A link between inflammation and metastasis: serum amyloid A1 and A3 induce metastasis, and are targets of metastasis-inducing S100A4

Abstract

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.

S100A4 promotes colon inflammation and colitis-associated colon tumorigenesis

“…The secretion of S100A4 by tumor and stromal cells is believed to serve as a key player in the metastasis of cancer cells or affecting angiogenesis. 28-30 Although we did not know which form of S100A4 plays more important roles in colon tumorigenesis, our IHC staining of colon tumors suggests the weak intracellular staining, and our functional studies support a major source of myeloid cell-producing S100A4 during colon cancer development. It is certainly also important to analyze the role of intracellular S100A4 in myeloid cells during the development of colon tumorigenesis in the future.…”

“…21 , 29 , 30 To test whether S100A4 is secreted by S100A4 + cells in the CRC tissue, CD11b + S100A4 + cells were isolated from DSS-treated colon tissues and were cultured in vitro, and the supernatant was analyzed for S100A4 by ELISA. CD11b + S100A4 − cells were used as control.…”

“…26 , 27 However, the secretion of S100A4 by tumor and stromal cells is believed to serve as a key player in promoting the metastasis of cancer cells or affecting angiogenesis. 28-30 Studies have shown that some cytokines, particularly chemokine (C-C motif) ligand 5 (CCL5), are necessary and sufficient for inducing the release of S100A4 from fibroblasts contributing to the formation of pre-metastatic niches. 31 Furthermore, it has been demonstrated that the ablation of S100A4 in stromal cells significantly reduced metastatic colonization by regulating matrix protein tenascin-C and growth factor vascular endothelial growth factor (VEGF)-A.…”

Comprehensive site-specific whole genome profiling of stromal and epithelial colonic gene signatures in human sigmoid colon and rectal tissue

“…In comparison, Oh et al (41) reported 929 significant epithelial-stromal coexpression interactions among 11,700 ϫ 11,700 ϭ 136,890,000 pairwise associations tested in normal breast tissue. Interestingly, all the top detected genes have been implicated in the link between inflammation and cancer of the colon (5,18,20,35,39,44,46,49,56,62). Additional systems-level analyses on independent RNA-Seq data sets are needed to further explore how colonic stromal and epithelial interactions temporally evolve during malignant transformation.…”

Basal‐like breast cancer engages tumor‐supportive macrophages via secreted factors induced by extracellular S100A4

“…Both endogenous and extracellular S100A4 have been linked to metastasis. Endogenous S100A4 is known to enhanced cell motility and invasion (Grundker et al ., 2016), while extracellular, stromal S100A4 has been shown to instigate inflammatory events promoting metastasis (Hansen et al ., 2014). …”