Discoidin domain receptors (DDR), including DDR1 and DDR2, are special types of the transmembrane receptor tyrosine kinase superfamily. DDR are activated by binding to the triple‐helical collagen and, in turn, DDR can activate signal transduction pathways that regulate cell‐collagen interactions involved in multiple physiological and pathological processes such as cell proliferation, migration, apoptosis, and cytokine secretion. Recently, DDR have been found to contribute to various diseases, including cancer. In addition, aberrant expressions of DDR have been reported in various human cancers, which indicates that DDR1 and DDR2 could be new targets for cancer treatment. Considerable effort has been made to design DDR inhibitors and several molecules have shown therapeutic effects in pre–clinical models. In this article, we review the recent literature on the role of DDR in cancer progression, the development status of DDR inhibitors, and the clinical potential of targeting DDR in cancer therapies.
Immunotherapies represented by programmed cell death protein 1/programmed cell death ligand 1 (PD‐1/PD‐L1) immune checkpoint inhibitors have made great progress in the field of anticancer treatment, but most colorectal cancer patients do not benefit from immunotherapy. Discoidin domain receptor 1 (DDR1), a tyrosine kinase receptor, is activated by collagen binding and overexpressed in various malignancies. However, the role of DDR1 in colorectal cancer and immunoregulation remains unclear. In this study, we found DDR1 is highly expressed in colorectal cancer tissues and negatively associated with patient survival. We demonstrated that DDR1 promotes colorectal tumor growth only in vivo. Mechanistically, DDR1 is a negative immunomodulator in colorectal cancer and is involved in low infiltration of CD4+ and CD8+ T cells by inhibiting IL‐18 synthesis. We also reported that DDR1 enhances the expression of PD‐L1 through activating the c‐Jun amino terminal kinase (JNK) signaling pathway. In conclusion, our findings elucidate the immunosuppressive role of DDR1 in colorectal cancer, which may represent a novel target to enhance the efficacy of immunotherapy in colorectal cancer.
Main observation and conclusion
Four previously undescribed ent‐abietane diterpenoids (1—4), along with eleven known analogues (5—15), were isolated from the roots of wild Euphorbia fischeriana. Their gross structures were determined via extensive spectroscopic data, and the absolute configurations were elucidated by means of single‐crystal X‐ray diffraction analysis, Rh2(OCOCF3)4‐induced CD spectrum and ECD calculations. Their cervical carcinoma inhibition activities counteract HeLa cells were screened by MTT assay, and the structure‐activity relationships were further examined. The results demonstrated that 2 (IC50 value at 3.75 μmol/L) was more potent than cisplatin. The underlying mechanism study revealed that 2 could distinctly induce apoptosis accompanied by increasing reactive oxygen species (ROS) production, Ca2+ influx and decreasing mitochondrial membrane potential. Furthermore, signal pathways including MAPKs/AKT might play a significant role in 2‐induced cervical cancer cells death.
Background
The incidence and mortality rate of gastrointestinal cancers are high worldwide. Increasing studies have illustrated that the occurrence, progression, metastasis and prognosis of cancers are intimately linked to the immune system. Mitochondria, as the main source of cellular energy, play an important role in maintaining the physiological function of immune cells. However, the relationship between mitochondrial function of immune cells and tumorigenesis has not yet been systematically investigated.
Methods
A total of 150 cases, including 60 healthy donors and 90 primary gastrointestinal cancer patients without anti-tumor treatments (30 with gastric cancer, 30 with liver cancer and 30 with colorectal cancer) were involved in our study. The oxidant/antioxidant and cytokine levels in plasma, the ROS level, mitochondrial function and apoptosis ratio of peripheral blood mononuclear cells (PBMCs) were evaluated.
Results
The imbalance between oxidant and antioxidant in plasma was discovered in the primary gastrointestinal cancer patients. The levels of cell reactive oxygen species (ROS) and mitochondrial ROS in PBMCs of primary gastrointestinal cancers were significantly increased compared with that in healthy donors. Meanwhile, the ATP content, the mtDNA copy number and the mitochondrial membrane potential (MMP) in PBMCs of patients with primary gastrointestinal cancers were lower than those in control group. The decreased MMP also occurred in immune cells of gastrointestinal cancers, including T cell, B cell, NK cell and monocyte. Furthermore, the PBMCs apoptosis ratio of primary gastrointestinal cancer patients was significantly higher than that of control group. Importantly, an increase of IL-2 and IL-6 and a decrease of IgG in plasma were found in the patients with primary gastrointestinal cancers. These changes of mitochondrial function in immune cells were consistent among primary gastrointestinal cancers without anti-tumor treatments, such as liver cancer, gastric cancer and colorectal cancer.
Conclusion
Our study demonstrated that the imbalance of oxidation/antioxidation in primary gastrointestinal cancer patients without anti-tumor treatments results in excessive ROS. The oxidative stress was associated to the mitochondrial dysfunction, the apoptosis of immune cells and eventually the abnormal immune function in primary gastrointestinal cancers. The application of immune cell mitochondrial dysfunction into clinical evaluation is anticipated.
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