Upregulated Nuclear Expression of Soluble Epoxide Hydrolase Predicts Poor Outcome in Breast Cancer Patients: Importance of the Digital Pathology Approach.

Breast cancer (BC) is the most common cancer in women, with incidence rates increasing globally in recent years. Therefore, it is important to find new molecules with prognostic and therapeutic value to improve therapeutic response and quality of life. The polyunsaturated fatty acids (PUFAs) metabolic pathway participates in various physiological processes, as well as in the development of malignancies. Although aberrancies in the PUFAs metabolic pathway have been implicated in carcinogenesis, the functional and clinical relevance of this pathway has not been well explored in BC. To evaluate the clinical significance of soluble epoxide hydrolase (EPHX2) expression in Mexican patients with BC using tissue microarrays (TMAs) and digital pathology (DP). Immunohistochemical analyses were performed on 11 TMAs with 267 BC samples to quantify this enzyme. Using DP, EPHX2 protein expression was evaluated solely in tumor areas. The association of EPHX2 with overall survival (OS) was detected through bioinformatic analysis in public databases and confirmed in our cohort via Cox regression analysis. Clear nuclear expression of EPHX2 was identified. Receiver operating characteristics (ROC) curves revealed the optimal cutoff point at 2.847062 × 10-3 pixels, with sensitivity of 69.2% and specificity of 67%. Stratification based on this cutoff value showed elevated EPHX2 expression in multiple clinicopathological features, including older age and nuclear grade, human epidermal growth factor receptor 2 (HER2) and triple negative breast cancer (TNBC) subtypes, and recurrence. Kaplan-Meier curves demonstrated how higher nuclear expression of EPHX2 predicts shorter OS. Consistently, multivariate analysis confirmed EPHX2 as an independent predictor of OS, with a hazard ratio (HR) of 3.483 and a 95% confidence interval of 1.804-6.724 (p < 0.001). Our study demonstrates for the first time that nuclear overexpression of EPHX2 is a predictor of poor prognosis in BC patients. The DP approach was instrumental in identifying this significant association. Our study provides valuable insights into the potential clinical utility of EPHX2 as a prognostic biomarker and therapeutic target in BC.

The Involvement of Polyunsaturated Fatty Acids in Apoptosis Mechanisms and Their Implications in Cancer.

Cancer is a significant global public health issue and, despite advancements in detection and treatment, the prognosis remains poor. Cancer is a complex disease characterized by various hallmarks, including dysregulation in apoptotic cell death pathways. Apoptosis is a programmed cell death process that efficiently eliminates damaged cells. Several studies have indicated the involvement of polyunsaturated fatty acids (PUFAs) in apoptosis, including omega-3 PUFAs such as alpha-linolenic acid, docosahexaenoic acid, and eicosapentaenoic acid. However, the role of omega-6 PUFAs, such as linoleic acid, gamma-linolenic acid, and arachidonic acid, in apoptosis is controversial, with some studies supporting their activation of apoptosis and others suggesting inhibition. These PUFAs are essential fatty acids, and Western populations today have a high consumption rate of omega-6 to omega-3 PUFAs. This review focuses on presenting the diverse molecular mechanisms evidence in both in vitro and in vivo models, to help clarify the controversial involvement of omega-3 and omega-6 PUFAs in apoptosis mechanisms in cancer.

Omega-6 Polyunsaturated Fatty Acids Enhance Tumor Aggressiveness in Experimental Lung Cancer Model: Important Role of Oxylipins.

