High M2-TAM Infiltration and STAT3/NF-κB Signaling Pathway as a Predictive Factor for Tumor Progression and Death in Cervical Cancer.

INTRODUCTION: The tumor microenvironment (TME) plays a crucial role in the progression, invasion, and metastasis of cervical carcinoma (CC). Tumor-associated macrophages (TAMs) are significant components of the CC TME, but studies on their correlation with CC progression are still controversial. This study aimed to investigate the relationship between TAM infiltration, the STAT3/NF-κB signaling pathway, and Overall Survival (OS) in CC patients. METHODS: In a retrospective study, 691 CC patients who had received a definitive histopathologic diagnosis of CC scored by the FIGO staging system and not undergone preoperative treatment were selected from a database. The effect of TAM infiltration on tumor progression biomarkers using Tissue Microarray (TMA) and immunohistochemistry was evaluated. Furthermore, the impact of the expression of these biomarkers and clinical-pathological parameters on recurrence-free (RF) and OS using Kaplan-Meier and multivariable Cox regression methods was also analyzed. RESULTS: High stromal CD163 + 204 + TAMs density and via STAT3 and NF-κB pathways was relevant to the expression of E-cadherin, Vimentin, MMP9, VEGFα, Bcl-2, Ki-67, CD25, MIF, FOXP3, and IL-17 (all p < 0.0001). In addition, elevated TNM staging IV had a strong association correlation with STAT3 and NF-κB pathways (p < 0.0001), CD25 (p < 0.001), VEGFα (p < 0.001), MIF (p < 0.0001), and Ki-67 (p < 0.0001). On the other hand, overall and recurrence survival was shown to be strongly influenced by the expression of SNAIL (HR = 1.52), E-cadherin (HR = 1.78), and Ki-67 (HR = 1.44). CONCLUSION: M2-TAM and via STAT3/NF-κB pathways had a strong effect on CC tumor progression which reverberated in the severity of clinicopathological findings, becoming an important factor of poor prognosis.

Melatonin changes energy metabolism and reduces oncogenic signaling in ovarian cancer cells.

Ovarian cancer (OC) adjusts energy metabolism in favor of its progression and dissemination. Because melatonin (Mel) has antitumor actions, we investigated its impact on energy metabolism and kinase signaling in OC cells (SKOV-3 and CAISMOV-24). Cells were divided into control and Mel-treated groups, in the presence or absence of the antagonist luzindole. There was a decrease in the levels of HIF-1α, G6PDH, GAPDH, PDH, and CS after Mel treatment even in the presence of luzindole in both OC cells. Mel treatment also reduced the activity of OC-related enzymes including PFK-1, G6PDH, LDH, CS, and GS whereas PDH activity was increased. Lactate and glutamine levels dropped after Mel treatment. Mel further promoted a reduction in the concentrations of CREB, JNK, NF-kB, p-38, ERK1/2, AKT, P70S6K, and STAT in both cell lines. Mel reverses Warburg-type metabolism and possibly reduces glutaminolysis, thereby attenuating various oncogenic molecules associated with OC progression and invasion.

Potential role of the Eph/ephrin system in colorectal cancer: emerging druggable molecular targets.

The Eph/ephrin system regulates many developmental processes and adult tissue homeostasis. In colorectal cancer (CRC), it is involved in different processes including tumorigenesis, tumor angiogenesis, metastasis development, and cancer stem cell regeneration. However, conflicting data regarding Eph receptors in CRC, especially in its putative role as an oncogene or a suppressor gene, make the precise role of Eph-ephrin interaction confusing in CRC development. In this review, we provide an overview of the literature and highlight evidence that collaborates with these ambiguous roles of the Eph/ephrin system in CRC, as well as the molecular findings that represent promising therapeutic targets.

The Expression of Hsa-Mir-1225-5p Limits the Aggressive Biological Behaviour of Luminal Breast Cancer Cell Lines.

