Journal
NEOPLASIA
Volume 14, Issue 10, Pages 943-951Publisher
ELSEVIER SCIENCE INC
DOI: 10.1593/neo.121092
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Funding
- European Union [201279]
- Fonds National de la Recherche Scientifique (Belgium)
- Federation belge contre le Cancer
- Fonds speciaux de la Recherche (University of Liege)
- Centre Anticancereux pres l'Universite de Liege
- Fonds Leon Fredericq (University of Liege)
- D.G.T.R.E. from Region Wallonne
- Interuniversity Attraction Poles Program-Belgian Science Policy (Brussels, Belgium)
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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) transgenicmice. We provide evidence that one third of BM-derived GFP(+) cells infiltrating the tumor expressed the chondroitin sulfate proteoglycan NG2 (pericytic marker) or alpha-smooth muscle actin (alpha-SMA, myofibroblast marker), whereas almost 90% of Thy1(+) fibroblasts were originating from resident GFP-negative cells. MMP13-producing cells were exclusively alpha-SMA(+) cells and derived from GFP(+) BM cells. To investigate their impact on tumor invasion, we isolated mesenchymal stemcells (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 alpha-SMA(+) cells being the main source of MMP13, a stromal mediator of cancer cell invasion.
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