaplasia11Goldenring J.R. Nomura S. Differentiation of the gastric mucosa III Animal models of oxyntic atrophy and metaplasia.Am J Physiol Gastrointest Liver Physiol. 2006; 291: G999-G1004Crossref PubMed Scopus (77) Google Scholar in corpus and antrum by 6 months of age. Although frank tumors are not observed in this model, polyploid lesions are detected by 1 year, the latest timepoint analyzed.10Katz J.P. Perreault N. Goldstein B.G. et al.Loss of Klf4 in mice causes altered proliferation and differentiation and precancerous changes in the adult stomach.Gastroenterology. 2005; 128: 935-945Abstract Full Text Full Text PDF PubMed Scopus (192) Google Scholar In the present study, Li et al use a Villin-Cre transgene to conditionally delete Klf4 only in VGPC, rare progenitor cells of the gastric antrum,3Qiao X.T. Ziel J.W. McKimpson W. et al.Prospective identification of a multilineage progenitor in murine stomach epithelium.Gastroenterology. 2007; 133: 1989-1998Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar rather than throughout the epithelium. Interestingly, the antral phenotypes of the VGPC-specific and pangastric epithelial Klf4 deletion models are similar, suggesting that precancerous changes arising in this quiescent progenitor population have important implications for gastric epithelial homeostasis. After VGPC-specific Klf4 deletion, hypertrophic changes are present by 35 weeks and are widespread by 50 weeks; these changes are restricted to the antrum, consistent with the localization of VGPC exclusively in this region of the stomach.3Qiao X.T. Ziel J.W. McKimpson W. et al.Prospective identification of a multilineage progenitor in murine stomach epithelium.Gastroenterology. 2007; 133: 1989-1998Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar By 80 weeks of age, spontaneous antral gastric adenomas are observed in this model, although these lesions do not progress to adenocarcinoma. Loss of Klf4 in VGPC also accelerates tumor formation after N-nitroso-N-methylurea (MNU) administration (although whether MNU-treated mice develop adenocarcinomas is not discussed). These findings support the notion that KLF4 loss may be an early event in gastric carcinogenesis but alone is likely not sufficient for tumor progression. Interestingly, Li et al also report tumors after Klf4 deletion in the liver and gastrointestinal lymph nodes, suggesting that, although not previously described,12Madison B.B. Dunbar L. Qiao X.T. et al.Cis elements of the villin gene control expression in restricted domains of the vertical (crypt) and horizontal (duodenum, cecum) axes of the intestine.J Biol Chem. 2002; 277: 33275-33283Abstract Full Text Full Text PDF PubMed Scopus (542) Google Scholar Villin-Cre might drive low-level recombination in these tissues and that KLF4 may function as a tumor suppressor in these tissues as well. In probing the mechanism of tumor formation after Klf4 deletion, the authors focus on FOXM1, a forkhead family transcription factor and cell-cycle promoter implicated in cancer initiation and progression in multiple tissues, including in the stomach.13Koo C.Y. Muir K.W. Lam E.W. FOXM1: from cancer initiation to progression and treatment.Biochim Biophys Acta. 2011; 1819: 28-37Crossref PubMed Scopus (296) Google Scholar, 14Li Q. Zhang N. Jia Z. et al.Critical role and regulation of transcription factor FoxM1 in human gastric cancer angiogenesis and progression.Cancer Res. 2009; 69: 3501-3509Crossref PubMed Scopus (186) Google Scholar In the normal stomach, FOXM1 is expressed, in contrast with KLF4, only in regions of cellular proliferation, including the mucous neck cells.14Li Q. Zhang N. Jia Z. et al.Critical role and regulation of transcription factor FoxM1 in human gastric cancer angiogenesis and progression.Cancer Res. 2009; 69: 3501-3509Crossref PubMed Scopus (186) Google Scholar This is also the region of cellular expansion in mice with Klf4 deletion driven by Foxa3Cre.10Katz J.P. Perreault N. Goldstein B.G. et al.Loss of Klf4 in mice causes altered proliferation and differentiation and precancerous changes in the adult stomach.Gastroenterology. 2005; 128: 935-945Abstract Full Text Full Text PDF PubMed Scopus (192) Google Scholar The authors demonstrate both in their mouse model and in human tumors that KLF4 loss correlates with robust expression of FOXM1. Using cellular assays, they further show that Klf4 represses FoxM1 and binds to the FoxM1 promoter in vivo (although the functional importance of this binding site in the intact locus in vivo remains to be tested). Thus, loss of Klf4 seems to be directly tied to up-regulation of FoxM1, a perfect storm that takes the breaks off the cell cycle, promoting hyperplasia. Other factors, such as the pro-proliferative Klf5, a KLF4 target in other tissues,15Tetreault M.P. Yang Y. Travis J. et al.Esophageal squamous cell dysplasia and delayed differentiation with deletion of Kruppel-like factor 4 in murine esophagus.Gastroenterology. 