Alicia Viloria-petit - Academia.edu (original) (raw)

Papers by Alicia Viloria-petit

Biomedicines

Obesity has been identified as a serious health concern in domestic cats. Feline mammary cancer (... more Obesity has been identified as a serious health concern in domestic cats. Feline mammary cancer (FMC) is also a concern, as it is highly prevalent and aggressive. Considering the identified connection between obesity and breast cancer, it is worthwhile to investigate the potential obesity–cancer relationship in FMC. This review investigated the association between adipokines and other obesity-associated molecules and FMC, with the aim of identifying gaps in the current literature for future research. Based on the reports to date, it was found that tissue concentrations of leptin, serum concentrations of leptin receptor, serum amyloid A, and estrogen correlate positively with FMC, and serum concentrations of leptin correlate negatively with FMC. The roles of adiponectin and prolactin in FMC development were also investigated, but the reports are either lacking or insufficient to suggest an association. Numerous research gaps were identified and could be used as opportunities for futu...

Table S1. Duplex Sequences. (DOCX 18 kb)

Figure S2. Representative immunoblots and densitometry demonstrating reduction in TAZ protein lev... more Figure S2. Representative immunoblots and densitometry demonstrating reduction in TAZ protein levels post siRNA transfection at 24 hours. TAZ levels were decreased with siRNA treatment by varying levels, as indicated by the percentages, when compared to the siRNA control (siCtrl), while YAP levels remained fairly consistent. Experimental groups were normalized to loading control β-actin. Graphs depict the average fold change in TAZ or YAP expression relative to siCtrl ± SEM from three independent experiments. (PDF 527 kb)

Figure S1. Immunoblotting of TAZ (WWTR1) and YAP in canine osteosarcoma cell lines to determine a... more Figure S1. Immunoblotting of TAZ (WWTR1) and YAP in canine osteosarcoma cell lines to determine antibody specificity. TAZ antibody (cat no. HPA007415, Sigma-Aldrich) was used at a 1:80,000 dilution. The blot demonstrated a strong band at the predicted weight of 55 kDa (arrow) and slight reactivity to YAP. YAP antibody (cat no. D8H1X, Cell Signalling), used at a 1:1,000 dilution, identified a strong band at the predicted weight of 65 kDa (arrow). (PNG 9754 kb)

International Journal of Molecular Medicine, 2013

Frontiers in Veterinary Science, 2021

Canine osteosarcoma (OSA) is an aggressive malignancy that frequently metastasizes to the lung an... more Canine osteosarcoma (OSA) is an aggressive malignancy that frequently metastasizes to the lung and bone. Not only has there been essentially no improvement in therapeutic outcome over the past 3 decades, but there is also a lack of reliable biomarkers in clinical practice. This makes it difficult to discriminate which patients will most benefit from the standard treatment of amputation and adjuvant chemotherapy. The development of reliable diagnostic biomarkers could aid in the clinical diagnosis of primary OSA and metastasis; while prognostic, and predictive biomarkers could allow clinicians to stratify patients to predict response to treatment and outcome. This review summarizes biomarkers that have been explored in canine OSA to date. The focus is on molecular biomarkers identified in tumor samples as well as emerging biomarkers that have been identified in blood-based (liquid) biopsies, including circulating tumor cells, microRNAs, and extracellular vesicles. Lastly, we propose ...

