Page 57 - Read Online
P. 57

Page 6 of 15                      Sawayama et al. J Cancer Metastasis Treat 2018;4:10  I  http://dx.doi.org/10.20517/2394-4722.2017.79





























               Figure 1. The mechanisms of GC progression affected by TAMs. M2 macrophages secrete EGF or TGFB. EGF activates the AKT pathway,
               which regulates b-catenin translocation. MMP7 and CD44 are involved in macrophage-activated GC cell invasion. TAM receptors (Tyro3,
               Axl and Mertk) upregulate the expression of PD-L1. GC: gastric cancer; TAM: tumor-associated macrophage; EGF: epidermal growth factor;
               TGFB: transforming growth factor-b1; MMP: matrix metalloproteinase; PD-L1: programmed death-ligand-1; TIL: tumor-infiltrating lymphocyte
               CAFs. CAFs acquire the properties of myofibroblasts, including expression of smooth muscle alpha-
                   [60]
               actin . Formation of myofibroblasts is associated with fibrosis and increases the risk of cancer. Many other
               studies have demonstrated that fibroblasts often have a position at center stage, orchestrating and actively
                                                                                               [61]
               participating in the transformation process. They are also spectators in the tumorigenic process . Fibroblast
               activation protein-a (FAP) is a protein expressed in fibroblasts, such as CAFs, which are major components
                                                                                        [62]
               of the tumor microenvironment. FAP is potentially associated with GC patient survival .

               Recent investigations have demonstrated that interleukins, such as IL1A, IL1B, IL-6 and IL-17B, produced
               by CAFs, are associated with cancer progression and metastasis. In CAFs isolated from human diffuse-type
               GCs, inflammatory cytokines, such as IL1A, IL1B, and tumor necrosis factor (TNF), secreted by diffuse-type
               GC, induce rhomboid 5 homolog (RHBDF2) expression. RHBDF2 promotes cleavage of TGFB receptor 1
               (TGFBR1) and motility of CAFs in response to TGFB1. These highly motile CAFs induce diffuse-type GCs to
               invade the ECM and lymphatic vessels. IL1A, IL1B and TNF status is associated with shorter overall survival
                                       [63]
               of diffuse-type GC patients . IL-6 is also associated with CAFs; it has been produced by CAFs isolated
               from GC. The migration and EMT of GC cells are enhanced by CAFs through the secretion of IL-6, which
               activates JAK2/STAT3 pathway in GC cells. Inhibiting the JAK2/STAT3 pathway with a specific inhibitor
                                                                         [64]
               markedly attenuates these phenotypes in GC cells induced by CAFs . IL-17B increases the expression of
               stemness-related genes Nanog, Sox2 and Oct4 in MSCs, and the tumor promoting effect is enhanced. The
               condition medium from cultured MSCs after being treated with exogenous recombinant interleukin-17B
               (rIL-17B) promotes the proliferation and migration of GC cells. rIL-17B also activates the NF-kB, STAT3,
                                                                                             [65]
               b-catenin pathway in MSCs and the progression of GC is induced by IL-17B activating MSCs .

               miRNAs are a class of non-coding small RNA molecules, and expression of miRNAs in CAFs regulates an
               essential role in the communication between tumor cells and CAFs, as well as the expression of a number of
                         [66]
               target genes . A miRNA microarray analysis from GC revealed the different expression of miRNA between
               CAFs and normal fibroblasts (NFs). In the study, four miRNAs were increased (miRNA-34b, 301a 106b and
               93) and seven miRNAs were decreased (miRNA-483-3p, 26a, 7g, 148a, 145, 424 and 214) in CAFs compared
               with NFs. The expression of miRNA-106b is upregulated in CAFs established from patients with GC, and the
               expression level of miRNA-106b is associated with poor prognosis of GC patients. CAFs with downregulated
               miRNA-106b could significantly inhibit GC cell migration and invasion by targeting the phosphatase and
   52   53   54   55   56   57   58   59   60   61   62