Loss of function of mismatch repair (MMR) genes underlies hereditary nonpolyposis colorectal cancer (HNPCC). However, the inability to maintain primary colon epithelial cells in culture has limited the analysis of the contribution of MMR gene defects to colorectal tumorigenesis. We have now established primary cultures of epithelial cells from the colon crypts of Msh2-/- p53-/- double-knockout mice. These cells undergo spontaneous transformation (soft agar colonies and s.c. tumor formation), with a progressively shorter latency as a function of increasing passages in culture. Treatment of early passage cells with the mutagen methylmethane thiosulfonate (MMS) further decreases the transformation latency of Msh2-/- p53-/- cells. Spontaneous transformation of p53-/- colonocytes is only observed using late passage cells, and methylmethane thiosulfonate-treated early passage p53-/- colonocytes do not form tumors when injected into immunodeficient mice. Together, these findings support the pathogenic role of MMR gene inactivation in colorectal tumorigenesis and provide an experimental model for the serial assessment of the molecular phenotype associated with Msh2 deficiency.

Spontaneous and mutagen-induced transformation of primary coltures of Msh2-/- p53-/- colonocytes / Sevignani, C; Cranston, A; Iozzo, Rv; Fishel, R; Calabretta, Bruno. - In: CANCER RESEARCH. - ISSN 0008-5472. - STAMPA. - 59:(1999), pp. 5882-5886.

Spontaneous and mutagen-induced transformation of primary coltures of Msh2-/- p53-/- colonocytes

CALABRETTA, Bruno
1999

Abstract

Loss of function of mismatch repair (MMR) genes underlies hereditary nonpolyposis colorectal cancer (HNPCC). However, the inability to maintain primary colon epithelial cells in culture has limited the analysis of the contribution of MMR gene defects to colorectal tumorigenesis. We have now established primary cultures of epithelial cells from the colon crypts of Msh2-/- p53-/- double-knockout mice. These cells undergo spontaneous transformation (soft agar colonies and s.c. tumor formation), with a progressively shorter latency as a function of increasing passages in culture. Treatment of early passage cells with the mutagen methylmethane thiosulfonate (MMS) further decreases the transformation latency of Msh2-/- p53-/- cells. Spontaneous transformation of p53-/- colonocytes is only observed using late passage cells, and methylmethane thiosulfonate-treated early passage p53-/- colonocytes do not form tumors when injected into immunodeficient mice. Together, these findings support the pathogenic role of MMR gene inactivation in colorectal tumorigenesis and provide an experimental model for the serial assessment of the molecular phenotype associated with Msh2 deficiency.
1999
59
5882
5886
Spontaneous and mutagen-induced transformation of primary coltures of Msh2-/- p53-/- colonocytes / Sevignani, C; Cranston, A; Iozzo, Rv; Fishel, R; Calabretta, Bruno. - In: CANCER RESEARCH. - ISSN 0008-5472. - STAMPA. - 59:(1999), pp. 5882-5886.
Sevignani, C; Cranston, A; Iozzo, Rv; Fishel, R; Calabretta, Bruno
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11380/449852
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