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  • Cell migration and invasion are central


    Cell migration and invasion are central processes in the development and metastasis of cancer. The regulation of cell migration by DDR1 has been reported in many types of cancer cell lines; however, conflicting results have been reported regarding the inhibitory as well as promotive effects of DDR1 in cell migration [31], [32], [33], [34]. Cancer invasion is a process that requires protease-mediated degradation of the stroma and tissue remodeling. Reports from various laboratories using Matrigel as a matrix barrier suggest that DDR1 promotes the invasion of various human cancer cell lines [11], [35], [36]. We also showed that DDR1 is required for the invasion of GC influenza m2 protein using a Matrigel invasion assay. The upregulation of matrix metalloproteinase (MMP) activity has been reported to accelerate the proinvasive activity of DDR1, and most ECM and basement membrane components can be degraded by MMP-2 and MMP-9 [11], [30], [36]. Consistent with other reports, DDR1-silenced GC cells exhibited significantly inhibited migration and invasion activities compared to control cells in the present study. In an orthotopic transplantation model, we found that the mean microvascular area was significantly lower in DDR1-silenced tumors than in controls. These findings suggest that DDR1 plays an important role in the angiogenic activity of tumor progression. The majority of the DDR1-silenced tumors consisted of necrotic tissue, and proliferating cells were detected only in the peripheries of the tumors. We speculated that tumor center necrosis was due to the absence of angiogenesis and that the peripheries of tumors were maintained by surrounding normal tissue. In contrast, angiogenic activity was sufficient to maintain control tumors. Little has been reported on the relationship between DDR1 and angiogenesis. Song et al. reported that conditioned medium from DDR1-overexpressing renal cell cancer cells significantly increased the number of tubular structures according to a tube formation assay [37]. Interestingly, DDR1 silencing significantly suppressed the expression of VEGF-A, VEGF-C, and PDGF-B, which are important angiogenic and lymph-angiogenic regulators in GC [38], [39]. Therefore, DDR1 silencing seems to concurrently inhibit several steps of the metastasis cascade, such as angiogenesis, migration, and invasion. Recently, DDR1 has been reported to be capable of inducing multiorgan site metastatic reactivation in breast cancer via noncanonical DDR1 signaling [40]. Consistent with this report, DDR1-silenced GC cells were almost completely suppressed in our liver metastatic model. We found that DDR1-silenced micrometastatic foci did not grow, and the mean microvessel area was significantly reduced compared to that of controls. These results suggest that DDR1 could be used as a novel target for preventing liver metastasis, especially if GC is detected at an early stage of progression. DDR1 is also known to mediate cell adhesion to collagen. The overexpression of DDR1 promotes cell adhesion to collagen in several cancer cells, such as leukocytes, glioma cells, and pituitary adenoma cells [41], [42], whereas DDR1 knockout in smooth muscle cells reduced adhesion to collagen [43]. These findings support the notion that DDR1 expression in cancer cells could facilitate colonization at distant organs during the metastatic process. However, the precise molecular mechanisms underlying these processes are not clearly understood, and further investigation is required. The following are the supplementary data related to this article.
    Introduction Idiopathic pulmonary fibrosis (IPF) is a deadly interstitial lung disease involving chronic and progressive alveolar fibrosis and/or diffuse pulmonary fibrosis [[1], [2], [3]]. The incidence of IPF has continued to increase in recent years, partly because of persistent air pollution, haze, and smoking [4]. Most IPF finally progress to lethal respiratory failure within five years of diagnosis, with the average survival time of an IPF patient being only three to five years [[5], [6], [7]]. Although the etiology and pathogenesis of IPF remains unclear, there exists sufficient evidence that immune damage and inflammation can contribute to the occurrence and progress of IPF [[8], [9], [10]]. Therefore, the development of novel effective therapies against IPF remain in urgent demand. The pulmonary specimens showed varied features of fibrotic foci, and the peripheral blood analysis reflected more prominent immune abnormalities, while bronchoalveolar lavage fluid (BALF) showed enhanced inflammatory response in IPF patients. [[11], [12], [13]] It is generally believed that alveolar epithelial cell injury and abnormal wound healing can induce the main mechanism of IPF. After injury occurs, the normal process of re-epithelization cannot be completed during the repair process, leading to alveolar-capillary damage [14,15]. IPF is accompanied by fibrotic remodeling of alveolar architecture, the proliferation of atypical epithelial cells, and fibroblasts expressing cytokine characteristics of submucosal glands and/or proximal airways [16].