Tumour but not stromal expression of β3 integrin is essential, and is required early, for spontaneous dissemination of bone‐metastatic breast cancer

Abstract

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.

‘Normalizing’ the malignant phenotype of luminal breast cancer cells via alpha(v)beta(3)-integrin

“…5, 7, 8 Moreover, regulation of tumor progression by tumor and stromal β 3 integrin (Int -β 3) were shown to vary in breast cancer models. 9 Here we demonstrate that Int- α v β 3 is selectively expressed in the epithelium of the benign stage of breast tissues and is lost during early stages of luminal A (positive for estrogen and progesterone receptors) breast cancer progression. Hence, these surprising results suggest that Int -β 3 expression might maintain the differentiated state of premalignant tissue via its engagement with its restrictive normal microenvironment, the latter acting as a gatekeeper during neoplastic progression.…”

Extracellular matrix mediators of metastatic cell colonization characterized using scaffold mimics of the pre-metastatic niche

“…By comparing the log2 fold change of quantified peptide spectral matches, we have identified multiple proteins present in diseased lung and liver samples (Supplementary Table 1). In these lists, ECM-associated proteins such as tenascin [32], MMP9 [33], and vitronectin [34] have been associated previously with colonization and metastasis. Interestingly, MPO was the only protein identified in both our D-Lung and D-Liver top 10 lists.…”

Inhibition of integrin β3, a binding partner of kallistatin, leads to reduced viability, invasion and proliferation in NCI-H446 cells

“…Integrin signals can also originate inside cells and affect receptor affinity, thereby controlling ligand binding, initiating a cross talk with other receptors, and altering cell adhesion and proliferation. In multiple tumor types, including glioma, breast cancer, and melanoma, integrin β3 expression promotes invasion and metastasis [29]. On the other hand, more and more studies indicate that kallistatin exerts pleiotropic effects in not only inhibiting tumor angiogenesis and inflammation, but also reducing tumor growth and metastasis directly.…”