A Therapeutic Perspective

AF was funded by a Ph.D. fellowship (PD/BD/135506/2018) from the Fundação para a Ciência e a Tecnologia (FCT) and DB by the FCT Investigator Program (IF/00501/2014/CP1252/CT0001).The Adenosine diphosphate-Ribosylation Factor (ARF) family belongs to the RAS superfamily of small GTPases and is involved in a wide variety of physiological processes, such as cell proliferation, motility and differentiation by regulating membrane traffic and associating with the cytoskeleton. Like other members of the RAS superfamily, ARF family proteins are activated by Guanine nucleotide Exchange Factors (GEFs) and inactivated by GTPase-Activating Proteins (GAPs). When active, they bind effectors, which mediate downstream functions. Several studies have reported that cancer cells are able to subvert membrane traffic regulators to enhance migration and invasion. Indeed, members of the ARF family, including ARF-Like (ARL) proteins have been implicated in tumorigenesis and progression of several types of cancer. Here, we review the role of ARF family members, their GEFs/GAPs and effectors in tumorigenesis and cancer progression, highlighting the ones that can have a pro-oncogenic behavior or function as tumor suppressors. Moreover, we propose possible mechanisms and approaches to target these proteins, toward the development of novel therapeutic strategies to impair tumor progression.publishersversionpublishe

Influence of planetary gas accretion on the shape and depth of gaps in protoplanetary discs

It is widely known that giant planets have the capacity to open deep gaps in their natal gaseous protoplanetary discs. It is unclear, however, how gas accretion onto growing planets influences the shape and depth of their growing gaps. We performed isothermal hydrodynamical simulations with the Fargo-2D1D code, which assumes planets accreting gas within full discs that range from 0.1 to 260 AU. The gas accretion routine uses a sink cell approach, in which different accretion rates are used to cope with the broad range of gas accretion rates cited in the literature. We find that the planetary gas accretion rate increases for larger disc aspect ratios and greater viscosities. Our main results show that gas accretion has an important impact on the gap-opening mass: we find that when the disc responds slowly to a change in planetary mass (i.e., at low viscosity), the gap-opening mass scales with the planetary accretion rate, with a higher gas accretion rate resulting in a larger gap-opening mass. On the other hand, if the disc response time is short (i.e., at high viscosity), then gas accretion helps the planet carve a deep gap. As a consequence, higher planetary gas accretion rates result in smaller gap-opening masses. Our results have important implications for the derivation of planet masses from disc observations: depending on the planetary gas accretion rate, the derived masses from ALMA observations might be off by up to a factor of two. We discuss the consequences of the change in the gap-opening mass on the evolution of planetary systems based on the example of the grand tack scenario. Planetary gas accretion also impacts stellar gas accretion, where the influence is minimal due to the presence of a gas-accreting planet

Simultaneous gas accretion onto a pair of giant planets: Impact on their final mass and on the protoplanetary disk structure

Several planetary systems are known to host multiple giant planets. However, when two giant planets are accreting from the same disk, it is unclear what effect the presence of the second planet has on the gas accretion process of both planets. In this paper we perform long-term 2D isothermal hydrodynamical simulations (over more than 0.5 Myr) with the FARGO-2D1

Constraining giant planet formation with synthetic ALMA images of the Solar System’s natal protoplanetary disk

New ALMA observations of protoplanetary disks allow us to probe planet formation in other planetary systems, giving us new constraints on planet formation processes. Meanwhile, studies of our own Solar System rely on constraints derived in a completely different way. However, it is still unclear what features the Solar System protoplanetary disk could have produced during its gas phase. By running 2D isothermal hydro-simulations used as inputs for a dust evolution model, we derive synthetic images at millimeter wavelengths using the radiative transfer code RADMC3D. We find that the embedded multiple giant planets strongly perturb the radial gas velocities of the disk. These velocity perturbations create traffic jams in the dust, producing over-densities different from the ones created by pressure traps and located away from the planets’ positions in the disk. By deriving the images at λ = 1.3 mm from these dust distributions, we show that very high resolution observations are needed to distinguish the most important features expected in the inner part (<15 AU) of the disk. The traffic jams, observable with a high resolution, further blur the link between the number of gaps and rings in disks and the number of embedded planets. We additionally show that a system capable of producing eccentric planets by scattering events that match the eccentricity distributions in observed exoplanets does not automatically produce bright outer rings at large radii in the disk. This means that high resolution observations of disks of various sizes are needed to distinguish between different giant planet formation scenarios during the disk phase, where the giants form either in the outer regions of the disks or in the inner regions. In the second scenario, the disks do not present planet-related features at large radii. Finally, we find that, even when the dust temperature is determined self-consistently, the dust masses derived observationally might be off by up to a factor of ten compared to the dust contained in our simulations due to the creation of optically thick regions. Our study clearly shows that in addition to the constraints from exoplanets and the Solar System, ALMA has the power to constrain different stages of planet formation already during the first few million years, which corresponds to the gas disk phase

