Inhibition of integrin αVβ6 changes fibril thickness of stromal collagen in experimental carcinomas

• Published in: Cell communication and signaling 2018-07, Vol.16 (1), p.36-36, Article 36
• Main Authors: Olof Olsson, P., Gustafsson, Renata, Salnikov, Alexei V., Göthe, Maria, Zeller, Kathrin S., Friman, Tomas, Baldetorp, Bo, Koopman, Louise A., Weinreb, Paul H., Violette, Shelia M., Kalamajski, Sebastian, Heldin, Nils-Erik, Rubin, Kristofer
• Format: Article
• Language: English
• Subjects: Adenocarcinoma; Animal models; Cancer and Oncology; Cancer och onkologi; Carcinoma; Clinical Medicine; Collagen; Colon; Extracellular matrix; Fibroblasts; Gene expression; Glycoproteins; Growth factors; Imatinib; Kinases; Klinisk medicin; Medical and Health Sciences; Medicin och hälsovetenskap; Metastasis; Monoclonal antibodies; Pancreatic cancer; Pancreatic carcinoma; Proteins; Signal transduction; Stroma; Structure-function relationships; Transforming growth factor-b1; Tumors; Xenografts
• ISSN: 1478-811X; 1478-811X
• DOI: 10.1186/s12964-018-0249-7

BackgroundChemotherapeutic 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.MethodsThe 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.ResultsBoth 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.ConclusionOur 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.