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  • Two in vitro reports using lung fibroblasts have shown that

    2019-08-13

    Two in vitro reports using lung fibroblasts have shown that cell transmigration, using transwell migration experiments, through collagen I-coated inserts is mediated by DDR2 and the DDR2-associated signaling kinases JAK2 and ERK1/2, but not DDR1 [63] and that DDR2 regulates the adhesion of fibroblasts to 3D collagen matrices [64]. DDR1 has also been shown to be expressed in bronchial epithelium [3]. In vitro knockdown of DDR1 slows bronchial epithelial repair by 50%, which was associated with a reduction in levels of MMP-7. DDR1 knockdown also reduces human bronchial epithelial cell proliferation, but has no significant effects on adhesion to type I collagen or other matrix substrates [65]. More recently, upregulated DDR1 expression was observed in single cell sequencing of bronchial epithelial niclosamide of idiopathic pulmonary fibrosis (IPF) patients by Tao et al. [57] and DDR1 inhibition using CQ-061 (a small-molecule DDR1 inhibitor of undisclosed selectivity) was shown to have antifibrotic and anti-inflammation effects in BLM-induced IPF murine models.
    DDR1 role in liver Little is known about the expression and role of DDR1 in liver. Expression of DDR1 in liver is lower than in brain, kidney, lung or even heart [47]. In normal liver, in situ hybridization and immunofluorescence detects DDR1 mRNA and protein expression in epithelial cells, hepatocytes at the portal-parenchymal interface, the luminal part of biliary epithelium, and bile niclosamide duct epithelial cells [66]. Increased DDR1 expression has been reported in hepatocytes and bile duct epithelial cells of cirrhotic liver [66]. In contrast, hepatic stellate cells (fibroblasts localized in the Disse space of the liver) or portal fibroblasts in normal liver, or myofibroblasts (activated hepatic stellate cells or activated portal fibroblasts) in cirrhotic liver do not express DDR1. Overexpression of DDR1a, one of the five DDR1 isoforms generated by alternative splicing, alters hepatocyte behavior including increased adhesion and reduced migration on ECM substrates. In addition, DDR1a regulates extracellular expression of MMP-1 and -2 [66]. However, even if pro-fibrotic and pro-inflammatory roles for DDR1 are true, the biological significance of increased DDR1 expression in liver fibrosis is largely unknown [16]. The same group later demonstrated that loss of DDR2 promotes chronic liver fibrosis after CCl4 injury through altered paracrine interactions between hepatic stellate cells and Kupffer cells (liver-associated macrophages) [67].
    DDR1 in stromal reaction in cancer Though not the topic of this review, we briefly wanted to mention the role of DDR1 in cancer and specifically in the stromal reaction (i.e., new matrix formation occurring in the presence of cancer resulting from activation of resident stromal cells). Stromal reaction shares characteristic biologic and pathophysiologic traits with organ fibrosis and wound healing processes [68]. In the cancer setting, DDR1 has been shown to be uniquely expressed by normal and tumoral epithelial cells [18,69] with high levels of DDR1 observed in fast growing invasive mammary, ovarian, and lung tumors [18]. Interestingly, in cholangiocarcinoma, DDR1 is expressed in proliferating tumoral epithelial cells but not in myofibroblasts present in the surrounding stromal reaction [69]. Some studies have demonstrated that DDR1 overexpression increased tumorigenesis and was correlated with a bad prognosis [18]. More recently, Takai et al., suggest that the absence of DDR1 provides a growth and adhesion advantage that favors the expansion of basal cells, potentiates fibrosis, and enhances necrosis/hypoxia and basal differentiation of transformed cells to increase their aggression and metastatic potential [70]. At the same time, a recent study also established a causal relationship between stromal DDR1 expression and cancer progression, underlining the role of stromal DDR1 in breast tumor growth [71]. Thus, the actions of DDR1 in cancer are complex, either promoting or suppressing tumor cell behavior and definitively, additional studies are necessary to carefully assess the role of DDR1 in stromal reaction in cancer.