Effect of PACAP on Hypoxia-Induced Angiogenesis and Epithelial–Mesenchymal Transition in Glioblastoma
Abstract
:1. Introduction
2. Methods
2.1. Human Glioblastoma Samples and Cell Line
2.2. Treatments
2.3. ELISA
2.4. Wound Healing Assay
2.5. Conditioned Medium and Preparation and Tube Formation Assay
2.6. Western Blot Analysis
2.7. Immunolocalization
2.8. Statistical Analysis
3. Results
3.1. PACAP and PAC1R Expression in GBM Hypoxic Area
3.2. PACAP Effect on VEGF Production in GBM Cells Exposed to DFX-Induced Hypoxia
3.3. PACAP Reduces New Vessels Formation Induced by Conditioned Media from GBM Cell Cultures
3.4. PACAP Counteracts the Hypoxia Mimetic Condition-Induced EMT in U87MG Cells
4. Discussion
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- Wen, P.Y.; Kesari, S. Malignant gliomas in adults. N. Engl. J. Med. 2008, 359, 92–507. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Louis, D.N.; Perry, A.; Reifenberger, G.; von Deimling, A.; Figarella-Branger, D.; Cavenee, W.K.; Ohgaki, H.; Wiestler, O.D.; Kleihues, P.; Ellison, D.W. The 2016 World Health Organization Classification of Tumors of the Central Nervous System: A summary. Acta Neuropathol. 2016, 131, 803–820. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Furnari, F.B.; Fenton, T.; Bachoo, R.M.; Mukasa, A.; Stommel, J.M.; Stegh, A.; Hahn, W.C.; Ligon, K.L.; Louis, D.N.; Brennan, C.; et al. Malignant astrocytic glioma: Genetics, biology, and paths to treatment. Genes Dev. 2007, 21, 2683–2710. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- McNeill, K.A. Epidemiology of brain tumors. Neurol. Clin. 2016, 34, 981–998. [Google Scholar] [CrossRef] [PubMed]
- Rong, Y.; Durden, D.L.; Van Meir, E.G.; Brat, D.J. ‘Pseudopalisading’ necrosis in glioblastoma: A familiar morphologic feature that links vascular pathology, hypoxia, and angiogenesis. J. Neuropathol. Exp. Neurol. 2006, 65, 529–539. [Google Scholar] [CrossRef]
- Brat, D.J.; Van Meir, E.G. Glomeruloid microvascular proliferation orchestrated by VPF/VEGF: A new world of angiogenesis research. Am. J. Pathol. 2001, 158, 789–796. [Google Scholar] [CrossRef]
- Maynard, M.A.; Ohh, M. Von Hippel-Lindau tumor suppressor protein and hypoxia-inducible factor in kidney cancer. Am. J. Nephrol. 2004, 24, 1–13. [Google Scholar] [CrossRef] [Green Version]
- Scuderi, S.; D’amico, A.G.; Federico, C.; Saccone, S.; Magro, G.; Bucolo, C.; Drago, F.; D’Agata, V. Different Retinal Expression Patterns of IL-1α, IL-1β, and Their Receptors in a Rat Model of Type 1 STZ-Induced Diabetes. J. Mol. Neurosci. 2015, 56, 431–439. [Google Scholar] [CrossRef]
- D’Amico, A.G.; Maugeri, G.; Reitano, R.; Bucolo, C.; Saccone, S.; Drago, F.; D’Agata, V. PACAP Modulates Expression of Hypoxia-Inducible Factors in Streptozotocin-Induced Diabetic Rat Retina. J. Mol. Neurosci. 2015, 57, 501–509. [Google Scholar] [CrossRef]
- Yeung, Y.T.; McDonald, K.L.; Grewal, T.; Munoz, L. Interleukins in glioblastoma pathophysiology: Implications for therapy. Br. J. Pharm. 2013, 168, 591–606. [Google Scholar] [CrossRef] [Green Version]
