S100A4 is implicated in metastasis and chronic inflammation, but its function remains uncertain. Here we establish an S100A4-dependent link between inflammation and metastatic tumor progression. We found that the acute-phase response proteins serum amyloid A (SAA) 1 and SAA3 are transcriptional targets of S100A4 via Toll-like receptor 4 (TLR4)/nuclear factor-κB signaling. SAA proteins stimulated the transcription of RANTES (regulated upon activation normal T-cell expressed and presumably secreted), G-CSF (granulocyte-colony-stimulating factor) and MMP2 (matrix metalloproteinase 2), MMP3, MMP9 and MMP13. We have also shown for the first time that SAA stimulate their own transcription as well as that of proinflammatory S100A8 and S100A9 proteins. Moreover, they strongly enhanced tumor cell adhesion to fibronectin, and stimulated migration and invasion of human and mouse tumor cells. Intravenously injected S100A4 protein induced expression of SAA proteins and cytokines in an organ-specific manner. In a breast cancer animal model, ectopic expression of SAA1 or SAA3 in tumor cells potently promoted widespread metastasis formation accompanied by a massive infiltration of immune cells. Furthermore, coordinate expression of S100A4 and SAA in tumor samples from colorectal carcinoma patients significantly correlated with reduced overall survival. These data show that SAA proteins are effectors for the metastasis-promoting functions of S100A4, and serve as a link between inflammation and tumor progression.

The sand rat Psammomys obesus is a gerbil species native to deserts of North Africa and the Middle East, and is constrained in its ecology because high carbohydrate diets induce obesity and type II diabetes that, in extreme cases, can lead to pancreatic failure and death. We report the sequencing of the sand rat genome and discovery of an unusual, extensive, and mutationally biased GC-rich genomic domain. This highly divergent genomic region encompasses several functionally essential genes, and spans the ParaHox cluster which includes the insulin-regulating homeobox gene Pdx1. The sequence of sand rat Pdx1 has been grossly affected by GC-biased mutation, leading to the highest divergence observed for this gene across the Bilateria. In addition to genomic insights into restricted caloric intake in a desert species, the discovery of a localized chromosomal region subject to elevated mutation suggests that mutational heterogeneity within genomes could influence the course of evolution.

BackgroundThe tumor microenvironment has been described as a critical milieu determining tumor growth and metastases. A pivotal role of metastasis-inducing S100A4 in the development of tumor stroma has been proven in animal models and verified in human breast cancer biopsies. Expression and release of S100A4 has been shown in various types of stroma composing cells, including fibroblasts and immune cells. However, the events implicated in upstream and downstream pathways regulating the activity of the extracellular S100A4 protein in the tumor milieu remain unsolved.Methodology/Principal FindingsWe studied the interplay between the tumor cell-derived cytokine regulated-upon-activation, normal T-cell expressed and secreted (RANTES; CCL5) and S100A4 which were shown to be critical factors in tumor progression. We found that RANTES stimulates the externalization of S100A4 via microparticle shedding from the plasma membrane of tumor and stroma cells. Conversely, the released S100A4 protein induces the upregulation of fibronectin (FN) in fibroblasts and a number of cytokines, including RANTES in tumor cells as well as stimulates cell motility in a wound healing assay. Importantly, using wild type and S100A4-deficient mouse models, we demonstrated a substantial influence of tumor cell-derived RANTES on S100A4 release into blood circulation which ultimately increases the metastatic burden in mice.Conclusions/SignificanceAltogether, the data presented strongly validate the pro-metastatic function of S100A4 in the tumor microenvironment and define how the tumor cell-derived cytokine RANTES acts as a critical regulator of S100A4-dependent tumor cell dissemination. Additionally, for the first time we demonstrated the mechanism of S100A4 release associated with plasma membrane microparticle shedding from various cells types.

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The sand rat Psammomys obesus is a gerbil native to deserts of North Africa and the Middle East 1 . 22Sand rats survive with low caloric intake and when given high carbohydrate diets can become obese 23 and develop type II diabetes 2 which, in extreme cases, leads to pancreatic failure and death 3,4 . 24Previous studies have reported inability to detect the Pdx1 gene or protein in gerbils 5-7 , suggesting 25 that absence of this key insulin-regulating homeobox gene might underlie diabetes susceptibility. 26Here we report sequencing of the sand rat genome and discovery of an extensive, mutationally-27 biased GC-rich genomic domain encompassing many essential genes, including the elusive Pdx1. The 28 sequence of Pdx1 has been grossly affected by GC-biased mutation leading to the highest divergence 29 observed in the animal kingdom. In addition to molecular insights into restricted caloric intake in a 30 desert species, the discovery that specific chromosomal regions can be subject to elevated mutation 31 rate has widespread significance to evolution. 32Linking molecular change to phenotypic change is a central goal of evolutionary biology. Adaptation to 33 arid environments is particularly interesting because of the extreme physiological demands imposed by 34 low food and water availability. The sand rat Psammomys obesus (Fig. 1a) is a member of the subfamily 35Gerbillinae, most species of which live in deserts and arid environments (Fig. 1b). P. obesus has emerged 36 as a model for research into diet-induced type II diabetes because, if provided with high carbohydrate 37diets, the majority of individuals become obese and develop classic diabetes symptoms, in the most 38 extreme cases leading to pancreatic failure and death 2,3 . 39