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• W1684202987 abstract "Familial adenomatous polyposis patients, who have a germline APC mutation, develop adenomas in normal-appearing colonic mucosa, and in the process usually acquire a mutation in the other APC allele as well. Nonetheless, the cellular mechanisms that link these initiating genetic changes with the earliest tissue changes (upward shift in the labeling index) in colon tumorigenesis are unclear. Based on the tenet that colorectal cancer originates from crypt stem cells (SCs) and on our kinetic modeling, we hypothesized that overpopulation of mutant colonic SCs is the missing link. Directly testing this hypothesis requires measuring changes in the size of the SC population, but specific markers for human colonic SCs are lacking. Hence, we used immunohistochemical mapping to study crypt base cells, of which SCs are a subset. Using colectomy specimens from 16 familial adenomatous polyposis and 11 control cases, we determined the topographic profiles of various cell populations along the crypt axis and the proportions of each cell type. In the formation of adenomatous crypts, the distribution of cells expressing crypt base cell markers (MSH2, Bcl-2, survivin) expanded toward the crypt surface and showed the greatest proportional increase (fivefold to eightfold). Cells expressing a marker for the upper crypt (p27kip1) shifted to the crypt bottom and showed the smallest increase. This suggests that: 1) during adenoma development, APC mutations cause expansion of the crypt base cell population, including crypt SCs; 2) SC overpopulation can explain the shifts in pattern of proliferative crypt cell populations in early colon tumorigenesis, and 3) mutant crypt SCs clonally expand to form colonic adenomas and carcinomas. Familial adenomatous polyposis patients, who have a germline APC mutation, develop adenomas in normal-appearing colonic mucosa, and in the process usually acquire a mutation in the other APC allele as well. Nonetheless, the cellular mechanisms that link these initiating genetic changes with the earliest tissue changes (upward shift in the labeling index) in colon tumorigenesis are unclear. Based on the tenet that colorectal cancer originates from crypt stem cells (SCs) and on our kinetic modeling, we hypothesized that overpopulation of mutant colonic SCs is the missing link. Directly testing this hypothesis requires measuring changes in the size of the SC population, but specific markers for human colonic SCs are lacking. Hence, we used immunohistochemical mapping to study crypt base cells, of which SCs are a subset. Using colectomy specimens from 16 familial adenomatous polyposis and 11 control cases, we determined the topographic profiles of various cell populations along the crypt axis and the proportions of each cell type. In the formation of adenomatous crypts, the distribution of cells expressing crypt base cell markers (MSH2, Bcl-2, survivin) expanded toward the crypt surface and showed the greatest proportional increase (fivefold to eightfold). Cells expressing a marker for the upper crypt (p27kip1) shifted to the crypt bottom and showed the smallest increase. This suggests that: 1) during adenoma development, APC mutations cause expansion of the crypt base cell population, including crypt SCs; 2) SC overpopulation can explain the shifts in pattern of proliferative crypt cell populations in early colon tumorigenesis, and 3) mutant crypt SCs clonally expand to form colonic adenomas and carcinomas. Even though the genetic changes (APC mutations) associated with tissue changes (upward shift of the crypt proliferative compartment and adenoma formation) have been characterized in familial adenomatous polyposis (FAP) patients, the cellular mechanism linking the changes at these two levels is not fully established. It has been inferred that changes in the crypt stem cell (SC) population are involved in carcinogenesis in general, and in this mechanism in particular.1Bach SP Renehan AG Potten CS Stem cells: the intestinal stem cell as a paradigm.Carcinogenesis. 