Identifying structural shocks behind loan supply fluctuations in Russia

We examine the drivers behind loan supply fluctuations in Russia using Bayesian vector autoregressive model with sign restrictions on impulse response functions. We identify two types of structural innovations: loan supply shock and monetary stance shock. We find that contractionary shocks of both types contributed significantly and in the roughly equal measure to the decrease of bank lending after the Lehman Brothers collapse.loan supply; Bayesian VAR; sign restrictions; financial crisis; Russia

Compensation mechanism in tumor cell migration: mesenchymal–amoeboid transition after blocking of pericellular proteolysis

Invasive tumor dissemination in vitro and in vivo involves the proteolytic degradation of ECM barriers. This process, however, is only incompletely attenuated by protease inhibitor–based treatment, suggesting the existence of migratory compensation strategies. In three-dimensional collagen matrices, spindle-shaped proteolytically potent HT-1080 fibrosarcoma and MDA-MB-231 carcinoma cells exhibited a constitutive mesenchymal-type movement including the coclustering of β1 integrins and MT1–matrix metalloproteinase (MMP) at fiber bindings sites and the generation of tube-like proteolytic degradation tracks. Near-total inhibition of MMPs, serine proteases, cathepsins, and other proteases, however, induced a conversion toward spherical morphology at near undiminished migration rates. Sustained protease-independent migration resulted from a flexible amoeba-like shape change, i.e., propulsive squeezing through preexisting matrix gaps and formation of constriction rings in the absence of matrix degradation, concomitant loss of clustered β1 integrins and MT1-MMP from fiber binding sites, and a diffuse cortical distribution of the actin cytoskeleton. Acquisition of protease-independent amoeboid dissemination was confirmed for HT-1080 cells injected into the mouse dermis monitored by intravital multiphoton microscopy. In conclusion, the transition from proteolytic mesenchymal toward nonproteolytic amoeboid movement highlights a supramolecular plasticity mechanism in cell migration and further represents a putative escape mechanism in tumor cell dissemination after abrogation of pericellular proteolysis

Intratumoral Cancer Cell Intravasation Can Occur Independent of Invasion into the Adjacent Stroma

Summary: Intravasation, active entry of cancer cells into the circulation, is often considered to be a relatively late event in tumor development occurring after stromal invasion. Here, we provide evidence that intravasation can be initiated early during tumor development and proceed in parallel to or independent of tumor invasion into surrounding stroma. By applying direct and unbiased intravasation-scoring methods to two histologically distinct human cancer types in live-animal models, we demonstrate that intravasation takes place almost exclusively within the tumor core, involves intratumoral vasculature, and does not involve vasculotropic cancer cells invading tumor-adjacent stroma and migrating along tumor-converging blood vessels. Highlighting an additional role for EGFR in cancer, we find that EGFR is required for the development of an intravasation-sustaining intratumoral vasculature. Intratumoral localization of intravasation supports the notion that overt metastases in cancer patients could be initiated much earlier during cancer progression than appreciated within conventional clinical tumor staging systems. : Deryugina and Kiosses investigate the localization of intravasation within primary tumors. They find that the majority of intravasation events occur within the tumor core and not at the invasive edge within tumor outgrowths into adjacent stroma in the models examined. Mechanistically, EGFR appears to impact intratumoral intravasation by regulating development of a fully interconnected angiogenic vasculature. Keywords: cancer metastasis, cell intravasation, tumor invasion, stromal invasion, tumor cell migration, tumor angiogenesis, EGFR, animal models of cancer, mouse ear tumor model, chorioallantoic membrane mode

Attenuating adaptive VEGF-A and IL-8 signaling restores durable tumor control in AR-antagonist-treated prostate cancers

Inhibiting androgen signaling using androgen signaling inhibitors (ASI) remains the primary treatment for castrate-resistant prostate cancer. Acquired resistance to androgen receptor (AR)-targeted therapy represents a major impediment to durable clinical response. Understanding resistance mechanisms, including the role of AR expressed in other cell types within the tumor microenvironment, will extend the clinical benefit of AR-targeted therapy. Here, we show the ASI enzalutamide induces vascular catastrophe and promotes hypoxia and microenvironment adaptation. We characterize treatment-induced hypoxia, and subsequent induction of angiogenesis, as novel mechanisms of relapse to enzalutamide, highlighting the importance of two hypoxia-regulated cytokines in underpinning relapse. We confirmed AR expression in CD34(+) vascular endothelium of biopsy tissue and human vascular endothelial cells (HVEC). Enzalutamide attenuated angiogenic tubule formation and induced cytotoxicity in HVECs in vitro, and rapidly induced sustained hypoxia in LNCaP xenografts. Subsequent reoxygenation, following prolonged enzalutamide treatment, was associated with increased tumor vessel density and accelerated tumor growth. Hypoxia increased AR expression and transcriptional activity in prostate cells in vitro. Coinhibition of IL8 and VEGF-A restored tumor response in the presence of enzalutamide, confirming the functional importance of their elevated expression in enzalutamide-resistant models. Moreover, coinhibition of IL8 and VEGF-A resulted in a durable, effective resolution of enzalutamide-sensitive prostate tumors. We conclude that concurrent inhibition of two hypoxia-induced factors, IL8 and VEGF-A, prolongs tumor sensitivity to enzalutamide in preclinical models and may delay the onset of enzalutamide resistance. IMPLICATIONS: Targeting hypoxia-induced signaling may extend the therapeutic benefit of enzalutamide, providing an improved treatment strategy for patients with resistant disease