Inhibition of integrin α(V)β(6) changes fibril thickness of stromal collagen in experimental carcinomas

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 α(V)β(6) 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 α(V)β(6) integrin-specific monoclonal antibody 3G9 was used to inhibit the α(V)β(6) integrin activity. RESULTS: Both KAT-4 and Capan-2 cells expressed the α(V)β(6) 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 α(V)β(6)-directed activation of latent TGF-β plays a pivotal role in modulating the stromal collagen network in carcinoma, but that the sensitivity to α(V)β(6) inhibition depends on the simultaneous presence of alternative paths for latent TGF-β activation and the extent of desmoplasia. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12964-018-0249-7) contains supplementary material, which is available to authorized users.