How Free is Free? : Restrictive Agency and Optimism

This study explored the effect of restricting participants’ agentic choice on their levels of optimism. This study used the pre-test, post-test design to investigate the impact of non-agentic choice in meaningful scenarios on feelings of optimism. 147 participants completed a measure of optimism, were assigned to conditions of simulated choice, and were instructed to freely write about their decisions. The association between personality traits and optimism was also explored. Study findings showed that assigning participants to restrictive and agentic conditions had no effect on optimism. However, a significant negative correlation trait neuroticism and optimism was found. Content analyses run on the responses found that the most common themes, in order, were seeking change in employment, seeking support from family and friends, and public assistance. Additional research, with a larger sample, should be completed to more fully determine the nature of the relationship among these variables

FUS-CHOP promotes invasion in myxoid liposarcoma through a SRC/FAK/RHO/ROCK-dependent pathway

Deregulated SRC/FAK signaling leads to enhanced migration and invasion in many types of tumors. In myxoid and round cell liposarcoma (MRCLS), an adipocytic tumor characterized by the expression of the fusion oncogene FUS-CHOP, SRC have been found as one of the most activated kinases. Here we used a cell-of-origin model of MRCLS and an MRCLS cell line to thoroughly characterize the mechanisms of cell invasion induced by FUS-CHOP using in vitro (3D spheroid invasion assays) and in vivo (chicken chorioallantoic membrane model) approaches. FUS-CHOP expression activated SRC-FAK signaling and increased the invasive ability of MRCLS cells. In addition, FAK expression was found to significantly correlate with tumor aggressiveness in sarcoma patient samples. The involvement of SRC/FAK activation in FUS-CHOP–mediated invasion was further confirmed using the SRC inhibitor dasatinib, the specific FAK inhibitor PF-573228, and FAK siRNA. Notably, dasatinib and PF573228 could also efficiently block the invasion of cancer stem cell subpopulations. Downstream of SRC/FAK signaling, we found that FUS-CHOP expression increases the levels of the RHO/ROCK downstream effector phospho-MLC2 (T18/S19) and that this activation was prevented by dasatinib or PF573228. Moreover, the ROCK inhibitor RKI-1447 was able to completely abolish invasion in FUS-CHOP–expressing cells. These data uncover the involvement of SRC/FAK/RHO/ROCK signaling axis in FUS-CHOP–mediated invasion, thus providing a rationale for testing inhibitors of this pathway as potential novel antimetastatic agents for MRCLS treatmentPeer ReviewedPostprint (author's final draft

Cold atmospheric plasma enhances doxorubicin selectivity in metastasic bone cancer

High-dose systemic chemotherapy constitutes a main strategy in the management of bone metastases, employing drugs like doxorubicin (DOX), related with severe side effects. To solve this issue, Cold Atmospheric Plasmas (CAP) have been proposed as potential non-invasive anti-cancer agents capable of improving the efficacy of traditional drugs. Here, we investigate the cytotoxic effects of Plasma Conditioned Medium (PCM) in combination with DOX in prostate cancer cells from bone metastases (PC-3) as well as in non-malignant bone-cells. PCM was able to enhance the cytotoxic potential of DOX both in monolayer and in a 3D bioengineered model mimicking the bone matrix. The combined treatment of PCM + DOX resulted in a profound downregulation of the redox defenses (CAT1, SOD2, GPX1) and drug resistance genes (MRP1, MDR1, BCRP1), resulting in an enhanced uptake of DOX coupled to an overload of intracellular ROS. Besides, PCM improved the cytotoxic potential of DOX interfering on the migratory and clonogenic potential of PC-3 cells. Importantly, non-malignant bone cells were unaffected by the combination of PCM + DOX. Overall, these new findings may represent a new therapeutic approach for the management of bone metastatic prostate cancer in the future.Peer ReviewedPostprint (published version

Evaluation on the effects of cold atmospheric plasma and plasma-treated liquids in cancer cell cultures

Cold atmospheric plasma (CAP) is a potential anticancer therapy. CAP has cytotoxic effects when applied either directly to cancer cell cultures or indirectly through plasma-conditioned liquids. This protocol describes how to treat adherent cultures of human cancer cell lines with CAP or plasma-conditioned medium and determine cell viability following treatment. The protocol also includes details on how to quantify the reactive oxygen and nitrogen species present in medium following CAP treatment, using chemical probes using UV-visible or fluorescence spectroscopy. CAP treatment takes ~30 min, and 3 h are required to complete quantification of reactive oxygen and nitrogen species. By providing a standardized protocol for evaluation of the effects of CAP and plasma-conditioned medium, we hope to facilitate the comparison and interpretation of results seen across different laboratories.Peer ReviewedPostprint (author's final draft

Influence of the composition of plasma-activated medium on osteosarcoma

Postprint (published version

Aldh1 Expression and Activity Increase during Tumor Evolution in Sarcoma Cancer Stem Cell Populations

