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      Interstitial Cajal-like cells in rat mesentery: an ultrastructural and immunohistochemical approach

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          Abstract

          Interstitial Cajal-like Cells (ICLC) were recently recognized in a plethora of non-digestive organs. Here, we describe a cell type of rat mesentery sharing ultrastructural and immunohistochemical features with ICLC. Mesenteric ICLC were demonstrated by transmission electron microscopy (TEM) and further tested by light microscope immunohistochemistry. The cell described here fulfils the TEM diagnostic criteria accepted for ICLC: location in the connective interstitium; close vicinity to nerves, capillaries and other interstitial cells; characteristic long, moniliform cell processes; specialized cell-to-cell junctions; caveolae; mitochondria at 5–10% of cytoplasmic volume; rough endoplasmic reticulum at about 1–2%; intermediate and thin filaments, microtubules; undetectable thick filaments. The processes of this mesenteric ICLC were particularly long, with a mean length of 24.91 μm (10.27–50.83 μm), and a convolution index of 2.32 (1.37–3.63) was calculated in order to measure their potential length. Mean distances versus main target cells of ICLC–nerve bundles, vessels, adipocytes and macrophages–were 110.69, 115.80, 205.07 and 34.65 nm, respectively. We also tested the expression of CD117/c-kit, CD34, vimentin, α-smooth muscle actin, nestin, NK-1, tryptase and chymase and the antigenic profile of the mesenteric ICLC was comparable if not identical with that recently observed in ICLC from other extra-digestive tissues. Due to the peculiar aspect of the mesenteric ICLC processes it can be hypothesized that these cells form a three-dimensional network within the mesentery that is at the same time resistant and deformable following stretches consequent to intestine movements, mainly avoiding blood vessels closure or controlling blood vessels rheology. It remains, however, to be established if and how such cells are connected with the archetypal enteric ICC.

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          Most cited references45

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          Gastrointestinal stromal tumors--definition, clinical, histological, immunohistochemical, and molecular genetic features and differential diagnosis.

          Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal (GI) tract. They are defined here as KIT (CD117, stem cell factor receptor)-positive mesenchymal spindle cell or epithelioid neoplasms primary in the GI tract, omentum, and mesentery. GISTs typically present in older individuals and are most common in the stomach (60-70%), followed by small intestine (20-25%), colon and rectum (5%), and esophagus (<5%). Benign tumors outnumber the malignant ones by a wide margin. Approximately 70% of GISTs are positive for CD34, 20-30% are positive for smooth muscle actin (SMA), 10% are positive for S100 protein and <5% are positive for desmin. The expression of CD34 and SMA is often reciprocal. GISTs commonly have activating mutations in exon 11 (or rarely exon 9 and exon 13) of the KIT gene that encodes a tyrosine kinase receptor for the growth factor named stem cell factor or mast cell growth factor. Ligand-independent activation of KIT appears to be a strong candidate for molecular pathogenesis of GISTs, and it may be a target for future treatment for such tumors. Other genetic changes in GISTs discovered using comparative genomic hybridization include losses in 14q and 22q in both benign and malignant GISTs and occurrence in various gains predominantly in malignant GISTs. GISTs have phenotypic similarities with the interstitial cells of Cajal and, therefore, a histogenetic origin from these cells has been suggested. An alternative possibility, origin of pluripotential stem cells, is also possible; this is supported by the same origin of Cajal cells and smooth muscle and by the common SMA expression in GISTs. GISTs differ clinically and pathogenetically from true leiomyosarcomas (very rare in the GI tract) and leiomyomas. The latter occur in the GI tract, predominantly in the esophagus (intramural tumors) and the colon and rectum (muscularis mucosae tumors). They also differ from schwannomas that are benign S100-positive spindle cell tumors usually presenting in the stomach. GI autonomic nerve tumors (GANTs) are probably a subset of GIST. Other mesenchymal tumors that have to be separated from GISTs include inflammatory myofibroblastic tumors in children, desmoid, and dedifferentiated liposarcoma. Angiosarcomas and metastatic melanomas, both of which are often KIT-positive, should not be confused with GISTs.
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            Gastrointestinal stromal tumors/smooth muscle tumors (GISTs) primary in the omentum and mesentery: clinicopathologic and immunohistochemical study of 26 cases.

