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Secreted semaphorin 5A suppressed pancreatic tumour burden but increased metastasis and endothelial cell proliferation

BACKGROUND: Our earlier reports demonstrated that membrane-bound semaphorin 5A (SEMA5A) is expressed in aggressive pancreatic cancer cells and tumours, and promotes tumour growth and metastasis. In this study, we examine whether (1) pancreatic cancer cells secrete SEMA5A and (2) that secreted SEMA5A...

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Autores principales: Sadanandam, A, Sidhu, S S, Wullschleger, S, Singh, S, Varney, M L, Yang, C-S, Ashour, A E, Batra, S K, Singh, R K
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3405228/
https://www.ncbi.nlm.nih.gov/pubmed/22782341
http://dx.doi.org/10.1038/bjc.2012.298
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author Sadanandam, A
Sidhu, S S
Wullschleger, S
Singh, S
Varney, M L
Yang, C-S
Ashour, A E
Batra, S K
Singh, R K
author_facet Sadanandam, A
Sidhu, S S
Wullschleger, S
Singh, S
Varney, M L
Yang, C-S
Ashour, A E
Batra, S K
Singh, R K
author_sort Sadanandam, A
collection PubMed
description BACKGROUND: Our earlier reports demonstrated that membrane-bound semaphorin 5A (SEMA5A) is expressed in aggressive pancreatic cancer cells and tumours, and promotes tumour growth and metastasis. In this study, we examine whether (1) pancreatic cancer cells secrete SEMA5A and (2) that secreted SEMA5A modulates certain phenotypes associated with tumour progression, angiogenesis and metastasis through various other molecular factors and signalling proteins. METHODS AND RESULTS: In this study, we show that human pancreatic cancer cell lines secrete the extracellular domain (ECD) of SEMA5A (SEMA5A-ECD) and overexpression of mouse Sema5A-ECD in Panc1 cells (not expressing SEMA5A; Panc1-Sema5A-ECD; control cells - Panc1-control) significantly increases their invasion in vitro via enhanced ERK phosphorylation. Interestingly, orthotopic injection of Panc1-Sema5A-ECD cells into athymic nude mice results in a lower primary tumour burden, but enhances the micrometastases to the liver as compared with Panc1-control cells. Furthermore, there is a significant increase in proliferation of endothelial cells treated with conditioned media (CM) from Panc1-Sema5A-ECD cells and a significant increase in microvessel density in Panc1-Sema5A-ECD orthotopic tumours compared with those from Panc1-control cells, suggesting that the increase in liver micrometastases is probably due to increased tumour angiogenesis. In addition, our data demonstrate that this increase in endothelial cell proliferation by Sema5A-ECD is mediated through the angiogenic molecules – interleukin-8 and vascular endothelial growth factor. CONCLUSION: Taken together, these results suggest that a bioactive, secreted form of Sema5A-ECD has an intriguing and potentially important role in its ability to enhance pancreatic tumour invasiveness, angiogenesis and micrometastases.
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spelling pubmed-34052282013-07-24 Secreted semaphorin 5A suppressed pancreatic tumour burden but increased metastasis and endothelial cell proliferation Sadanandam, A Sidhu, S S Wullschleger, S Singh, S Varney, M L Yang, C-S Ashour, A E Batra, S K Singh, R K Br J Cancer Molecular Diagnostics BACKGROUND: Our earlier reports demonstrated that membrane-bound semaphorin 5A (SEMA5A) is expressed in aggressive pancreatic cancer cells and tumours, and promotes tumour growth and metastasis. In this study, we examine whether (1) pancreatic cancer cells secrete SEMA5A and (2) that secreted SEMA5A modulates certain phenotypes associated with tumour progression, angiogenesis and metastasis through various other molecular factors and signalling proteins. METHODS AND RESULTS: In this study, we show that human pancreatic cancer cell lines secrete the extracellular domain (ECD) of SEMA5A (SEMA5A-ECD) and overexpression of mouse Sema5A-ECD in Panc1 cells (not expressing SEMA5A; Panc1-Sema5A-ECD; control cells - Panc1-control) significantly increases their invasion in vitro via enhanced ERK phosphorylation. Interestingly, orthotopic injection of Panc1-Sema5A-ECD cells into athymic nude mice results in a lower primary tumour burden, but enhances the micrometastases to the liver as compared with Panc1-control cells. Furthermore, there is a significant increase in proliferation of endothelial cells treated with conditioned media (CM) from Panc1-Sema5A-ECD cells and a significant increase in microvessel density in Panc1-Sema5A-ECD orthotopic tumours compared with those from Panc1-control cells, suggesting that the increase in liver micrometastases is probably due to increased tumour angiogenesis. In addition, our data demonstrate that this increase in endothelial cell proliferation by Sema5A-ECD is mediated through the angiogenic molecules – interleukin-8 and vascular endothelial growth factor. CONCLUSION: Taken together, these results suggest that a bioactive, secreted form of Sema5A-ECD has an intriguing and potentially important role in its ability to enhance pancreatic tumour invasiveness, angiogenesis and micrometastases. Nature Publishing Group 2012-07-24 2012-07-10 /pmc/articles/PMC3405228/ /pubmed/22782341 http://dx.doi.org/10.1038/bjc.2012.298 Text en Copyright © 2012 Cancer Research UK https://creativecommons.org/licenses/by-nc-sa/3.0/From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/
spellingShingle Molecular Diagnostics
Sadanandam, A
Sidhu, S S
Wullschleger, S
Singh, S
Varney, M L
Yang, C-S
Ashour, A E
Batra, S K
Singh, R K
Secreted semaphorin 5A suppressed pancreatic tumour burden but increased metastasis and endothelial cell proliferation
title Secreted semaphorin 5A suppressed pancreatic tumour burden but increased metastasis and endothelial cell proliferation
title_full Secreted semaphorin 5A suppressed pancreatic tumour burden but increased metastasis and endothelial cell proliferation
title_fullStr Secreted semaphorin 5A suppressed pancreatic tumour burden but increased metastasis and endothelial cell proliferation
title_full_unstemmed Secreted semaphorin 5A suppressed pancreatic tumour burden but increased metastasis and endothelial cell proliferation
title_short Secreted semaphorin 5A suppressed pancreatic tumour burden but increased metastasis and endothelial cell proliferation
title_sort secreted semaphorin 5a suppressed pancreatic tumour burden but increased metastasis and endothelial cell proliferation
topic Molecular Diagnostics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3405228/
https://www.ncbi.nlm.nih.gov/pubmed/22782341
http://dx.doi.org/10.1038/bjc.2012.298
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