INTRODUCTION: Numerous genetic and biological processes have been linked to the function of microRNAs (miRNAs), which regulate gene expression by targeting messenger RNA (mRNA). It is commonly acknowledged that miRNAs play a role in the development of disease and the embryology of mammals. METHOD: To further understand its function in the oncogenic process, the expression of the miRNA profile in cancer has been investigated. Despite being referred to as a noteworthy miRNA in cancer, it is unknown whether hsa-miR-1225-5p plays a part in the in vitro progression of the luminal A and luminal B subtypes of breast cancer. We proposed that a synthetic hsa-miR-1225-5p molecule be expressed in breast cancer cell lines and its activity be evaluated with the aim of studying its function in the development of luminal breast cancer. In terms of the typical cancer progression stages, such as proliferation, survival, migration, and invasion, we investigated the role of hsa-miR-1225-5p in luminal A and B breast cancer cell lines. RESULTS: Additionally, using bioinformatics databases, we thoroughly explored the target score-based prediction of miRNA-mRNA interaction. Our study showed that the expression of miR-1225-5p significantly inhibited the in vitro growth of luminal A and B breast cancer cell lines. CONCLUSION: The results were supported by a bioinformatic analysis and a detailed gene network that boosts the activation of signaling pathways required for cancer progression.

Prostaglandin E2 Exposure Disrupts E-Cadherin/Caveolin-1-Mediated Tumor Suppression to Favor Caveolin-1-Enhanced Migration, Invasion, and Metastasis in Melanoma Models.

Caveolin-1 (CAV1) is a membrane-bound protein that suppresses tumor development yet also promotes metastasis. E-cadherin is important in CAV1-dependent tumor suppression and prevents CAV1-enhanced lung metastasis. Here, we used murine B16F10 and human A375 melanoma cells with low levels of endogenous CAV1 and E-cadherin to unravel how co-expression of E-cadherin modulates CAV1 function in vitro and in vivo in WT C57BL/6 or Rag-/- immunodeficient mice and how a pro-inflammatory environment generated by treating cells with prostaglandin E2 (PGE2) alters CAV1 function in the presence of E-cadherin. CAV1 expression augmented migration, invasion, and metastasis of melanoma cells, and these effects were abolished via transient co-expression of E-cadherin. Importantly, exposure of cells to PGE2 reverted the effects of E-cadherin expression and increased CAV1 phosphorylation on tyrosine-14 and metastasis. Moreover, PGE2 administration blocked the ability of the CAV1/E-cadherin complex to prevent tumor formation. Therefore, our results support the notion that PGE2 can override the tumor suppressor potential of the E-cadherin/CAV1 complex and that CAV1 released from the complex is phosphorylated on tyrosine-14 and promotes migration/invasion/metastasis. These observations provide direct evidence showing how a pro-inflammatory environment caused here via PGE2 administration can convert a potent tumor suppressor complex into a promoter of malignant cell behavior.

EV-miRNA-Mediated Intercellular Communication in the Breast Tumor Microenvironment.

Cancer research has prioritized the study of the tumor microenvironment (TME) as a crucial area of investigation. Understanding the communication between tumor cells and the various cell types within the TME has become a focal point. Bidirectional communication processes between these cells support cellular transformation, as well as the survival, invasion, and metastatic dissemination of tumor cells. Extracellular vesicles are lipid bilayer structures secreted by cells that emerge as important mediators of this cell-to-cell communication. EVs transfer their molecular cargo, including proteins and nucleic acids, and particularly microRNAs, which play critical roles in intercellular communication. Tumor-derived EVs, for example, can promote angiogenesis and enhance endothelial permeability by delivering specific miRNAs. Moreover, adipocytes, a significant component of the breast stroma, exhibit high EV secretory activity, which can then modulate metabolic processes, promoting the growth, proliferation, and migration of tumor cells. Comprehensive studies investigating the involvement of EVs and their miRNA cargo in the TME, as well as their underlying mechanisms driving tumoral capacities, are necessary for a deeper understanding of these complex interactions. Such knowledge holds promise for the development of novel diagnostic and therapeutic strategies in cancer treatment.

Advances in Central Nervous System Tumor Classification.