2000; 21: 469-476Crossref PubMed Scopus (271) Google Scholar This inference is based on several lines of evidence: 1) SCs are the only cells to reside in the colonic crypt long enough to acquire the multiple mutations required for colon cancer;2Potter JD Colorectal cancer: molecules and populations.J Natl Cancer Inst. 1999; 91: 916-932Crossref PubMed Scopus (739) Google Scholar 2) SCs already have several characteristics of transformed cells—lifetime capacity for self-renewal and proliferation, and anchorage in the crypt; 3) histological evidence from adenomas in APCMin/+ mice3Moser AR Dove WF Roth KA Gordon JI The Min (multiple intestinal neoplasia) mutation: its effect on gut epithelial cell differentiation and interaction with a modifier system.J Cell Biol. 1992; 116: 1517-1526Crossref PubMed Scopus (264) Google Scholar and colon carcinomas in rodents4Pierce GB Stevens LC Nakane PK Ultrastructural comparison of differentiation of stem cells of adenocarcinomas of colon and breast with their normal counterparts.J Natl Cancer Inst. 1967; 39: 755-773PubMed Google Scholar indicates that multiple differentiated intestinal cell types exist in these tumors, which suggests that they must have arisen from a multipotent cell, such as a crypt SC. Based on our studies that modeled the kinetics of crypt dynamics and the proliferative abnormality in FAP crypts,5Boman BM Fields JZ Bonham-Carter O Runquist OA Computer modeling implicates stem cell overproduction in colon cancer initiation.Cancer Res. 2001; 61: 8408-8411PubMed Google Scholar we hypothesized that SC overpopulation underlies the upwards proliferative shifts in the crypt in early colorectal cancer (CRC) initiation and adenoma development. Directly testing this hypothesis, however, is hampered because there are no unambiguous molecular markers for SCs, and because the crypt is a rather complex system. Accordingly, we used immunohistochemistry to study changes in the number of crypt cells expressing markers for cells in the crypt base, the region where SCs reside. Markers were selected based on their known staining patterns in normal colonic epithelium showing that their expression is restricted to specific colonocyte populations residing within different regions of the crypt. MSH2, Bcl-2, and survivin were selected as markers for crypt base cells (which includes SCs);6Palazzo JP Kafka NJ Grasso L Chakrani F Hanau C Cuesta KH Mercer WE The role of p53, p21WAF1/C1P1, and bcl-2 in radioresistant colorectal carcinoma.Hum Pathol. 1997; 28: 1189-1195Abstract Full Text PDF PubMed Scopus (41) Google Scholar, 7Sinicrope FA Hart J Michelassi F Lee JJ Prognostic value of bcl-2 oncoprotein expression in stage II colon carcinoma.Clin Cancer Res. 1995; 1: 1103-1110PubMed Google Scholar, 8Thibodeau SN French AJ Roche PC Cunningham JM Tester DJ Lindor NM Moslein G Baker SM Liskay RM Burgart LJ Honchel R Halling KC Altered expression of hMSH2 and hMLH1 in tumors with microsatellite instability and gene alterations in mismatch repair genes.Cancer Res. 1996; 56: 4836-4840PubMed Google Scholar, 9Gianani R Jarboe E Frost M Bobak J Lehner R Shroyer KR Expression of survivin in normal, hyperplastic, and neoplastic colonic mucosa.Hum Pathol. 2001; 32: 119-125Abstract Full Text Full Text PDF PubMed Scopus (166) Google Scholar, 10Zhang T Otevrel T Gao ZQ Gao ZP Ehrlich SM Fields JZ Boman BM Evidence that APC regulates survivin expression: a possible mechanism contributing to the stem cell origin of colon cancer.Cancer Res. 2001; 61: 8664-8667PubMed Google Scholar, 11Edmonston TB Cuesta KH Burkholder S Barusevicius A Rose D Kovatich AJ Boman B Fry R Fishel R Palazzo JP Colorectal carcinomas with high microsatellite instability: defining a distinct immunologic and molecular entity with respect to prognostic markers.Hum Pathol. 2000; 31: 1506-1514Abstract Full Text PDF PubMed Scopus (76) Google Scholar Ki-67 and topoisomerase II for proliferative cells in the lower crypt;6Palazzo JP Kafka NJ Grasso L Chakrani F Hanau C Cuesta KH Mercer WE The role of p53, p21WAF1/C1P1, and bcl-2 in radioresistant colorectal carcinoma.Hum Pathol. 1997; 28: 1189-1195Abstract Full Text PDF PubMed Scopus (41) Google Scholar, 11Edmonston TB Cuesta KH Burkholder S Barusevicius A Rose D Kovatich AJ Boman B Fry R Fishel R Palazzo JP Colorectal carcinomas with high microsatellite instability: defining a distinct immunologic and molecular entity with respect to prognostic markers.Hum Pathol. 