Abstract
Fibroblasts are some of the major cells in tumour tissues that influence tumour progression and drug resistance. However, our understanding on fibroblast-mediated tumour malignancy remains incomplete. Munc18-1-interacting protein 3 (Mint3) is known as an activator of hypoxia-inducible factor-1 (HIF-1) even during normoxia in cancer cells, macrophages and fibroblasts. Although Mint3 promotes ATP production via glycolysis by activating HIF-1 in cancer cells and macrophages, the biological role of Mint3-mediated HIF-1 activation in fibroblasts remains unclear. To address this, we examined whether Mint3 in fibroblasts contributes to tumour growth. Mint3 depletion in mouse embryonic fibroblasts (MEFs) decreased tumour growth of co-injected human breast cancer cells, MDA-MB-231 and epidermoid carcinoma A431 cells in mice. In MEFs, Mint3 also promoted cancer cell proliferation in vitro in a cell–cell contact-dependent manner. Mint3-mediated cancer cell proliferation depended on HIF-1, and further gene expression analysis revealed that the cell adhesion molecule, L1 cell adhesion molecule (L1CAM), was induced by Mint3 and HIF-1 in fibroblasts. Mint3-mediated L1CAM expression in fibroblasts stimulated the ERK signalling pathway via integrin α5β1 in cancer cells, and promoted cancer cell proliferation in vitro and tumour growth. In cancer-associated fibroblasts (CAFs), knockdown of MT1-MMP, which promotes Mint3-mediated HIF-1 activation, or Mint3 decreased L1CAM expression. As MEFs, CAFs also promoted cancer cell proliferation in vitro, and tumour growth via Mint3 and L1CAM. In human breast cancer specimens, the number of fibroblasts expressing L1CAM, Mint3 and MT1-MMP was higher in cancer regions than in adjacent benign regions. In addition, more phospho-ERK1/2-positive cancer cells existed in the peripheral region surrounded by the stroma than in the central region of solid breast cancer nest. Thus, Mint3 in fibroblasts might be a good target for cancer therapy by regulating cancer cell-stromal cell communication.
Highlights
Tumour tissues comprise cancer cells, and various types of stromal cells
Munc18-1-interacting protein 3 (Mint3)-mediated L1 cell adhesion molecule (L1CAM) expression in cancer-associated fibroblasts (CAFs) promotes tumour growth we investigated whether Mint[3] in human CAFs controls L1CAM expression and tumour growth as observed in mouse embryonic fibroblasts (MEFs)
We further examined whether L1CAM expression in Mint[3] KO MEFs restores tumour growth of co-injected cancer cells
Summary
Tumour tissues comprise cancer cells, and various types of stromal cells. HIF-1 activation in cancer and stromal cells contributes to tumour malignancy.[8,9] We recently revealed that Munc18-1-interacting protein 3 (Mint). Mint[3] requires the membrane-type matrix metalloproteinase MT1-MMP to activate HIF-1.11,14 Mint[3] is expressed in many cell types and increases moderately in tumour tissues.[15,16] On the other hand, MT1-MMP is not expressed in normal epithelial cells, but in cancer cells, macrophages, fibroblasts and endothelial tip cells.[17,18,19] Mint3-mediated HIF-1 activation is limited to these cells. Mint[3] in fibroblasts promotes tumour growth HJ Nakaoka et al[2] defect in ATP production.[10] the biological role of contributes to tumour growth by co-injection in mice, and Mint3-mediated HIF-1 activation in fibroblasts remains unclear. The biological role of contributes to tumour growth by co-injection in mice, and Mint3-mediated HIF-1 activation in fibroblasts remains unclear. co-culture of cancer cells with control or Mint3-depleted In this study, we addressed whether Mint[3] in fibroblasts fibroblasts
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