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The Precision Medicine Approach in Oncology
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
In a study published in 2015, researchers reported the discovery of the serum-based proteins, AGR2 and AGR3, which have potential use in the early detection of breast cancer and as prognostic biomarkers. Both proteins were detected by an ELISA technique, and their concentrations were found to be significantly elevated in blood from breast cancer patients compared to age-matched serum samples from healthy women. AGR3 is a member of the protein disulfide isomerase (PDI)-related family of proteins which, in breast disease, was shown to be up-regulated in luminal compared with triple-negative breast cancer. It was also shown to have potential prognostic relevance in Grade 1 and 2 breast tumors. However, although diagnostic performance tests for AGR3 were found to result in high specificity, sensitivity toward breast cancer tissues was very low. Therefore, although promising, further validation steps are required using independent serum collections to strengthen the robustness of the AGR2/AGR3 biomarker test.
Secreted effectors of the innate mucosal barrier
Published in Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald, Principles of Mucosal Immunology, 2020
Michael A. McGuckin, Andre J. Ouellette, Gary D. Wu
Genetic defects in secretory cell pathology may become apparent under specific environmental conditions. For example, the Paneth cell phenotype in Atg16l1 hypomorphic mice is codependent on the genetic defect and infection by a particular strain of murine norovirus. Also, severe disruption of the unfolded protein response by deletion of Xbp1 in epithelial cells induces massive Paneth cell apoptosis and fulminant ileitis. Germline and inducible gene deletions of Agr2 result in goblet cell Muc2 deficiency, expansion of the Paneth cell compartment, and accumulation of intermediate cells (discussed earlier). Severe terminal ileitis and colitis are associated with ER stress induced by loss of Agr2. Thus, a diversity of genetic defects can disrupt Paneth cell function in mice, resulting in chronic ileitis that mimics adult human disease. When autophagy in Paneth cells is fully functional, ER stress-induced chronic inflammation of the intestine is averted, perhaps by restraining cytosolic IRE1α activity and NF-κB activation. Under normal conditions, autophagy controls Paneth cell unfolded protein responses (UPRs) to maintain homeostasis. However, when hypomorphisms in one or more autophagy components combine with environmental factors such as the microbiota or infectious agents, the UPR becomes chronically active in Paneth cells, thereby inducing enteric inflammation. In humans, familial and sporadic interstitial lung disease has been linked to misfolding mutations in the SFTPC gene that encodes the SP-C surfactant protein produced by lung epithelial cells. Interestingly, viral infection appears to precipitate the emergence of the phenotype in this disease, possibly through increased SP-C production and ER stress.
Quantitative proteomic analysis to the first commercialized liposomal paclitaxel nano-platform Lipusu revealed the molecular mechanism of the enhanced anti-tumor effect
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2018
Minzhi Zhao, Haiyun Li, Linyang Fan, Yan Ma, He Gong, Wenjia Lai, Qiaojun Fang, Zhiyuan Hu
AGR2 is expressed by the normal intestine and by most human adenocarcinomas, including those derived from the esophagus, pancreas, lung, breast, ovary, and prostate. It was previously demonstrated that AGR2 supported tumor growth and cellular transformation [19]. It is a normal endoplasmic reticulum protein that has the important abnormal functions of human cancer metastasis promotion. It was also reported that AGR2 could promote cell adhesion [20]. It was implicated in stimulation of cell proliferation, anti-apoptosis and cell cycle regulation [21]. The cell adhesion and anti-apoptosis functions were also verified in our results (Figures 5 and 6). With a less expressed level of AGR2, lip induced a higher adhesion than PTX. Meanwhile, the flow cytometry analysis combined the expression of cleaved caspase-3 suggested an enhanced apoptosis situation of lip-treated cells compared with PTX.
Characterising acquired resistance to erlotinib in non-small cell lung cancer patients
Published in Expert Review of Respiratory Medicine, 2019
Niki Karachaliou, Jordi Codony-Servat, Jillian Wilhelmina Paulina Bracht, Masaoki Ito, Martyna Filipska, Carlos Pedraz, Imane Chaib, Jordi Bertran-Alamillo, Andres Felipe Cardona, Miguel Angel Molina, Rafael Rosell
AGR2 encodes an endoplasmic reticulum (ER) resident protein and enhanced intracellular AGR2 expression is observed in many cancers. Epithelial tumors secrete the ER-resident AGR2 in the extracellular matrix, and therefore screening for tumor secreted extracellular AGR2 may be relevant for the design of new therapeutic approaches [40]. Mechanistically AGR2 suppresses p53 activation through inhibition of p58 mitogen activation kinase [41]. It has been shown that ER retention motif of AGR2 activates the mammalian target of rapamycin complex (mTORC) signaling (Figure 2). In addition, the localization of AGR2 influences the Hippo signaling pathway [40]. Proteosome inhibitors, like bortezomib, significantly downregulate AGR2 and augment the efficacy of bevacizumab (Table 1) [42].