Pathological features of vessel co-option versus sprouting angiogenesis.

Cancer cells can use existing blood vessels to acquire a vasculature. This process is termed 'vessel co-option'. Vessel co-option is an alternative to the growth of new blood vessels, or angiogenesis, and is adopted by a wide range of human tumour types growing within numerous tissues. A complementary aspect of this process is extravascular migratory tumour spread using the co-opted blood vessels as a trail. Vessel co-opting tumours can be discriminated from angiogenic tumours by specific morphological features. These features give rise to distinct histopathological growth patterns that reflect the interaction of cancer cells with the microenvironment of the organ in which they thrive. We will discuss the histopathological growth patterns of vessel co-option in the brain, the liver and the lungs. The review will also highlight evidence for the potential clinical value of the histopathological growth patterns of cancer. Vessel co-option can affect patient outcomes and resistance to cancer treatment. Insight into the biological drivers of this process of tumour vascularization will yield novel therapeutic strategies.

Glioblastoma: a pathogenic crosstalk between tumor cells and pericytes.

Cancers likely originate in progenitor zones containing stem cells and perivascular stromal cells. Much evidence suggests stromal cells play a central role in tumor initiation and progression. Brain perivascular cells (pericytes) are contractile and function normally to regulate vessel tone and morphology, have stem cell properties, are interconvertible with macrophages and are involved in new vessel formation during angiogenesis. Nevertheless, how pericytes contribute to brain tumor infiltration is not known. In this study we have investigated the underlying mechanism by which the most lethal brain cancer, Glioblastoma Multiforme (GBM) interacts with pre-existing blood vessels (co-option) to promote tumor initiation and progression. Here, using mouse xenografts and laminin-coated silicone substrates, we show that GBM malignancy proceeds via specific and previously unknown interactions of tumor cells with brain pericytes. Two-photon and confocal live imaging revealed that GBM cells employ novel, Cdc42-dependent and actin-based cytoplasmic extensions, that we call flectopodia, to modify the normal contractile activity of pericytes. This results in the co-option of modified pre-existing blood vessels that support the expansion of the tumor margin. Furthermore, our data provide evidence for GBM cell/pericyte fusion-hybrids, some of which are located on abnormally constricted vessels ahead of the tumor and linked to tumor-promoting hypoxia. Remarkably, inhibiting Cdc42 function impairs vessel co-option and converts pericytes to a phagocytic/macrophage-like phenotype, thus favoring an innate immune response against the tumor. Our work, therefore, identifies for the first time a key GBM contact-dependent interaction that switches pericyte function from tumor-suppressor to tumor-promoter, indicating that GBM may harbor the seeds of its own destruction. These data support the development of therapeutic strategies directed against co-option (preventing incorporation and modification of pre-existing blood vessels), possibly in combination with anti-angiogenesis (blocking new vessel formation), which could lead to improved vascular targeting not only in Glioblastoma but also for other cancers.

Live imaging of glioblastoma cells in brain tissue shows requirement of actin bundles for migration.

Live-cell imaging of glioblastoma U373 and U87 cells transfected with actin cytoskeleton markers has been used to study there-arrangements that are associated with migration in two- and three-dimensional matrices and in brain tissue. In collagen gels and in brain slices, both cell types developed neuronal-like processes with ruffling membranes and filopodia. Blebbing cells were also observed, but these were mainly immobile. The retraction of trailing cell processes in a tissue environment was associated with the transient development and contraction of bundles of axial stress fibers. The inhibition of Rho-kinase caused glioblastoma cells in brain slices to become immobile and develop neurite-like processes at random, which indicates the requirement of Rho signaling and contractility for migration. Actin stress fibers were also observed in glioblastoma cells injected into the brains of living mice. Thus, invading glioblastoma cells use neurite-like extensions to penetrate between neuronal fibers and contractile actin bundles for traction of the cell body.

The heart rate response to exercise and circulating catecholamines in heart transplant recipients.

The plasma concentration of noradrenaline ([NA]) is higher than that of adrenaline ([A]) both in normal subjects and in heart transplant recipients (HTR). Since in both groups the myocardial density of beta1-adrenergenic receptors is much greater than that of beta2-adrenergenic receptors, the chronotropic response of a denervated heart to changes in plasma [NA] and [A] in the absence of reinnervation should be similar to that of agonist stimulation of beta1-receptors. To test this hypothesis, 17 HTR and 9 healthy subjects (CTL) performed incremental exercise on a cycle ergometer to voluntary exhaustion. Heart rate (HR) was recorded by electrocardiography. [NA] and [A] were measured by high-pressure liquid chromatography at rest and at increasing workloads (w). In both groups, HR and [NA+A] increased with w, and HR with [NA+A]. Normalized HR values, plotted against the logarithm of [NA+A], fitted significantly logistic curves. The affinity constants were different, i.e. 2599+/-350 and 487+/-37 ng.l(-1), for HTR and CTL, respectively. The chronotropic effect of changes in [NA+A] in HTR was similar to that of combined beta1- and beta2-adrenergic activation evoked by applying isoprenaline to isolated heart myocytes (Brodde OE, Pharmacol Ther 60:405-430, 1993). These findings suggest that over time sympathetic reinnervation and the modulation of beta-receptors may take place in HTR, ruling out the hypothesis of persistent heart denervation.