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Inhibition of integ...
Inhibition of integrin αvβ6 changes fibril thickness of stromal collagen in experimental carcinomas
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- Olof Olsson, P. (author)
- Lund University,Lunds universitet,Institutionen för experimentell medicinsk vetenskap,Medicinska fakulteten,Department of Experimental Medical Science,Faculty of Medicine
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- Gustafsson, Renata (author)
- Lund University,Lunds universitet,Institutionen för experimentell medicinsk vetenskap,Medicinska fakulteten,Department of Experimental Medical Science,Faculty of Medicine
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- Salnikov, Alexei V. (author)
- Skåne University Hospital
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- Göthe, Maria (author)
- Uppsala University
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- Zeller, Kathrin S. (author)
- Uppsala University
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- Friman, Tomas (author)
- Uppsala University
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- Baldetorp, Bo (author)
- Lund University,Lunds universitet,Skåne University Hospital
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- Koopman, Louise A. (author)
- Biogen, Inc.
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- Weinreb, Paul H. (author)
- Biogen, Inc.
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- Violette, Shelia M. (author)
- Biogen, Inc.
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- Kalamajski, Sebastian (author)
- Uppsala University
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- Heldin, Nils Erik (author)
- Uppsala University
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- Rubin, Kristofer (author)
- Uppsala University
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(creator_code:org_t)
- 2018-07-02
- 2018
- English.
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In: Cell Communication and Signaling. - : Springer Science and Business Media LLC. - 1478-811X. ; 16:1
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Abstract
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- Background: Chemotherapeutic efficacy can be improved by targeting the structure and function of the extracellular matrix (ECM) in the carcinomal stroma. This can be accomplished by e.g. inhibiting TGF-β1 and -β3 or treating with Imatinib, which results in scarcer collagen fibril structure in xenografted human KAT-4/HT29 (KAT-4) colon adenocarcinoma. Methods: The potential role of αVβ6 integrin-mediated activation of latent TGF-β was studied in cultured KAT-4 and Capan-2 human ductal pancreatic carcinoma cells as well as in xenograft carcinoma generated by these cells. The monoclonal αVβ6 integrin-specific monoclonal antibody 3G9 was used to inhibit the αVβ6 integrin activity. Results: Both KAT-4 and Capan-2 cells expressed the αVβ6 integrin but only KAT-4 cells could utilize this integrin to activate latent TGF-β in vitro. Only when Capan-2 cells were co-cultured with human F99 fibroblasts was the integrin activation mechanism triggered, suggesting a more complex, fibroblast-dependent, activation pathway. In nude mice, a 10-day treatment with 3G9 reduced collagen fibril thickness and interstitial fluid pressure in KAT-4 but not in the more desmoplastic Capan-2 tumors that, to achieve a similar effect, required a prolonged 3G9 treatment. In contrast, a 10-day direct inhibition of TGF-β1 and -β3 reduced collagen fibril thickness in both tumor models. Conclusion: Our data demonstrate that the αVβ6-directed activation of latent TGF-β plays a pivotal role in modulating the stromal collagen network in carcinoma, but that the sensitivity to αVβ6 inhibition depends on the simultaneous presence of alternative paths for latent TGF-β activation and the extent of desmoplasia.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
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- art (subject category)
- ref (subject category)
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- By the author/editor
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Olof Olsson, P.
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Gustafsson, Rena ...
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Salnikov, Alexei ...
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Göthe, Maria
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Zeller, Kathrin ...
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Friman, Tomas
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Baldetorp, Bo
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Koopman, Louise ...
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Weinreb, Paul H.
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Violette, Shelia ...
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Kalamajski, Seba ...
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Heldin, Nils Eri ...
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Rubin, Kristofer
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Cancer and Oncol ...
- Articles in the publication
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Cell Communicati ...
- By the university
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Lund University