Isolated lymphoid follicles in colon - World Journal of Gastroenterology

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ing with the pericytes surrounding the blood vessels [52,53] . SEMFs are involved in two epithelial repair processes [54,55] . One process is called restitution [56] . This is an important response to minor to moderate injury. The other process is observed when the wound is deep, and the subepithelial tissues and the basement membrane need to be reconstituted [55] . According to recent studies [54,57,58] , myofibroblasts are thought to derive from two major sources, bone marrow or locally activated fibroblasts, in response to transforming growth factor-β1. In the case of serious tissue injury (i.e. active ulcerative colitis) the regeneration capacity of local stem cells is not enough to complete tissue repair. In this case, bone marrow derived mesenchymal stem cells migrate into the gastrointestinal wall where they may contribute to the repair progress [59,60] as differentiated mesenchymal cells (e.g. myofibroblasts) [61] . Despite the increasing number of publications illustrating the role of tumor-associated stromal cells in cancer progression, there still exists a significant ambiguity with respect to the identification of cancer-associated fibroblasts, myofibroblasts and peritumoral fibroblasts in the cancer tissue. SEMFs appear early in the cancer’s development. The mutual interaction (through direct cell-cell contacts and paracrine signals) between cancer cells and SEMFs is essential for invasive growth and is translated into a poor clinical prognosis [62] . TOLL-LIKE RECEPTOR EXPRESSION IN ILFS Beside immune functions, PPs and ILFs are supposed to be involved in mucosal repair via Toll-like receptors (TLRs). In ILFs, TLRs are expressed on the cells of the monocyte/macrophage system, on some kinds of T cells, as well as on intestinal epithelial, endothelial and stromal cells [63] . Using the dextran sodium sulfate (DSS) model of colitis, mice lacking TLR2, TLR4 or MyD88 all developed more severe colitis than wild type mice when exposed to orally administered DSS [64] . These findings suggest that signaling from commensal bacteria throughout TLRs resulted in protection from DSS colitis through enhanced epithelial cell proliferation, and worked as a compensatory factor against epithelial damage [64] . TLRs can also bind endogenous ligands including necrotic cells, heat shock proteins, and extracellular matrix components [65-67] . Necrotic cells may activate NF-κB through TLR2, leading to the expression of tissue repairassociated genes [65] . It is supposed that necrosis induced inflammation in tissue damage may provide danger signals functioning as inducers of tissue repair responses through TLRs. The TLR ligands released from necrotic cells have not been identified, although heat shock proteins produced by damaged cells are known to be TLR ligands [66] . Components of the extracellular matrix, such as hyaluronan, can be an endogenous ligand for TLR4 [67] . Increased hyaluronan production has been demonstrated in both DSS colitis in mice and in human Crohn’s disease [68] . It WJG|www.wjgnet.com Sipos F et al . Colonic isolated lymphoid follicles is possible that TLR activation may occur in the absence of microbial products [68] . In the case of inflammatory mucosal damage, ILFs may induce repair mechanisms via endogenous TLR activation. TLR4 was also shown to be expressed on human colon carcinoma cells and functionally active. It may play important roles in promoting immune escape of human colon carcinoma cells by inducing immunosuppressive factors and apoptosis resistance, and it may also promote the proliferation and migration of cancer cells [69,70] . The analysis of isolated tumor cells from primary colon cancers showed co-expression of TLR7 and TLR8 with CD133 and gave evidence for a subpopulation of colon cancer-initiating cells [71] . Persistent TLR-specific activation of NF-κB in colorectal cancer, particularly in tumor-initiating cells, may sustain further tumor growth and progression through perpetuated signaling known from inflammatory and tissue repair mechanisms with consecutive self-renewal in pluripotent tumor cells. Activation through self-ligands or viral RNA fragments from tumor-associated lymphoid aggregates may putatively maintain this inflammatory process, suggesting a key role in cancer progression. THE EFFECT