Asporin activates coordinated invasion of scirrhous gastric cancer and cancer-associated fibroblasts.
Scirrhous gastric cancer, which has the worst prognosis among the various types of gastric cancer, is highly invasive and associated with abundant stromal fibroblasts. Although cancer-associated fibroblasts (CAFs) have been proposed to generate a tumor-supportive extracellular matrix that promotes the expansion of this type of cancer, the molecular mechanisms by which CAFs assist cancer cells are not yet fully understood. Here, we show for the first time that Asporin, a small leucine-rich proteoglycan (SLRP), is predominantly expressed in CAFs, and has essential roles in promoting co-invasion of CAFs and cancer cells. CAFs of scirrhous gastric cancer possess high potential for invasion, and invasion by CAFs frequently proceeded invasion by cancer cells, both in vitro and in vivo. Expression of Asporin was induced in fibroblasts by exposure to gastric cancer cells. Asporin secreted from CAFs activates Rac1 via an interaction with CD44 and promotes invasion by CAFs themselves. Moreover, Asporin promoted invasion by neighboring cancer cells, via paracrine effects mediated by activation of the CD44-Rac1 pathway. These results suggest that Asporin is a unique SLRP that promotes progression of scirrhous gastric cancer and is required for coordinated invasion by CAFs and cancer cells. Therefore, Asporin may represent a new therapeutic target molecule for the development of drugs aimed at manipulating the cancer microenvironment.
Department of Molecular Medicine and Biochemistry, Akita University Graduate School of Medicine, Akita, Japan.
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Satoyoshi
Department of Molecular Medicine and Biochemistry, Akita University Graduate School of Medicine, Akita, Japan.
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Kuriyama
Department of Molecular Medicine and Biochemistry, Akita University Graduate School of Medicine, Akita, Japan.
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Aiba
Department of Surgical Oncology, Osaka City University Graduate School of Medicine, Abeno-ku, Osaka, Japan.
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Yashiro
Department of Molecular Medicine and Biochemistry, Akita University Graduate School of Medicine, Akita, Japan.
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Tanaka
D002293:Adenocarcinoma, Scirrhous / Q000235:genetics* / Q000473:pathology; D000818:Animals; D018920:Coculture Techniques; D005109:Extracellular Matrix / Q000235:genetics; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis* / Q000235:genetics; D005347:Fibroblasts / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D051379:Mice; D009361:Neoplasm Invasiveness / Q000235:genetics*; D019899:Paracrine Communication / Q000235:genetics; D013274:Stomach Neoplasms / Q000235:genetics* / Q000473:pathology; D059016:Tumor Microenvironment / Q000235:genetics; D023041:Xenograft Model Antitumor Assays; D020830:rac1 GTP-Binding Protein
C439889:ASPN protein, human; C497483:CD44 protein, human; D016326:Extracellular Matrix Proteins; D018960:Hyaluronan Receptors; C107953:RAC1 protein, human; D020830:rac1 GTP-Binding Protein