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growth factor receptor trafficking as a potential therapeutic target in pediatric cancer

Frontiers in Biology 2012年第1期7卷 1-13页

作者： Peter E. ZAGE Andrew J. BEAN Department of Pediatrics Section of Hematology-Oncology 1102 Bates Suite 1220 Houston TX 77030 USA Texas Children＇s Cancer and Hematology Centers Houston TX 77030 USA Dan L. Duncan Cancer Center Baylor College of Medicine Houston TX 77030 USA Department of Neurobiology and Anatomy The University of Texas Health Science Center at Houston Houston TX 77030 USA Division of Pediatrics The University of Texas M.D. Anderson Cancer Center Houston TX 77030 USA

growth factor receptors （GFRs） are often aberrantly expressed in tumor cells, and altered GFR expressionand activity contribute to the pathogenesis of many types of cancer. A variety of mechanisms have been identified that result in enhanced GFR expression and activity in cancer cells. Defects in the pathways responsible for GFR internalization and intraceilular trafficking are likely to be involved in altered GFR expression in a variety of cancers. The roles of GFR trafficking pathways in the regulation of GFR expression, in the pathogenesis of tumors, and in the response of tumors to treatment have not been fully delineated, but the likely contributions of GFR signaling to the development and progression of various malignancies suggest that therapies that modify GFR trafficking may be effective as anticancer treatments. The intraceHular trafficking of GFRs is regulated by a number of protein complexes and by protein ubiquitination. Many of the proteins required for this trafficking are products of tumor suppressor genes, and the expression and function of the protein machinery utilized for intracellular trafficking is frequently altered in tumor cells, consistent with the likely role of GFR trafficking in tumorigenesis. Many of the proteins involved in GFR trafficking have been identified as potential targets for anticancer treatment, and novel treatments directed against these targets are currently in preclinical development and in clinical trials. Ubiquitin ligases are critical for GFR trafficking and represent potentially important targets for the development of novel therapies. The genes for the ubiquitin ligases c-Cbl and UBE4B are located in chromosome regions commonly altered in a variety of tumors and therefore are likely to be important for tumorigenesis, c-Cbl nbiquitinates a number of GFRs and directs them for degradation. Mutations in c-Cbl have been identified in cases of myeloid leukemia and myelodysplasia, providing a link between GFR ubiquitinatio

关键词： growth factor receptor tyrosine kinase trafficking UBE4B neuroblastoma

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Dynamic changes in the expression of growth factor receptors in the myocardium microvascular endothelium after murine myocardial infarction

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Chinese Medical Journal 2007年第6期120卷 485-490页

作者： WANG Xin-hong ZHANG Guo-ping JIN Hui-ming CHEN Si-feng Department of Physiology and Pathophysiology Shanghai Medical College Fudan University Shanghai 200032 China

Background After myocardial infarction, specific growth factors promote cardiac angiogenisis, leading to a therapeutic effect. Although this effect is mediated by specific receptors in the endothelium of the cardiac microvasculature, few studies have investigated dynamic changes in their expression. We explored this phenomenon in a murine model. Methods We observed the mRNA expression of receptors by specific angiogenesis gene microarray at day 3 and day 7 after infarction. The vascular endothelial growth factor （VEGF） receptor FIk-1 was observed at the protein level at day 3 and day 7 by immunohistochemistry. The dynamic expression of fibroblast growth factor receptor-1 （FGFR-1） mRNA in the border zone and the noninfarcted zone at day 3, day 7, day 14, and day 42 was investigated by real-time PCR. Statistical significance was analyzed with SPSS 10o0 software using one-way analysis of variance （ANOVA）. Results Three days after infarction, 9 receptors in the border zone and 7 receptors in the noninfarcted zone were down-regulated. Two receptors in the infarct edge and 5 receptors in the distant myocardium were up-regulated. However at day 7, 11 receptors in the border zone were up-regulated, and only one was down-regulated. In the border zone, FIk-1 levels decreased at day 3 but increased significantly at day 7. Real-time PCR showed that FGFR-1 mRNA decreased markedly in the border zone at day 3 but increased afterward for at least 6 weeks. In the early stage （3 days） after infarction, the expression of receptors had decreased to some extent. However, at day 7, receptor expression was active and had moved from the distant noninfarcted zone to the border zone as a part of the acute repair process. Conclusion Selecting the proper growth factors to target receptors with protective activity, and determining appropriate therapeutic timing may be important to the success of therapeutic angiogenesis.