Lung cancer is currently the leading cause of cancer death worldwide; it is often diagnosed at an advanced stage and bears poor prognosis. It has been shown that diet is an important environmental factor that contributes to the risk and mortality of several types of cancers. Intake of ω-3 and ω-6 PUFAs plays an important role in cancer risk and progression. Current Western populations have high consumption of ω-6 PUFAs with a ratio of ω-6/ω-3 PUFAs at 15:1 to 16.7:1 This high consumption of ω-6 PUFAs is related to increased cancer risk and progression. However, whether a diet rich in ω-6 PUFAs can contribute to tumor aggressiveness has not been well investigated. We used a murine model of pulmonary squamous cell carcinoma to study the aggressiveness of tumors in mice fed with a diet rich in ω-6 PUFAs and its relationship with oxylipins. Our results shown that the mice fed a diet rich in ω-6 showed a marked increase in proliferation, angiogenesis and pro-inflammatory markers and decreased expression of pro-apoptotic proteins in their tumors. Oxylipin profiling revealed an upregulation of various pro-tumoral oxylipins including PGs, HETEs, DiHETrEs and HODEs. These results demonstrate for the first time that high intake of ω-6 PUFAs in the diet enhances the malignancy of tumor cells by histological changes on tumor dedifferentiation and increases cell proliferation, angiogenesis, pro-inflammatory oxylipins and molecular aggressiveness targets such as NF-κB p65, YY1, COX-2 and TGF-ß.

Importance of the Role of ω-3 and ω-6 Polyunsaturated Fatty Acids in the Progression of Brain Cancer.

Brain cancer is one of the most malignant types of cancer in both children and adults. Brain cancer patients tend to have a poor prognosis and a high rate of mortality. Additionally, 20-40% of all other types of cancer can develop brain metastasis. Numerous pieces of evidence suggest that omega-3-polyunsaturated fatty acids (ω-PUFAs) could potentially be used in the prevention and therapy of several types of cancer. PUFAs and oxylipins are fundamental in preserving physiological events in the nervous system; it is, therefore, necessary to maintain a certain ratio of ω-3 to ω-6 for normal nervous system function. Alterations in PUFAs signaling are involved in the development of various pathologies of the nervous system, including cancer. It is well established that an omega-6-polyunsaturated fatty acid (ω-6 PUFA)-rich diet has a pro-tumoral effect, whereas the consumption of an ω-3 rich diet has an anti-tumoral effect. This review aims to offer a better understanding of brain cancer and PUFAs and to discuss the role and impact of PUFAs on the development of different types of brain cancer. Considering the difficulty of antitumor drugs in crossing the blood-brain barrier, the therapeutic role of ω-3/ω-6 PUFAs against brain cancer would be a good alternative to consider. We highlight our current understanding of the role of PUFAs and its metabolites (oxylipins) in different brain tumors, proliferation, apoptosis, invasion, angiogenesis, and immunosuppression by focusing on recent research in vitro and in vivo.

Dual role of hypoxia-inducible factor 1 α in experimental pulmonary tuberculosis: its implication as a new therapeutic target.

AIM: Investigate the role of hypoxia-inducible factor-1α (HIF-1α) in pulmonary tuberculosis (TB). METHODS & RESULTS: A model of progressive pulmonary TB in BALB/c mice, immunohistochemistry and digital pathology were used. High HIF-1α expression was observed during early TB in activated macrophages. During late TB, even higher HIF-1α expression was observed in foamy macrophages, which are resistant to apoptosis. Blocking HIF-1α during early infection with 2-methoxyestradiol worsened the disease, while during late TB, it induced macrophage apoptosis and decreased bacillary loads. CONCLUSION: HIF-1α has a dual role in experimental TB. This finding could have therapeutic implications because combined treatment with 2-methoxyestradiol and antibiotics appeared to eliminate mycobacteria more efficiently than conventional chemotherapy during advanced disease.

Role of Yin Yang-1 (YY1) in the transcription regulation of the multi-drug resistance (MDR1) gene.