Historically, the classification of tumors of the central nervous system (CNS) relies on the histologic appearance of cells under a microscope; however, the molecular era of medicine has resulted in new diagnostic paradigms anchored in the intrinsic biology of disease. The 2021 World Health Organization (WHO) reformulated the classification of CNS tumors to incorporate molecular parameters, in addition to histology, to define many tumor types. A contemporary classification system with integrated molecular features aims to provide an unbiased tool to define tumor subtype, the risk of tumor progression, and even the response to certain therapeutic agents. Meningiomas are heterogeneous tumors as depicted by the current 15 distinct variants defined by histology in the 2021 WHO classification, which also incorporated the first moelcular critiera for meningioma grading: homozygous loss of CDKN2A/B and TERT promoter mutation as criteria for a WHO grade 3 meningioma. The proper classification and clinical management of meningioma patients requires a multidisciplinary approach, which in addition to the information on microscopic (histology) and macroscopic (Simpson grade and imaging), should also include molecular alterations. In this chapter, we present the most up-to-date knowledge in CNS tumor classification, particularly in meningioma, in the molecular era and how it could affect their future classification and clinical management of patients with these diseases.

Bj-PRO-10c, as an allosteric regulator of argininosuccinate synthase, is a potential therapy for neuroblastoma metastasis.

Cancer is a global public health issue. Neuroblastoma (NB) originates from any tissue of the sympathetic nervous system, and the most affected site is the abdomen. The adrenal gland is the primary site in 38% of cases. Approximately 50% of patients have metastatic disease at diagnosis, and bone marrow is often affected. Metastatic disease is characterized by the spreading of cancer cells that are frequently resistant to chemotherapy and radiotherapy from the primary tumor to other specific parts of the body and is responsible for 90% of cancer-related deaths. Increasing evidence has indicated that nitric oxide (NO) signaling is implicated in the pathophysiology of many types of cancer, particularly in tumorigenesis and cancer progression. However, the effect of NO on metastasis cannot be easily classified as prometastatic or antimetastatic. An understanding at the molecular level of the role of NO in cancer will have profound therapeutic implications for the diagnosis and treatment of disease. Here, the proline-rich decapeptide isolated from Bothrops jararaca venom (Bj-PRO-10c) that enhances and sustains the generation of NO was used to unravel the role of metabolic NO in steps of metastasis. Bj-PRO-10c showed an antimetastatic effect, mainly by interfering with actin cytoskeleton rearrangement, controlling cell proliferation, and decreasing the seeding efficiency of NB in metastatic niches. Therefore, we proposed that an approach for controlled NO induction with the right molecular strategies can hopefully inhibit metastasis and increase the lifespan of NB patients.

GATA-3 expression and its correlation with prognostic factors and survival in canine mammary tumors.

Introduction: The transcription factor GATA-3 plays a significant role in mammary gland development and differentiation. Recent studies on human oncology have demonstrated its association with favorable pathologic factors in breast cancer. Canine mammary tumours, proposed as comparative and translational study models, have epidemiological, clinical, biological, and genetic characteristics similar to those of human breast cancers. Methods: Here, we evaluated the frequency of GATA-3 expression in mammary tumors of dogs and its relationship with prognostic factors and survival. Tumor samples were obtained from 40 female dogs and grouped according to histological type into benign tumors (n = 10), carcinoma in mixed tumors (CMTs) (n = 20), and aggressive tumors (n = 10). CMTs were further separated according to histological grade, and data on clinical staging and diagnosis, histopathological grading, and survival rate were collected. Results: GATA-3 and estrogen receptor (ER) expression were higher in benign and well-differentiated carcinomas than in aggressive tumors, which showed greater Ki-67 expression. The expression rate of ER in the studied groups was equivalent to that of GATA-3. We identified a strong positive correlation between GATA-3 and ER expression frequencies and a negative correlation between those of GATA-3 and Ki-67. There were associations between GATA-3 (p < 0.001), Ki-67 (p = 0.003), tumor size (p < 0.001), clinical stage (p = 0.002), lymph node metastasis (p < 0.001), and histological grade (p < 0.001) by univariate survival analysis. The parameters ER (p = 0.015) and GATA-3 (p = 0.005) also influenced survival in a multifactorial manner. Discussion: Kaplan-Meier analysis of survival curves validated our previous findings that dogs with GATA-3 expression in ≥79.4% of cells had significantly higher survival rates (p < 0.001). The performance analysis showed that the expression of GATA-3 in ≥79.4% of cells effectively predicted survival or death in dogs with mammary tumors. Collectively, these results suggest that GATA-3 can be a relevant marker in the study of mammary tumor progression and has potential as a prognosis marker for predicting outcomes in canine mammary tumors.