- Zhang, W.; Petrovic, J.M.; Callaghan, D.; Jones, A.; Cui, H.; Howlett, C.; Stanimirovic, D. Evidence that hypoxia-inducible factor-1 (HIF-1) mediates transcriptional activation of interleukin-1beta (IL-1beta) in astrocyte cultures. J. Neuroimmunol. 2006, 174, 63–73. [Google Scholar] [CrossRef] [PubMed]
- Shweiki, D.; Itin, A.; Soffer, D.; Keshet, E. Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature 1992, 359, 843–845. [Google Scholar] [CrossRef] [PubMed]
- Fathima Hurmath, K.; Ramaswamy, P.; Nandakumar, D.N. IL-1β microenvironment promotes proliferation, migration, and invasion of human glioma cells. Cell Biol. Int. 2014, 38, 1415–1422. [Google Scholar] [CrossRef]
- Ferrara, N. VEGF as a therapeutic target in cancer. Oncology 2005, 69, 11–16. [Google Scholar] [CrossRef] [PubMed]
- Bracken, C.P.; Fedele, A.O.; Linke, S.; Balrak, W.; Lisy, K.; Whitelaw, M.L.; Peet, D.J. Cell-specific regulation of hypoxia-inducible factor (HIF)-1alpha and HIF-2alpha stabilization and transactivation in a graded oxygen environment. J. Biol. Chem. 2006, 281, 22575–22585. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kaur, B.; Khwaja, F.W.; Severson, E.A.; Matheny, S.L.; Brat, D.J.; Van Meir, E.G. Hypoxia and the hypoxia-inducible-factor pathway in glioma growth and angiogenesis. Neuro Oncol. 2005, 7, 134–153. [Google Scholar] [CrossRef] [Green Version]
- Maugeri, G.; D’Amico, A.G.; Reitano, R.; Magro, G.; Cavallaro, S.; Salomone, S.; D’Agata, V. PACAP and VIP Inhibit the Invasiveness of Glioblastoma Cells Exposed to Hypoxia through the Regulation of HIFs and EGFR Expression. Front. Pharm. 2016, 7, 139. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Tam, S.Y.; Wu, V.W.C.; Law, H.K.W. Hypoxia-Induced Epithelial-Mesenchymal Transition in Cancers: HIF-1α and Beyond. Front. Oncol. 2020, 10, 486. [Google Scholar] [CrossRef]
- Monteiro, A.R.; Hill, R.; Pilkington, G.J.; Madureira, P.A. The Role of Hypoxia in Glioblastoma Invasion. Cells 2017, 6, 45. [Google Scholar] [CrossRef] [Green Version]
- Jing, Y.; Han, Z.; Zhang, S.; Liu, Y.; Wei, L. Epithelial-Mesenchymal Transition in tumor microenvironment. Cell Biosci. 2011, 1, 29. [Google Scholar] [CrossRef] [Green Version]
- Ye, X.Z.; Xu, S.L.; Xin, Y.H.; Yu, S.C.; Ping, Y.F.; Chen, L.; Xiao, H.L.; Wang, B.; Yi, L.; Wang, Q.L.; et al. Tumor-associated microglia/macrophages enhance the invasion of glioma stem-like cells via TGF-β1 signaling pathway. J. Immunol. 2012, 189, 444–453. [Google Scholar] [CrossRef] [Green Version]
- Iwadate, Y. Epithelial-mesenchymal transition in glioblastoma progression. Oncol. Lett. 2016, 11, 1615–1620. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Arimura, A. Perspectives on pituitary adenylate cyclase activating polypeptide (PACAP) in the neuroendocrine, endocrine, and nervous systems. Jpn. J. Physiol. 1998, 48, 301–331. [Google Scholar] [CrossRef] [Green Version]
- Moody, T.W.; Nuche-Berenguer, B.; Jensen, R.T. Vasoactive intestinal peptide/pituitary adenylate cyclase activating polypeptide, and their receptors and cancer. Curr. Opin. Endocrinol. Diabetes Obes. 2016, 23, 38–47. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- D’Amico, A.G.; Maugeri, G.; Saccone, S.; Federico, C.; Cavallaro, S.; Reglodi, D.; D’Agata, V. PACAP Modulates the Autophagy Process in an In Vitro Model of Amyotrophic Lateral Sclerosis. Int. J. Mol. Sci. 2020, 21, 2943. [Google Scholar] [CrossRef] [PubMed]
