ENPP1 induces blood-brain barrier dysfunction and promotes brain metastasis formation in HER2-positive breast cancer.

Background: Brain metastasis (BrM) is a devastating end-stage neurological complication that occurs in up to 50% of HER2+ breast cancer patients. Understanding how disseminating tumor cells manage to cross the blood-brain barrier (BBB) is essential for developing effective preventive strategies. We identified the ecto-nucleotidase ENPP1 as specifically enriched in the secretome of HER2+ brain metastatic cells, prompting us to explore its impact on BBB dysfunction and BrM formation.

Unveiling the role of osteosarcoma-derived secretome in premetastatic lung remodelling.

Background: Lung metastasis is the most adverse clinical factor and remains the leading cause of osteosarcoma-related death. Deciphering the mechanisms driving metastatic spread is crucial for finding open therapeutic windows for successful organ-specific interventions that may halt or prevent lung metastasis.

Methods: We employed a mouse premetastatic lung-based multi-omics integrative approach combined with clinical features to uncover the specific changes that precede lung metastasis formation and identify novel molecular targets and biomarker of clinical utility that enable the design of novel therapeutic strategies.

Polo-like kinase 4 (Plk4) potentiates anoikis-resistance of p53KO mammary epithelial cells by inducing a hybrid EMT phenotype.

Polo-like kinase 4 (Plk4), the major regulator of centriole biogenesis, has emerged as a putative therapeutic target in cancer due to its abnormal expression in human carcinomas, leading to centrosome number deregulation, mitotic defects and chromosomal instability. Moreover, Plk4 deregulation promotes tumor growth and metastasis in mouse models and is significantly associated with poor patient prognosis. Here, we further investigate the role of Plk4 in carcinogenesis and show that its overexpression significantly potentiates resistance to cell death by anoikis of nontumorigenic p53 knock-out (p53KO) mammary epithelial cells.

The Chick CAM as an In Vivo System to Study Stem Cell Activity.

The chick embryo chorioallantoic membrane (CAM), an extensively vascularized extraembryonic membrane, has been widely used to study several aspects of tumor development including tumor-induced angiogenesis, tumor cell proliferation, and metastasis. Based on the tumor cell/CAM system, we focused here on the identification and quantification of cancer stem cells. We validated the CAM model as a suitable model to evaluate stem cell activity in a given mixed cell population.

Biotinylated Polymer-Ruthenium Conjugates: In Vitro and In Vivo Studies in a Triple-Negative Breast Cancer Model.

The need for new therapeutic approaches for triple-negative breast cancer is a clinically relevant problem that needs to be solved. Using a multi-targeting approach to enhance cancer cell uptake, we synthesized a new family of ruthenium(II) organometallic complexes envisaging simultaneous active and passive targeting, using biotin and polylactide (PLA), respectively. All compounds with the general formula, [Ru(η-CpR)(P)(2,2'-bipy-4,4'-PLA-biotin)][CFSO], where R is -H or -CH and P is P(CH), P(CHF) or P(CHOCH), were tested against triple-negative breast cancer cells MDA-MB-231 showing IC values between 2.

Breast Cancer Stem Cell Membrane Biomarkers: Therapy Targeting and Clinical Implications.

Breast cancer is the most common malignancy affecting women worldwide. Importantly, there have been significant improvements in prevention, early diagnosis, and treatment options, which resulted in a significant decrease in breast cancer mortality rates. Nevertheless, the high rates of incidence combined with therapy resistance result in cancer relapse and metastasis, which still contributes to unacceptably high mortality of breast cancer patients.

Cadherin Expression and EMT: A Focus on Gliomas.

Cadherins are calcium-binding proteins with a pivotal role in cell adhesion and tissue homeostasis. The cadherin-dependent mechanisms of cell adhesion and migration are exploited by cancer cells, contributing to tumor invasiveness and dissemination. In particular, cadherin switch is a hallmark of epithelial to mesenchymal transition, a complex development process vastly described in the progression of most epithelial cancers.

The Chick Chorioallantoic Membrane Model: A New In Vivo Tool to Evaluate Breast Cancer Stem Cell Activity.

The high plasticity of cancer stem-like cells (CSCs) allows them to differentiate and proliferate, specifically when xenotransplanted subcutaneously into immunocompromised mice. CSCs are highly tumorigenic, even when inoculated in small numbers. Thus, in vivo limiting dilution assays (LDA) in mice are the current gold standard method to evaluate CSC enrichment and activity.

BR-BCSC Signature: The Cancer Stem Cell Profile Enriched in Brain Metastases that Predicts a Worse Prognosis in Lymph Node-Positive Breast Cancer.

Brain metastases remain an unmet clinical need in breast oncology, being frequently found in HER2-overexpressing and triple-negative carcinomas. These tumors were reported to be highly cancer stem-like cell-enriched, suggesting that brain metastases probably arise by the seeding of cancer cells with stem features. Accordingly, we found that brain-tropic breast cancer cells show increased stem cell activity and tumorigenic capacity in the chick embryo choriallantoic membrane when compared to the parental cell line.

Heterogeneity and Plasticity of Breast Cancer Stem Cells.

In the last 20 years, the conventional view of breast cancer as a homogeneous collection of highly proliferating malignant cells was totally replaced by a model of increased complexity, which points out that breast carcinomas are tissues composed of multiple populations of transformed cells. A large diversity of host cells and structural components of the extracellular matrix constitute the mammary tumour microenvironment, which supports its growth and progression, where individual cancer cells evolve with cumulative phenotypic and genetic heterogeneity. Moreover, contributing to this heterogeneity, it has been demonstrated that breast cancers can exhibit a hierarchical organization composed of tumour cells displaying divergent lineage biomarkers and where, at the apex of this hierarchy, some neoplastic cells are able to self-renew and to aberrantly differentiate.