            Gastrointestinal stromal tumor or smooth muscle tumor (GIST) is the designation for a major subset of gastrointestinal mesenchymal tumors that histologically, immunohistochemically, and genetically differ from typical leiomyomas, leiomyosarcomas, and schwannomas. Because GISTs, like the interstitial cells of Cajal, the gastrointestinal pacemaker cells, express CD117 (c-kit protein), the origin of GISTs from the interstitial cells of Cajal has been recently proposed. Comparison of GISTs primary in the omentum and mesentery to GISTs primary in the tubular gastrointestinal tract is of particular diagnostic and histogenetic interest in view of the possible similarity of these tumors with the GIST group. In this study, we analyzed 14 omental and 12 mesenteric primary mesenchymal tumors representing smooth muscle tumors or GISTs. These tumors were phenotypically compared with gastric and small intestinal GISTs, leiomyomas of the esophagus, and leiomyosarcomas of the retroperitoneum. Most (13 of 14) omental and mesenteric (10 of 12) tumors showed histologic features similar to GISTs with elongated spindle cells or epithelioid cells with high cellularity; most of these tumors showed low mitotic activity. Omental and mesenteric GISTs were typically positive for CD117 and less consistently for CD34. They often showed alpha-smooth muscle actin reactivity but were virtually negative for desmin and S-100 protein. One omental and two mesenteric tumors showed features of leiomyosarcoma with ovoid, less elongated nuclei, cytoplasmic eosinophilia; all these tumors had significant mitotic activity. These tumors were positive for alpha-smooth muscle actin and two of them for desmin, but all were negative for CD34 and CD117, similar to retroperitoneal leiomyosarcomas. Tumor-related mortality occurred in the group of mesenteric GISTs, but not in the group of omental GISTs. In contrast, all three patients with a true leiomyosarcoma of the omentum or mesentery had documented liver metastases or died of tumor. In summary, we show that tumors phenotypically identical with GISTs occur as primary tumors in the omentum and mesentery. The occurrence of CD117-positive tumors outside the gastrointestinal tract militates against an origin of these tumors exclusively from the interstitial cells of Cajal.
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              Interstitial Cajal-like cells in human uterus and fallopian tube.

              Recently, parallels have been drawn between enteric interstitial cells of Cajal (ICC) and similar cells outside the gut-interstitial Cajal-like cells (ICLC). This article reviews our laboratory findings on ICLC in the female reproductive tract. Since the morphology and function of ICLC are still a subject of debate, our purpose was to investigate whether ICLC are present in the fallopian tube and/or uterus, and if they share ultrastructural and immunohistochemical (IHC) features and/or functional roles. We studied ICLC presence in the human fallopian tube and myometrium primarily by light microscopy, and then by transmission electron microscopy (TEM), in tissue samples and at a single cell level. Taking advantage of our ICLC studies of several organs (pancreas, mammary gland, myocardium), we assembled a set of criteria, derived from ultrastructural features of ICLC, called "platinum standard." Besides the putative pacemaker function, ICLC might have other physiological roles, depending on tissue type (e.g., intercellular signaling, immune surveillance, steroid sensors). Consequently, there is a great urge for a conceptual framework that could allow a better understanding, from a functional point of view, and more so, as the ICLC processes are the longest cellular prolongations (except neurons).
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                Author and article information

                Journal
                J Cell Mol Med
                J. Cell. Mol. Med
                jcmm
                Journal of Cellular and Molecular Medicine
                Blackwell Publishing Ltd (Oxford, UK )
                1582-1838
                1582-4934
                January 2008
                09 January 2008
                : 12
                : 1
                : 260-270
                Affiliations
                [a ]‘Victor Babes’National Institute of Pathology, Bucharest, Romania
                [b ]Department of Cellular and Molecular Medicine, ‘Carol Davila’University of Medicine and Pharmacy, Bucharest, Romania
                [c ]Department of Anatomy, Histology and Forensic Medicine, Section of Histology, University of Florence, Florence, Italy
                Author notes
                Correspondence to: L. M. POPESCU, MD, PhD, Department of Cellular and Molecular Medicine, ‘Carol Davila’ University of Medicine and Pharmacy, P. O. Box 35–29, Bucharest 35, Romania. E-mail: lpopescu@ 123456jcmm.org S. FAUSSONE-PELLEGRINI MD, PhD, Department of Anatomy, Histology and Forensic Medicine, Viale Pieraccini 650139 Florence, Italy. Tel.: +39 0554271389 Email: s_faussone@ 123456unifi.it
                Article
                10.1111/j.1582-4934.2008.00226.x
                3823487
                18194443
                1ad76cbc-deae-40b1-b728-19d510dd04f2
                2008 The Authors Journal compilation © 2008 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd
                History
                : 12 September 2007
                : 15 November 2007
                Categories
                In Focus

                Molecular medicine
                interstitial cells of cajal,cd117/c-kit,cd34,vimentin,rat mesentery,immunohistochemistry

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