- Lauretta, G.; Ravalli, S.; Szychlinska, M.A.; Castorina, A.; Maugeri, G.; D’Amico, A.G.; D’Agata, V.; Musumeci, G. Current knowledge of pituitary adenylate cyclase activating polypeptide (PACAP) in articular cartilage. Histol. Histopathol. 2020, 16, 18233. [Google Scholar]
- Cavallaro, S.; D’Agata, V.; Guardabasso, V.; Travali, S.; Stivala, F.; Canonico, P.L. Differentiation induces pituitary adenylate cyclase-activating polypeptide receptor expression in PC-12 cells. Mol. Pharm. 1995, 48, 56–62. [Google Scholar]
- D’Agata, V.; Cavallaro, S.; Stivala, F.; Canonico, P.L. Tissue-specific and developmental expression of pituitary adenylate cyclase-activating polypeptide (PACAP) receptors in rat brain. Eur. J. Neurosci. 1996, 8, 310–318. [Google Scholar] [CrossRef]
- Canonico, P.L.; Copani, A.; D’Agata, V.; Musco, S.; Petralia, S.; Travali, S.; Stivala, F.; Cavallaro, S. Activation of pituitary adenylate cyclase-activating polypeptide receptors prevents apoptotic cell death in cultured cerebellar granule cells. Ann. N. Y. Acad. Sci. 1996, 805, 470–472. [Google Scholar] [CrossRef] [PubMed]
- Waschek, J.A. VIP and PACAP: Neuropeptide modulators of CNS inflammation, injury, and repair. Br. J. Pharm. 2013, 169, 512–523. [Google Scholar] [CrossRef] [Green Version]
- Toth, D.; Szabo, E.; Tamas, A.; Juhasz, T.; Horvath, G.; Fabian, E.; Opper, B.; Szabo, D.; Maugeri, G.; D’Amico, A.G.; et al. Protective Effects of PACAP in Peripheral Organs. Front. Endocrinol. 2020, 11, 377. [Google Scholar] [CrossRef]
- Reglodi, D.; Kiss, P.; Lubics, A.; Tamas, A. Review on the protective effects of PACAP in models of neurodegenerative diseases in vitro and in vivo. Curr. Pharm. Des. 2011, 17, 962–972. [Google Scholar] [CrossRef]
- Maugeri, G.; D’Amico, A.G.; Gagliano, C.; Saccone, S.; Federico, C.; Cavallaro, S.; D’Agata, V. VIP Family Members Prevent Outer Blood Retinal Barrier Damage in a Model of Diabetic Macular Edema. J. Cell Physiol. 2017, 232, 1079–1085. [Google Scholar] [CrossRef] [PubMed]
- Maugeri, G.; D’Amico, A.G.; Saccone, S.; Federico, C.; Cavallaro, S.; D’Agata, V. PACAP and VIP Inhibit HIF-1α-Mediated VEGF Expression in a Model of Diabetic Macular Edema. J. Cell Physiol. 2017, 232, 1209–1215. [Google Scholar] [CrossRef]
- Maugeri, G.; D’Amico, A.G.; Bucolo, C.; D’Agata, V. Protective effect of PACAP-38 on retinal pigmented epithelium in an in vitro and in vivo model of diabetic retinopathy through EGFR-dependent mechanism. Peptides 2019, 119, 170108. [Google Scholar] [CrossRef]
- Maugeri, G.; D’Amico, A.G.; Castrogiovanni, P.; Saccone, S.; Federico, C.; Reibaldi, M.; Russo, A.; Bonfiglio, V.; Avitabile, T.; Longo, A.; et al. PACAP through EGFR transactivation preserves human corneal endothelial integrity. J. Cell Biochem. 2019, 120, 10097–10105. [Google Scholar] [CrossRef]
