In some tumors, a small number of cancer cells are scattered in a large fibrotic stroma. Here, we demonstrate a novel mechanism for expansion of pro-tumor fibroblasts via cancer-associated fibroblast (CAF)-mediated education of normal fibroblasts (NFs). When NFs were incubated with conditioned medium from CAFs, the resulting CAF-educated fibroblasts (CEFs) generated reactive oxygen species (ROS), which induced NF-B-mediated expression of inflammatory cytokines and the extracellular matrix protein asporin (ASPN), while expression of a common CAF marker gene, -SMA, was not increased. ASPN further increased CEF expression of downstream molecules, including indoleamine 2,3-dioxygenase 1 (IDO-1), kynureninase (KYNU) and pregnancy-associated plasma protein-A (PAPP-A). These CEFs induce cytocidal effects against CD8 + T cells and IGF-I activation in cancer cells. CEFs were generated without cancer cells by the direct mixture of NFs and CAFs in mouse xenografts and, once CEFs were generated, they sequentially educated NFs, leading to continuous generation of CEFs.In diffuse-type gastric cancers, ASPN high /IDO-1 high /KYNU high /-SMA -CEFs were located at the distal invading front. These CEFs expanded in the fibrotic stroma and caused dissemination of cancer cells. ASPN may therefore be a key molecule in facilitating tumor spreading and T cell suppression.
Asporin (ASPN), a small leucine‐rich proteoglycan expressed predominantly by cancer associated fibroblasts (CAFs), plays a pivotal role in tumor progression. ASPN is also expressed by some cancer cells, but its biological significance is unclear. Here, we investigated the effects of ASPN expression in gastric cancer cells. Overexpression of ASPN in 2 gastric cancer cell lines, HSC‐43 and 44As3, led to increased migration and invasion capacity, accompanied by induction of CD44 expression and activation of Rac1 and MMP9. ASPN expression increased resistance of HSC‐43 cells to oxidative stress by reducing the amount of mitochondrial reactive oxygen species. ASPN induced expression of the transcription factor HIF1α and upregulated lactate dehydrogenase A (LDHA) and PDH‐E1α, suggesting that ASPN reprograms HSC‐43 cells to undergo anaerobic glycolysis and suppresses ROS generation in mitochondria, which has been observed in another cell line HSC‐44PE. By contrast, 44As3 cells expressed high levels of HIF1α in response to oxidant stress and escaped apoptosis regardless of ASPN expression. Examination of xenografts in the gastric wall of ASPN–/– mice revealed that growth of HSC‐43 tumors with increased micro blood vessel density was significantly accelerated by ASPN; however, ASPN increased the invasion depth of both HSC‐43 and 44As3 tumors. These results suggest that ASPN has 2 distinct effects on cancer cells: HIF1α‐mediated resistance to oxidative stress via reprogramming of glucose metabolism, and activation of CD44‐Rac1 and MMP9 to promote cell migration and invasion. Therefore, ASPN may be a new therapeutic target in tumor fibroblasts and cancer cells in some gastric carcinomas.
According to the amyloid hypothesis, amyloid β accumulates in brains with Alzheimer’s disease (AD) and triggers cell death and memory deficit. Previously, we developed a rice Aβ vaccine expressing Aβ, which reduced brain Aβ levels in the Tg2576 mouse model of familial AD. We used senescence-accelerated SAMP8 mice as a model of sporadic AD and investigated the relationship between Aβ and oxidative stress. Insoluble Aβ and 4-hydroxynonenal (4-HNE) levels tended to be reduced in SAMP8 mice-fed the rice Aβ vaccine. We attempted to clarify the relationship between oxidative stress and Aβ in vitro. Addition of Aβ peptide to the culture medium resulted in an increase in 4-HNE levels in SH-SY5Y cells. Tg2576 mice, which express large amounts of Aβ in their brain, also exhibited increased 4-HNE levels; this increase was inhibited by the Aβ vaccine. These results indicate that Aβ induces oxidative stress in cultured cells and in the mouse brain.
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