Cancer: Limitations of therapies exposed

Anti-angiogenic drugs, used for cancer treatment, target blood-vessel formation in tumours. Two studies commented here show that such drugs can reduce the efficiency of other anticancer agents and increase the aggressiveness of tumours

Exploiting pleiotropic activities of semaphorins as multi-target therapies for cancer

Semaphorins (SEMAs) are a superfamily of secreted or membrane‐associated glycoproteins implicated in the control of axonal wiring and involved in angiogenesis and cancer progression. Class‐3 SEMAs are the only secreted vertebrate SEMAs and several of them are regulated by protease‐mediated cleavage (Capparuccia & Tamagnone, 2009). Their high‐affinity receptors, Plexins and co‐receptor Neuropilins, are expressed in a wide variety of cell types including endothelial and tumour cells. Plexins show an intrinsic R‐Ras GAP activity, but interestingly also form complexes with additional transmembrane molecules, including certain receptor tyrosine kinases (RTKs) such as c‐Met, ErbB2 and vascular endothelial growth factor receptor 2 (VEGFR2), that are transactivated by Plexins and initiate critical signalling pathways. These functional interactions with transactivated kinase receptors are key to define the cellular activities of SEMAs and convert the SEMAs into pleiotropic molecules. Thus, SEMAs can positively or negatively modulate many intrinsic properties of tumour cells, such as proliferation, cell survival, alteration in cell adhesion and tumour invasiveness, but also modulate several stromal components including endothelial cell migration and survival (Capparuccia & Tamagnone, 2009; Serini et al, 2009)..

Relevance of angiogenesis in neuroendocrine tumors

While traditional cytotoxic drugs have shown limited efficacy in neuroendocrine tumors (NETs), their biological features have been characterized and can be exploited therapeutically. Their most prominent trait is an extraordinary vascularization in low-grade NETs and an hypoxia-dependent angiogenesis in high-grade NETs, which is associated to a significant expression of many pro-angiogenic molecules. Therefore, several antiangiogenic compounds have been tested in these malignancies and among these, sunitinib has demonstrated activity in pancreatic NET patients by dually targeting the VEGFR and PDGFR pathways. In spite of these efficacious clinical results, apparent resistance to antiangiogenic therapies has been described in NETs animal models and in clinical trials. Therefore, overcoming anti-angiogenic resistance is a crucial step in the subsequent development of antiangiogenic therapies. Several strategies have been postulated to fight resistance, but pre-clinical studies and clinical trials will investigate and address these therapeutic approaches in the coming years in order to overcome resistance anti-angiogenic therapies in NETs

Angiogenesis and Metabolism: Entwined for Therapy Resistance

Angiogenesis and metabolism are entwined processes that permit tumor growth and progression. Blood vessel supply is necessary for tumor survival by providing oxygen and nutrients for anabolism, but also by removing waste products from cellular metabolism. On the other hand, blocking angiogenesis with antiangiogenic therapies shows clinical benefits in several tumor types. Nevertheless, resistance to therapy emerges over time. In this review, we will discuss a novel mechanism of adaptive resistance involving metabolic adaptation of tumor cells, as well as provide examples of tumor adaptation to therapy, which may represent a new mechanism of resistance in several types of cancer. Thus, targeting this metabolic tumor adaptation could be a way to avoid resistance in cancer patients

Antiangiogenic Resistance: Novel Angiogenesis Axes Uncovered by Antiangiogenic Therapies Research

The mechanisms of tumor growth and progression involve the activation of different processes such as neovascularization and angiogenesis. These processes involve tumoral cells and stromal cells. Hence, inhibiting angiogenesis affects tumor growth and proliferation in patients with different types of cancer. Nevertheless, tumoral cells and stromal components are responsible for the resistance to antiangiogenic therapies. The majority of tumors respond to this type of therapy; however, some tumors may be indifferent to antiangiogenic therapies (intrinsic resistance) and other tumors become resistant during treatment (acquired resistance). Different strategies have been proposed to prevent resistance. Preclinical studies and clinical trials are focused to fight this therapeutic approach in order to prevent or delay tumor resistance to antiangiogenic therapies