2000; 31: 1506-1514Abstract Full Text PDF PubMed Scopus (76) Google Scholar and p21WAF1/C1P1 and p27kip1 for differentiated cells in the upper crypt.6Palazzo JP Kafka NJ Grasso L Chakrani F Hanau C Cuesta KH Mercer WE The role of p53, p21WAF1/C1P1, and bcl-2 in radioresistant colorectal carcinoma.Hum Pathol. 1997; 28: 1189-1195Abstract Full Text PDF PubMed Scopus (41) Google Scholar, 12Fredersdorf S Burns J Milne AM Packham G Fallis L Gillett CE Royds JA Peston D Hall PA Hanby AM Barnes DM Shousha S O'Hare MJ Lu X High levels of p27kip1 and cyclin D1 in some breast cancer cells: inverse correlation between the expression of p27kip1 and degree of malignancy in human breast and colorectal cancers.Proc Natl Acad Sci USA. 1997; 94: 6380-6385Crossref PubMed Scopus (366) Google Scholar, 13Sinicrope FA Roddey G Lemoine M Ruan S Stephens LC Frazier ML Shen Y Zhang W Loss of p21WAF1/Cip1 protein expression accompanies progression of sporadic colorectal neoplasms but not hereditary nonpolyposis colorectal cancers.Clin Cancer Res. 1998; 4: 1251-1261PubMed Google Scholar, 14Viale G Pellegrini C Mazzarol G Maisonneuve P Silverman ML Bosari S p21WAF/CIP! expression in colorectal carcinoma correlates with advanced disease stage and p53 mutations.J Pathol. 1999; 187: 302-307Crossref PubMed Scopus (54) Google Scholar We performed immunostaining on both normal-appearing and adenomatous crypts from FAP patients because these patients represent a genetically well-defined model in which the APC genotype has been correlated with histopathological changes that occur during colon tumorigenesis. Sixteen patients with FAP were selected from the Pathology Department at Thomas Jefferson University. Inclusion criteria included: 1) surgical treatment involving a total proctocolectomy that was performed at Thomas Jefferson University; 2) availability of the pathology report from the colectomy to verify histopathological evidence of the classical, multiple polyposis phenotype (documenting FAP diagnosis); and 3) availability of formalin-fixed paraffin-embedded tissue blocks containing both normal and adenomatous colonic epithelium. Four of the sixteen patients had CRC present at colectomy. Ages ranged from 16 to 60 years (median, 29 years) and there were 11 males and 5 females. Patients were also registered in Jefferson's Familial Colorectal Cancer Registry (institutional review board approved) and had documentation of nuclear pedigrees. Immunohistochemistry was also done on colectomy specimens from 11 non-FAP patients with no history of CRC or inflammatory bowel disease. The pathology reports and hematoxylin and eosin-stained slides were reviewed by one pathologist (J.P.P.) to determine that each case had both suitable normal-appearing colonic mucosa and adenomatous epithelium for immunohistochemical analysis. Table 1 summarizes the antibodies used in our study. Immunohistochemistry was performed on colon samples according to methods we previously reported.6Palazzo JP Kafka NJ Grasso L Chakrani F Hanau C Cuesta KH Mercer WE The role of p53, p21WAF1/C1P1, and bcl-2 in radioresistant colorectal carcinoma.Hum Pathol. 1997; 28: 1189-1195Abstract Full Text PDF PubMed Scopus (41) Google Scholar, 11Edmonston TB Cuesta KH Burkholder S Barusevicius A Rose D Kovatich AJ Boman B Fry R Fishel R Palazzo JP Colorectal carcinomas with high microsatellite instability: defining a distinct immunologic and molecular entity with respect to prognostic markers.Hum Pathol. 2000; 31: 1506-1514Abstract Full Text PDF PubMed Scopus (76) Google Scholar Briefly, 5-μm-thick sections of formalin-fixed paraffin-embedded tissues were cut onto neoprene-coated slides (Aldrich Chemical, Milwaukee, WI). Routine deparaffinization from xylene to 95% alcohol and rehydration before patented microwave antigen recovery were performed on a Leica autostainer (Leica, Inc., Deerfield, IL). The deparaffinization included a 30-minute methanol peroxide block for endogenous peroxidase activity.Table 1Primary Antibodies Used for ImmunohistochemistryAntigenSourceDilutionHMSH2Clone FE11, mouse IgG1 kappa (Zymed Laboratories, San Francisco, CA)1:400Bcl2Clone 124, mouse IgG1 kappa (DAKO Co., Carpenteria, CA)1:400SurvivinRabbit polyclonal antibody (Alpha Diagnostics, San Antonio, TX)1:400Ki67Clone MIB1, mouse IgG1 (Immunotech, Westbrook, ME)1:100Topoisomerase IIClone