- Maugeri, G.; D’Amico, A.G.; Rasà, D.M.; Federico, C.; Saccone, S.; Morello, G.; La Cognata, V.; Cavallaro, S.; D’Agata, V. Molecular mechanisms involved in the protective effect of pituitary adenylate cyclase-activating polypeptide in an in vitro model of amyotrophic lateral sclerosis. J. Cell Physiol. 2019, 234, 5203–5214. [Google Scholar] [CrossRef] [PubMed]
- Maugeri, G.; D’Amico, A.G.; Musumeci, G.; Reglodi, D.; D’Agata, V. Effects of Pacap on Schwann Cells: Focus on Nerve Injury. Int. J. Mol. Sci. 2020, 21, 8233. [Google Scholar] [CrossRef] [PubMed]
- Maugeri, G.; D’Amico, A.G.; Morello, G.; Reglodi, D.; Cavallaro, S.; D’Agata, V. Differential Vulnerability of Oculomotor Versus Hypoglossal Nucleus During ALS: Involvement of PACAP. Front. Neurosci. 2020, 14, 805. [Google Scholar] [CrossRef] [PubMed]
- Maugeri, G.; D’Amico, A.G.; Rasà, D.M.; Saccone, S.; Federico, C.; Cavallaro, S.; D’Agata, V. PACAP and VIP regulate hypoxia-inducible factors in neuroblastoma cells exposed to hypoxia. Neuropeptides 2018, 69, 84–91. [Google Scholar] [CrossRef]
- Castorina, A.; Scuderi, S.; D’Amico, A.G.; Drago, F.; D’Agata, V. PACAP and VIP increase the expression of myelin-related proteins in rat schwannoma cells: Involvement of PAC1/VPAC2 receptor-mediated activation of PI3K/Akt signaling pathways. Exp. Cell Res. 2014, 322, 108–121. [Google Scholar] [CrossRef] [PubMed]
- Castorina, A.; Giunta, S.; Scuderi, S.; D’Agata, V. Involvement of PACAP/ADNP signaling in the resistance to cell death in malignant peripheral nerve sheath tumor (MPNST) cells. J. Mol. Neurosci. 2012, 48, 674–683. [Google Scholar] [CrossRef] [PubMed]
- D’Amico, A.G.; Scuderi, S.; Saccone, S.; Castorina, A.; Drago, F.; D’Agata, V. Antiproliferative effects of PACAP and VIP in serum-starved glioma cells. J. Mol. Neurosci. 2013, 51, 503–513. [Google Scholar] [CrossRef] [PubMed]
- Vertongen, P.; d’Haens, J.; Michotte, A.; Velkeniers, B.; van Rampelbergh, J.; Svoboda, M.; Robberecht, P. Expression of pituitary adenylate cyclase activating polypeptide and receptors in human brain tumors. Peptides 1995, 16, 713–719. [Google Scholar] [CrossRef]
- Jaworski, D.M. Expression of pituitary adenylate cyclase-activating polypeptide (PACAP) and the PACAP-selective receptor in cultured rat astrocytes, human brain tumors, and in response to acute intracranial injury. Cell Tissue Res. 2000, 300, 219–230. [Google Scholar] [CrossRef] [PubMed]
- Robberecht, P.; Woussen-Colle, M.C.; Vertongen, P.; De Neef, P.; Hou, X.; Salmon, I.; Brotchi, J. Expression of pituitary adenylate cyclase activating polypeptide (PACAP) receptors in human glial cell tumors. Peptides 1994, 15, 661–665. [Google Scholar] [CrossRef]
- Reubi, J.C.; Läderach, U.; Waser, B.; Gebbers, J.O.; Robberecht, P.; Laissue, J.A. Vasoactive intestinal peptide/pituitary adenylate cyclase-activating peptide receptor subtypes in human tumors and their tissues of origin. Cancer Res. 2000, 60, 3105–3112. [Google Scholar] [PubMed]
- Sharma, A.; Walters, J.; Gozes, Y.; Fridkin, M.; Brenneman, D.; Gozes, I.; Moody, T.W. A vasoactive intestinal peptide antagonist inhibits the growth of glioblastoma cells. J. Mol. Neurosci. 2001, 17, 331–339. [Google Scholar] [CrossRef]
- Available online: https://www.proteinatlas.org/ENSG00000141433-ADCYAP1/pathology/glioma (accessed on 12 July 2021).