How planetary gas accretion changes the shape and depth of gaps in protoplanetary discs

It is well known that giant planets open deep gaps in their natal gaseous protoplanetary discs. However, it is unclear how gas accretion onto growing planets influences the shape and depth of their growing gaps. We perform isothermal hydrodynamical simulations with the Fargo-2D1D code in which planets accrete gas within full discs that range from 0.1 to 260 AU. The gas accretion routine uses a sink cell approach, where we use different accretion rates to cope with the large span of gas accretion rates in the literature. We find that the planetary gas accretion rate increases for larger disc aspect ratios and larger viscosities. Our main result shows that gas accretion has an important impact on the gap opening mass: we find that when the disc responds slowly to a change in planetary mass (i.e. at low viscosity), the gap opening mass scales with the planetary accretion rate, with a higher gas accretion rate resulting in a larger gap opening mass. On the other hand, if the disc response time is short (i.e. at high viscosity), then gas accretion helps the planet carve a deep gap. As a consequence higher planetary gas accretion rates result in smaller gap opening masses. Our results have important implications for the derivation of planet masses from disc observations: depending on the planetary gas accretion rate, the derived masses from ALMA observations might be off by up to a factor 2. We discuss the consequence of the change of the gap opening mass on the evolution of planetary systems by taking the example of the Grand Tack scenario. Planetary gas accretion also impacts the stellar gas accretion, where we find only a small influence due to the presence of a gas accreting planet

Expression of vascular endothelial growth factor (VEGF) and its receptors in thyroid carcinomas of follicular origin: a potential autocrine loop.

OBJECTIVE: The aim of this study was to clarify the role of vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR) pathways in thyroid tumourigenesis. METHODS: We examined VEGF, VEGFR-1 and VEGFR-2 expression on 34 papillary thyroid carcinomas (PTCs), 18 follicular thyroid carcinomas (FTCs), eight poorly differentiated thyroid carcinomas (PDTCs) and on a thyroid tumour-derived cell line (NPA'87) by immunohistochemistry, reverse transcriptase PCR, immunofluorescence and Western blotting. RESULTS: We have demonstrated that VEGF expression was significantly (P &lt; 0.05) more prevalent in PTCs (79%) than in FTCs (50%) or PDTCs (37%). Similarly, 76% of PTCs, 83% of FTCs and 25% of PDTCs expressed VEGFR-1, whereas 68% of PTCs, 56% of FTCs and 37% of PDTCs expressed VEGFR-2. Coexpression of VEGF and its receptors was observed in 50% of PTCs, 39% of FTCs and 12% of PDTCs, raising the possibility that VEGF may signal in an autocrine loop in these neoplasias, as observed previously for other types of cancer. In agreement with the idea that autocrine VEGF signalling plays an important role in thyroid carcinogenesis, the blockade of either VEGF or its receptors with neutralizing antibodies significantly reduced cell viability and increased apoptosis levels of the VEGFR-positive thyroid tumour cell line NPA'87. CONCLUSIONS: Our results highlight a previously undefined VEGF autocrine action in thyroid carcinomas which could play a crucial role in tumour cell survival and could represent a useful therapeutic target for thyroid tumours

Expression and function of the chemokine receptor CCR7 in thyroid carcinomas.

The chemokine receptor CCR7 plays a critical role in lymphocyte and dendritic cell trafficking into and within lymph nodes, the preferential metastatic site for papillary (PTC) and medullary (MTC) thyroid carcinomas. In order to determine a possible role for CCR7 in mediating the metastatic behaviour of thyroid carcinomas, we analysed its expression in normal and tumoral thyroid tissues of different histotypes and studied the in vitro effects of its activation by the CCR7 ligand, CCL21. Using real-time quantitative-PCR, we observed that CCR7 expression was higher in PTCs and MTCs than in follicular and poorly differentiated thyroid carcinomas. CCR7 expression was ninefold higher in classic compared with follicular variants of PTCs, and its expression in MTCs was significantly correlated with lymph node metastases. Immunohistochemical staining for CCR7 showed protein expression in neoplastic thyroid cells, with higher intensity in PTCs, MTCs and their lymph node metastases (LNMs). We further showed that CCL21 stimulation of a CCR7-expressing thyroid tumour cell line (TPC-1) promotes cell proliferation and migration, and the chemotactic effect of CCL21 in these cells involves actin polymerization, increased beta1-integrin expression and increased matrix metalloproteinase secretion. Taken together, our results demonstrate that CCR7 activation on thyroid carcinoma cells by CCL21 - a chemokine abundantly expressed in lymph nodes - favours tissue invasion and cell proliferation, and therefore may promote thyroid carcinoma growth and LNM