F25P preproinsulin abrogates the secretion of pro-growth factors from EGFRvIII cells and suppresses tumor growth in an EGFRvIII/wt heterogenic model.
Extensive heterogeneity is a defining hallmark of glioblastoma multiforme (GBM) at the cellular and molecular levels. EGFRvIII, the most common EGFR mutant, is expressed in 24-67% of cases and strongly indicates a poor survival prognosis. By co-expressing EGFRvIII and EGFRwt, we established an EGFRvIII/wt heterogenic model. Using this approach, we confirmed that a mixture of EGFRvIII and EGFRwt at a certain ratio could clearly enhance tumor growth in vitro and in vivo compared with EGFRwt cells, thereby indicating that EGFRvIII cells promote tumor growth. Furthermore, we demonstrated that the EGFRvIII cells could support the growth of EGFRwt cells by secreting growth factors, thus acting as the principal source for maintaining tumor survival. F25P preproinsulin effectively reduced the concentrations of EGF, VEGF, and MMP-9 in the blood of tumor-bearing mice by competitively inhibiting the endoplasmic reticulum signal peptidase and increased the overall survival in orthotopic models. Taken together, our results provided an effective therapy of F25P preproinsulin in the EGFRvIII/wt heterogenic model.
Department of Neurosurgery, Tianjin Medical University General Hospital, Laboratory of Neuro-Oncology, Tianjin Neurological Institute, Key Laboratory of Post-trauma Neuro-repair and Regeneration in Central Nervous System, Ministry of Education, Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin 300052, China.
Jian-Wei
JW
Wei
Department of Endocrinology and Metabolism, Tianjin Medical University General Hospital, Tianjin 300052, China.
Jing-Qiu
JQ
Cui
Department of Head & Neck, Tianjin Cancer Institute and Hospital, Tianjin 300060, China.
Xuan
X
Zhou
Department of Neurosurgery, The Hospital affiliated to Hebei University, Baoding 071000, China.
Chuan
C
Fang
College of Fundamental Medicine, Hebei University, Baoding 071000, China.
Yan-Li
YL
Tan
Department of Neurosurgery, Tianjin Medical University General Hospital, Laboratory of Neuro-Oncology, Tianjin Neurological Institute, Key Laboratory of Post-trauma Neuro-repair and Regeneration in Central Nervous System, Ministry of Education, Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin 300052, China.
Lu-Yue
LY
Chen
Department of Neurosurgery, Tianjin Medical University General Hospital, Laboratory of Neuro-Oncology, Tianjin Neurological Institute, Key Laboratory of Post-trauma Neuro-repair and Regeneration in Central Nervous System, Ministry of Education, Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin 300052, China.
Chao
C
Yang
Department of Endocrinology and Metabolism, Tianjin Medical University General Hospital, Tianjin 300052, China.
Ming
M
Liu
Department of Neurosurgery, Tianjin Medical University General Hospital, Laboratory of Neuro-Oncology, Tianjin Neurological Institute, Key Laboratory of Post-trauma Neuro-repair and Regeneration in Central Nervous System, Ministry of Education, Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin 300052, China. Electronic address: kang97061@tmu.edu.cn.
Chun-Sheng
CS
Kang
D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015536:Down-Regulation; D004815:Epidermal Growth Factor / Q000097:blood*; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D015316:Genetic Therapy / Q000379:methods*; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D006801:Humans; D007328:Insulin / Q000235:genetics / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000097:blood; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009154:Mutation; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden; D042461:Vascular Endothelial Growth Factor A / Q000097:blood*; D023041:Xenograft Model Antitumor Assays
D007328:Insulin; D011498:Protein Precursors; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C013737:preproinsulin; D004815:Epidermal Growth Factor; C512478:EGFR protein, human; D066246:ErbB Receptors; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9
EGFRvIII; External secretion; F25P preproinsulin; Glioblastoma