KiS 1, mouse IgG2a (DAKO Co.)1:100p21Clone EA 1O, mouse IgG1 (Oncogene Sciences, Cambridge, MA)1:100p27Clone 1B4, mouse IgG2a (Novocastra Laboratories, Newcastle, UK)1:160p53CM1, rabbit polyclonal (Novocastra/Vector, Burlingame, CA)1:500 Open table in a new tab The antigen recovery step (Microwave Antigen Retrieval, U.S. Patent no. 5244,787) was performed in a microwave oven (800 W, model no. NN-5602A; Panasonic, Franklin Park, IL). The slides were placed in Tissue Tek slide holders and staining dishes (Miles, Elkhart, IL) and submersed in 200 ml of Citra Plus solution, pH 6.0 (BioGenex, San Ramon, CA). The slide holder with slides was placed in the microwave oven for 5 minutes on the high-energy setting. Fifty ml of dH2O was added to the vessel to replenish the evaporative loss and the holder was returned to the microwave oven for an additional 5 minutes on the high setting. The holder and slides were then removed from the oven and cooled for 20 minutes before continuing the immunostaining procedure. For one antigen, Bcl-2, ethylenediaminetetraacetic acid solution, pH 8.0 (Zymed Laboratories, San Francisco, CA) was used instead of the citrate buffer in the antigen recovery step that was otherwise the same as described above. The slides were washed in dH2O and placed in DAKO Tris-buffered saline (TBS) (TBS containing carrier protein and sodium azide). The immunostaining was performed on a DAKO autostainer (Carpinteria, CA). The slides were incubated for 60 minutes with each predetermined primary antibody dilution (see Table 1). The slides were then washed and incubated for 5 minutes with TBS, which was followed by a 30-minute incubation with peroxidase-labeled polymer (EnVision +, DAKO). The slides were then washed and incubated for 5 minutes in TBS. The DAB/peroxide (DAB+, DAKO) was applied for 5 minutes. Slides were washed in TBS and then tap water. The slides were removed from the automated immunostainer and placed on the Leica autostainer for counterstaining and dehydration with xylene. The counterstain was Harris hematoxylin (Surgipath, Richmond, IL) followed by bluing in lithium carbonate (3%). The slides were then coverslipped using the Hacker robotic coverslipper (Hacker Instruments, Inc., Fairfield, NJ). Placenta and normal colonic mucosa served as positive controls for p2l and p27kip1, a p53-positive known colon cancer for p53; tonsil for Bcl-2, Ki-67, and topoisomerase II; and normal colonic mucosa for hSMH2 and survivin. Absence of primary antibody was used as a negative control. Immunostained sections from each tissue block—from normal, FAP, or adenomatous colonic mucosa—were scored to determine the percentage of crypt cells that were stained. We evaluated multiple fields, focusing on longitudinally oriented crypts. The proportion of cells in each crypt that showed staining was visually scored. Crypt cells were scored as positive for a marker if any staining (weak, moderate, or strong) was detectable, and negative if absent. We then determined average proportions across each slide, each sample, and each experimental group. We also identified whether staining was nuclear, cytoplasmic, or both. The intracryptal distribution—bottom, middle, top—of positively staining cells was evaluated for each experimental group. A secondary outcome—staining intensity—was rated as negative, weak, moderate, or strong. When staining was not uniform, the comment of heterogeneous was recorded. Staining of control colonic mucosa showed nuclear hMSH2 staining of epithelial cells (Figure 1A) in the lower crypt. In normal-appearing (nonadenomatous) FAP mucosa, the MSH2 staining intensity was greater and the population of MSH2-positive cells extended upwards into the middle of the crypt (Figure 1B). There were also some MSH2-positive cells with lower nuclear staining intensity at the luminal surface of the crypt in normal-appearing FAP crypts but not in control crypts. Staining for hMSH2 in adenomatous mucosa showed intense nuclear staining throughout the entire crypt with similar intensity of staining at the crypt surface and at the crypt base (Figure 1C). Staining for survivin was more intense in the nuclei of cells of normal crypts with some cytoplasmic staining of cells observed in adenomatous crypts. Survivin staining was preferentially