Epithelial-mesenchymal interaction protects normal colonocytes from 4-HNE-induced phenotypic transformation - Prévention et promotion de la cancérogénèse par les aliments
Journal Articles PLoS ONE Year : 2024

Epithelial-mesenchymal interaction protects normal colonocytes from 4-HNE-induced phenotypic transformation

Abstract

Introduction Recent studies have shown that epithelial-stromal interactions could play a role in the development of colorectal cancer. Here, we investigated the role of fibroblasts in the transformation of normal colonocytes induced by 4-HNE. Methods Normal Co colonocytes and nF fibroblasts from the same mouse colon were exposed, in monoculture (m) or coculture (c), to 4-HNE (5 μM) twice weekly for 3 weeks. Gene expression was then analysed and the ability of Co colonocytes to grow in anchorage-independent conditions was tested in soft agar. Fibroblasts previously treated or not with 4-HNE were also seeded in culture inserts positioned above the agar layers to allow paracrine exchanges with colonocytes. Results First, 60% of the genes studied were modulated by coculture in Co colonocytes, with notably increased expression of BMP receptors. Furthermore, while 4-HNE increased the ability of monoculture-treated Co colonocytes to form colonies, this effect was not observed in coculture-treated Co colonocytes. Adding a selective BMPR1 inhibitor during the treatment phase abolished the protective effect of coculture. Conversely, addition of a BMP4 agonist to the medium of monoculture-treated Co colonocytes prevented phenotypic transformation by 4-HNE. Second, the presence of nF(m)-HNE fibroblasts during the soft agar assay increased the number and size of Co(m) colonocyte colonies, regardless of whether these cells had been previously treated with 4-HNE in monoculture. For soft agar assays performed with nF(c) and Co(c) cells initially treated in coculture, only the reassociation between Co(c)-HNE and nF(c)-HNE resulted in a small increase in the number of colonies. Conclusions During the exposure phase, the epithelial-mesenchymal interaction protected colonocytes from 4-HNE-induced phenotypic transformation via activation of the BMP pathway. This intercellular dialogue also limited the ability of fibroblasts to subsequently promote colonocyte- anchorage-independent growth. In contrast, fibroblasts pre-exposed to 4-HNE in monoculture strongly increased the ability of Co(m) colonocytes to form colonies.

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Cancer
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hal-04675179 , version 1 (22-08-2024)

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Jacques Dupuy, Emma Cogo, Edwin Fouché, Françoise Guéraud, Fabrice Pierre, et al.. Epithelial-mesenchymal interaction protects normal colonocytes from 4-HNE-induced phenotypic transformation. PLoS ONE, 2024, 19, ⟨10.1371/journal.pone.0302932⟩. ⟨hal-04675179⟩
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