Mechanical Properties of Glioblastoma: Perspectives for YAP/TAZ Signaling Pathway and Beyond.

Glioblastoma is a highly aggressive brain tumor with a poor prognosis. Recent studies have suggested that mechanobiology, the study of how physical forces influence cellular behavior, plays an important role in glioblastoma progression. Several signaling pathways, molecules, and effectors, such as focal adhesions, stretch-activated ion channels, or membrane tension variations, have been studied in this regard. Also investigated are YAP/TAZ, downstream effectors of the Hippo pathway, which is a key regulator of cell proliferation and differentiation. In glioblastoma, YAP/TAZ have been shown to promote tumor growth and invasion by regulating genes involved in cell adhesion, migration, and extracellular matrix remodeling. YAP/TAZ can be activated by mechanical cues such as cell stiffness, matrix rigidity, and cell shape changes, which are all altered in the tumor microenvironment. Furthermore, YAP/TAZ have been shown to crosstalk with other signaling pathways, such as AKT, mTOR, and WNT, which are dysregulated in glioblastoma. Thus, understanding the role of mechanobiology and YAP/TAZ in glioblastoma progression could provide new insights into the development of novel therapeutic strategies. Targeting YAP/TAZ and mechanotransduction pathways in glioblastoma may offer a promising approach to treating this deadly disease.

MicroRNA­130a­3p inhibition suppresses cervical cancer cell progression.

MicroRNAs (miRNAs or miRs) play essential roles in the initiation and progression of human tumors, including cervical cancer. However, the mechanisms underlying their actions in cervical cancer remain unclear. The present study aimed to evaluate the functional role of miR­130a­3p in cervical cancer. Cervical cancer cells were transfected with a miRNA inhibitor (anti­miR­130a­3p) and a negative control. Adhesion­independent cell proliferation, migration and invasion were evaluated. The findings presented herein demonstrated that miR­130a­3p was overexpressed in HeLa, SiHa, CaSki, C­4I and HCB­514 cervical cancer cells. The inhibition of miR­130a­3p significantly reduced the proliferation, migration and invasion of cervical cancer cells. The canonical delta­like Notch1 ligand (DLL1) was identified as a possible direct target of miR­103a­3p. The DLL1 gene was further found to be significantly downregulated in cervical cancer tissues. On the whole, the present study demonstrates that miR­130a­3p contributes to the proliferation, migration and invasion of cervical cancer cells. Therefore, miR­130a­3p may be used as a biomarker to determine cervical cancer progression.

ABCB1 and ABCC1 Function during TGF-ß-Induced Epithelial-Mesenchymal Transition: Relationship between Multidrug Resistance and Tumor Progression.

Multidrug resistance (MDR) and induction of metastasis are some of the puzzles encountered during cancer chemotherapy. The MDR phenotype is associated with overexpression of ABC transporters, involved in drug efflux. Metastasis originates from the epithelial-mesenchymal transition (EMT), in which cells acquire a migratory phenotype, invading new tissues. ABC transporters' role during EMT is still elusive, though cells undergoing EMT exhibit enhanced ABCB1 expression. We demonstrated increased ABCB1 expression but no change in activity after TGF-ß-induced EMT in A549 cells. Moreover, ABCB1 inhibition by verapamil increased snail and fibronectin expression, an event associated with upregulation of ABCB1, evidencing coincident cell signaling pathways leading to ABCB1 and EMT-related markers transcription, rather than a direct effect of transport. Additionally, for the first time, increased ABCC1 expression and activity was observed after EMT, and use of ABCC1 inhibitors partially inhibited EMT-marker snail, although increased ABCC1 function translated into collateral sensibility to daunorubicin. More investigations must be done to evaluate the real benefits that the gain of ABC transporters might have on the process of metastasis. Considering ABCC1 is involved in the stress response, affecting intracellular GSH content and drug detoxification, this transporter could be used as a therapeutic target in cancer cells undergoing EMT.

Elemental profiles in distant tissues during tumor progression.