BMC Veterinary Research, 2018

Background: Osteosarcoma (OSA) is the most common bone cancer in canines. Both transforming growt... more Background: Osteosarcoma (OSA) is the most common bone cancer in canines. Both transforming growth factor beta (TGFβ) and Hippo pathway mediators have important roles in bone development, stemness, and cancer progression. The role of Hippo signalling effectors TAZ and YAP has never been addressed in canine OSA. Further, the cooperative role of TGFβ and Hippo signalling has yet to be explored in osteosarcoma. To address these gaps, this study investigated the prognostic value of TAZ and YAP alone and in combination with pSmad2 (a marker of active TGFβ signalling), as well as the involvement of a TGFβ-Hippo signalling crosstalk in tumourigenic properties of OSA cells in vitro. An in-house trial tissue microarray (TMA) which contained 16 canine appendicular OSA cases undergoing standard care and accompanying follow-up was used to explore the prognostic role of TAZ, YAP and pSmad2. Published datasets were used to test associations between TAZ and YAP mRNA levels, metastasis, and disease recurrence. Small interfering RNAs specific to TAZ and YAP were utilized in vitro alone or in combination with TGFβ treatment to determine their role in OSA viability, proliferation and migration. Results: Patients with low levels of both YAP and pSmad2 when evaluated in combination had a significantly longer time to metastasis (log-rank test, p = 0.0058) and a longer overall survival (log rank test, p = 0.0002). No similar associations were found for TAZ and YAP mRNA levels. In vitro, TAZ knockdown significantly decreased cell viability, proliferation, and migration in metastatic cell lines, while YAP knockdown significantly decreased viability in three cell lines, and migration in two cell lines, derived from either primary tumours or their metastases. The impact of TGFβ signaling activation on these effects was cell line-dependent. Conclusions: YAP and pSmad2 have potential prognostic value in canine appendicular osteosarcoma. Inhibiting YAP and TAZ function could lead to a decrease in viability, proliferation, and migratory capacity of canine OSA cells. Assessment of YAP and pSmad2 in larger patient cohorts in future studies are needed to further elucidate the role of TGFβ-Hippo signalling crosstalk in canine OSA progression.

Molecular cancer, Feb 19, 2018

Lung cancer is the leading cause of death by cancer in North America. A decade ago, genomic rearr... more Lung cancer is the leading cause of death by cancer in North America. A decade ago, genomic rearrangements in the anaplastic lymphoma kinase (ALK) receptor tyrosine kinase were identified in a subset of non-small cell lung carcinoma (NSCLC) patients. Soon after, crizotinib, a small molecule ATP-competitive ALK inhibitor was proven to be more effective than chemotherapy in ALK-positive NSCLC patients. Crizotinib and two other ATP-competitive ALK inhibitors, ceritinib and alectinib, are approved for use as a first-line therapy in these patients, where ALK rearrangement is currently diagnosed by immunohistochemistry and in situ hybridization. The clinical success of these three ALK inhibitors has led to the development of next-generation ALK inhibitors with even greater potency and selectivity. However, patients inevitably develop resistance to ALK inhibitors leading to tumor relapse that commonly manifests in the form of brain metastasis. Several new approaches aim to overcome the var...

Developmental Dynamics, 2013

Introduction: The transforming growth factor beta (TGFb)/activin signaling pathway has a number o... more Introduction: The transforming growth factor beta (TGFb)/activin signaling pathway has a number of documented roles during wound healing and is increasingly appreciated as an essential component of multi-tissue regeneration that occurs in amphibians and fish. Among amniotes (reptiles and mammals), less is known due in part to the lack of an appropriate model organism capable of multi-tissue regeneration. The leopard gecko Eublepharis macularius is able to spontaneously, and repeatedly, regenerate its tail following tail loss. We examined the expression and localization of several key components of the TGFb/activin signaling pathway during tail regeneration of the leopard gecko. Results: We observed a marked increase in phosphorylated Smad2 expression within the regenerate blastema indicating active TGFb/activin signaling. Interestingly, during early regeneration, TGFb1 expression is limited whereas activin-bA is strongly upregulated. We also observe the expression of EMT transcription factors Snail1 and Snail2 in the blastema. Conclusions: Combined, these observations provide strong support for the importance of different TGFb ligands during multi-tissue regeneration and the potential role of TGFb/ activin-induced EMT programs during this process.

International Journal of Molecular Sciences, 2022

Osteosarcoma (OS) is a highly malignant bone tumour that has seen little improvement in treatment... more Osteosarcoma (OS) is a highly malignant bone tumour that has seen little improvement in treatment modalities in the past 30 years. Understanding what molecules contribute to OS biology could aid in the discovery of novel therapies. Extracellular vesicles (EVs) serve as a mode of cell-to-cell communication and have the potential to uncover novel protein signatures. In our research, we developed a novel pipeline to isolate, characterize, and profile EVs from normal bone and osteosarcoma tissue explants from canine OS patients. Proteomic analysis of vesicle preparations revealed a protein signature related to protein metabolism. One molecule of interest, PSMD14/Rpn11, was explored further given its prognostic potential in human and canine OS, and its targetability with the drug capzimin. In vitro experiments demonstrated that capzimin induces apoptosis and reduces clonogenic survival, proliferation, and migration in two metastatic canine OS cell lines. Capzimin also reduces the viabili...

