Generalized Hopf Bifurcation in a Cancer Model with Antigenicity under Weak and Strong Allee Effects

This article deals with an autonomous differential equation model that studies the interaction between the immune system and the growth of tumor cells with strong and weak Allee effects. The Allee effect refers to interspecific competition, and when the population is small, it can retard population growth. The work focuses on describing analytically, using a set of parameters, the conditions in the phases of the immunoediting theory, particularly in the equilibrium phase, where a latent tumor would exist. Saddle-Node, Saddle-symmetric, Hopf, generalized Hopf, and Takens-Bogdanov bifurcations get presented for both Allee effects, and their biological interpretation regarding cancer dynamics gets discussed. The Hopf and generalized Hopf bifurcation curves get analyzed through hyper-parameter projections of the model, where it gets observed that with a strong Allee effect, more tumor control persists as it has higher antigenicity, in contrast to the weak Allee effect, where lower antigenicity gets observed. Also, we observe that the equilibrium phase persists as antigenicity increases with a strong Allee effect. Finally, the numerical continuation gets performed to replicate the analytical curves' bifurcations and draw the limit and double limit cycles

La leptina promueve la expresión de Hic-5 y la formación de puntos de actina por la vía dependiente de FAK-Src en células epiteliales mamarias MCF10A.

Introduction: Leptin is a hormone secreted by adipocytes that has been associated with the epithelial-mesenchymal transition (EMT). Additionally, leptin promotes the migration and invasion of mammary epithelial cells through the activation of FAK and Src kinases, which are part of a regulatory complex of signaling pathways that promotes the expression of proteins related to the formation of proteolytic structures involved in the invasion and progression of cancer. Recently, overexpression and activation of Hic-5 during the EMT have been shown to induce the formation of actin puncta; these structures are indicative of the formation and functionality of invadopodia, which promote the local degradation of extracellular matrix components and cancer metastasis.Objective: To evaluate the role of FAK and Src kinases in the expression of Hic-5 during the epithelial-mesenchymal transition induced by leptin in MCF10A cells.Materials and methods: We used specific inhibitors of FAK (PF-573228) and Src (PP2) to evaluate Hic-5 expression and subcellular localization by Western blot and immunofluorescence assays and to investigate the formation of actin puncta by epifluorescence in MCF10A cells stimulated with leptin.Results: Leptin induced an increase in Hic-5 expression and the formation of actin puncta. Pretreatment with inhibitors of FAK (PF-573228) and Src (PP2) promoted a decrease in Hic-5 expression and actin puncta formation in the non-tumorigenic mammary epithelial cell line MCF10A.Conclusion: In MCF10A cells, leptin-induced Hic-5 expression and perinuclear localization, as well as the formation of actin puncta through a mechanism dependent on the kinase activity of FAK and Src.Introducción. La leptina es una hormona secretada por los adipocitos que se ha relacionado con el proceso de la transición de epitelio a mesénquima (Epithelial-Mesenchymal Transition, EMT). Promueve la migración e invasión de las células del epitelio mamario mediante la activación de las cinasas FAK y Src, un complejo regulador de vías de señalización que favorecen la expresión de las proteínas relacionadas con la formación de estructuras proteolíticas implicadas en la invasión y progresión del cáncer. Recientemente, se ha descrito que la sobreexpresión y activación de la proteína Hic-5 durante el mencionado proceso de transición, favorece la formación de los puntos de actina (indicativa de la formación y funcionalidad de los invadopodios), lo cual promueve la degradación local de los componentes de la matriz extracelular y la metástasis del cáncer.Objetivos. Evaluar el papel de las cinasas FAK y Src sobre la expresión y localización subcelular de Hic-5 y la formación de puntos de actina inducida por la leptina en la línea celular MCF10A de epitelio mamario no tumoral.Materiales y métodos. Se utilizaron los inhibidores específicos de la FAK (PF-573228) y la Src (PP2) para evaluar el papel de ambas cinasas en los niveles de expresión y localización subcelular de la proteína Hic-5 mediante Western blot e inmunofluorescencia, así como la formación de puntos de actina mediante la tinción con faloidina-TRITC en células MCF10A estimuladas con leptina.Resultados. La leptina indujo el incremento en la expresión de Hic-5 y la formación de puntos de actina. El tratamiento previo con los inhibidores de las cinasas FAK (PF-573228) y Src (PP2), promovió la disminución en la expresión de Hic-5 y de los puntos de actina en la línea celular MCF10A de epitelio mamario no tumoral.Conclusión. La leptina indujo la expresión y la localización perinuclear de Hic-5 y la formación de puntos de actina mediante un mecanismo dependiente de la actividad de las cinasas FAK y Src en las células MCF10A

