Kinins are generated within inflammatory tissue microenvironments, where they exert diverse functions, including cell proliferation, leukocyte activation, cell migration, endothelial cell activation and nociception. These pleiotropic functions depend on signaling through two cross talking receptors, the constitutively expressed kinin receptor 2 (B2R) and the inducible kinin receptor 1 (B1R). We have reviewed evidence, which supports the concept that kinin receptors, especially kinin receptor 1, are promising targets for cancer therapy, since (1) many tumor cells express aberrantly high levels of these receptors; (2) some cancers produce kinins and use them as autocrine factors to stimulate their growth; (3) activation of kinin receptors leads to activation of macrophages, dendritic cells and other cells from the tumor microenvironment; (4) kinins have pro-angiogenic properties; (5) kinin receptors have been implicated in cancer migration, invasion and metastasis; and (6) selective antagonists for either B1R or B2R have shown anti-proliferative, anti-inflammatory, anti-angiogenic and anti-migratory properties. The multiple cross talks between kinin receptors and renin-angiotensin system (RAS) as well as its implications for targeting KKS or RAS for the treatment of malignancies are also discussed. It is expected that B1R antagonists would interfere less with housekeeping functions and therefore would be attractive compounds to treat selected types of cancer. Reliable clinical studies are needed to establish the translatability of these data to human settings and the usefulness of kinin receptor antagonists.

Pancreatic ductal adenocarcinoma (PDAC) has a grim prognosis with less than 5% survivors after 5 years. High expression levels of ADAM8, a metalloprotease-disintegrin, are correlated with poor clinical outcome. We show that ADAM8 expression is associated with increased migration and invasiveness of PDAC cells caused by activation of ERK 1/2 and higher MMP activities. For biological function, ADAM8 requires multimerisation and associates with β1-integrin on the cell surface. A peptidomimetic ADAM8 inhibitor, BK-1361, designed by structural modelling of the disintegrin domain, prevents ADAM8 multimerisation. In PDAC cells, BK-1361 affects ADAM8 function leading to reduced invasiveness, and less ERK 1/2 and MMP activation. BK-1361 application in mice decreased tumour burden and metastasis of implanted pancreatic tumour cells and provides improved metrics of clinical symptoms and survival in a KrasG12D-driven mouse model of PDAC. Thus, our data integrate ADAM8 in pancreatic cancer signalling and validate ADAM8 as a target for PDAC therapy.

Micropatterning techniques, such as photolithography and microcontact printing, provide robust tools for controlling the adhesive interactions between cells and their extracellular environment. However, the ability to modify these interactions in real time and examine dynamic cellular responses remains a significant challenge. Here we describe a novel strategy to create dynamically adhesive, micropatterned substrates, which afford precise control of cell adhesion and migration over both space and time. Specific functionalization of micropatterned poly(ethylene glycol methacrylate) (POEGMA) brushes with synthetic peptides, containing the integrin-binding arginine-glycine-aspartic acid (RGD) motif, was achieved using thiol-yne coupling reactions. RGD activation of POEGMA brushes promoted fibroblast adhesion, spreading and migration into previously non-adhesive areas, and migration speed could be tuned by adjusting the surface ligand density. We propose that this technique is a robust strategy for creating dynamically adhesive biomaterial surfaces and a useful assay for studying cell migration.

BackgroundTreatment of solid tumors with vascular disrupting agent OXi4503 results in over 90% tumor destruction. However, a thin rim of viable cells persists in the tumor periphery following treatment, contributing to subsequent recurrence. This study investigates inherent differences in the microenvironment of the tumor periphery that contribute to treatment resistance.MethodsUsing a murine colorectal liver metastases model, spatial morphological and molecular differences within the periphery and the center of the tumor that may account for differences in resistance to OXi4503 treatment were investigated. H&E staining and immunostaining were used to examine vessel maturity and stability, hypoxia and HIF1α levels, accumulation of immune cells, expression of proangiogenic factors/receptors (VEGF, TGF-β, b-FGF, and AT1R) and expression of EMT markers (ZEB1, vimentin, E-cadherin and β-catenin) in the periphery and center of established tumors. The effects of OXi4503 on tumor vessels and cell kinetics were also investigated.ResultsSignificant differences were found between tumor periphery and central regions, including association of the periphery with mature vessels, higher accumulation of immune cells, increased growth factor expression, minimal levels of hypoxia and increased evidence of EMT. OXi4503 treatment resulted in collapse of vessels in the tumor center; however vasculature in the periphery remained patent. Similarly, tumor apoptosis and proliferation were differentially modulated between centre and periphery after treatment.ConclusionsThe molecular and morphological differences between tumor periphery and center may account for the observed differential resistance to OXi4503 treatment and could provide targets for drug development to totally eliminate metastases.