2010; 139: 171-181Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar may be similarly up-regulated but were not examined here. Over time and likely with additional “hits,” antral tumors emerge. Still, if Klf4 loss and FoxM1 up-regulation lead eventually to tumor formation in the mouse model generated by Li et al, what is the importance of VGPC in this process? VGPC were first identified in the mouse as rare progenitor cells that are capable of repopulating entire antral glands.3Qiao X.T. Ziel J.W. McKimpson W. et al.Prospective identification of a multilineage progenitor in murine stomach epithelium.Gastroenterology. 2007; 133: 1989-1998Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar Because VGPC express villin mRNA (but not villin protein), the villin promoter can be exploited to alter gene expression in these cells. Transgenes such as Villin-Cre are expressed only in VGPC and not in VGPC daughters; thus, the initial Cre-mediated loss of Klf4 in the Li et al model is restricted to VGPC. Previous lineage tracing studies are consistent with 2 types of VGPC division (Figure, panel A).3Qiao X.T. Ziel J.W. McKimpson W. et al.Prospective identification of a multilineage progenitor in murine stomach epithelium.Gastroenterology. 2007; 133: 1989-1998Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar Symmetrical divisions produce 2 VGPC in the gland; this event may be followed by gland fission, thus increasing the number of glands that contain a VGPC. Asymmetrical divisions serve to repopulate the glands with VGPC progeny of all antral lineages. In Villin-Cre Klf4f/f mice, such asymmetrical divisions also serve to populate the glands with Klf4 null, thus likely hyperplastic, cells. But, does the hypertrophic lesion actually begin in VGPCs or in their daughters? Although it is established that in both human and mouse, KLF4/Klf4 is expressed predominantly in differentiated epithelial cells, it is unclear whether this factor is also expressed at low levels in VGPC. Indeed, KLF4 is expressed in embryonic stem cells, where it inhibits differentiation (in contrast with its function in epithelial tissues) and is 1 of the original 4 Yamanaka factors capable of reprogramming somatic cells to pluripotency.16Nandan M.O. Yang V.W. The role of Kruppel-like factors in the reprogramming of somatic cells to induced pluripotent stem cells.Histol Histopathol. 2009; 24: 1343-1355PubMed Google Scholar, 17Takahashi K. Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors.Cell. 2006; 126: 663-676Abstract Full Text Full Text PDF PubMed Scopus (18230) Google Scholar The lack of information about Klf4 expression in VGPC leaves open 2 distinct but equally plausible models to explain the origin and initial spread of the phenotypic changes seen by Li et al (Figure, panel B). Model 1 posits that Klf4 is not expressed in VGPC. If so, genomic deletion of Klf4 in VGPC would not alter the biology these progenitor cells nor that of any daughter produced by symmetric division (by definition, also VGPCs). However, asymmetric VGPC division would produce non-VGPC daughters that should normally express Klf4 and suppress FoxM1; loss of Klf4 in these cells will result in hypertrophic glands. Because, in the absence of inflammation or MNU, asymmetric division of VGPCs is quite rare,3Qiao X.T. Ziel J.W. McKimpson W. et al.Prospective identification of a multilineage progenitor in murine stomach epithelium.Gastroenterology. 2007; 133: 1989-1998Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar the initiation of such lesions should be slow, perhaps taking several weeks or months. However, once accomplished, such hypertrophic glands might promote secondary changes in nearby glands and/or in the stem cells of the same gland, leading to spreading lesions from localized areas of VGPC division. In this model, VGPC passively convey, but do not actively participate in, the hypertrophic initiation that sets the stage for later tumorigenesis. Model 2 postulates that Klf4 is expressed at low levels in VGPC, perhaps acting to promote quiescence or self-renewal of these stem cells. In this case, Klf4 deletion, which should occur in mid-fetal life concomitant with activation of the Villin-Cre transgene,12Madison B.B. Dunbar L. Qiao X.T. et al.Cis elements of the villin gene control expression in restricted domains of the vertical (crypt) and horizontal (duodenum, cecum) axes of the intestine.J Biol Chem. 2002; 277: 33275-33283Abstract Full Text Full Text PDF PubMed Scopus (542) Google Scholar could immediately alter the cycling kinetics of VGPC. In this model, widespread hypertrophy would likely occur rapidly and early (Figure, panel B), with VGPC acting as direct purveyors (suppliers) of the ensuing precancerous change. Acceleration of tumorigenesis by MNU in either model could be accounted for by the ability of this agent to promote both symmetric and asymmetric divisions, in a manner similar to that previously seen with inflammatory cytokines,3Qiao X.T. Ziel J.W. McKimpson W. et al.Prospective identification of a multilineage progenitor in murine stomach epithelium.Gastroenterology. 