OF THE PRESENCE OF ILFS ON MUCOSAL REPAIR The epithelia of intestinal crypts associated with ILFs and PPs have an increased proliferation rate [10,14] . Saxena et al [10] showed that PPs in rats have a facilitative effect on the healing of intestinal wounds by promoting both epithelial cell migration on the defect and epithelial cell proliferation in the crypts adjacent to the wound and by decreasing the rate of wound contraction. In rats, a difference in epithelial apoptosis between the FAE of PPs and intestinal villi was described [72] . Onishi et al [72] showed that the progression of the apoptotic process in the epithelial cells of FAE occurs later than in the intestinal villi, so the possibility of epithelial differentiation might remain in FAE, unlike in intestinal villi. PPs are supposed to have a regulatory effect on the epithelial proliferation as well [73] . The Wnt signaling pathway is critical for regulating a number of basic cell functions, such as cell proliferation, cell fate, polarity, differentiation, and migration, leading to morphogenesis and organogenesis [74,75] . There is strong genetic evidence that Wnt signaling play critical roles in the regulation of epithelial stem cells in the intestinal tract [76] . The Wnt target gene Lgr5 has been recently identified as a novel stem cell marker of the intestinal epithelium and the hair follicle [77] . In the intestine, Lgr5 is exclusively expressed in cycling crypt base columnar cells [77] . Many Wnt family proteins are expressed in hematopoietic tissues, and can also be secreted by lymphoid cells [78,79] . The Wnt-Lgr5 pathway may be a potential switch between the ILFs and colonic epithelial renewal. Lymphoid cells of ILFs may produce Wnts which are essential components of a milieu in which bone marrow derived stem cells immigrated to ILFs to engage in epithelial differentiation (Figure 2). 1669 April 7, 2011|Volume 17|Issue 13|
Sipos F et al . Colonic isolated lymphoid follicles * Figure 2 3D reconstruction of a human colonic surgical sample (MIRAX Viewer, 3D, 3DHISTECH Ltd., Budapest). A large subepithelial isolated lymphoid follicle (white star) can be seen. Colonic crypts (white arrow) with no connection to the luminal surface “outgrow” from the isolated lymphoid follicle. THE EFFECT OF THE PRESENCE OF ILFS ON COLORECTAL CARCINOGENESIS Results from experimental colon cancer studies indicated that ILFs might promote the development of adenocarcinomas [7,8] . However, studies in experimental animals have also shown that the intestinal lymphoid system plays an important role in immunologic defense mechanisms; that is, antigenic stimuli result in germinal center formation, antibody production, and finally enlargement of the follicles [80] . In humans, the presence of tumor-infiltrating lymphocytes is associated with an improved prognosis in colorectal cancers, as does the presence of high level DNA microsatellite instability [81] . These results suggest that ILFs in early colorectal neoplasms play an important role in defense rather than in promotion. In a recent study, Fu et al [9] found that the incidence of ILFs in early human colorectal neoplasms significantly differs by gender, location, macroscopic type, and histology, but moreover, their localization significantly differs by macroscopic type. In squamous cell carcinomas of the esophagus, cyclin A expression in the germinal center cells of ILFs beneath the superficial tumorous lesions was shown to be an immunological signal toward the proliferation and progression of the tumors [82] . Gutfeld et al [83] found that the cells of colonic ILFs, inflammatory cells, ganglion cells, and endothelial cells express serum amyloid A, an acute phase reactant, whose level in the blood is elevated in response to trauma, infection, inflammation, and neoplasia, on both mRNA and protein levels. The serum amyloid A mRNA expression in epithelial cells was found to gradually increase as it progressed through different stages of dysplasia to overt carcinoma. While expression of the serum amyloid A1 and -4 genes in colon carcinomas was confirmed by RT-PCR analysis, this expression was barely detectable in normal colon tissues. Their findings indicate local and differential expression of serum amyloid A in human colon cancer and tumor-associated ILFs, and suggest its role in colorectal carcinogenesis. WJG|www.wjgnet.com MESENCHYMAL-EPITHELIAL AND EPI- THELIAL-MESENCHYMAL