Efecto del cloruro de cadmio sobre la expresión del represor transcripcional REST/NRSF y su gen blanco CDH1 en tejido pulmonar de ratones ICR-CD1

REST (RE1-Silencing Transcription factor) is a transcription factor with zinc fingers that represses its transcriptional targets through its interaction with the RE1 (Restrictive Element 1) sequence. Although some metals such as cadmium can alter protein function by competing with zinc, studies at the molecular level have not been performed to determine this effect on REST. The CDH1 gene is a transcriptional target of REST that codes for the cell adhesion glycoprotein E-cadherin and the deregulation of its expression has been associated with the cancerous process. The objective of this work was to evaluate the effect of exposure to 1.3 µM/3 days with CdCl2 in ICR-CD1 mice on the levels of REST and its target gene CDH1 in lung tissue. CDH1 mRNA levels were determined by RT-PCR, while E-cadherin and REST protein levels were assessed by Western blot. After CdCl2 treatment, the levels of CDH1 and its product E-cadherin increased in relation to the loss of REST expression. In conclusion, cadmium promotes a decrease in REST at the protein level, as well as an increase in the levels of CDH1 messenger RNA and its E-cadherin product. The increase in E-cadherin is probably due to CDH1 transcriptional relaxation mediated by loss of REST expression.REST (RE1-Silencing Transcription factor) es un factor de transcripción con dedos de zinc que reprime a sus blancos transcripcionales a través de su interacción con la secuencia RE1 (Restrictive Element 1). Aunque algunos metales como el cadmio pueden alterar la función de proteínas al competir con el zinc, no se han realizado estudios a nivel molecular para para determinar dicho efecto sobre REST. El gen CDH1 es un blanco transcripcional de REST que codifica para la glicoproteína de adhesión celular E-cadherina y la desregulación de su expresión ha sido asociada al proceso canceroso. El objetivo de este trabajo fue evaluar el efecto de la exposición a 1.3 µM/3 días con CdCl2 en ratones ICR-CD1 sobre los niveles de REST y de su gen blanco CDH1 en tejido pulmonar. Los niveles del mRNA de CDH1 se determinaron por RT-PCR, mientras que los niveles de las proteínas E-cadherina y REST se evaluaron mediante Western blot. Después del tratamiento con CdCl2 los niveles de CDH1 y de su producto E-cadherina se incrementaron en relación con la pérdida de la expresión de REST. En conclusión, el cadmio promueve la disminución de REST a nivel de proteína, así como el incremento de los niveles de ARN mensajero de CDH1 y de su producto E-cadherina. El incremento de E-cadherina probablemente se debe a la relajación transcripcional de CDH1 mediado por la pérdida de la expresión de REST

Signaling Pathways Induced by Leptin during Epithelial–Mesenchymal Transition in Breast Cancer

Leptin is an adipokine that is overexpressed in obese and overweight people. Interestingly, women with breast cancer present high levels of leptin and of its receptor ObR. Leptin plays an important role in breast cancer progression due to the biological processes it participates in, such as epithelial⁻mesenchymal transition (EMT). EMT consists of a series of orchestrated events in which cell⁻cell and cell⁻extracellular matrix interactions are altered and lead to the release of epithelial cells from the surrounding tissue. The cytoskeleton is also re-arranged, allowing the three-dimensional movement of epithelial cells into the extracellular matrix. This transition provides cells with the ability to migrate and invade adjacent or distal tissues, which is a classic feature of invasive or metastatic carcinoma cells. In recent years, the number of cases of breast cancer has increased, making this disease a public health problem worldwide and the leading cause of death due to cancer in women. In this review, we focus on recent advances that establish: (1) leptin as a risk factor for the development of breast cancer, and (2) leptin as an inducer of EMT, an event that promotes tumor progression

Peptide-Based Vaccines in Clinical Phases and New Potential Therapeutic Targets as a New Approach for Breast Cancer: A Review

