Connective tissue growth factor inhibits gastric cancer peritoneal metastasis by blocking integrin α3β1-dependent adhesion

Chen, Chiung-Nien; Chang, Cheng-Chi; Lai, Hong‐Shiee; Jeng, Yung‐Ming; Chen, Chia-I; Chang, King‐Jen; Lee, Po‐Huang; Lee, Hsinyu

doi:10.1007/s10120-014-0400-0

Cited by 27 publications

(15 citation statements)

References 36 publications

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“…Furthermore, a recent study reported that CXCL12/CXCR4 signaling upregulated the expression of an integrin at the transcriptional level . Many studies have reported that integrin β1 strongly contributes to invasion and metastasis in cancer cells, including GC cells . The ligands of integrin β1 include not only fibronectin but also laminin and type IV collagen, which are components of Matrigel .…”

Section: Discussionmentioning

confidence: 99%

“…43 Many studies have reported that integrin b1 strongly contributes to invasion and metastasis in cancer cells, including GC cells. 21,[44][45][46] The ligands of integrin b1 include not only fibronectin but also laminin and type IV collagen, which are components of Matrigel. 30,31,47 In our study, although GC cell migration was not significantly affected when the cells were co-cultured with fibroblasts on normal dishes (data not shown), both invasiveness and motility of the cells were significantly enhanced when they were plated on Matrigel, as demonstrated by the invasion and migration assays that were performed on Matrigel-coated dishes.…”

Section: Discussionmentioning

confidence: 99%

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CXCL12/CXCR4 activation by cancer‐associated fibroblasts promotes integrin β1 clustering and invasiveness in gastric cancer

Izumi

Ishimoto

Miyake

et al. 2015

Intl Journal of Cancer

142

102

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Cancer-associated fibroblasts (CAFs) are reportedly involved in invasion and metastasis in several types of cancer, including gastric cancer (GC), through the stimulation of CXCL12/CXCR4 signaling. However, the mechanisms underlying these tumorpromoting effects are not well understood, which limits the potential to develop therapeutic targets against CAF-mediated CXCL12/CXCR4 signaling. CXCL12 expression was analyzed in resected GC tissues from 110 patients by immunohistochemistry (IHC). We established primary cultures of normal fibroblasts (NFs) and CAFs from the GC tissues and examined the functional differences between these primary fibroblasts using co-culture assays with GC cell lines. We evaluated the efficacy of a CXCR4 antagonist (AMD3100) and a FAK inhibitor (PF-573,228) on the invasive ability of GC cells. High CXCL12 expression levels were significantly associated with larger tumor size, increased tumor depth, lymphatic invasion and poor prognosis in GC. CXCL12/CXCR4 activation by CAFs mediated integrin b1 clustering at the cell surface and promoted the invasive ability of GC cells. Notably, AMD3100 was more efficient than PF-573,228 at inhibiting GC cell invasion through the suppression of integrin b1/FAK signaling. These results suggest that CXCL12 derived from CAFs promotes GC cell invasion by enhancing the clustering of integrin b1 in GC cells, resulting in GC progression. Taken together, the inhibition of CXCL12/CXCR4 signaling in GC cells may be a promising therapeutic strategy against GC cell invasion.Gastric cancer (GC) is the fourth most commonly diagnosed cancer and the third leading cause of cancer mortality worldwide. 1,2 The range of therapeutic strategies available for the treatment of GC has improved in recent decades. However, the prognosis of patients with advanced GC remains poor even after curative resection, mainly because of recurrence, such as peritoneal dissemination and liver metastases. The development of new molecular targets may improve the prognostic predictability and prognosis of GC.Solid tumors, including GC, consist of cancer cells and various types of stromal cells; thus, tumor progression is not only determined by the cancer cells themselves but also by the tumor stroma. Previous studies have shown that the interaction between cancer cells and their surrounding

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

CXCL12/CXCR4 activation by cancer‐associated fibroblasts promotes integrin β1 clustering and invasiveness in gastric cancer