Clinical spectrum and pleiotropic nature of germline mutations.

encodes E-cadherin, a key protein in adherens junctions. Given that E-cadherin is involved in major cellular processes such as embryogenesis and maintenance of tissue architecture, it is no surprise that deleterious effects arise from its loss of function. E-cadherin is recognised as a tumour suppressor gene, and it is well established that genetic alterations cause diffuse gastric cancer and lobular breast cancer-the foremost manifestations of the hereditary diffuse gastric cancer syndrome.

SRC inhibition prevents P-cadherin mediated signaling and function in basal-like breast cancer cells.

Background: Basal-like breast cancer (BLBC) is a poor prognosis subgroup of triple-negative carcinomas that still lack specific target therapies and accurate biomarkers for treatment selection. P-cadherin is frequently overexpressed in these tumors, promoting cell invasion, stem cell activity and tumorigenesis by the activation of Src-Family kinase (SRC) signaling. Therefore, our aim was to evaluate if the treatment of BLBC cells with dasatinib, the FDA approved SRC inhibitor, would impact on P-cadherin induced tumor aggressive behavior.

Structural and temporal patterns of the first global trading market.

Little is known about the structural patterns and dynamics of the first global trading market (FGTM), which emerged during the sixteenth century as a result of the Iberian expansion, let alone how it compares to today's global financial markets. Here we build a representative network of the FGTM using information contained in 8725 (handwritten) Bills of Exchange from that time-which were (human) interpreted and digitalized into an online database. We show that the resulting temporal network exhibits a hierarchical, highly clustered and disassortative structure, with a power-law dependence on the connectivity that remains remarkably robust throughout the entire period investigated.

Optimization of photo-Fenton process for the treatment of prednisolone.

Prednisolone is a widely prescribed synthetic glucocorticoid and stated to be toxic to a number of non-target aquatic organisms. Its extensive consumption generates environmental concern due to its detection in wastewater samples at concentrations ranged from ng/L to μg/L that requests the application of suitable degradation processes. Regarding the actual treatment options, advanced oxidation processes (AOPs) are presented as a viable alternative.

Role of endogenous hydrogen sulfide in nerve-evoked relaxation of pig terminal bronchioles.

Hydrogen sulfide (HS) is a gasotransmitter employed for intra- and inter-cellular communication in almost all organ systems. This study investigates the role of endogenous HS in nerve-evoked relaxation of pig terminal bronchioles with 260 μm medium internal lumen diameter. High expression of the HS synthesis enzyme cystathionine γ-lyase (CSE) in the bronchiolar muscle layer and strong CSE-immunoreactivity within nerve fibers distributed along smooth muscle bundles were observed.

Quantification of topological features in cell meshes to explore E-cadherin dysfunction.

In cancer, defective E-cadherin leads to cell detachment, migration and metastization. Further, alterations mediated by E-cadherin dysfunction affect cell topology and tissue organization. Herein, we propose a novel quantitative approach, based on microscopy images, to analyse abnormal cellular distribution patterns.

P-Cadherin Linking Breast Cancer Stem Cells and Invasion: A Promising Marker to Identify an "Intermediate/Metastable" EMT State.

Epithelial-mesenchymal transition (also known as EMT) is a fundamental mechanism occurring during embryonic development and tissue differentiation, being also crucial for cancer progression. Actually, the EMT program contributes to the dissemination of cancer cells from solid tumors and to the formation of micro-metastasis that subsequently develop into clinically detectable metastases. Besides being a process that is defined by the progressive loss of epithelial cell characteristics and the acquisition of mesenchymal features, EMT has also been implicated in therapy resistance, immune escape, and maintenance of cancer stem cell properties, such as self-renewal capacity.

The basal epithelial marker P-cadherin associates with breast cancer cell populations harboring a glycolytic and acid-resistant phenotype.

Background: Cancer stem cells are hypoxia-resistant and present a preponderant glycolytic metabolism. These characteristics are also found in basal-like breast carcinomas (BLBC), which show increased expression of cancer stem cell markers.Recently, we demonstrated that P-cadherin, a biomarker of BLBC and a poor prognostic factor in this disease, mediates stem-like properties and resistance to radiation therapy.

P-cadherin signals through the laminin receptor α6β4 integrin to induce stem cell and invasive properties in basal-like breast cancer cells.

P-cadherin is a classical cell-cell adhesion molecule that, in contrast to E-cadherin, has a positive role in breast cancer progression, being considered a poor prognostic factor in this disease. In previous reports, we have shown that this protein induces cancer stem cell and invasive properties to basal-like breast cancer cells. Here, we clarify the downstream signaling pathways that are triggered by P-cadherin to mediate these effects.

High-throughput molecular profiling of a P-cadherin overexpressing breast cancer model reveals new targets for the anti-cancer bacterial protein azurin.

Azurin is a bacterial protein from Pseudomonas aeruginosa which exerts an inhibitory activity in cancer cells. In P-cadherin-overexpressing models, a bad prognosis marker in breast cancer increasing invasion and other malignant features, azurin decreases the invasion of cancer cells. We performed a microarray analysis to compare the expression profile of azurin treated cells with different P-cadherin expression levels.