Identification of Mucin Depleted Foci in the Human Colon

Abstract

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...

Multiple mucin depleted foci, high proliferation and low apoptotic response in the onset of colon carcinogenesis of the PIRC rat, mutated in Apc

“…3,6 Similarly, the number of MDF/colon in FAP is much higher than that in CRC. 7 We also showed that PIRC rat MDF have a high proliferative activity and a shift in the distribution of proliferating cells in the upper part of the MDF crypt, compared with the NM. Similar alterations in proliferation have been reported in dysplastic FAP polyps and in MDF present in carcinogentreated rats.…”

A Central Role for Heme Iron in Colon Carcinogenesis Associated with Red Meat Intake

“…Most human colon cancers have an Apc mutation, as do MDF in humans and rats (32). To unravel the mechanisms, we used a cellular model that represented the colorectal cancer stages that we investigated in vivo.…”

Red Wine and Pomegranate Extracts Suppress Cured Meat Promotion of Colonic Mucin-Depleted Foci in Carcinogen-Induced Rats

“…Promotion was evidenced on a surrogate end point biomarker, mucin-depleted foci. MDF, formed by dysplastic crypts devoid of mucin, have been identified in the colon of humans at high risk for colon cancer (41). Like tumors, MDF harbor mutations in genes affecting colon carcinogenesis (Apc and K-ras) and show Wnt signaling activation (42), a dramatic reduction of MUC2 expression (43), and a strong activation of the inflammatory process (44), all features suggesting that MDF are precancerous.…”