Breast cancer is the leading cause of death in women from 20 to 59 years old. The conventional treatment includes surgery, chemotherapy, hormonal therapy, and immunotherapy. This immunotherapy is based on administering monoclonal therapeutic antibodies (passive) or vaccines (active) with therapeutic purposes. Several types of vaccines could be used as potential treatments for cancer, including whole-cell, DNA, RNA, and peptide-based vaccines. Peptides used to develop vaccines are derived from tumor-associated antigens or tumor-specific antigens, such as HER-2, MUC1, ErbB2, CEA, FRα, MAGE A1, A3, and A10, NY-ESO-1, among others. Peptide-based vaccines provide some advantages, such as low cost, purity of the antigen, and the induction of humoral and cellular immune response. In this review, we explore the different types of vaccines against breast cancer with a specific focus on the description of peptide-based vaccines, their composition, immune response induction, and the description of new potential therapeutic targets

Biological Role and Aberrant Overexpression of Syntenin-1 in Cancer: Potential Role as a Biomarker and Therapeutic Target

Syntenin-1 is a 298 amino acid protein codified by the melanoma differentiation-associated gene-9 (MDA-9). Structurally, it is composed of four domains: N-terminal, PDZ1, PDZ2, and C-terminal. The PDZ domains of syntenin-1 are involved in the stability and interaction with other molecules such as proteins, glycoproteins, and lipids. Domains are also associated with several biological functions such as the activation of signaling pathways related to cell-to-cell adhesion, signaling translation, and the traffic of intracellular lipids, among others. The overexpression of syntenin-1 has been reported in glioblastoma, colorectal, melanoma, lung, prostate, and breast cancer, which promotes tumorigenesis by regulating cell migration, invasion, proliferation, angiogenesis, apoptosis, and immune response evasion, and metastasis. The overexpression of syntenin-1 in samples has been associated with worst prognostic and recurrence, whereas the use of inhibitors such as shRNA, siRNA, and PDZli showed a diminution of the tumor size and reduction in metastasis and invasion. Syntenin-1 has been suggested as a potential biomarker and therapeutic target in cancer for developing more effective diagnostic/prognostic tests or passive/active immunotherapies

New Actors Driving the Epithelial–Mesenchymal Transition in Cancer: The Role of Leptin

Leptin is a hormone secreted mainly by adipocytes; physiologically, it participates in the control of appetite and energy expenditure. However, it has also been linked to tumor progression in different epithelial cancers. In this review, we describe the effect of leptin on epithelial–mesenchymal transition (EMT) markers in different study models, including in vitro, in vivo, and patient studies and in various types of cancer, including breast, prostate, lung, and ovarian cancer. The different studies report that leptin promotes the expression of mesenchymal markers and a decrease in epithelial markers, in addition to promoting EMT-related processes such as cell migration and invasion and poor prognosis in patients with cancer. Finally, we report that leptin has the greatest biological relevance in EMT and tumor progression in breast, lung, prostate, esophageal, and ovarian cancer. This relationship could be due to the key role played by the enriched tumor microenvironment in adipose tissue. Together, these findings demonstrate that leptin is a key biomolecule that drives EMT and metastasis in cancer

Cytotoxicity of Ficus Crocata Extract on Cervical Cancer Cells and Protective Effect against Hydrogen Peroxide-Induced Oxidative Stress in HaCaT Non-Tumor Cells

Oxidative stress causes several chronic diseases including cancer. Some chemotherapeutic agents are not selective against tumor cells, causing oxidative stress in non-tumor cells. This study aimed to evaluate the cytotoxic effect of acetone extract of Ficus crocata(Miq.) Mart. ex Miq. (F. crocata) leaves (Ace-EFc) on cervical cancer cells, as well as its protective effect on hydrogen peroxide (H2O2)-induced lipoperoxidation and cytotoxicity in non-tumor HaCaT cells. Antioxidant activity was determined using the DPPH and ABTS radicals. Cell viability and lipoperoxidation were determined with MTT and 1-methyl-2-phenylindole assays, respectively. A model of H2O2-induced cytotoxicity and oxidative damage in HaCaT cells was established. HaCaT cells were exposed to the extract before or after exposure to H2O2, and oxidative damage and cell viability were evaluated. Ace-EFc inhibited the DPPH and ABTS radicals and showed a cytotoxic effect on SiHa and HeLa cells. Furthermore, the extract treatment had a protective effect on hydrogen peroxide-induced lipoperoxidation and cytotoxicity, avoiding the increase in MalonDiAldehyde (MDA) levels and the decrease in cell viability (p F. crocata leaves possess antioxidant and cytoprotective activity against oxidative damage. Thus, they could be useful for protecting cells from conditions that cause oxidative stress

Additional file 1: of Ezrin and E-cadherin expression profile in cervical cytology: a prognostic marker for tumor progression in cervical cancer

Table S1. Correlation of Ezrin and E-cadherin expression with validated biomarkers. (TIFF 2264 kb