TRANSITION IN ILFS Epithelial-mesenchymal transition (EMT) is a physiological mechanism present during development, and is also encountered in several pathological situations such as renal interstitial fibrosis, endometrial adhesion, and cancer metastasis [84] . A reverse phenomenon, mesenchymal-epithelial transition (MET) also takes place during normal development in processes such as somitogenesis, kidney development and coelomic cavity formation [85] . In adult organisms, it has been proposed that restrictive mechanisms repress EMT and MET [86] . During tumor development, these mechanisms appear to fail, allowing EMT described in metastasis generation [87] . In inflammation, MET can also be altered because mesenchymal stem cells are mobilized to these sites of injury and consequently subjected to the inflammatory response [88] . BMDCs could differentiate into mature-appearing epithelial cells in response to tissue damage [89] . It was recently published that versican, a large chondroitin sulfate proteoglycan, mediates MET [90] . The results of Hirose et al [91] indicate that versican can bind specific chemokines through its chondroitin sulfate chains and that the binding tends to down-regulate the chemokine function. This raises the possibility that versican may act as a regenerative factor in colonic mucosa, and may be an important switch point between ILFs and MET. The presence of CDX2 and cytokeratin positive subepithelial cells in the marginal zone of ILFs also suggests that MET may take place in these immune formations [2] . Stroma-tissue, including lymphoid aggregates and ILFs surrounding the cancer cells, plays an important role in the tumor behavior. Mesker et al [92] analyzed the expression of markers involved in pathways related to stroma production and EMT (β-catenin, TGF-β-R2, SMAD4) in highrisk colorectal cancer patients, and found that patients with stroma-high and SMAD4 loss are of high risk. The anti- EMT effect of SMAD4 was also proven in colon carcinoma cells [93] . CONCLUSION Based on the summarized results of literature, it seems that ILFs act like a switch between colonic mucosal regeneration and colorectal carcinogenesis. Subepithelial revascularization after mucosal damage takes place partly under the direction of ILFs with the prominent help of vascular endothelial growth factor and its receptors. Immigrating stem cells from bone marrow may leave circulation via high endothelial venules in ILFs and their surroundings. Their differentiation throughout mesenchymal-to-epithelial transition may also happen in ILFs, and follicular dendritic cells, as well as the subepithelial myofibroblasts, seem to be crucial parts of colonic crypt formation and epithelial renewal. Vasculogenesis in ILFs supports not just tumor growth 1670 April 7, 2011|Volume 17|Issue 13|
Page 1 and 2: World Journal of Gastroenterology W
Page 3 and 4: Robert JL Fraser, Daw Park Jacob Ge
Page 5 and 6: Italy Donato F Altomare, Bari Piero
Page 7 and 8: Fernando Azpiroz, Barcelona Ramon B
Page 9 and 10: S Contents EDITORIAL TOPIC HIGHLIGH
Page 11 and 12: Contents APPENDIX FLYLEAF EDITORS F
Page 13 and 14: Santos BF et al . Progress in human
Page 16 and 17: dures, along with some form of lumi
Page 18 and 19: Figure 4 EndoSamurai is a prototype
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Page 23 and 24: Online Submissions: http://www.wjgn
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Page 32: INTRODUCTION Over the past two deca
Page 38 and 39: Table 2 Relative incidence of sub-s
Page 41 and 42: Enríquez-Navascués JM et al . Rec
Page 43 and 44: Zhang ZM et al . Treatment of inter
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Page 62: A B C D E ed in the 7 patients that
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Page 69: Zhang YZ et al . Prognostic markers
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Table 1 MR-arterioportography stand
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29 Takahara T, Imai Y, Yamashita T,
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Peer reviewer: Damian Casadesus Rod
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Water absorption rate (mL/h.m) Hu S
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Hu S et al . Carbachol, gastrointes
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Research frontiers Nutritional supp
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