关键词： growth factor receptor gene microarray acute myocardial infarction

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growth factor receptors: promising drug targets in cancer

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Journal of Cancer Metastasis and Treatment 2015年第1期1卷 190-200页

作者： Snigdha Tiash Ezharul Hoque Chowdhury Jeffrey Cheah School of Medicine and Health Sciences Faculty of MedicineNursing and Health SciencesMonash University46150 Bandar SunwaySelangorMalaysia

Genetic,epigenetic and somatic changes deregulate the expression of growth factor receptors(GFRs),leading to cancer initiation and *** cell growth and survival are orchestrated by clonal expansion and evasion of apoptotic signals in cancer *** growth of cells is further supported by angiogenesis and metastasis to distant *** expression of GFRs also contributes to the development of ***,therapeutics to target GFRs is a potentially attractive molecular approach to treat cancer more *** this review,we have discussed the contribution of GFRs to cancer development and addressed molecular approaches undertaken to inhibit GFR-mediated pathways.A wide number of monoclonal antibodies(mAbs)and protein kinase inhibitors targeting these GFR-mediated functions are in clinical trials to treat human ***,most drugs that target GFRs lead to the development of drug resistance and generate adverse *** acid-based therapeutics,*** interfering RNA(siRNA)could be harnessed to selectively silence GFR genes in cancer *** polymer,liposome-based nanocarriers,and the most recently developed pH-sensitive inorganic carbonate apatite nanoparticles have been used in cell culture and preclinical trials for cytoplasmic delivery of the siRNAs targeting different GFR ***-based therapeutics have been shown to have signifi cant potential to suppress GFR expression and functions and thus could be developed as molecular ***-targeting of tumors at different levels by combining various approaches along with chemotherapy would be a promising therapeutic approach to fight the *** nanocarriers capable of entrapping siRNA,mAb,GFR inhibitors and classical drugs targeting GFR have potential therapeutic applications.

关键词： Carbonate apatite nanoparticles growth factor receptor monoclonal antibodies protein kinase inhibitor short interfering RNA tyrosine kinase inhibitor

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Oncogenesis of RON receptor tyrosine kinase:a molecular target for malignant epithelial cancers

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Acta Pharmacologica Sinica 2006年第6期27卷 641-650页

作者： Ming-hai WANG~(2,3,4)Hang-ping YAO~2 Yong-qing ZHOU~2 2 Laboratory of Chang-Kung Scholars Program for Tumor Biology,First Affiliated Hospital,Zhejiang University School of Medicine,Hangzhou 310003.China 3 Cancer Biology Center and Department of Pharmaceutical Sciences,Texas Tech University Health Sciences Center School of Pharmacy,Amarillo,TX 79106,USA Laboratory of Chang-Kung Scholars Program for Tumor Biology First Affiliated Hospital Zhejiang University School of Medicine Hangzhou China Cancer Biology Center and Department of Pharmaceutical Sciences Texas Tech University Health Sciences Center School of Pharmacy Amarillo USA

Recepteur d’origine nantais(RON)belongs to a subfamily of receptor tyrosinekinases(RTK)with unique expression patterns and biological *** isactivated by a serum-derived growth factor macrophage stimulating protein(MSP).The RON gene transcription is essential for embryonic development and critical inregulating certain physiological *** studies have indicated thataltered RON expression contributes significantly to cancer progression *** primary tumors,such as colon and breast cancers,overexpressionof RON exists in large numbers and is often accompanied by the generation ofdifferent splicing *** RON variants direct a unique program thatcontrols cell transformation,growth,migration,and invasion,indicating that al-tered RON expression has the ability to regulate motile/invasive *** activities were also seen in transgenic mice,in which targeted expression ofRON in lung epithelial cells resulted in numerous tumors with pathological fea-tures of human bronchioloalveolar ***,abnormal RON activation isa pathogenic factor that transduces oncogenic signals leading to uncontrolledcell growth and subsequent malignant *** these facts,RON and its variants can be considered as potential targets for *** using small interfering RNA and neutralizing mono-clonal antibodies demonstrated that suppressing RON expression and activationdecreases cancer cell proliferation,increases apoptotic death,prevents tumorformation in nude mice,and reduces malignant ***,blocking RONexpression and activation has clinical significance in reversing malignant pheno-types and controlling tumor growth.

关键词： growth factor receptor signal transduction tumorigenesis monoclonal antibody small molecule inhibitor therapeutics

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