Metastasis-associated protein S100A4 induces a network of inflammatory cytokines that activate stromal cells to acquire pro-tumorigenic properties.
Tumor cells have the ability to exploit stromal cells to facilitate metastasis. By using malignant melanoma as a model, we show that the stroma adjacent to metastatic lesions is enriched in the known metastasis-promoting protein S100A4. S100A4 stimulates cancer cells to secrete paracrine factors, such as inflammatory cytokines IL8, CCL2 and SAA, which activate stromal cells (endothelial cells and monocytes) so that they acquire tumor-supportive properties. Our data establishes S100A4 as an inducer of a cytokine network enabling tumor cells to engage angiogenic and inflammatory stromal cells, which might contribute to pro-metastatic activity of S100A4.
Department of Tumor Biology, Institute for Cancer Research, Division of Cancer, Surgery and Transplantation, Oslo University Hospital, Oslo, Norway.
Ingrid J
IJ
Bettum
Department of Tumor Biology, Institute for Cancer Research, Division of Cancer, Surgery and Transplantation, Oslo University Hospital, Oslo, Norway.
Kotryna
K
Vasiliauskaite
Department of Tumor Biology, Institute for Cancer Research, Division of Cancer, Surgery and Transplantation, Oslo University Hospital, Oslo, Norway.
Vigdis
V
Nygaard
Department of Tumor Biology, Institute for Cancer Research, Division of Cancer, Surgery and Transplantation, Oslo University Hospital, Oslo, Norway.
Trevor
T
Clancy
Department of Tumor Biology, Institute for Cancer Research, Division of Cancer, Surgery and Transplantation, Oslo University Hospital, Oslo, Norway.
Solveig J
SJ
Pettersen
Department of Tumor Biology, Institute for Cancer Research, Division of Cancer, Surgery and Transplantation, Oslo University Hospital, Oslo, Norway; The K.G. Jebsen Center for Breast Cancer Research, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
Ellen
E
Tenstad
Department of Tumor Biology, Institute for Cancer Research, Division of Cancer, Surgery and Transplantation, Oslo University Hospital, Oslo, Norway; Institute for Pharmacy, Faculty of Health Science, University of Tromsø, Tromsø, Norway.
Gunhild M
GM
Mælandsmo
Department of Tumor Biology, Institute for Cancer Research, Division of Cancer, Surgery and Transplantation, Oslo University Hospital, Oslo, Norway. Electronic address: linap@rr-research.no.
Lina
L
Prasmickaite
D000818:Animals; D045744:Cell Line, Tumor; D016207:Cytokines / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D064593:Heterografts; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation / Q000378:metabolism; D008545:Melanoma / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D060888:Real-Time Polymerase Chain Reaction; D020239:Receptor Cross-Talk / Q000502:physiology; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins / Q000378:metabolism*; D017154:Stromal Cells / Q000378:metabolism* / Q000473:pathology; D059016:Tumor Microenvironment / Q000502:physiology*
D016207:Cytokines; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins; C077591:S100A4 protein, human
Cytokines; Melanoma; Metastasis; S100A4; Tumor-stroma interactions