BACKGROUND: Essential elements have functions in tumor progression by promoting protumoral cellular processes, such as proliferation, and migration, among others. Obtaining an understanding of how these elements relate to tumor progression processes is of great importance for research. Elemental profile studies in distant tissues, which can be modulated by tumor cells to promote metastasis, have not been sufficiently investigated. The main goal of this study is to evaluate multielemental distribution during tumor progression, focusing on tumor tissue and distant tissues that may be affected. METHODS: Tumor progression in vivo was simulated by inoculating C57BL/6 mice with Lewis Lung Carcinoma (LLC) cells. Samples of the primary tumor and distant tissues were collected during 5 weeks of tumor progression for the control and experimental (tumor-bearing) groups. The biological samples were analyzed using the synchrotron radiation X-Ray fluorescence technique. Data on the concentration of P, S, K, Ca, Mn, Fe, Cu, and Zn in the samples were obtained and statistically analyzed to evaluate the distribution of the elements during tumor progression in the primary tumor as well as distant tissues. RESULTS: It was possible to observe significant changes in the concentrations' distribution of P, S, K, Ca, Mn, Fe, and Cu in distant tissues caused by the presence of tumor cells. It was also possible to detect a greater similarity between tumor tissue (which has the lung as tissue of origin) and a tissue of non-origin, such as the liver, which is an unprecedented result. Moreover, changes in the distributions of concentrations were detected and studied over time for the different tissues analyzed, such as primary tumor, liver and lung, in Control and Tumor groups. CONCLUSIONS: Among other results, this paper could explore the modulation of distant tissues caused by the presence of a primary tumor. This could be achieved by the evaluation of several elements of known biological importance allowing the study of different biological processes involved in cancer. The role of essential elements as modulators of the tumor microenvironment is a relevant aspect of tumor progression and this work is a contribution to the field of tumoral metallomics.

Purinergic P2X7R as a potential target for pancreatic cancer.

Pancreatic cancer is one of the deadliest types of cancer, with a death rate nearly equal to the incidence. The P2X7 receptor (P2X7R) is a kind of extracellular adenosine triphosphate (ATP)-gated ion channel with special permeability, which exists in most tissues of human body and mediates inflammation-related signaling pathways and immune signal transduction after activation. P2X7R is also present on the surface of several tumor cells and is involved in tumor growth and progression. P2X7R expression in pancreatic cancer has also been identified in recent studies. Activation of P2X7R in pancreatic cancer can support the proliferation of pancreatic stellate cells, participate in protein interactions, and mediate ERK1/2, IL-6/STAT3, hCAP-18/LL-37, PI3K/AKT signaling pathways to promote pancreatic cancer progression. Inhibitors targeting P2X7R can inhibit the development of pancreatic cancer and are expected to be used in clinical therapy. Therefore, P2X7R is promising as a potential therapeutic target for pancreatic cancer. This article reviews the progress of research on P2X7R in pancreatic cancer.

Early contribution of germline and nevi genetic alterations to a rapidly-progressing cutaneous melanoma patient: a case report.

BACKGROUND: Cutaneous melanoma is the skin cancer with the highest mutational burden and metastatic rate. Early genetic alterations and biomarkers of distant progression are a point of interest. In addition to germline-susceptibility loci, almost 30% of melanomas arise from precursor benign nevi lesions, providing a source for malignant transformation. CASE PRESENTATION: Patient#009 developed a cutaneous melanoma over a nevus, followed by progression to regional and distant metastases in months, unresponsive to targeted therapy. To search for the genetic contribution to this rapid progression, a longitudinal analysis was performed through WES of germline, nevi, primary tumor, and a metastatic lymph node. Differential SNP/INDEL and CNV gene alterations, with functional impact on key pathways and cancer hallmarks in each step of evolution, were discerned. Tumor-associated nevus was, for the first time, split into two sections, distant and adjacent to the primary tumor, to study its heterogeneity. Shared SNP alterations, with stable allele fraction from germline to metastasis were detected, mainly affecting DNA repair genes and promoting genome instability. Early somatic alterations, shared by nevi and primary and metastatic tumors, included BRAFV600E and focal copy-loss of several genes, acquiring additional cancer hallmarks. Phylogenetic analyses revealed that these common somatic alterations would provide a "bridge", allowing progression from a benign to a malignant state. Distant and adjacent nevi were rich in alterations, presenting differential SNP and CNV alterations. Upon tumor transformation, a marked increase in CNV over SNP alterations was determined. Both the number of SNP and CNV-affected genes, including known driver genes, increased throughout progression, although TMB levels remained lower than expected for melanoma. Typical alterations in BRAFV600E tumors related to intrinsic resistance to targeted therapy were found, including BRAF amplification and loss of PTEN, CDKN2A/B, and TP53 surveillance genes. Finally, numerous metastatic alterations were detected, further promoting tumor progression. CONCLUSIONS: In this patient, longitudinal WES analysis revealed a sequential and cumulative pattern of genetic alterations, where germline and nevi somatic events contributed early to its rapid clinical progression. In this case report, we found tumor-associated nevi as genetically heterogeneous precursor entities, in which potential prognostic biomarkers should be studied prospectively.

