Cancer-associated fibroblasts might sustain the stemness of scirrhous gastric cancer cells via transforming growth factor-β signaling

Abstract

Cancer-associated fibroblasts (CAFs) have recently been implicated in tumor growth and metastasis in gastric cancer. Cancer stem cells (CSCs) have been proposed to have an important role in cancer progression. The aim of this study was to clarify the effect of CAFs on CSCs characteristics in gastric carcinoma. Scirrhous gastric cancer cell lines, OCUM-12 and OCUM-2MD3, and non-scirrhous gastric cancer cell lines, MKN-45 and MKN-74, were used. OCUM-12=side population (SP) cells and OCUM-2MD3=SP cells were sorted by flow cytometry as CSC-rich cells from the parent cells. CaF-37 was established from the tumoral gastric specimens as CAFs. Flow cytometric analysis of SP fraction, spheroid colony assay, and RT-PCR analysis of CSC markers were performed to identify CSCs properties. Effect of CAFs on the tumorigenicity by OCUM-12=SP cells was examined using nude mice. CAF CM significantly increased the percentages of the SP fraction of OCUM-12=SP and OCUM-2MD3=SP cells, but not that of MKN-45=SP and MKN-74=SP cells. Taken together, CM from CaF-37 significantly increased the number of spheroid colonies and the expression level of CSC markers of OCUM-12=SP and OCUM-2MD3=SP cells. These stimulatingactivities by CM were significantly decreased by TGFb inhibitors, but not FGFR and cMet inhibitor. Tumorigenicity by subcutaneous coinoculation of OCUM-12=SP cells with CAFs was significantly high in comparison with that by OCUM-12=SP cells alone. Phospho-Smad2 expression level was significantly increased by co-inoculation with CAFs. These findings suggested that CAFs might regulate the stemness of CSCs in scirrhous gastric cancer by TGFb signaling.

Antitumour efficacy of the selumetinib and trametinib MEK inhibitors in a combined human airway–tumour–stroma lung cancer model

“…1F). Many studies have reported the critical role played by cancer associated fibroblasts in the metabolism of the tumour via growth factor signalling (Chen et al, 2014;Hasegawa et al, 2014).…”

Significance of the Lysyl Oxidase Members Lysyl Oxidase Like 1, 3, and 4 in Gastric Cancer

“…The role of the LOX family is widely accepted as a poor prognosis factor for patients with several kinds of cancer [5][6][7][8][9], while comparatively few papers examined tumor-suppressive roles of the LOX family in bladder and lung cancers [10,11]. It has been reported that transforming growth factor β (TGFβ) plays an important role in various aspects of the metastatic spread of cancer cells, such as migration, invasion, and epithelial-mesenchymal transition, via autocrine or paracrine manner [12][13][14][15][16]. We previously reported that LOX and LOXL2 expressions are associated with gastric cancer progression [17,18].…”

Therapeutic targets against gastric cancer stem cells interacting with tumor microenvironment

“…The influence of CAFs was significantly inhibited by TGF-b inhibitors, but not by fibroblast growth factor receptor or cMet inhibitors. These findings suggest that CAFs might promote CSC properties in scirrhous GC through TGF-b signaling [44] . IL-17B induced the expression of the self-renewal-related genes Nanog, Sox2, and Oct4 in mesenchymal stem cells and promoted tumor progression.…”