2007; 133: 1989-1998Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar thereby increasing the frequency of hypertrophic glands. The appearance of an increased number of glands with single Cre-positive cells in Villin-Cre;Klf4f/f mice after MNU challenge (Li et al, Supplemental Figure 2A) is evidence that expansion of VGPC is stimulated under these conditions. Another aspect that needs to be considered is whether the spread of hyperplasia results solely from Klf4 deletion in VGPC or is aided in later stages by ectopic activation of the Villin-Cre transgene in areas of intestinal metaplasia. The authors note widespread activation of villin protein in the stomach, particularly after MNU treatment (Li et al, Supplemental Figure 2B and D), but these villin-positive cells are likely not VGPC, because VGPC do not express villin protein.3Qiao X.T. Ziel J.W. McKimpson W. et al.Prospective identification of a multilineage progenitor in murine stomach epithelium.Gastroenterology. 2007; 133: 1989-1998Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar Because the initial deletion of Klf4 occurs in VGPC only, such metaplastic regions must arise as a consequence of the initial VGPC response, not the other way around. Nonetheless, progressive development of intestinal metaplasia could accelerate the spread of hyperplasia in this model. The results of this study suggest that a single genetic manipulation targeted specifically to a population of rare, highly quiescent antral stem cells can, over time, promote tumorigenesis. Although the existence of quiescent VGPC has not yet been demonstrated in the human, this murine model of VGPC-targeted Klf4 deletion is an important experimental paradigm that deserves additional exploration. Yet, because these mice develop only gastric adenomas, the factors leading to malignant progression in the stomach are not discernible here. To follow up, it will be important to examine earlier time points in the model, determine whether Klf4 is expressed in VGPC, add a lineage trace to the model, and determine whether and how the more numerous Lgr5-marked stem cells18Barker N. Huch M. Kujala P. et al.Lgr5+ve Stem cells drive self-renewal in the stomach and build long-lived gastric units in vitro.Cell Stem Cell. 2010; 6: 25-36Abstract Full Text Full Text PDF PubMed Scopus (1069) Google Scholar might participate. It would also be interesting to examine the progression of tumors in these mice after infection with Helicobacter. It has long been speculated that, in a constantly renewing tissue such as stomach epithelium, the most likely cellular roots of gastric cancer lie in a quiescent stem cell population, the only population long-lived enough to accumulate a sufficient load of cancer-promoting mutations and/or epigenetic changes. Interestingly, the stem cells targeted here are concentrated on the lesser curvature of the antrum3Qiao X.T. Ziel J.W. McKimpson W. et al.Prospective identification of a multilineage progenitor in murine stomach epithelium.Gastroenterology. 2007; 133: 1989-1998Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar and tumors seen in 80-week-old Villin-Cre;Klf4f/f mice are located at this site. This is also a common site of origin for human gastric tumors.19Merchant J.L. Inflammation, atrophy, gastric cancer: connecting the molecular dots.Gastroenterology. 2005; 129: 1079-1082Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar Thus, both the tumor locations and molecular alterations described by Li et al clearly parallel those of human gastric cancers, indicating that this mouse model is highly relevant to human disease. Disruption of Klf4 in Villin-Positive Gastric Progenitor Cells Promotes Formation and Progression of Tumors of the Antrum in MiceGastroenterologyVol. 142Issue 3PreviewKrüppel-like factor 4 (Klf4) is a putative gastric tumor suppressor gene. Rare, villin-positive progenitor cells in the gastric antrum have multilineage potential. We investigated the function of Klf4 in these cells and in gastric carcinogenesis. Full-Text PDF" @default.
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• W2000936557 title "Villin-Marked Gastric Progenitor Cells: Conveyors or Purveyors of Precancerous Change?" @default.
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