The hsa-miR-516a-5p and hsa-miR-516b-5p microRNAs reduce the migration and invasion on T98G glioblastoma cell line.

microRNAs (miRNAs) are involved in numerous functions and processes in the brain and other organs through the regulation of gene and protein expression. miRNA dysregulation is associated with the development of several diseases, including the brain and Central Nervous System cancer (CNS). The hsa-miR-516a-5p and hsa-miR-516b-5p are involved in proliferation, migration, and invasion in different tumor models, but their antitumor effect has not been evaluated in cancer of CNS. Therefore, we aimed to assess the effect of the miRNAs hsa-miR-516a-5p and miRNA hsa-miR-516b-5p on the Glioblastoma cell line (T98G). We used synthetic miRNA mimics to induce the overexpression of both miRNAs in the cell line, which was corroborated by RT-qPCR. Next, we evaluated the effect on proliferation, migration, and invasion using the CyQuant direct kit, ThinCert ™ inserts and invasion BioCoat ™ Matrigel® Invasion Chambers. We found upregulation of these miRNAs induced significant changes on the migration and invasion processes of T98G cells, but not affected the proliferation rate. These results suggest that both microRNAs could be playing an important role in the control of tumor progression towards metastasis. The bioinformatics analysis showed that target genes for these miRNAs are involved in different biological processes such as in cell adhesion molecule binding and cell junction disassembly, which are important for cancer progression. Further studies and experimental validation are needed to identify the genes regulated by microRNAs.

Suppression of CD56bright NK cells in breast cancer patients is associated with the PD-1 and TGF-ßRII expression.

BACKGROUND: Natural killer (NK) cells, as professional cytotoxic cells, play a key role against cancer in the early and metastatic stages. Their functional defects are highly associated with the initiation or progression of breast cancer (BC). Here, we investigated the phenotypic characterization of NK cells in 26 newly diagnosed BC patients in comparison to 12 healthy counterparts. METHODS: Expression of CXCR3 and PD-1, and also NKG2D, and TGF-ßRII were studied on CD56dim and CD56bright NK cells from fresh peripheral blood (PB) samples using flow cytometry. The plasma levels of IFN-γ and soluble MIC-A levels were also assessed by ELISA. RESULTS: Both CD56dim and CD56bright NK subtypes showed lower CXCR3 and NKG2D expression in BC patients than healthy subjects. Furthermore, patients' CD56bright NK cells significantly showed higher expression levels of TGF-ßRII and PD-1. Interestingly, increased concentration of MIC-A level in plasma of BC patients was associated with the higher TGF-ßRII and PD-1 expression in all NK cells, while the plasma level of IFN-γ was associated with the lower TGF-ßRII expression on CD56bright NK cells in these patients. CONCLUSION: Our results demonstrated phenotypically suppressed-NK cells, especially in the CD56bright subset of BC patients. It specifies their potential incompetence and outlines decrement of their anti-tumor activity, which could be interrelated with the tumor pathogenesis, TME immunosuppression, and so disease progression. The induction of compensatory mechanisms revives NK cells function and could be used in combination with the conventional treatments as a putative therapeutic approach for targeted immunotherapy.

Ion Channels in Endometrial Cancer.

