Bone marrow-derived myofibroblasts are the providers of pro-invasive matrix metalloproteinase 13 in primary tumor.

Abstract

Carcinoma-associated fibroblasts are key contributors of the tumor microenvironment that regulates carcinoma progression. They consist of a heterogeneous cell population with diverse origins, phenotypes, and functions. In the present report, we have explored the contribution of bone marrow (BM)-derived cells to generate different fibroblast subsets that putatively produce the matrix metalloproteinase 13 (MMP13) and affect cancer cell invasion. A murine model of skin carcinoma was applied to mice, irradiated, and engrafted with BM isolated from green fluorescent protein (GFP) transgenic mice. We provide evidence that one third of BM-derived GFP(+) cells infiltrating the tumor expressed the chondroitin sulfate proteoglycan NG2 (pericytic marker) or α-smooth muscle actin (α-SMA, myofibroblast marker), whereas almost 90% of Thy1(+) fibroblasts were originating from resident GFP-negative cells. MMP13producing cells were exclusively α-SMA(+) cells and derived from GFP(+) BM cells. To investigate their impact on tumor invasion, we isolated mesenchymal stem cells (MSCs) from the BM of wild-type and MMP13-deficient mice. Wild-type MSC promoted cancer cell invasion in a spheroid assay, whereas MSCs obtained from MMP13-deficient mice failed to. Our data support the concept of fibroblast subset specialization with BM-derived α-SMA(+) cells being the main source of MMP13, a stromal mediator of cancer cell invasion.

• Authors: Julie Lecomte, Anne Masset, Silvia Blacher, Ludovic Maertens, André Gothot, Marie Delgaudine, Françoise Bruyère, Oriane Carnet, Jenny Paupert, Martin Illemann, Jean-Michel Foidart, Ida K Lund, Gunilla Høyer-Hansen, Agnes Noel
• Journal: Neoplasia (New York, N.Y.) (Neoplasia) Vol. 14 Issue 10 Pg. 943-51 (Oct 2012) ISSN: 1476-5586 [Electronic] United States
• PMID: 23097628 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers, Tumor
• RNA, Messenger
• Matrix Metalloproteinase 13
• Mmp13 protein, mouse

Topics

• Animals
• Biomarkers, Tumor (genetics, metabolism)
• Blotting, Western
• Bone Marrow (metabolism, pathology)
• Female
• Fibroblasts (metabolism, pathology)
• Flow Cytometry
• Humans
• Immunoenzyme Techniques
• In Situ Hybridization
• Matrix Metalloproteinase 13 (physiology)
• Mesenchymal Stem Cells (metabolism, pathology)
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Myofibroblasts (metabolism, pathology)
• Neoplasm Invasiveness
• Neoplasms (genetics, metabolism, pathology)
• RNA, Messenger (genetics)
• Real-Time Polymerase Chain Reaction
• Reverse Transcriptase Polymerase Chain Reaction
• Tumor Cells, Cultured
• Tumor Microenvironment