Tumors evolve from initial tumorigenic events into increasingly aggressive behaviors in a process usually driven by subpopulations of cancer stem cells (CSCs). Mesenchymal stromal/stem cells (MSCs) may act as the cell-of-origin for sarcomas, and CSCs that present MSC features have been identified in sarcomas due to their ability to grow as self-renewed floating spheres (tumorspheres). Accordingly, we previously developed sarcoma models using human MSCs transformed with relevant oncogenic events. To study the evolution/emergence of CSC subpopulations during tumor progression, we compared the tumorigenic properties of bulk adherent cultures and tumorsphere-forming subpopulations both in the sarcoma cell-of-origin models (transformed MSCs) and in their corresponding tumor xenograft-derived cells. Tumor formation assays showed that the tumorsphere cultures from xenograft-derived cells, but not from the cell-of-origin models, were enriched in CSCs, providing evidence of the emergence of bona fide CSCs subpopulations during tumor progression. Relevant CSC-related factors, such as ALDH1 and SOX2, were increasingly upregulated in CSCs during tumor progression, and importantly, the increased levels and activity of ALDH1 in these subpopulations were associated with enhanced tumorigenicity. In addition to being a CSC marker, our findings indicate that ALDH1 could also be useful for tracking the malignant potential of CSC subpopulations during sarcoma evolution.This work was supported by the Plan Nacional de I + D + i 2008-2011 [ISC III/FEDER (Miguel Servet Program CP11/00024) and RTICC (RD12/0036/0015)], the Plan Nacional de I + D + i 2013-2016 [MINECO/FEDER (SAF-2013-42946-R)] and the Plan de Ciencia Tecnología e Innovación del Principado de Asturias (GRUPIN14-003) to R.R; and the Plan Nacional de I + D + i 2008-2011 [ISC III/FEDER RTICC (RD12/0036/0027)] to J.G.-C.S

Osteosarcoma: Cells-of-Origin, Cancer stem cells, and targeted therapies

Osteosarcoma (OS) is the most common type of primary solid tumor that develops in bone. Although standard chemotherapy has significantly improved long-term survival over the past few decades, the outcome for those patients with metastatic or recurrent OS remains dismally poor and, therefore, novel agents and treatment regimens are urgently required. A hypothesis to explain the resistance of OS to chemotherapy is the existence of drug resistant CSCs with progenitor properties that are responsible of tumor relapses and metastasis. These subpopulations of CSCs commonly emerge during tumor evolution from the cell-of-origin, which are the normal cells that acquire the first cancer-promotingmutations to initiate tumor formation. In OS, several cell types along the osteogenic lineage have been proposed as cell-of-origin. Both the cell-of-origin and their derived CSC subpopulations are highly influenced by environmental and epigenetic factors and, therefore, targeting the OS-CSC environment and niche is the rationale for many recently postulated therapies. Likewise, some strategies for targeting CSC-associated signaling pathways have already been tested in both preclinical and clinical settings. This review recapitulates current OS cell-of-origin models, the properties of the OS-CSC and its niche, and potential new therapies able to target OS-CSCs

The multikinase inhibitor EC‐70124 synergistically increased the antitumor activity of doxorubicin in sarcomas

Cytotoxic drugs like doxorubicin remain as the most utilized agents in sarcoma treatment. However, advanced sarcomas are often resistant, thus stressing the need for new therapies aimed to overcome this resistance. Multikinase inhibitors provide an efficient way to target several pro-tumorigenic pathways using a single agent and may constitute a valuable strategy in the treatment of sarcomas, which frequently show an aberrant activation of pro-tumoral kinases. Therefore, we studied the antitumor activity of EC-70124, an indolocarbazole analog that have demonstrated a robust ability to inhibit a wide range of pro-survival kinases. Evaluation of the phospho-kinase profile in cell-of-origin sarcoma models and/or sarcoma primary cell lines evidenced that PI3K/AKT/mTOR, JAK/STAT or SRC were among the most highly activated pathways. In striking contrast with the structurally related drug midostaurin, EC-70124 efficiently prevented the phosphorylation of these targets and robustly inhibited proliferation through a mechanism associated to the induction of DNA damage, cell cycle arrest and apoptosis. In addition, EC-70124 was able to partially reduce tumor growth in vivo. Importantly, this compound inhibited the expression and activity of ABC efflux pumps involved in drug resistance. In line with this ability, we found that the combined treatment of EC-70124 with doxorubicin resulted in a synergistic cytotoxic effect in vitro and an increased antitumor activity of this cytotoxic drug in vivo. Altogether, these results uncover the capability of the novel multikinase inhibitor EC-70124 to counteract drug resistance in sarcoma and highlight its therapeutic potential when combined with current treatmentsPeer ReviewedPostprint (author's final draft