- Sokolowska, P.; Nowak, J.Z. Effects of PACAP and VIP on cAMP-generating system and proliferation of C6 glioma cells. J. Mol. Neurosci. 2008, 36, 286–291. [Google Scholar] [CrossRef]
- Dufes, C.; Alleaume, C.; Montoni, A.; Olivier, J.C.; Muller, J.M. Effects of the vasoactive intestinal peptide (VIP) and related peptides on glioblastoma cell growth in vitro. J. Mol. Neurosci. 2003, 21, 91–102. [Google Scholar] [CrossRef] [Green Version]
- Vertongen, P.; Camby, I.; Darro, F.; Kiss, R.; Robberecht, P. VIP and pituitary adenylate cyclase activating polypeptide (PACAP) have an antiproliferative effect on the T98G human glioblastoma cell line through interaction with VIP2 receptor. Neuropeptides 1996, 30, 491–496. [Google Scholar] [CrossRef]
- Cochaud, S.; Chevrier, L.; Meunier, A.C.; Brillet, T.; Chadéneau, C.; Muller, J.M. The vasoactive intestinal peptide-receptor system is involved in human glioblastoma cell migration. Neuropeptides 2010, 44, 373–383. [Google Scholar] [CrossRef]
- Cochaud, S.; Meunier, A.C.; Monvoisin, A.; Bensalma, S.; Muller, J.M.; Chadéneau, C. Neuropeptides of the VIP family inhibit glioblastoma cell invasion. J. Neurooncol. 2015, 122, 63–73. [Google Scholar] [CrossRef]
- Kubiatowski, T.; Jang, T.; Lachyankar, M.B.; Salmonsen, R.; Nabi, R.R.; Quesenberry, P.J.; Litofsky, N.S.; Ross, A.H.; Recht, L.D. Association of increased phosphatidylinositol 3-kinase signaling with increased invasiveness and gelatinase activity in malignant gliomas. J. Neurosurg. 2001, 95, 480–488. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Bensalma, S.; Turpault, S.; Balandre, A.C.; De Boisvilliers, M.; Gaillard, A.; Chadéneau, C.; Muller, J.M. PKA at a Cross-Road of Signaling Pathways Involved in the Regulation of Glioblastoma Migration and Invasion by the Neuropeptides VIP and PACAP. Cancers 2019, 11, 123. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Paw, I.; Carpenter, R.C.; Watabe, K.; Debinski, W.; Lo, H.W. Mechanisms regulating glioma invasion. Cancer Lett. 2015, 362, 1–7. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Li, M.; Hering-Smith, K.S.; Simon, E.E.; Batuman, V. Myeloma light chains induce epithelial-mesenchymal transition in human renal proximal tubule epithelial cells. Nephrol. Dial. Transplant. 2008, 23, 860–870. [Google Scholar] [CrossRef] [Green Version]
- Maugeri, G.; D’Amico, A.G.; Rasà, D.M.; Saccone, S.; Federico, C.; Magro, G.; Cavallaro, S.; D’Agata, V. Caffeine effect on HIFs/VEGF pathway in human glioblastoma cells exposed to hypoxia. Anticancer Agents Med. Chem. 2018, 18, 1432–1439. [Google Scholar] [CrossRef]
- Maugeri, G.; Longo, A.; D’Amico, A.G.; Rasà, D.M.; Reibaldi, M.; Russo, A.; Bonfiglio, V.; Avitabile, T.; D’Agata, V. Trophic effect of PACAP on human corneal endothelium. Peptides 2018, 99, 20–26. [Google Scholar] [CrossRef]
- D’Amico, A.G.; Scuderi, S.; Maugeri, G.; Cavallaro, S.; Drago, F.; D’Agata, V. NAP reduces murine microvascular endothelial cells proliferation induced by hyperglycemia. J. Mol. Neurosci. 2014, 54, 405–413. [Google Scholar] [CrossRef]
- Maugeri, G.; D’Amico, A.G.; Rasà, D.M.; La Cognata, V.; Saccone, S.; Federico, C.; Cavallaro, S.; D’Agata, V. Nicotine promotes blood retinal barrier damage in a model of human diabetic macular edema. Toxicol. In Vitro 2017, 44, 182–189. [Google Scholar] [CrossRef] [PubMed]