Unraveling the Role of Angiogenesis in Cancer Ecosystems

Activation of the tumor and stromal cell-driven angiogenic program is one of the first requirements in the tumor ecosystem for growth and dissemination. The understanding of the dynamic angiogenic tumor ecosystem has rapidly evolved over the last decades. Beginning with the canonical sprouting angiogenesis, followed by vasculogenesis and intussusception, and finishing with vasculogenic mimicry, the need for different neovascularization mechanisms is further explored. In addition, an overview of the orchestration of angiogenesis within the tumor ecosystem cellular and molecular components is provided. Clinical evidence has demonstrated the effectiveness of traditional vessel-directed antiangiogenics, stressing on the important role of angiogenesis in tumor establishment, dissemination, and growth. Particular focus is placed on the interaction between tumor cells and their surrounding ecosystem, which is now regarded as a promising target for the development of new antiangiogenics

El empleo de drones armados: una encrucijada normativa

Sumario: 1. Introducción. 2. La legalidad del empleo de drones armados. 3. Jurisprudencia de la Corte Internacional de Justicia sobre la relación entre Derecho internacional humanitario y Derecho internacional de los derechos humanos. 4. Alegación de las normas internacionales sobre el uso e la fuerza. 5. Apoyo en el Derecho internacional humanitario. 6. La protección internacional del derecho a la vida

Certificar l'eficiència energètica dels edificis existents

L'obligació de certificar l'eficiència energètica dels edificis s'inicià amb la Directiva Europea 2002/91/CE, posteriorment modificada per la Directiva 2010/31/UE relativa a l'eficiència energètica dels edificis. A l'Estat espanyol es va començar a certificar els edificis nous l'any 2007, amb l'entrada en vigor del Decret 47/2007, i el passat 1 de juny s'hi van afegir els edificis existents. Ara bé, aquests últims només s'han de certificar quan es vulguin vendre o llogar, o en el cas dels edificis públics de més de 250 m2. Avui, tant els edificis nous com els existents queden regulats pel Decret 235/2013

Scanning, non-contact, hybrid broadband diffuse optical spectroscopy and diffuse correlation spectroscopy system

A scanning system for small animal imaging using non-contact, hybrid broadband diffuse optical spectroscopy (ncDOS) and diffuse correlation spectroscopy (ncDCS) is presented. The ncDOS uses a two-dimensional spectrophotometer retrieving broadband (610-900 nm) spectral information from up to fifty-seven source-detector distances between 2 and 5 mm. The ncDCS data is simultaneously acquired from four source-detector pairs. The sample is scanned in two dimensions while tracking variations in height. The system has been validated with liquid phantoms, demonstrated in vivo on a human fingertip during an arm cuff occlusion and on a group of mice with xenoimplanted renal cell carcinoma. (C) 2016 Optical Society of Americ

Contrasting responses of non-small cell lung cancer to antiangiogenic therapies depend on histological subtype

The vascular endothelial growth factor (VEGF) pathway is a clinically validated antiangiogenic target for non-small cell lung cancer (NSCLC). However, some contradictory results have been reported on the biological effects of antiangiogenic drugs. In order to evaluate the efficacy of these drugs in NSCLC histological subtypes, we analyzed the anticancer effect of two anti-VEGFR2 therapies (sunitinib and DC101) in chemically induced mouse models and tumorgrafts of lung adenocarcinoma (ADC) and squamous cell carcinoma (SCC). Antiangiogenic treatments induced vascular trimming in both histological subtypes. In ADC tumors, vascular trimming was accompanied by tumor stabilization. In contrast, in SCC tumors, antiangiogenic therapy was associated with disease progression and induction of tumor proliferation. Moreover, in SCC, anti-VEGFR2 therapies increased the expression of stem cell markers such as aldehyde dehydrogenase 1A1, CD133, and CD15, independently of intratumoral hypoxia. In vitro studies with ADC cell lines revealed that antiangiogenic treatments reduced pAKT and pERK signaling and inhibited proliferation, while in SCC-derived cell lines the same treatments increased pAKT and pERK, and induced survival. In conclusion, this study evaluates for the first time the effect of antiangiogenic drugs in lung SCC murine models in vivo and sheds light on the contradictory results of antiangiogenic therapies in NSCLC