Mucin depleted foci (MDF) new biomarkers in colon carcinogenesis,     are decreased by calorie-restriction and show alterations in mucin production similar to colorectal tumors.

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Mucin depleted foci (MDF) are putative preneoplastic lesions identified in the colon of carcinogen-treated rats by our group (1). To obtain further data on the preneoplastic nature of MDF, we studied the correlation between MDF and colon carcinogenesis in F344 rats initiated with 1,2 dimethylhydrazine and treated with a calorie-restricted (CR) diet (70% of the calories consumed by Controls). CR, known to reduce colon cancer, also significantly reduced MDF (MDF/rat were 6.5 ±2.4 and 3.6±1.9 in Controls and CR, respectively, means±SD, P= 0.01). Moreover, to characterize MDF we tested with immunohistochemistry MUC2, a mucin abundantly expressed in normal colon and MUCA5C, a mucin up-regulated in colon carcinogenesis (2). MDF and tumours show a dramatic reduction in the expression of MUC2 (Labelling Index (LI): 1.5±2.5 (n=16), 0.9 ±0.8 (n=11), and 83.6 ±12 in MDF, tumours, and matched normal mucosa, respectively, means±SD). The results on MUC5AC expression showed that while the expression of this antigen is almost absent in normal mucosa (LI: 0.31±0.5, mean ±SD), it is significantly increased in MDF (LI: 7.4 ± 4.9, n= 13) as well in tumours (1.7±1.2, n=11). Lack of MUC2 has been related to colon cancer development (3) and abrogation of Wnt-signaling has been reported to up-regulates MUC2 (4). Since we previously demonstrated that MDF show upregulation of Wnt-signalling (5), it is possible that the depletion of MUC2 seen in these lesions is related to the activation of this pathway. Moreover, the fact that MDF, as well as tumours, do not express MUC2, and show an increase in MUC5AC suggest a similar molecular defect in these lesions and support the hypothesis that MDF are cancer precursors. Acknowledgements. We thank Dr. J. Bara (Hopital St-Antoine, Paris, France) for the generous gift of antibodies against MUC5AC. Supported by grant “ 05A019-REV” from the American Institute for Cancer Research, by AIRC (Italian Association for Cancer Research, Regional Grant) and by Fondo Ateneo ex-60% of the University of Florence.

References: 1) Caderni G et al.Cancer Res. 63: 2388-92, 2003. 2) Bara J et al., Tumour Biol. 24:109-15, 2003. 3) Velcich A et al.,. Science. 295: 1726-9, 2002. 4) van de Wetering et al., Cell. 111:241-50, 2002. 5) Femia AP et al., Int J Cancer, 116: 9-15, 2005.