- D’Amico, A.G.; Maugeri, G.; Bucolo, C.; Saccone, S.; Federico, C.; Cavallaro, S.; D’Agata, V. Nap Interferes with Hypoxia-Inducible Factors and VEGF Expression in Retina of Diabetic Rats. J. Mol. Neurosci. 2017, 61, 256–266. [Google Scholar] [CrossRef]
- Maugeri, G.; D’Amico, A.G.; Rasà, D.M.; Reitano, R.; Saccone, S.; Federico, C.; Parenti, R.; Magro, G.; D’Agata, V. Expression profile of Wilms Tumor 1 (WT1) isoforms in undifferentiated and all-trans retinoic acid differentiated neuroblastoma cells. Genes Cancer 2016, 7, 47–58. [Google Scholar] [CrossRef]
- Danielsson, F.; Peterson, M.K.; Caldeira Araújo, H.; Lautenschläger, F.; Gad, A.K.B. Vimentin Diversity in Health and Disease. Cells 2018, 7, 147. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- McNeil, E.; Capaldo, C.T.; Macara, I.G. Zonula Occludens-1 Function in the Assembly of Tight Junctions in Madin-Darby Canine Kidney Epithelial Cells. Mol. Biol. Cell 2006, 17, 1922–1932. [Google Scholar] [CrossRef] [Green Version]
- Toole, B.P. Hyaluronan-CD44 interactions in cancer: Paradoxes and possibilities. Clin. Cancer Res. 2009, 15, 7462–7468. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Wolf, K.J.; Shukla, P.; Springer, K.; Lee, S.; Coombes, J.D.; Choy, C.J.; Kenny, S.J.; Xu, K.; Kumar, S. A mode of cell adhesion and migration facilitated by CD44-dependent microtentacles. Proc. Natl. Acad. Sci. USA 2020, 117, 11432–11443. [Google Scholar] [CrossRef]
- Yu, R.; Zhong, J.; Li, M.; Guo, X.; Zhang, H.; Chen, J. PACAP induces the dimerization of PAC1 on the nucleus associated with the cAMP increase in the nucleus. Neurosci. Lett. 2013, 549, 92–96. [Google Scholar] [CrossRef] [PubMed]
- Yu, R.; Lin, Z.; Ouyang, Z.; Tao, Z.; Fan, G. Blue light induces the nuclear translocation of neuropeptide receptor PAC1-R associated with the up-regulation of PAC1-R its own in reactive oxygen species associated way. Biochim. Biophys. Acta Gen. Subj. 2021, 1865, 129884. [Google Scholar] [CrossRef]
- Mottet, D.; Michel, G.; Renard, P.; Ninane, N.; Raes, M.; Michiels, C. ERK and calcium in activation of HIF-1. Ann. N. Y. Acad. Sci. 2002, 973, 448–453. [Google Scholar] [CrossRef]
- Lim, J.H.; Lee, E.S.; You, H.J.; Lee, J.W.; Park, J.W.; Chun, Y.S. Ras-dependent induction of HIF-1alpha785 via the Raf/MEK/ERK pathway: A novel mechanism of Ras-mediated tumor promotion. Oncogene 2004, 23, 9427–9431. [Google Scholar] [CrossRef] [Green Version]
- Park, J.H.; Lee, J.Y.; Shin, D.H.; Jang, K.S.; Kim, H.J.; Kong, G. Loss of Mel-18 induces tumor angiogenesis through enhancing the activity and expression of HIF-1alpha mediated by the PTEN/PI3K/Akt pathway. Oncogene 2011, 10, 4578–4589. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Sharma, V.; Dixit, D.; Koul, N.; Mehta, V.S.; Sen, E. Ras regulates interleukin-1β-induced HIF-1α transcriptional activity in glioblastoma. J. Mol. Med. 2011, 89, 123–136. [Google Scholar] [CrossRef] [PubMed]
- Bergers, G.; Benjamin, L.E. Tumorigenesis and the angiogenic switch. Nat. Rev. Cancer 2003, 3, 401–410. [Google Scholar] [CrossRef] [PubMed]
- Plate, K.H.; Breier, G.; Weich, H.A.; Risau, W. Vascular endothelial growth factor is a potential tumour angiogenesis factor in human gliomas in vivo. Nature 1992, 359, 845–848. [Google Scholar] [CrossRef]