Izumi

Ishimoto

Miyake

et al. 2015

Intl Journal of Cancer

142

102

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“…Connective tissue growth factor (CTGF) has been reported to be involved in peritoneal metastasis and gastric cancer progression [ 114 ]. High expression of CTGF, as well as treatment with the recombinant protein considerably reduced cell adhesion [ 115 ]. CTGF enduring transfectants displayed a lower number and size of tumor nodules in the mesentery, during in vivo peritoneal metastasis.…”

Section: Factors That Influence High Progression Of Gastric Cancementioning

confidence: 99%

The Pattern of Signatures in Gastric Cancer Prognosis

Machlowska

Maciejewski

Sitarz

2018

IJMS

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Gastric cancer is one of the most common malignancies worldwide and it is a fourth leading cause of cancer-related death. Carcinogenesis is a multistage disease process specified by the gradual procurement of mutations and epigenetic alterations in the expression of different genes, which finally lead to the occurrence of a malignancy. These genes have diversified roles regarding cancer development. Intracellular pathways are assigned to the expression of different genes, signal transduction, cell-cycle supervision, genomic stability, DNA repair, and cell-fate destination, like apoptosis, senescence. Extracellular pathways embrace tumour invasion, metastasis, angiogenesis. Altered expression patterns, leading the different clinical responses. This review highlights the list of molecular biomarkers that can be used for prognostic purposes and provide information on the likely outcome of the cancer disease in an untreated individual.

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“…The molecular mechanisms that mediate the tumor-mesothelium interaction during the mesenchymal conversion of MCs would require further analysis. However, a growing body of experimental evidence on adhesion concurs that, at initial stages of peritoneal metastasis, MMT enhances the binding of cancer cells on the peritoneum in a β1-integrin-dependent manner [ 9 , 98 , 99 ]. In agreement with this notion, it has been reported that cleavage of MC-associated matrix proteins fibronectin and vitronectin by MMP-2 enhances integrin-mediated carcinoma-mesothelium attachment [ 100 , 101 ].…”

Section: Implication Of Mesothelial-derived Carcinoma-associated Fmentioning

confidence: 99%

The Mesothelial Origin of Carcinoma Associated-Fibroblasts in Peritoneal Metastasis

Rynne-Vidal¹,

Jiménez‐Heffernan²,

Fernández-Chacón³

et al. 2015

Cancers

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Solid tumors are complex and unstructured organs that, in addition to cancer cells, also contain other cell types. Carcinoma-associated fibroblasts (CAFs) represent an important population in the tumor microenviroment and participate in several stages of tumor progression, including cancer cell migration/invasion and metastasis. During peritoneal metastasis, cancer cells detach from the primary tumor, such as ovarian or gastrointestinal, disseminate through the peritoneal fluid and colonize the peritoneum. Tumor cells metastasize by attaching to and invading through the mesothelial cell (MC) monolayer that lines the peritoneal cavity, then colonizing the submesothelial compact zone where CAFs accumulate. CAFs may derive from different sources depending on the surrounding metastatic niche. In peritoneal metastasis, a sizeable subpopulation of CAFs originates from MCs through a mesothelial-to-mesenchymal transition (MMT), which promotes adhesion, invasion, vascularization and subsequent tumor growth. The bidirectional communication between cancer cells and MC-derived CAFs via secretion of a wide range of cytokines, growth factors and extracellular matrix components seems to be crucial for the establishment and progression of the metastasis in the peritoneum. This manuscript provides a comprehensive review of novel advances in understanding how peritoneal CAFs provide cancer cells with a supportive microenvironment, as well as the development of future therapeutic approaches by interfering with the MMT in the peritoneum.

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Connective tissue growth factor inhibits gastric cancer peritoneal metastasis by blocking integrin α3β1-dependent adhesion

Cited by 27 publications

References 36 publications

CXCL12/CXCR4 activation by cancer‐associated fibroblasts promotes integrin β1 clustering and invasiveness in gastric cancer

CXCL12/CXCR4 activation by cancer‐associated fibroblasts promotes integrin β1 clustering and invasiveness in gastric cancer

The Pattern of Signatures in Gastric Cancer Prognosis

The Mesothelial Origin of Carcinoma Associated-Fibroblasts in Peritoneal Metastasis

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