located in the lower region of normal control crypts (Figure 1D). Staining showed an expansion of the survivin-positive cell population into the middle of normal-appearing FAP crypts (Figure 1E) compared to control crypts. Staining of adenomatous mucosa (Figure 1F) showed strong survivin-positive staining of colonocytes along the entire crypt axis, with the greatest number of positively staining cells in the upper crypt (Figure 1F). Bcl-2 staining was seen in the cytoplasm of epithelial cells and did not show significant differences between normal-appearing FAP crypts (Figure 2A) and control crypts (not shown), both showing staining confined to the crypt base. In contrast, adenomatous mucosa, showed positive staining cells diffusely distributed along the entire crypt axis and often displayed a heterogeneous pattern (Figure 2B). Ki-67 nuclear staining in normal control colonic mucosa was observed mainly in the lower crypt (Figure 1G). Ki-67 staining of cell nuclei was intense and showed an expansion of this cell population into the middle of normal-appearing FAP crypts (Figure 1H) compared to control crypts. In comparison, adenomatous mucosa showed positive nuclear Ki-67 staining throughout the crypt, with increased staining intensity from the mid-crypt region to the lumenal surface (Figure 1I). Staining for topoisomerase II did not show significant differences between normal-appearing FAP crypts (Figure 2C) and control crypts (not shown). Topoisomerase II staining in both cases showed nuclear staining mainly in the lower portion of the crypt (Figure 2C). Staining of adenomatous mucosa (Figure 2D) showed strong expression throughout the crypts. Staining for p21WAF1/C1P1 did not show significant differences between normal-appearing FAP crypts (Figure 2E) and control crypts (data not shown). Immunohistochemical staining for p21WAF1/C1P1 in both cases showed nuclear staining and this was restricted to the surface epithelium (Figure 2E). p21WAF1/C1P1 staining of adenomatous mucosa (Figure 2F) also showed nuclear staining in the upper third and lumenal surface of crypts with scattered cells showing nuclear positivity in the crypt bottom. p27kip1 staining, which was mainly nuclear and to a lesser extent cytoplasmic, was present in the upper portions of normal control crypts, although there were occasional isolated p27kip1-positive cells at the crypt base (Figure 1J). Compared to control crypts, normal-appearing FAP crypts showed p27kip1-positive cells with greater staining intensity at the lumenal surface and showed an increased number of isolated p27kip1-positive cells at the crypt bottom (Figure 1K). p27kip1 staining of adenomatous mucosa (Figure 1L) showed both nuclear and cytoplasmic staining of epithelial cells, mainly in the lower crypt (Figure 1L). Staining for p53 was also done because it is considered by some15Sherley JL Asymmetric cell kinetics genes: the key to expansion of adult stem cells in culture.Stem Cells. 2002; 20: 561-572Crossref PubMed Scopus (100) Google Scholar to be a marker for SCs. This showed solitary p53-positive cells at the base of the normal control crypt (data not shown), but only in half of the samples. In normal-appearing FAP crypts, approximately two-thirds of the samples showed p53 staining of isolated cells at the crypt base. There was an increased number of p53-positive cells per crypt compared to controls. Adenomatous crypts showed staining for p53 in approximately three-fourths of the cases. The staining was heterogeneous with a variable number of positively staining cells (5 to 30%) throughout the crypt. Overall, the pattern of staining for any given marker was similar among all samples in any given experimental group. Table 2 summarizes these staining patterns.Table 2Immunostaining Patterns in Normal Control Crypts, Normal-Appearing FAP Crypts, and Adenomatous FAP CryptsAntigenAssociated functionPattern in normal control cryptsPattern in normal-appearing FAP cryptsPattern in adenomatous cryptsHMSH2Mismatch repair proteinLower cryptLower and middle cryptDiffuse staining throughout crypts with greatest number of positive cells in the upper cryptBcl2Anti-apoptotic proteinCrypt baseLower cryptDiffuse staining throughout cryptsSurvivinAnti-apoptotic proteinLower cryptLower and middle cryptStaining throughout