- Moreno, M.J.; Ball, M.; Andrade, M.F.; McDermid, A.; Stanimirovic, D.B. Insulin-like growth factor binding protein-4 (IGFBP-4) is a novel anti-angiogenic and anti-tumorigenic mediator secreted by dibutyryl cyclic AMP (dB-cAMP)-differentiated glioblastoma cells. Glia 2006, 53, 845–857. [Google Scholar] [CrossRef] [PubMed]
- Pen, A.; Moreno, M.J.; Durocher, Y.; Deb-Rinker, P.; Stanimirovic, D.B. Glioblastoma-secreted factors induce IGFBP7 and angiogenesis by modulating Smad-2-dependent TGF-beta signaling. Oncogene 2008, 27, 6834–6844. [Google Scholar] [CrossRef] [Green Version]
- Papale, M.; Buccarelli, M.; Mollinari, C.; Russo, M.A.; Pallini, R.; Ricci-Vitiani, L.; Tafani, M. Hypoxia, Inflammation and Necrosis as Determinants of Glioblastoma Cancer Stem Cells Progression. Int. J. Mol. Sci. 2020, 21, 2660. [Google Scholar] [CrossRef] [Green Version]
- Joseph, J.V.; Conroy, S.; Pavlov, K.; Sontakke, P.; Tomar, T.; Eggens-Meijer, E.; Balasubramaniyan, V.; Wagemakers, M.; den Dunnen, W.F.; Kruyt, F.A. Hypoxia enhances migration and invasion in glioblastoma by promoting a mesenchymal shift mediated by the HIF1α-ZEB1 axis. Cancer Lett. 2015, 359, 107–116. [Google Scholar] [CrossRef] [Green Version]
- Roomi, M.W.; Kalinovsky, T.; Rath, M.; Niedzwiecki, A. Modulation of MMP-2 and MMP-9 secretion by cytokines, inducers and inhibitors in human glioblastoma T-98G cells. Oncol. Rep. 2017, 37, 1907–1913. [Google Scholar] [CrossRef] [Green Version]
- Marhaba, R.; Zöller, M. CD44 in cancer progression: Adhesion, migration and growth regulation. J. Mol. Histol. 2004, 35, 211–231. [Google Scholar] [CrossRef] [PubMed]
- Fakhri, S.; Mehrjardi, A.Z.; Noori, M. Expression of CD44 and CD133 in glioma stem cells. Int. J. Tumor Ther. 2018, 7, 27–33. [Google Scholar]
- Kinashi, Y.; Ikawa, T.; Takahashi, S. The combined effect of neutron irradiation and temozolomide on glioblastoma cell lines with different MGMT and P53 status. Appl. Radiat. Isot. 2020, 163, 109204. [Google Scholar] [CrossRef] [PubMed]
U87MG Cell Line-Derived Conditioned Media | CM1 (Vehicle) Mean ± SEM | CM2 (PACAP) Mean ± SEM | CM3 (DFX) Mean ± SEM | CM4 (DFX + PACAP) Mean ± SEM |
---|---|---|---|---|
VEGF (pg/mL) | 6584 ± 9.85 | 6041 ± 5.77 **** | 7203 ± 8.54 **** | 7013 ± 11.55 ### |
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Maugeri, G.; D’Amico, A.G.; Saccone, S.; Federico, C.; Rasà, D.M.; Caltabiano, R.; Broggi, G.; Giunta, S.; Musumeci, G.; D’Agata, V. Effect of PACAP on Hypoxia-Induced Angiogenesis and Epithelial–Mesenchymal Transition in Glioblastoma. Biomedicines 2021, 9, 965. https://doi.org/10.3390/biomedicines9080965
Maugeri G, D’Amico AG, Saccone S, Federico C, Rasà DM, Caltabiano R, Broggi G, Giunta S, Musumeci G, D’Agata V. Effect of PACAP on Hypoxia-Induced Angiogenesis and Epithelial–Mesenchymal Transition in Glioblastoma. Biomedicines. 2021; 9(8):965. https://doi.org/10.3390/biomedicines9080965
Chicago/Turabian StyleMaugeri, Grazia, Agata Grazia D’Amico, Salvatore Saccone, Concetta Federico, Daniela Maria Rasà, Rosario Caltabiano, Giuseppe Broggi, Salvatore Giunta, Giuseppe Musumeci, and Velia D’Agata. 2021. "Effect of PACAP on Hypoxia-Induced Angiogenesis and Epithelial–Mesenchymal Transition in Glioblastoma" Biomedicines 9, no. 8: 965. https://doi.org/10.3390/biomedicines9080965