Although many preclinical studies have implicated β3 integrin receptors (αvβ3 and αIIbβ3) in cancer progression, β3 inhibitors have shown only modest efficacy in patients with advanced solid tumours. The limited efficacy of β3 inhibitors in patients could arise from our incomplete understanding of the precise function of β3 integrin and, consequently, inappropriate clinical application. Data from animal studies are conflicting and indicate heterogeneity with respect to the relative contributions of β3-expressing tumour and stromal cell populations in different cancers. Here we aimed to clarify the function and relative contributions to metastasis of tumour versus stromal β3 integrin in clinically relevant models of spontaneous breast cancer metastasis, with particular emphasis on bone metastasis. We show that stable down-regulation of tumour β3 integrin dramatically impairs spontaneous (but not experimental) metastasis to bone and lung without affecting primary tumour growth in the mammary gland. Unexpectedly, and in contrast to subcutaneous tumours, orthotopic tumour vascularity, growth and spontaneous metastasis were not altered in mice null for β3 integrin. Tumour β3 integrin promoted migration, protease expression and trans-endothelial migration in vitro and increased vascular dissemination in vivo, but was not necessary for bone colonization in experimental metastasis assays. We conclude that tumour, rather than stromal, β3 expression is essential and is required early for efficient spontaneous breast cancer metastasis to bone and soft tissues. Accordingly, differential gene expression analysis in cohorts of breast cancer patients showed a strong association between high β3 expression, early metastasis and shorter disease-free survival in patients with oestrogen receptor-negative tumours. We propose that β3 inhibitors may be more efficacious if used in a neoadjuvant setting, rather than after metastases are established.

No abstract

ADAM9 (A Disintegrin And Metalloproteinase 9) is a member of the ADAM protein family which contains a disintegrin domain. This protein family plays key roles in many physiological processes, including fertilization, migration, and cell survival. The ADAM proteins have also been implicated in various diseases, including cancer. Specifically, ADAM9 has been suggested to be involved in metastasis. To address this question, we generated ADAM9 knockdown clones of MDA-MB-231 breast tumor cells using silencing RNAs that were tested for cell adhesion, proliferation, migration and invasion assays. In RNAi-mediated ADAM9 silenced MDA-MB-231 cells, the expression of ADAM9 was lower from the third to the sixth day after silencing and inhibited tumor cell invasion in matrigel by approximately 72% when compared to control cells, without affecting cell adhesion, proliferation or migration. In conclusion, the generation of MDA-MB-231 knockdown clones lacking ADAM9 expression inhibited tumor cell invasion in vitro, suggesting that ADAM9 is an important molecule in the processes of invasion and metastasis.

Scaffolds of poly(ε-caprolactone) (PCL) and their biocomposites with 0, 1, 3, and 5 wt.% Biosilicate® were fabricated by the generative manufacturing process coupled with a vertical miniscrew extrusion head to application for restoration of bone tissue. Their morphological characterization indicated the designed 0°/90° architecture range of pore sizes and their interconnectivity is feasible for tissue engineering applications. Mechanical compression tests revealed an up to 57% increase in the stiffness of the scaffold structures with the addition of 1 to 5 wt.% Biosilicate® to the biocomposite. No toxicity was detected in the scaffolds tested by in vitro cell viability with MC3T3-E1 preosteoblast cell line. The results highlighted the potential application of scaffolds fabricated with poly(ε-caprolactone)/Biosilicate® to tissue engineering.

No abstract