Debanjan Chakroborty1,2,3,4,5, Sandeep Goswami1,3,4, Hao Fan1, Wendy L Frankel1,2, Sujit Basu1,2,6, Chandrani Sarkar7,8,9,10,11. 1. Department of Pathology, The Ohio State University, Columbus, OH, 43210, USA. 2. Comprehensive Cancer Center, The Ohio State University, Columbus, OH, 43210, USA. 3. Department of Pathology, University of South Alabama, Mobile, AL, 36617, USA. 4. Cancer Biology Program, Mitchell Cancer Institute, University of South Alabama, Mobile, AL, 36604, USA. 5. Department of Biochemistry and Molecular Biology, College of Medicine, University of South Alabama, Mobile, AL, 36688, USA. 6. Division of Medical Oncology, Department of Internal Medicine, The Ohio State University, Columbus, OH, 43210, USA. 7. Department of Pathology, The Ohio State University, Columbus, OH, 43210, USA. csarkar@southalabama.edu. 8. Comprehensive Cancer Center, The Ohio State University, Columbus, OH, 43210, USA. csarkar@southalabama.edu. 9. Department of Pathology, University of South Alabama, Mobile, AL, 36617, USA. csarkar@southalabama.edu. 10. Cancer Biology Program, Mitchell Cancer Institute, University of South Alabama, Mobile, AL, 36604, USA. csarkar@southalabama.edu. 11. Department of Biochemistry and Molecular Biology, College of Medicine, University of South Alabama, Mobile, AL, 36688, USA. csarkar@southalabama.edu.
Abstract
BACKGROUND: Resistance to anti-angiogenic therapies targeting vascular endothelial growth factor-A (VEGF-A) stems from VEGF-A independent angiogenesis mediated by other proangiogenic factors. Therefore identifying these factors in colon adenocarcinoma (CA) will reveal new therapeutic targets. METHODS: Neuropeptide Y (NPY) and Y2 receptor (Y2R) expressions in CA were studied by immunohistochemical analysis. Orthotopic HT29 with intact VEGF-A gene and VEGF-A knockdown (by CRISPR/Cas9 gene-editing technique) HT29 colon cancer-bearing mice were treated with specific Y2R antagonists, and the effects on angiogenesis and tumour growth were studied. The direct effect of NPY on angiogenesis and the underlying molecular mechanism was elucidated by the modulation of Y2R receptors expressed on colonic endothelial cells (CEC). RESULTS: The results demonstrated that NPY and Y2R are overexpressed in human CA, orthotopic HT29, and most interestingly in VEGF-A-depleted orthotopic HT29 tumours. Treatment with Y2R antagonists inhibited angiogenesis and thereby HT29 tumour growth. Blocking /silencing Y2R abrogated NPY-induced angiogenic potential of CEC. Mechanistically, NPY regulated the activation of the ERK/MAPK signalling pathway in CEC. CONCLUSIONS: NPY derived from cancer cells independently regulates angiogenesis in CA by acting through Y2R present on CEC. Targeting NPY/Y2R thus emerges as a novel potential therapeutic strategy in CA.
BACKGROUND: Resistance to anti-angiogenic therapies targeting vascular endothelial growth factor-A (VEGF-A) stems from VEGF-A independent angiogenesis mediated by other proangiogenic factors. Therefore identifying these factors in colon adenocarcinoma (CA) will reveal new therapeutic targets. METHODS: Neuropeptide Y (NPY) and Y2 receptor (Y2R) expressions in CA were studied by immunohistochemical analysis. Orthotopic HT29 with intact VEGF-A gene and VEGF-A knockdown (by CRISPR/Cas9 gene-editing technique) HT29 colon cancer-bearing mice were treated with specific Y2R antagonists, and the effects on angiogenesis and tumour growth were studied. The direct effect of NPY on angiogenesis and the underlying molecular mechanism was elucidated by the modulation of Y2R receptors expressed on colonic endothelial cells (CEC). RESULTS: The results demonstrated that NPY and Y2R are overexpressed in human CA, orthotopic HT29, and most interestingly in VEGF-A-depleted orthotopic HT29 tumours. Treatment with Y2R antagonists inhibited angiogenesis and thereby HT29 tumour growth. Blocking /silencing Y2R abrogated NPY-induced angiogenic potential of CEC. Mechanistically, NPY regulated the activation of the ERK/MAPK signalling pathway in CEC. CONCLUSIONS: NPY derived from cancer cells independently regulates angiogenesis in CA by acting through Y2R present on CEC. Targeting NPY/Y2R thus emerges as a novel potential therapeutic strategy in CA.
Authors: A M Dvorak; A B Onderdonk; R S McLeod; R A Monahan-Earley; J Cullen; D A Antonioli; J E Blair; E S Morgan; R L Cisneros; P Estrella Journal: Ann Surg Date: 1993-03 Impact factor: 12.969
Authors: Sjoerd H den Uil; Evert van den Broek; Veerle M H Coupé; Thomas T Vellinga; Pien M Delis-van Diemen; Herman Bril; Eric J Th Belt; Onno Kranenburg; Hein B A C Stockmann; Jeroen A M Belien; Gerrit A Meijer; Remond J A Fijneman Journal: BMC Gastroenterol Date: 2019-08-16 Impact factor: 3.067