Chemotherapy combined with or without targeted therapy is the fundamental treatment for metastatic colorectal cancer (mCRC). Due to the adverse effects of chemotherapeutic drugs and the biological characteristics of the tumor cells, it is difficult to make breakthroughs in traditional strategies. The immune checkpoint blockades (ICB) therapy has made significant progress in the treatment of advanced malignant tumors, and patients who benefit from this therapy may obtain a long-lasting response. Unfortunately, immunotherapy is only effective in a limited number of patients with microsatellite instability—high (MSI-H), and segment initial responders can subsequently develop acquired resistance. From September 4, 2014, the first anti-PD-1/PD-L1 drug Pembrolizumab was approved by the FDA for the second-line treatment of advanced malignant melanoma. Subsequently, it was approved for mCRC second-line treatment in 2017. Immunotherapy has rapidly developed in the past 7 years. The in-depth research of the ICB treatment indicated that the mechanism of colorectal cancer immune-resistance has become gradually clear, and new predictive biomarkers are constantly emerging. Clinical trials examining the effect of immune checkpoints are actively carried out, in order to produce long-lasting effects for mCRC patients. This review summarizes the treatment strategies for mCRC patients, discusses the mechanism and application of ICB in mCRC treatment, outlines the potential markers of the ICB efficacy, lists the key results of the clinical trials, and collects the recent basic research results, in order to provide a theoretical basis and practical direction for immunotherapy strategies.
COMP may be a novel prognostic indicator and biomarker and also a potential therapeutic target for colon cancer.
The results of a cDNA array revealed that protocadherin gamma subfamily A, 9 (PCDHGA9) was significantly decreased in SGC-7901 gastric cancer (GC) cells compared with GES-1 normal gastric cells and was strongly associated with the Wnt/β-catenin and transforming growth factor-β (TGF-β)/Smad2/3 signaling pathway. As a member of the cadherin family, PCDHGA9 functions in both cell–cell adhesion and nuclear signaling. However, its role in tumorigenicity or metastasis has not been reported. In the present study, we found that PCDHGA9 was decreased in GC tissues compared with corresponding normal mucosae and its expression was correlated with the GC TNM stage, the UICC stage, differentiation, relapse, and metastasis (p < 0.01). Multivariate Cox analysis revealed that PCDHGA9 was an independent prognostic indicator for overall survival (OS) and disease-free survival (DFS) (p < 0.01). The effects of PCDHGA9 on GC tumor growth and metastasis were examined both in vivo and in vitro. PCDHGA9 knockdown promoted GC cell proliferation, migration, and invasion, whereas PCDHGA9 overexpression inhibited GC tumor growth and metastasis but induced apoptosis, autophagy, and G1 cell cycle arrest. Furthermore, PCDHGA9 suppressed epithelial–mesenchymal transition (EMT) induced by TGF-β, decreased the phosphorylation of Smad2/3, and inhibited the nuclear translocation of pSmad2/3. Our results suggest that PCDHGA9 might interact with β-catenin to prevent β-catenin from dissociating in the cytoplasm and translocating to the nucleus. Moreover, PCDHGA9 overexpression restrained cell proliferation and reduced the nuclear β-catenin, an indicator of Wnt/β-catenin pathway activation, suggesting that PCDHGA9 negatively regulates Wnt signaling. Together, these data indicate that PCDHGA9 acts as a tumor suppressor with anti-proliferative activity and anti-invasive ability, and the reduction of PCDHGA9 could serve as an independent prognostic biomarker in GC.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.