Crohn’s disease (CD) is a relapsing chronic inflammatory disorder that may involve all the gastrointestinal tract with a prevalence of terminal ileum. Intestinal lesions have a characteristic discontinuous and segmental distribution and may affect all layers of the gut wall. Telocytes (TC), a peculiar type of stromal cells, have been recently identified in a variety of tissues and organs, including gastrointestinal tract of humans and mammals. Several roles have been proposed for TC, including mechanical support, spatial relationships with different cell types, intercellular signalling and modulation of intestinal motility. The aim of our study was to investigate the presence and distribution of TC in disease-affected and -unaffected ileal specimens from CD patients compared with controls. TC were identified by CD34/PDGFRα immunohistochemistry. In affected CD specimens TC disappeared, particularly where fibrosis and architectural derangement of the intestinal wall were observed. In the thickened muscularis mucosae and submucosa, few TC entrapped in the fibrotic extracellular matrix were found. A discontinuous network of TC was present around smooth muscle bundles, ganglia and enteric strands in the altered muscularis propria. At the myenteric plexus, the loss of TC network was paralleled by the loss of interstitial cells of Cajal network. In the unaffected CD specimens, TC were preserved in their distribution. Our results suggest that in CD the loss of TC might have important pathophysiological implications contributing to the architectural derangement of the intestinal wall and gut dysmotility. Further functional studies are necessary to better clarify the role of TC loss in CD pathophysiology.

Hepatic stellate cells (HSC) play a key role in the hepatic wound-healing process. Following acute or chronic liver injury, HSC undergo a process of activation toward a phenotype characterized by increased proliferation, motility, contractility, and synthesis of extracellular matrix (ECM) components. 1

Aberrant crypt foci (ACF) originally described in rodents treated with colon-specific carcinogens have been identified also in humans at high risk of colon cancer (CRC) and are extensively used as cancer biomarkers. However, studies documenting the heterogeneity of ACF have questioned their precancerous nature. Recently, we described dysplastic foci depleted of mucins (MDF) in the colon of rats treated with colon-specific carcinogens. Like colon tumors, MDFs show activation of Wnt signaling driven by mutations in the β-catenin gene and Apc, a key gene in colorectal carcinogenesis. Because MDFs have been identified thus far only in rodents, we wanted to search for similar lesions in humans. Familial adenomatous polyposis (FAP) subjects, carrying germ-line mutations in the APC gene, are at high risk of CRC. Therefore, we first searched for MDF-like lesions in unsectioned colon samples from FAP patients and then in patients with sporadic CRC. MDFs were present in the colon of FAP patients (average of 0.0577 lesions/cm 2 ) and at a much lower density in CRC patients (average of 0.0006 lesions/cm 2 ). ACFs were also observed in all patients. Histologic preparations of all the MDFs identified in FAP and CRC consisted of microadenomas at variable grades of dysplasia. The occurrence of MDF-like lesions in high-risk patients provides evidence that these lesions have a counterpart in human pathology and, as observed in rodents, may represent the very early stages of CRC.Foci of aberrant crypts (ACF), microscopically visible in the unsectioned colon of carcinogen-treated mice, were originally described by Ranjana Bird in 1987 as being related to the early steps of colon carcinogenesis (1). The results of many studies characterizing ACF (2-4) and the demonstration that ACF-like lesions are also present in humans (5, 6) have reinforced the hypothesis that ACFs are precursors of colon cancer (CRC) and have led to their widespread use as biomarkers of colon carcinogenesis (7, 8). However, reports documenting the heterogeneity of ACF and their relationship with cancer not always straightforward (9-12) opened a debate on the validity of ACF as surrogate end points, stressing the need for additional biomarkers more robustly correlated with cancer (12-15).Recently, mucin depleted foci (MDF), formed by dysplastic crypts with scant or absent mucin production, were identified by our group in the colon of rodents treated with azoxymethane or 1,2-dimethylhydrazine (16), which induces CRC through histologic and molecular alterations similar to human carcinogenesis (17). Like ACFs, MDFs are easily identified in unsectioned colon. Moreover, studies carried out by us and others indicate that MDFs are correlated with carcinogenesis and can thus serve as cancer biomarkers in chemoprevention studies (18-21). We documented that MDFs share pathologic and molecular alterations with more advanced lesions, such as Wnt pathway activation, caused in part by mutations in the β-catenin gene (19). Moreover, the fact that MDFs carry mutations in...

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Summary We investigated in the rat the role of the Apc gene, which is mutated in familial adenomatous polyposis and sporadic colon cancer in the process leading from normal colonic mucosa to aberrant crypt foci (ACF) and finally to adenomas and adenocarcinomas. We analysed mutations in exon 15 of the rat Apc gene using in vitro synthesized protein assay in 66 ACF and in 28 colon tumours induced by azoxymethane. No Apc mutations were found in ACF, whereas five mutations were found in the tumours. The data suggest that mutations of the Apc gene are associated with the transition from ACF to adenoma and adenocarcinoma and not from normal mucosa to ACF.Keywords: Apc gene; aberrant crypt foci; colon cancer; experimental carcinogenesis; azoxymethane According to current views, colon carcinogenesis is a multistep process in which preneoplastic lesions accumulate in mucosa cells, finally leading to neoplastic transformation (Kinzler and Vogelstein, 1996). Many molecular events have been suggested to play a role in the transition from normal colon mucosa to cancer, such as the activation of oncogenes, the inactivation or loss of tumour-suppressor genes and mutations in DNA repair genes (Kinzler and Vogelstein, 1996). According to a commonly accepted model of colorectal tumorigenesis, K-ras and APC (adenomatous polyposis coli) gene mutations are early genetic events (Kinzler and Vogelstein, 1996). The APC gene in mutated in familial adenomatous polyposis (FAP) and in human sporadic colon tumours with a frequency ranging from 40% to 80% (Nakamura, 1993;De Benedetti et al, 1994;Kinzler and Vogelstein, 1996). The human APC gene (exons 1-15) contains an open reading frame of over 8500 nucleotides (Groden et al, 1991;Kinzler et al, 1991) and encodes for a cytoplasmic protein of 300 kDa that binds to 3-catenin (Rubinfeld et al, 1996), suggesting that APC product might regulate cell adhesion. About 50-60% of the somatic mutations of the APC gene are clustered in a 700-bp region, designated in humans as the mutation cluster region (MCR) (Nakamura, 1993). More than 95% of the mutations in the human APC gene are nonsense or frameshift mutations that result in truncated proteins (Nakamura, 1993;Powell et al, 1993).Aberrant crypt foci (ACF) have been suggested to be the first preneoplastic lesions preceding the development of adenomas and carcinomas (Bird, 1987). ACF are easily induced in experimental animals by a variety of carcinogens (Bird, 1987;Bruce et al, 1993) and have been described in humans with sporadic colon cancer and with familial adenomatous polyposis coli (Pretlow et al, 1991;Roncucci et al, 1991). ACF have been widely used as end points in experimental colon carcinogenesis , although some authors have not observed a correlation between ACF formation and colon cancer (Hardmann et al, 1991 Correspondence to: G Caderni Azoxymethane (AOM), one of the most extensively studied colon carcinogens, is able to induce both ACF and tumours in rats, and AOM-induced colon carcinogenesis is a widely used model for studying the mult...