Journal of Developmental Biology, 2016

Transforming growth factor beta (TGFβ) signalling is essential for wound healing, including both ... more Transforming growth factor beta (TGFβ) signalling is essential for wound healing, including both non-specific scar formation and tissue-specific regeneration. Specific TGFβ isoforms and downstream mediators of canonical and non-canonical signalling play different roles in each of these processes. Here we review the role of TGFβ signalling during tissue repair, with a particular focus on the prototypic isoforms TGFβ1, TGFβ2, and TGFβ3. We begin by introducing TGFβ signalling and then discuss the role of these growth factors and their key downstream signalling mediators in determining the balance between scar formation and tissue regeneration. Next we discuss examples of the pleiotropic roles of TGFβ ligands during cutaneous wound healing and blastema-mediated regeneration, and how inhibition of the canonical signalling pathway (using small molecule inhibitors) blocks regeneration. Finally, we review various TGFβ-targeting therapeutic strategies that hold promise for enhancing tissue repair.

Cancers

Osteosarcoma (OS) is the most common type of bone cancer, with ~30% of patients developing second... more Osteosarcoma (OS) is the most common type of bone cancer, with ~30% of patients developing secondary/metastatic tumors. The molecular complexity of tumor metastasis and the lack of effective therapies for OS has cultivated interest in exploiting the proteasome as a molecular target for anti-cancer therapy. As our understanding towards the behavior of malignant cells expands, it is evident that cancerous cells display a greater reliance on the proteasome to maintain homeostasis and sustain efficient biological activities. This led to the development and approval of first- and second-generation proteasome inhibitors (PIs), which have improved outcomes for patients with multiple myeloma and mantle cell lymphoma. Researchers have since postulated the therapeutic potential of PIs for the treatment of OS. As such, this review aims to summarize the biological effects and latest findings from clinical trials investigating PI-based treatments for OS. Integrating PIs into current treatment re...

A possible link between oncogenes and tumor angiogenesis has been implicated by the finding that ... more A possible link between oncogenes and tumor angiogenesis has been implicated by the finding that expression of various oncogenes, particularly mutant ras, can lead to a marked induction of a potent paracrine stimulator of angiogenesis, vascular endothelial growth factor (VEGF). We sought to determine how oncogenic ras induction of VEGF is mediated at the molecular level and whether the mechanisms involved differ fundamentally between transformed epithelial cells and fibroblasts. Our results suggest that in a subline (called RAS-3) of immortalized nontumorigenic rat intestinal epithelial cells (IEC-18) that acquired a tumorigenic phenotype upon transfection of mutant ras, up-regulation of VEGF occurs in the absence of an autocrine growth factor circuit. The expression of VEGF mRNA and protein by RAS-3 cells was strongly suppressed in the presence of LY294002, an inhibitor of phosphatidylinositol 3*-kinase, but remained largely unaffected in the same cells treated with an inhibitor (P...

International Journal of Molecular Sciences, 2020

Breast cancer is the second leading cause of cancer-related mortality among women globally with o... more Breast cancer is the second leading cause of cancer-related mortality among women globally with obesity being one risk factor. Obese breast cancer patients have at least a 30% increased risk of death from breast cancer compared to non-obese breast cancer patients because they present with larger tumors and generally have increased rates of metastasis. Moreover, obese breast cancer patients respond more poorly to treatment compared to non-obese patients, particularly pre-menopausal women diagnosed with triple negative breast cancer (TNBC). To help understand the molecular mechanisms underlying the increased metastasis associated with obesity, we previously established a three-dimensional culture system that permits the co-culture of adipocytes and TNBC cells in a manner that mimics an in vivo milieu. Using this system, we demonstrate that white adipose tissue from both lean and obese mice can induce a partial mesenchymal-to-epithelial transition (MET). Triple negative breast cancer c...

PeerJ, 2018

White adipose tissue (WAT) is essential for energy storage as well as being an active endocrine o... more White adipose tissue (WAT) is essential for energy storage as well as being an active endocrine organ. The secretion of adipokines by adipocytes can affect whole body metabolism, appetite, and contribute to overall health. WAT is comprised of lipid-laden mature adipocytes, as well as immune cells, endothelial cells, pre-adipocytes, and adipose-derived stem cells. In addition, the presence of extracellular matrix (ECM) proteins in WAT can actively influence adipocyte differentiation, growth, and function. Type I collagen is an abundant fibrous ECM protein in WAT that is secreted by developing adipocytes. However, the extent and overall effect of Type I collagen on adipokine secretion in mature adipocytes when added exogenously has not been established. We characterized the effects of Type I collagen overlays prepared using two different buffers on adipocyte physiology and function when added at different times during differentiation. In addition, we compared the effect of collagen ov...

