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Inhibition of integ...
Inhibition of integrin alpha(V)beta(6) changes fibril thickness of stromal collagen in experimental carcinomas
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- Olsson, P. Olof (author)
- Dept Expt Med Sci, Medicon Village 406, SE-22381 Lund, Sweden
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- Gustafsson, Renata (author)
- Dept Expt Med Sci, Medicon Village 406, SE-22381 Lund, Sweden
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- Salnikov, Alexei, V (author)
- Univ Hosp Lund, Dept Clin Sci, Oncol Clin, SE-22185 Lund, Sweden
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- Göthe, Maria (author)
- Uppsala universitet,Science for Life Laboratory, SciLifeLab,Institutionen för medicinsk biokemi och mikrobiologi
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- Zeller, Kathrin S. (author)
- Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi,Science for Life Laboratory, SciLifeLab
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- Friman, Tomas (author)
- Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi,Science for Life Laboratory, SciLifeLab
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- Baldetorp, Bo (author)
- Univ Hosp Lund, Dept Clin Sci, Oncol Clin, SE-22185 Lund, Sweden
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- Koopman, Louise A. (author)
- Biogen, 225 Binney St, Cambridge, MA 02142 USA
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- Weinreb, Paul H. (author)
- Biogen, 225 Binney St, Cambridge, MA 02142 USA
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- Violette, Shelia M. (author)
- Biogen, 225 Binney St, Cambridge, MA 02142 USA
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- Kalamajski, Sebastian (author)
- Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi,Science for Life Laboratory, SciLifeLab
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- Heldin, Nils-Erik (author)
- Uppsala universitet,Institutionen för immunologi, genetik och patologi
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- Rubin, Kristofer (author)
- Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi,Science for Life Laboratory, SciLifeLab
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(creator_code:org_t)
- 2018-07-02
- 2018
- English.
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In: Cell Communication and Signaling. - : BMC. - 1478-811X. ; 16
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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 beta 1 and -beta 3 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 a(v)beta(6) integrin-mediated activation of latent TGF-beta 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 a(v)beta(6) integrin-speafic monoclonal antibody 3G9 was used to inhibit the a(v)beta(6) integrin activity.Results: Both KAT-4 and Capan-2 cells expressed the a(v)beta(6) integrin but only KAT-4 cells could utilize this integrin to activate latent TGF-beta 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-beta 1 and -beta 3 reduced collagen fibril thickness in both tumor models.Conclusion: Our data demonstrate that the a(v)beta(6)-directed activation of latent TGF-beta plays a pivotal role in modulating the stromal collagen network in carcinoma, but that the sensitivity to a(v)beta(6) inhibition depends on the simultaneous presence of alternative paths for latent TGF-beta 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)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinsk bioteknologi -- Medicinsk bioteknologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Medical Biotechnology -- Medical Biotechnology (hsv//eng)
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Olsson, P. Olof
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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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- MEDICAL AND HEALTH SCIENCES
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and Clinical Medicin ...
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and Cancer and Oncol ...
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MEDICAL AND HEAL ...
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and Medical Biotechn ...
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Cell Communicati ...
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Uppsala University