Abstract
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.
Highlights
Chemotherapeutic efficacy can be improved by targeting the structure and function of the extracellular matrix (ECM) in the carcinomal stroma
The results show that both KAT-4 and Capan-2 carcinoma cells produced and secreted latent Transforming growth factor-β (TGF-β)
When KAT-4 cells were separated from the mink lung epithelial cells (MLEC) cells by a porous membrane that allowed free passage of growth factors (Transwell system) no TGF-β signaling was detected in the MLEC
Summary
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. Malignant and normal stromal cells, including infiltrating inflammatory cells, participate in reciprocal signaling that results in the buildup of the carcinomal stroma [2, 3]. Both human and experimental carcinomas have a pathologically elevated intratumoral. Carcinoma-associated fibroblasts (CAFs) originate from phenotypic switches of infiltrated or resident mesenchymal cells and may originate from epithelial-to-mesenchymal transition of carcinoma cells. The formation of CAFs is modulated by TGF-β [6] that stimulates collagen production
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