ADAMTS3 restricts cancer invasion in models of early breast cancer progression through enhanced fibronectin degradation.

Proteases have long been associated with cancer progression, due to their ability to facilitate invasion upon matrix remodelling. However, proteases are not simply degraders of the matrix, but also play fundamental roles in modulating cellular behaviour through the proteolytic processing of specific substrates. Indeed, proteases can elicit both pro- and anti- tumorigenic effects depending on context. Using a heterocellular spheroid model of breast cancer progression, we demonstrate the repressive function of myoepithelial ADAMTS3, with its loss directing myoepithelial-led invasion of luminal cells through a physiologically relevant matrix. Degradomic analysis, using terminal amine isotopic labelling of substrates (TAILS), combined with functional assays, implicate ADAMTS3 as a mediator of fibronectin degradation. We show further that loss of ADAMTS3 enhances levels of fibronectin in the microenvironment, promoting invasion through canonical integrin α5ß1 activation. Our data highlight a tumour suppressive role for ADAMTS3 in early stage breast cancer, and contribute to the growing evidence that proteases can restrain cancer progression.

Derivation of a nuclear heterogeneity image index to grade DCIS.

Abnormalities in cell nuclear morphology are a hallmark of cancer. Histological assessment of cell nuclear morphology is frequently used by pathologists to grade ductal carcinoma in situ (DCIS). Objective methods that allow standardization and reproducibility of cell nuclear morphology assessment have potential to improve the criteria needed to predict DCIS progression and recurrence. Aggressive cancers are highly heterogeneous. We asked whether cell nuclear morphology heterogeneity could be incorporated into a metric to classify DCIS. We developed a nuclear heterogeneity image index to objectively, and quantitatively grade DCIS. A whole-tissue cell nuclear morphological analysis, that classified tumors by the worst ten percent in a duct-by-duct manner, identified nuclear size ranges associated with each DCIS grade. Digital image analysis further revealed increasing heterogeneity within ducts or between ducts in tissues of worsening DCIS grade. The findings illustrate how digital image analysis comprises a supplemental tool for pathologists to objectively classify DCIS and in the future, may provide a method to predict patient outcome through analysis of nuclear heterogeneity.

Correction to: Association of invasion-promoting tenascin-C additional domains with breast cancers in young women.

After the publication of this work [1] an error was noticed in Fig. 6 (b). In the MCF-7/Vector columns, the same image was used accidentally for the 0 h and 24 h time points. Both images were taken from the 0 h time point.

Jekyll and Hyde: the role of the microenvironment on the progression of cancer.

It is now recognized that the host microenvironment undergoes extensive change during the evolution and progression of cancer. This involves the generation of cancer-associated fibroblasts (CAFs), which, through release of growth factors and cytokines, lead to enhanced angiogenesis, increased tumour growth and invasion. It has also been demonstrated that CAFs may modulate the cancer stem cell (CSC) phenotype, which has therapeutic implications. The altered fibroblast phenotype also contributes to the development of an altered extracellular matrix (ECM), with synthesis of ECM isoforms rarely found in normal tissues, including tenascin-C isoforms and the fibronectin EDA isoform. There is also emerging evidence of how the tensile strength of the tumour-associated ECM may be modified and lead to altered signalling in tumour cells. The hypoxic environment of the tumour stimulates angiogenesis and also impacts on other aspects of cell signalling, including the c-met pathway and lysyl oxidase-mediated signalling, which can directly promote tumour cell invasion. The inflammatory infiltrate associated with many solid tumours also modulates tumour function, having both anti- and pro-tumour effects. All of these components of the microenvironment provide potential targets for therapeutic attack, with a number of molecules already in clinical trials. It is also becoming evident that characterizing the tumour microenvironment can provide important prognostic and predictive information about tumours, independent of the tumour cell phenotype.

Bcl-2 is an independent prognostic factor and adds to a biological model for predicting outcome in operable non-small cell lung cancer.

INTRODUCTION: The underlying biology of a tumour may hold the key to predicting the outcome for an individual patient as well as identifying potential therapeutic targets. Using epidermal growth factor receptor (EGFR) and matrix metalloproteinase (MMP)-9 immunoexpression combined with microvessel counts we have developed a prognostic model for operable non-small cell lung cancer (NSCLC) which predicts outcome independent of stage (Thorax, 56 (2001) 561-566). The aim of this study was to evaluate the impact of bcl-2 expression upon survival in this model. METHODS: This was a retrospective analysis of 167 patients with resected stage I-IIIa NSCLC and >60 days post-operative survival. Minimum follow-up was 2 years. Immunohistochemistry was performed on paraffin-embedded tissue sections for bcl-2, EGFR, MMP-9 and the microvessel marker CD34 to evaluate the relationships between, and impact on survival of these biological markers. RESULTS: Tumour cell MMP-9 (P=0.002), microvessel count > median (P=0.01), bcl-2 (P=0.02) and stage (P=0.02) were independent prognostic factors. Bcl-2 expression was associated with an improved survival in all sub-groups of our prognostic model. CONCLUSION: bcl-2, EGFR and MMP-9 expression and angiogenesis provide prognostic information independent of TNM stage. Prognostic models offer the potential of tailoring the therapeutic management for an individual patient.