ScFv Anti-Heparan Sulfate Antibodies Unexpectedly Activate Endothelial and Cancer Cells through p38 MAPK: Implications for Antibody-Based Targeting of Heparan Sulfate Proteoglycans in Cancer.
(2012) In PLoS ONE 7(11).- Abstract
- Tumor development requires angiogenesis and anti-angiogenic therapies have been introduced in the treatment of cancer. In this context, heparan sulfate proteoglycans (HSPGs) emerge as interesting targets, owing to their function as co-receptors of major, pro-angiogenic factors. Accordingly, previous studies have suggested anti-tumor effects of heparin, i.e. over-sulfated HS, and various heparin mimetics; however, a significant drawback is their unspecific mechanism of action and potentially serious side-effects related to their anticoagulant properties. Here, we have explored the use of human ScFv anti-HS antibodies (αHS) as a more rational approach to target HSPG function in endothelial cells (ECs). αHS were initially selected for their... (More)
- Tumor development requires angiogenesis and anti-angiogenic therapies have been introduced in the treatment of cancer. In this context, heparan sulfate proteoglycans (HSPGs) emerge as interesting targets, owing to their function as co-receptors of major, pro-angiogenic factors. Accordingly, previous studies have suggested anti-tumor effects of heparin, i.e. over-sulfated HS, and various heparin mimetics; however, a significant drawback is their unspecific mechanism of action and potentially serious side-effects related to their anticoagulant properties. Here, we have explored the use of human ScFv anti-HS antibodies (αHS) as a more rational approach to target HSPG function in endothelial cells (ECs). αHS were initially selected for their recognition of HS epitopes localized preferentially to the vasculature of patient glioblastoma tumors, i.e. highly angiogenic brain tumors. Unexpectedly, we found that these αHS exhibited potent pro-angiogenic effects in primary human ECs. αHS were shown to stimulate EC differentiation, which was associated with increased EC tube formation and proliferation. Moreover, αHS supported EC survival under hypoxia and starvation, i.e. conditions typical of the tumor microenvironment. Importantly, αHS-mediated proliferation was efficiently counter-acted by heparin and was absent in HSPG-deficient mutant cells, confirming HS-specific effects. On a mechanistic level, binding of αHS to HSPGs of ECs as well as glioblastoma cells was found to trigger p38 MAPK-dependent signaling resulting in increased proliferation. We conclude that several αHS that recognize HS epitopes abundant in the tumor vasculature may elicit a pro-angiogenic response, which has implications for the development of antibody-based targeting of HSPGs in cancer. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/3218944
- author
- Christianson, Helena LU ; van Kuppevelt, Toin H and Belting, Mattias LU
- organization
- publishing date
- 2012
- type
- Contribution to journal
- publication status
- published
- subject
- in
- PLoS ONE
- volume
- 7
- issue
- 11
- article number
- e49092
- publisher
- Public Library of Science (PLoS)
- external identifiers
-
- wos:000312272600042
- pmid:23152853
- scopus:84869020025
- pmid:23152853
- ISSN
- 1932-6203
- DOI
- 10.1371/journal.pone.0049092
- language
- English
- LU publication?
- yes
- id
- 96dc21c4-10b4-4797-8310-ed49951e3869 (old id 3218944)
- alternative location
- http://www.ncbi.nlm.nih.gov/pubmed/23152853?dopt=Abstract
- date added to LUP
- 2016-04-01 12:51:43
- date last changed
- 2022-01-27 08:01:33
@article{96dc21c4-10b4-4797-8310-ed49951e3869,
abstract = {{Tumor development requires angiogenesis and anti-angiogenic therapies have been introduced in the treatment of cancer. In this context, heparan sulfate proteoglycans (HSPGs) emerge as interesting targets, owing to their function as co-receptors of major, pro-angiogenic factors. Accordingly, previous studies have suggested anti-tumor effects of heparin, i.e. over-sulfated HS, and various heparin mimetics; however, a significant drawback is their unspecific mechanism of action and potentially serious side-effects related to their anticoagulant properties. Here, we have explored the use of human ScFv anti-HS antibodies (αHS) as a more rational approach to target HSPG function in endothelial cells (ECs). αHS were initially selected for their recognition of HS epitopes localized preferentially to the vasculature of patient glioblastoma tumors, i.e. highly angiogenic brain tumors. Unexpectedly, we found that these αHS exhibited potent pro-angiogenic effects in primary human ECs. αHS were shown to stimulate EC differentiation, which was associated with increased EC tube formation and proliferation. Moreover, αHS supported EC survival under hypoxia and starvation, i.e. conditions typical of the tumor microenvironment. Importantly, αHS-mediated proliferation was efficiently counter-acted by heparin and was absent in HSPG-deficient mutant cells, confirming HS-specific effects. On a mechanistic level, binding of αHS to HSPGs of ECs as well as glioblastoma cells was found to trigger p38 MAPK-dependent signaling resulting in increased proliferation. We conclude that several αHS that recognize HS epitopes abundant in the tumor vasculature may elicit a pro-angiogenic response, which has implications for the development of antibody-based targeting of HSPGs in cancer.}},
author = {{Christianson, Helena and van Kuppevelt, Toin H and Belting, Mattias}},
issn = {{1932-6203}},
language = {{eng}},
number = {{11}},
publisher = {{Public Library of Science (PLoS)}},
series = {{PLoS ONE}},
title = {{ScFv Anti-Heparan Sulfate Antibodies Unexpectedly Activate Endothelial and Cancer Cells through p38 MAPK: Implications for Antibody-Based Targeting of Heparan Sulfate Proteoglycans in Cancer.}},
url = {{https://lup.lub.lu.se/search/files/3018791/3736757.pdf}},
doi = {{10.1371/journal.pone.0049092}},
volume = {{7}},
year = {{2012}},
}