Life Sciences, 2017

Mammary tumorigenesis can be modulated by melatonin, which has oncostatic action mediated by mult... more Mammary tumorigenesis can be modulated by melatonin, which has oncostatic action mediated by multiple mechanisms, including the inhibition of the activity of transcription factors such as NF-κB and modulation of interleukins (ILs) expression. IL-25 is an active cytokine that induces apoptosis in tumor cells due to differential expression of its receptor (IL-17RB). IL-17B competes with IL-25 for binding to IL-17RB in tumor cells, promoting tumorigenesis. This study purpose is to address the possibility of engaging IL-25/IL-17RB signaling to enhance the effect of melatonin on breast cancer cells. Breast cancer cell lines were cultured monolayers and 3D structures and treated with melatonin, IL-25, siIL-17B, each alone or in combination. Cell viability, gene and protein expression of caspase-3, cleaved caspase-3 and VEGF-A were performed by qPCR and immunofluorescence. In addition, an apoptosis membrane array was performed in metastatic cells. Treatments with melatonin and IL-25 significantly reduced tumor cells viability at 1 mM and 1 ng/mL, respectively, but did not alter cell viability of a non-tumorigenic epithelial cell line (MCF-10A). All treatments, alone and combined, significantly increased cleaved caspase-3 in tumor cells grown as monolayers and 3D structures (p b 0.05). Semi-quantitative analysis of apoptosis pathway proteins showed an increase of CYTO-C, DR6, IGFBP-3, IGFBP-5, IGFPB-6, IGF-1, IGF-1R, Livin, P21, P53, TNFRII, XIAP and hTRA proteins and reduction of caspase-3 (p b 0.05) after melatonin treatment. All treatments reduced VEGF-A protein expression in tumor cells (p b 0.05). Our results suggest therapeutic potential, with oncostatic effectiveness, pro-apoptotic and anti-angiogenic properties for melatonin and IL-25-driven signaling in breast cancer cells.

Cancer Research, 2017

Breast cancer (BC) is the most common cancer among women worldwide. Among the different subtypes ... more Breast cancer (BC) is the most common cancer among women worldwide. Among the different subtypes of breast cancer, triple negative breast cancer (TNBC) is the most aggressive disease. The breast tumor microenvironment, which is mainly composed of extracellular matrix (ECM) and stromal cells such as endothelial cells, immune cells and adipocytes, plays a crucial role in cancer progression. The ECM is considered a major regulator of epithelial architecture and function in mammary gland. ECM stiffness correlates with a more malignant breast cancer phenotype. BC progression is also influenced by other conditions of the patient such as obesity. Obesity increases the number of myofibroblasts in mammary adipose tissue which deposits a stiffer ECM and increases the malignant characteristics of mammary epithelial cells. Obese patients with TNBC have a reduced tendency to respond to therapy leading to poor outcome. The density of the mammary gland in terms of adipocyte to ECM ratio also contr...

Biochemical Basis and Therapeutic Implications of Angiogenesis, 2013

Transforming growth factor beta (TGFβ) is a pleiotropic factor that plays pivotal roles in both v... more Transforming growth factor beta (TGFβ) is a pleiotropic factor that plays pivotal roles in both vasculogenesis and angiogenesis and thus is indispensable for development and homeostasis of the vascular system. TGFβ drives vascular responses via its binding to a TGFβ receptor complex formed by type I and type II receptors, as well as type III co-receptors present on both endothelial and mural cells. Signaling by these receptors is context-dependent and tightly regulated, particularly on cultured endothelial cells, where TGFβ can either promote or suppress endothelial migration, proliferation, permeability, and sprouting. These, together with evidence obtained from knockout animals for different TGFβ receptor types, and genetic studies in humans linking mutations in TGFβ signaling components to cardiovascular syndromes, suggest that TGFβ is a central mediator of angiogenesis, where it may play contrasting roles depending on the stage of the process. This review presents an overview of knowledge accumulated to date on TGFβ’s role in angiogenesis as well as vascular biology and vascular disease and discusses potential applications of this knowledge to the treatment of angiogenesis-dependent diseases such as cancer.