crypts with greatest number of positive cells in the upper cryptKi-67Proliferation antigenLower cryptLower and middle cryptStaining throughout crypts with greatest number of positive cells in the upper cryptTopo IIPrevents DNA tanglingLower cryptLower cryptDiffuse staining throughout cryptsp21Cell cycle suppressorCrypt top and mucosal surfaceCrypt top and mucosal surfaceUpper crypt and mucosal surfacep27Cell cycle suppressorCrypt top and mucosal surface with rare positive cells in lower cryptCrypt top and mucosal surface with isolated positive cells in lower cryptLower crypt Open table in a new tab Figure 3 shows changes in the proportions of cells staining for different markers. In general, going from normal control crypts, to normal-appearing FAP crypts, to adenomatous FAP crypts, we found an increase in the proportion of cells that stained for each marker relative to the total number of cells in the crypt. The proportion of cells staining for crypt base cell markers changed the most dramatically. That is, in adenomatous crypts, a greater proportion of cells expressed MSH2, bcl-2 and survivin compared to cells expressing markers for other crypt phenotypes. In contrast, in normal control crypts, cells expressing markers for crypt base cells showed the lowest proportions relative to cells with other phenotypes. As noted above, this staining for crypt base cell markers occurred in cells throughout the adenomatous crypt, not just in the crypt base region. It is well known that when colonic crypts become adenomatous, as they do in FAP, there is an increase in the total number of colonocytes, an increase in the number of mitotic figures, and an apparent reversal in the distribution of proliferating cells from the crypt bottom toward the upper crypt and luminal surface.16Deschner E Lewis CM Lipkin M In vitro study of human rectal epithelial cells. 1. Atypical zone of H3 thymidine incorporation in mucosa of multiple polyposis.J Clin Invest. 1963; 42: 1922-1928Crossref PubMed Google Scholar, 17Cole JW McKalen A Studies on the morphogenesis of adenomatous polyps in the human colon.Cancer. 1963; 16: 998-1002Crossref PubMed Scopus (103) Google Scholar, 18Maskens AP Histogenesis of adenomatous polyps in the human large intestine.Gastroenterology. 1979; 77: 1245-1251PubMed Scopus (54) Google Scholar, 19Polyak K Hamilton SR Vogelstein B Kinzler KW Early alteration of cell-cycle-regulated gene expression in colorectal neoplasia.Am J Pathol. 1996; 149: 381-387PubMed Google Scholar The present results using markers for different cell phenotypes indicate that there is not only a change in the distribution of proliferative cells, but also, there is an increase in the proportion of certain types of crypt cells, which was greatest for cells having a crypt base cell phenotype. In this view, during adenoma development, the colonic epithelial cell population changes in number of cells (increased), location of cell types (different patterns of distribution), and composition (different proportions). We compared the proportion of cells staining positively for any given marker within adenomatous glands to that within normal-appearing FAP crypts and to normal control crypts. We found a step-wise increase, from control to FAP to adenomatous crypts, in the proportion of cells expressing MSH2, Bcl-2, survivin, and Ki-67. Increases for topoisomerase II, p21WAF1/C1P1, and p27kip1, were smaller. We conclude that during progression to adenoma there is a substantially increased proportion of cells having the crypt base cell phenotype. Because SCs are a subset of base cells in normal crypts, these data are consistent with the idea that the population of mutant SCs, or SC-like cells, in FAP and adenomatous FAP crypts has also increased in size. Our data do not exclude some other possibilities including the possibility that differentiated crypt cells in mutated crypts might recapitulate a dedifferentiated stem-cell phenotype. In such a scenario, the SCs would not be the origin of mutant cells that produce adenomas; rather it would be a differentiated cell. It has been argued that this latter possibility is an unlikely mechanism in adenoma morphogenesis.2Potter JD Colorectal cancer: molecules and populations.J Natl Cancer Inst. 1999; 91: 916-932Crossref PubMed Scopus (739) Google Scholar The concept of SC overpopulation is consistent with the results of our kinetic modeling studies.5Boman BM Fields JZ Bonham-Carter O Runquist OA Computer modeling implicates stem cell overproduction in colon cancer initiation.Cancer Res. 2001; 61: 8408-8411PubMed Google Scholar In that modeling study, we investigated how a germline APC mutation, the earliest molecular alteration in colon tumorigenesis, might be linked to the proliferative shift in normal-appearing FAP crypts, the earliest known tissue change. To address this, we used kinetic modeling to investigate the premalignant crypt phenotype in FAP patients. Our modeling showed that only an increase in crypt SC number, not changes in the rates of cell cycle proliferation, differentiation, or apoptosis of the non-SC population, simulated the biological data (the labeling index) for the change from normal to FAP crypts, which exhibit a proliferative abnormality. Our results suggested that the protein product of the APC gene regulates the number of colonic crypt SCs, and that when APC is mutant it causes expansion of the crypt SC population. This kinetic modeling study led to our hypothesis that colon tumor initiation results from crypt SC overpopulation. Because the SC phenotype includes immortality, and the ability to avoid apoptosis, the fact that more cells in adenomatous crypts express Bcl-2 and survivin, proteins that prevent apoptosis, is also consistent with SC overpopulation. Survivin has previously been reported to be overexpressed in adenomas.20Fogt F Poremba C Shibao K Itoh H Kohno K Zimmerman RL Gortz HG Dockhorn-Dworniczak B Urbanski SJ Alsaigh N Heinz D Noffsinger AE Shroyer KR Expression of survivin, YB-1, and Ki-67 in sporadic adenomas and dysplasia-associated lesions or masses in ulcerative colitis.Appl Immunohistochem Mol Morphol. 2001; 9: 143-149Crossref PubMed Scopus (35) Google Scholar Because SCs are immortal and drive cell renewal in the crypt throughout the life of the individual, MSH2 may also be crucial to the SCs by maintaining DNA fidelity through an intact mismatch repair mechanism. Indeed, it was recently reported21Ramalho-Santos M Yoon S Matsuzaki Y Mulligan RC Melton DA “Stemness”: transcriptional profiling of embryonic and adult stem cells.Science. 2002; 298: 597-600Crossref PubMed Scopus (1419) Google Scholar that MSH2 appears to be a marker for SCs in at least some tissues. Our data on MSH2 staining are therefore consistent with there being more SCs. If the size of the SC population increases, as our current and previous reports suggest, then the SC population will produce more offspring. Our results showing that adenomas contain an increased number of cells expressing markers for proliferative cells (Ki-67 and topoisomerase II) are consistent with this concept. These changes should cause an overall increase in the size of the proliferative cell population, which expands into the upper crypt and toward the luminal surface. Indeed, the presence in adenomas of proliferative cells throughout the crypt, including the upper crypt regions and superficial mucosa, has been well-documented by several studies using Ki-67 staining.19Polyak K Hamilton SR Vogelstein B Kinzler KW Early alteration of cell-cycle-regulated gene expression in colorectal neoplasia.Am J Pathol. 1996; 149: 381-387PubMed Google Scholar, 20Fogt F Poremba C Shibao K Itoh H Kohno K Zimmerman RL Gortz HG Dockhorn-Dworniczak B Urbanski SJ Alsaigh N Heinz D Noffsinger AE Shroyer KR Expression of survivin, YB-1, and Ki-67 in sporadic adenomas and dysplasia-associated lesions or masses in ulcerative colitis.Appl Immunohistochem Mol Morphol. 2001; 9: 143-149Crossref PubMed Scopus (35) Google Scholar, 22Moss SF Liu TC Petrotos A Hsu TM Gold LI Holt PR Inward growth of colonic adenomatous polyps.Gastroenterology. 1996; 111: 1425-1432Abstract Full Text PDF PubMed Scopus (69) Google Scholar, 23Shih I-M Wang T-L Traverso G Romans K Hamilton SR Ben-Sasson S Kinzler KW Vogelstein B Top-down morphogenesis of colorectal tumors.Proc Natl Acad Sci USA. 20" @default.
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• W1684202987 title "Colonic Crypt Changes during Adenoma Development in Familial Adenomatous Polyposis" @default.
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