Uterine or endometrial cancer (EC) is the sixth most common neoplasia among women worldwide. Cancer can originate from a myriad of causes, and increasing evidence suggests that ion channels (IC) play an important role in the process of carcinogenesis, taking part in many pathways such as self-sufficiency in growth signals, proliferation, evasion of programmed cell death (apoptosis), angiogenesis, cell differentiation, migration, adhesion, and metastasis. Hormones and growth factors are well-known to be involved in the development and/or progression of many cancers and can also regulate some ion channels and pumps. Since the endometrium is responsive and regulated by these factors, the ICs could make an important contribution to the development and progression of endometrial cancer. In this review, we explore what is beyond (ion) flow regulation by investigating the role of the main families of ICs in EC, including as possible targets for EC treatment.

Alpha2beta1 Integrin Polymorphism in Diffuse Astrocytoma Patients.

Integrins are heterodimeric transmembrane glycoproteins resulting from the non-covalent association of an α and ß chain. The major integrin receptor for collagen/laminin, α2ß1 is expressed on a wide variety of cell types and plays an essential role in the adhesion of normal and tumor cells to the extracellular matrix. Integrin-triggered signaling pathways promote the invasion and survival of glioma cells by modifying the brain microenvironment. In this study, we investigated the association of a specific genetic polymorphism of integrin α2ß1 with the incidence of diffusely infiltrating astrocytoma and the progression of these tumors. Single-nucleotide polymorphism in intron 7 of the integrin ITGA2 gene was examined in 158 patients and 162 controls using polymerase chain reaction and restriction enzyme analysis. The ITGA2 genotype +/+ (with a BglII restriction site in both alleles) exhibited higher frequency in grade II astrocytoma compared to control (P = 0.02) whereas the genotype -/- (lacking the BglII site) correlated with the poorest survival rate (P = 0.04). In addition, in silico analyses of ITGA2 expression from low-grade gliomas (LGG, n = 515) and glioblastomas (GBM, n = 159) indicated that the higher expression of ITGA2 in LGG was associated with poor overall survival (P < 0.0001). However, the distribution of integrin ITGA2 BglII genotypes (+/+, +/-, -/-) was not significantly different between astrocytoma subgroups III and IV (P = 0.65, 0.24 and 0.33; 0.29, 0.48, 0.25, respectively) compared to control. These results suggest a narrow association between the presence of this SNP and indicate that further studies with larger samples are warranted to analyze the relation between tumor grade and overall survival, highlighting the importance of determining these polymorphisms for prognosis of astrocytomas.

Cellular Model of Malignant Transformation of Primary Human Astrocytes Induced by Deadhesion/Readhesion Cycles.

Astrocytoma is the most common and aggressive tumor of the central nervous system. Genetic and environmental factors, bacterial infection, and several other factors are known to be involved in gliomagenesis, although the complete underlying molecular mechanism is not fully understood. Tumorigenesis is a multistep process involving initiation, promotion, and progression. We present a human model of malignant astrocyte transformation established by subjecting primary astrocytes from healthy adults to four sequential cycles of forced anchorage impediment (deadhesion). After limiting dilution of the surviving cells obtained after the fourth deadhesion/readhesion cycle, three clones were randomly selected, and exhibited malignant characteristics, including increased proliferation rate and capacity for colony formation, migration, and anchorage-independent growth in soft agar. Functional assay results for these clonal cells, including response to temozolomide, were comparable to U87MG-a human glioblastoma-derived cell lineage-reinforcing malignant cell transformation. RNA-Seq analysis by next-generation sequencing of the transformed clones relative to the primary astrocytes revealed upregulation of genes involved in the PI3K/AKT and Wnt/ß-catenin signaling pathways, in addition to upregulation of genes related to epithelial-mesenchymal transition, and downregulation of genes related to aerobic respiration. These findings, at a molecular level, corroborate the change in cell behavior towards mesenchymal-like cell dedifferentiation. This linear progressive model of malignant human astrocyte transformation is unique in that neither genetic manipulation nor treatment with carcinogens are used, representing a promising tool for testing combined therapeutic strategies for glioblastoma patients, and furthering knowledge of astrocytoma transformation and progression.