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The gastrointestinal system
Published in C. Simon Herrington, Muir's Textbook of Pathology, 2020
Sharon J. White, Francis A. Carey
It has been shown that approximately 75% of GISTs show a mutation of the c-kit oncogene, and overexpress the gene product CD117 on the cell membrane. Mutations of the platelet-derived growth factor receptor a (PDGFRA) gene are seen in a further 10% of GISTs. Detection of these mutations in tumour tissue is useful in diagnosing these neoplasms. It is also of great therapeutic importance, because the tyrosine kinase-inhibiting drug imatinib acts directly to inhibit the effect of the c-kit oncogene mutation. This drug can be remarkably effective in controlling inoperable and metastatic GISTs. However, efficacy is most marked in the presence of some specific mutations (e.g. in codon 11 of c-kit) whereas other mutations in c-kit and PDGFRA are markers of drug resistance. This story is an excellent example of how understanding tumour biology can lead to the development of specific, effective, non-toxic therapy.
GIST of the Lower Gastrointestinal Tract
Published in Peter Sagar, Andrew G. Hill, Charles H. Knowles, Stefan Post, Willem A. Bemelman, Patricia L. Roberts, Susan Galandiuk, John R.T. Monson, Michael R.B. Keighley, Norman S. Williams, Keighley & Williams’ Surgery of the Anus, Rectum and Colon, 2019
Rohin Mittal, Benjamin Perakath
About 5% of all GISTs are CD117 (c-kit) negative. This number is as high as 17% in colonic GISTs and 9% in rectal GISTs.24,25 Many of these have mutations in another tyrosine receptor kinase, the platelet derived growth factor receptor alpha (PDGFRA).26,27 The mechanism of tumourogenesis in these is similar to Kit gene mutations. Again, sensitivity to treatment with Imatinib depends on the specific mutation, and has a variable spectrum from being very sensitive to very resistant.28 Specific mutational analysis is not recommended in routine clinical practice,23 and all patient are given a trial of Imatinib, if indicated.
Precision medicine for brain gliomas
Published in Debmalya Barh, Precision Medicine in Cancers and Non-Communicable Diseases, 2018
Different than classical glioblastomas, TP53 is significantly mutated in proneural glioblastomas (54%). These glioblastomas are also characterized by having the most frequent mutations in the IDH1 gene. IDH1, when mutated, codes for a protein that can contribute to abnormal cell growth (Verhaak et al., 2010). Another gene, platelet derived growth factor receptor alpha (PDGFRA), was mutated and expressed in abnormally high amounts only in the proneural glioblastomas and not in any other subgroups. When PDGFRA is altered, too much of its protein can be produced, leading to uncontrolled tumor growth (Müller et al., 2016). Unlike the other groups, whose patients were similar in age on average, the proneural subgroup was significantly younger. They also tended to survive longer. However, patients in the proneural group who received aggressive treatment did not survive significantly longer than proneural patients who did not receive aggressive treatment. This is important for precision medicine in glioblastoma and clinicians may be able to use this information in the future to avoid unnecessary treatment regimens for patients in the proneural glioblastomas (Verma et al., 2016).
The prediction value of platelet-derived growth factor for major adverse cardiovascular events in patients with acute non-ST-segment elevation myocardial infarction
Published in Annals of Medicine, 2023
Yan Liang, Jing-xian Wang, Xiao-Yuan Wu, Yan Cui, Zhong-He Zou, Wen-Qing Li, Yin Liu, Jing Gao
In recent years, great advances have been made in the understanding of the molecular biology associated with MI, leading to faster diagnosis, improved staging and timely treatment of patients [4]. Platelet-derived growth factor (PDGF), a potent mitogen and chemo-attractant for vascular smooth muscle cells (SMCs), is mainly derived from platelets, but is also exists in damaged endothelial cells, fibroblasts, macrophages and mesangial cells [5]. Matrix metalloproteinase (MMP), which is functionally related to PDGF, is involved in the degradation of extracellular matrix proteins, leading to the migration of SMCs to the intima and the rupture of plaques [6]. PDGF is inactive in monomeric form and exerts biological functions when specifically binds to its receptor (platelet-derived growth factor receptor, PDGF-R). The binding of PDGF to PDGFR can promote the replication and migration of myofibroblasts and participate in the occurrence and development of fibrotic diseases [7].
Novel therapeutic perspectives for crescentic glomerulonephritis through targeting parietal epithelial cell activation and proliferation
Published in Expert Opinion on Therapeutic Targets, 2023
Yanjie Huang, Xueru Zhao, Qiushuang Zhang, Xiaoqing Yang, Gailing Hou, Chaoqun Peng, Mengzhen Jia, Li Zhou, Tatsuo Yamamoto, Jian Zheng
Platelet-derived growth factor (PDGF) is a family of growth regulator molecules composed of a sulfide-bonded dimeric structure [76]. The PDGF family consists of four isoforms (PDGF-A, -B, -C, and -D) and two receptor chains (PDGFR-α and -β), which play essential roles in multiple biological processes, such as wound healing, fibrosis, and malignancy. PDGF-mediated cell migration is involved in signal transduction through the phosphorylation of platelet-derived growth factor receptor (PDGFR). PDGFR has tyrosine kinase activity. It can autophosphorylate after binding to its ligand and activate the Ras/MAPK signaling system that contains the Src homology 2 domain. p-ERK1/2 then catalyzes the nuclear transcription factor, cyclin D1, to initiate the transcription of targeted genes and promote cell proliferation (Figure 2) [77–80]. Immunohistochemical experiments confirmed that PDGF-D was expressed in podocytes of normal human kidneys [81]. Parietal epithelial cells have been reported to express PDGFR-β in humans, and PDGFR-β has been detected in glomerular crescents. Overexpression of PDGF-D in podocytes can induce CrGN and glomerulosclerosis [7]. Thus, it was speculated that PEC proliferation might be caused by the activation of PDGFR through podocyte-derived PDGF-D (Table 1) [76].
An updated safety review of the drug treatments for idiopathic pulmonary fibrosis
Published in Expert Opinion on Drug Safety, 2021
Giacomo Sgalla, Alessia Comes, Luca Richeldi
Nintedanib, formerly known as BIBF 1120, is a small molecule that was originally designed as an anti-angiogenic drug for cancer indications. As nintedanib competitively binds to the kinase domains of platelet-derived growth factor receptor (PDGFR)-a and ß, fibroblast growth factor receptor (FGFR)-1 and vascular endothelial growth factor receptor (VEGFR)-2, inhibiting the fibroblast proliferation, migration and differentiation, and the secretion and deposition of extracellular matrix which are considered involved in the progression of fibrosis, it was selected as a potential treatment for IPF [10]. Nintedanib has been shown to slow disease progression, reducing the FVC decline, shorten the time to first acute exacerbation and improve quality of life at 1 year [11]. Nintedanib was approved, simultaneously with pirfenidone, as a treatment for IPF by the Food and Drug Administration (FDA) in the USA in October 2014 and by EMA (European Medicines Agency) in Europe since January 2015.