The Niche Component Periostin Is Produced by Cancer-Associated Fibroblasts, Supporting Growth of Gastric Cancer through ERK Activation

Abstract

Overexpression of periostin (POSTN), an extracellular matrix protein, has been observed in several cancers. We investigated the importance of POSTN in gastric cancer. Genome-wide gene expression analysis using publicly available microarray data sets revealed significantly high POSTN expression in cancer tissues from stage II-IV gastric cancer, compared with background normal tissues. The POSTN/vimentin mRNA expression ratio was highly associated with gene groups that regulate the cell cycle and cell proliferation. IHC showed that periglandular POSTN deposition, comprising linear deposition abutting the glandular epithelial cells in normal mucosa, disappeared during intestinal gastric cancer progression. Stromal POSTN deposition was also detected at the invasive front of intestinal-type and diffuse-type cancers. In situ hybridization confirmed POSTN mRNA in cancer-associated fibroblasts, but not in tumor cells themselves. POSTN enhanced the in vitro growth of OCUM-2MLN and OCUM-12 diffuse-type gastric cancer cell lines, accompanied by the activation of ERK. Furthermore, coinoculation of gastric cancer cells with POSTN-expressing NIH3T3 mouse fibroblast cells facilitated tumor formation. The OCUM-2MLN orthotopic inoculation model demonstrated that tumors of the gastric wall in Postn(-/-) mice were significantly smaller than those in wild-type mice. Ki-67 and p-ERK positive rates were both lower in Postn(-/-) mice. These findings suggest that POSTN produced by cancer-associated fibroblasts constitutes a growth-supportive microenvironment for gastric cancer.

Mechanisms of peritoneal dissemination in gastric cancer (Review)

“…Additionally, it may be possible to predict, prevent and treat peritoneal metastasis by targeting these molecules. Previous studies have primarily focused on the characteristics of malignant cancer cells, but an increasing number of studies have focused on the tumour microenvironment, particularly milky spots and the tumour stroma (54,64). Milky spots are specific sites for peritoneal metastasis and numerous studies have demonstrated that milky spots are the first metastasis location for free cancer cells.…”

“…Periostin (POSTN), produced by fibroblasts, participates in the adhesion and migration of epithelial cells (66). Kikuchi et al (64) reported that POSTN is secreted by CAFs and enhances the proliferation of gastric cancer cells via the activation of ERK. In vivo investigation has further demonstrated that co-inoculation of gastric cancer cells with fibroblasts expressing POSTN facilitates tumour formation (64).…”

“…Kikuchi et al (64) reported that POSTN is secreted by CAFs and enhances the proliferation of gastric cancer cells via the activation of ERK. In vivo investigation has further demonstrated that co-inoculation of gastric cancer cells with fibroblasts expressing POSTN facilitates tumour formation (64). The ECM proteins secreted by CAFs provide an optimal microenvironment for gastric cancer.…”

“…HGF enhances the proliferation and migration of gastric cancer cells via paracrine signalling (62). A number of ECM proteins secreted from CAFs also have a role in the promotion of gastric cancer, including asporin and periostin (63,64). Asporin belongs to a family of small leucine-rich proteoglycans and is a primary non-collagen component of ECM (65).…”

The role of periostin in neoplastic processes

“…Increased expression of POSTN has been observed in various tumor types, including breast [44,48,[56][57][58], NSCLC [27,49,[59][60][61][62], colorectal [19,29,63], stomach cancers [64][65][66][67][68], pancreatic [32,69], prostate [70][71][72][73][74][75], ovarian cancer [76][77][78][79], and glioblastomas [80][81][82] (Table 1).…”