The shape of uPAR involves a large INCB28060 contralateral external surface which is suggested to facilitate interaction/s with many of these ancillary proteins. This large repertoire of interactions suggests that uPAR has evolved a complex regulatory mechanism to control proteolysis, cell migration, proliferation, cell signalling and other aspects of cell behaviour. In fact, in the last decade, extensive evidence has shown uPAR is implicated in cell adhesion, proliferation, migration, tissue remodelling and in the regulation of signalling pathways. These are important features not only of ubiquitous developmental pathways, but also cancer metastasis. uPAR expression in various cancers has been extensively studied over the past two decades, as reflected by uPAR oncology-related publications. However, uPAR expression in the cancer microenvironment remains controversial, in particular with regard to the cell type/s on which uPAR is overexpressed or stromaassociated cells ). Association between uPAR and cancer was first recognised in 1991. Since then, numerous studies have evaluated the levels of uPARE and uPARS in various cancers using an extensive range of antibodies. However, there have been conflicting results. Specifically in CRC, Pyke et al., found that uPAR was strongly expressed in tumourinfiltrating macrophages, neutrophils and eosinophils ) but only weakly to moderately expressed in neoplastic tumour cells against human uPAR clones R2 and R4). Later, another study reported that uPAR expression occurred mainly in tumour epithelia rather than stroma. Despite this apparent contradiction, both studies agreed uPAR was highly expressed in the tumour microenvironment and was concentrated at the tumour invasive front. Further studies on uPARE and uPARS in CRC generally agreed that high uPARE is independently and adversely related to patient survival. Seetoo et al. suggested that uPAR is an independent predictor of liver metastasis and overall patient survival post CRC resection. In agreement, a more recent study showed significantly elevated uPAR in CRC tumours at infiltrating tumour margins which was associated with poorer survival. However, data on uPARS in CRC are contradictory in terms of survival association. It has been suggested that macrophages, which are a major source of uPAR in stroma, play a role in preventing haematogenous metastasis. Additionally, an inverse association between CRC liver metastasis and uPAR primary tumour stromal expression was observed. Whilst not directly correlating uPARS with patient survival, it is wellknown that CRC patients with liver metastasis have significantly shorter survival than those without. In WY 14643 contrast, a recent report suggested that both uPARE and uPARS were negatively associated with overall CRC patient survival, as well as with disease free survival. However, only uPARS was independently associated with DFS in multivariable analysis. Collectively, we propose that these conflicting observations are due to the use of particular MAbs with different uPAR epitope-specificity when uPAR is involved in cell-specific protein interactions.