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

A. Sadanandam, S. S. Sidhu, S. Wullschleger, S. Singh, M. L. Varney, C. S. Yang, A. E. Ashour, Surinder Kumar Batra, Rakesh K Singh

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)501-507
Number of pages7
JournalBritish journal of cancer
Volume107
Issue number3
DOIs
StatePublished - Jul 24 2012

Fingerprint

Semaphorins
Tumor Burden
Endothelial Cells
Cell Proliferation
Neoplasm Metastasis
Neoplasm Micrometastasis
Pancreatic Neoplasms
Neoplasms
Nude Mice
Liver
Conditioned Culture Medium
Microvessels
Interleukin-8
Vascular Endothelial Growth Factor A
Phosphorylation
Phenotype
Cell Line
Injections
Membranes

Keywords

  • angiogenic factors
  • pancreatic cancer
  • reduced tumour burden
  • secreted SEMA5A
  • semaphorin
  • tumour burden and metastasis

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

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, Surinder Kumar; Singh, Rakesh K.

In: British journal of cancer, Vol. 107, No. 3, 24.07.2012, p. 501-507.

Research output: Contribution to journalArticle

Sadanandam, A. ; Sidhu, S. S. ; Wullschleger, S. ; Singh, S. ; Varney, M. L. ; Yang, C. S. ; Ashour, A. E. ; Batra, Surinder Kumar ; Singh, Rakesh K. / Secreted semaphorin 5A suppressed pancreatic tumour burden but increased metastasis and endothelial cell proliferation. In: British journal of cancer. 2012 ; Vol. 107, No. 3. pp. 501-507.
@article{c130f28731d849beb5d2129a774b7694,
title = "Secreted semaphorin 5A suppressed pancreatic tumour burden but increased metastasis and endothelial cell proliferation",
abstract = "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.",
keywords = "angiogenic factors, pancreatic cancer, reduced tumour burden, secreted SEMA5A, semaphorin, tumour burden and metastasis",
author = "A. Sadanandam and Sidhu, {S. S.} and S. Wullschleger and S. Singh and Varney, {M. L.} and Yang, {C. S.} and Ashour, {A. E.} and Batra, {Surinder Kumar} and Singh, {Rakesh K}",
year = "2012",
month = "7",
day = "24",
doi = "10.1038/bjc.2012.298",
language = "English (US)",
volume = "107",
pages = "501--507",
journal = "British Journal of Cancer",
issn = "0007-0920",
publisher = "Nature Publishing Group",
number = "3",

}

TY - JOUR

T1 - Secreted semaphorin 5A suppressed pancreatic tumour burden but increased metastasis and endothelial cell proliferation

AU - Sadanandam, A.

AU - Sidhu, S. S.

AU - Wullschleger, S.

AU - Singh, S.

AU - Varney, M. L.

AU - Yang, C. S.

AU - Ashour, A. E.

AU - Batra, Surinder Kumar

AU - Singh, Rakesh K

PY - 2012/7/24

Y1 - 2012/7/24

N2 - 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.

AB - 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.

KW - angiogenic factors

KW - pancreatic cancer

KW - reduced tumour burden

KW - secreted SEMA5A

KW - semaphorin

KW - tumour burden and metastasis

UR - http://www.scopus.com/inward/record.url?scp=84864338143&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84864338143&partnerID=8YFLogxK

U2 - 10.1038/bjc.2012.298

DO - 10.1038/bjc.2012.298

M3 - Article

C2 - 22782341

AN - SCOPUS:84864338143

VL - 107

SP - 501

EP - 507

JO - British Journal of Cancer

JF - British Journal of Cancer

SN - 0007-0920

IS - 3

ER -