Resistance to chemotherapy hinders the successful treatment of acute lymphoblastic leukemia (ALL). The multi-drug resistance-1 (MDR1/ABCB1) gene encodes P-glycoprotein (P-gp), which plays an important role in chemoresistance; however, its transcriptional regulation remains unclear. We investigated the role of YY1 in the regulation of MDR1 and its relation to ALL outcomes. Analysis of the MDR1 promoter revealed four putative YY1-binding sites, which we analyzed using a reporter system and ChIP analysis. YY1 silencing resulted in the inhibition of MDR1 expression and function. The clinical roles of YY1 and MDR1 expression were evaluated in children with ALL. Expression of both proteins was increased in ALL patients compared to controls. We identified a positive correlation between YY1 and MDR1 expression. High levels of YY1 were associated with decreased overall survival. Our results demonstrated that YY1 regulates the transcription of MDR1. Therefore, YY1 may serve as a useful prognostic and/or therapeutic target.

Allergies: diseases closely related to cancer / Alergias: enfermedades estrechamente relacionadas con el cáncer

Abstract: Allergies are hypersensitivity reactions that occur through specific type Th2 immunological mechanisms characterized by different soluble mediators, as well as specific cells of the immune system. In recent decades, evidence has emerged relating this disease with cancer development. However, most of the results of epidemiology studies have been controversial and contradictory. There are mainly two trends. While the first indicates that allergies can reduce the risk of cancer, the other indicates that they may increase this risk. The first trend can be explained by the immunosurveillance hypothesis, which states that the increased immune surveillance after the immune hyper-responsiveness can inhibit or exert a protective effect against the development of cancer. Similarly, the prophylaxis hypothesis suggests that the physical effects of allergy symptoms can prevent cancer by removing potential carcinogens. In contrast, the opposing hypothesis propose that there is a deviation of the immune response toward Th2, which favors the development of cancer, or that the process of chronic inflammation favors the generation of mutations, and therefore the development of cancer. With the purpose of understanding more about these two hypotheses, the main soluble and cellular factors of allergic diseases that could be playing a key role in the development or inhibition of cancer were considered in this review.

Resumen: Las alergias son reacciones de hipersensibilidad que ocurren mediante mecanismos inmunológicos específicos de tipo Th2. Se caracterizan por distintos mediadores solubles, así como células específicas del sistema inmune. En las últimas décadas ha surgido evidencia que asocia esta enfermedad con el desarrollo de cáncer. Sin embargo, los resultados obtenidos, en su mayoría de estudios epidemiológicos, han sido controversiales y contradictorios. Lo anterior se debe a que existen dos principales tendencias. Mientras algunos estudios han demostrado que las alergias pueden reducir el riesgo de cáncer, otros estudios muestran que puede aumentarlo. Lo primero puede explicarse por la hipótesis de inmunovigilancia, que establece que el aumento de la vigilancia después de la hiperreactividad inmune puede inhibir o ejercer un efecto protector contra el desarrollo de cáncer. Del mismo modo, la hipótesis de la profilaxis sugiere que los efectos físicos de síntomas de las alergias pueden prevenir el cáncer mediante la eliminación de los carcinógenos potenciales. Las hipótesis opuestas proponen que existe un desvío de la respuesta inmune hacia Th2 lo cual favorece el desarrollo del cáncer, o que el proceso de inflamación crónica favorece la generación de mutaciones, y por tanto el desarrollo del cáncer. Con el propósito de entender más acerca de estas dos hipótesis, en esta revisión se consideraron los principales factores solubles y celulares de las enfermedades alérgicas que pudieran estar desempeñando un papel clave en el desarrollo o inhibición del cáncer.

Allergies: diseases closely related to cancer.

Allergies are hypersensitivity reactions that occur through specific type Th2 immunological mechanisms characterized by different soluble mediators, as well as specific cells of the immune system. In recent decades, evidence has emerged relating this disease with cancer development. However, most of the results of epidemiology studies have been controversial and contradictory. There are mainly two trends. While the first indicates that allergies can reduce the risk of cancer, the other indicates that they may increase this risk. The first trend can be explained by the immunosurveillance hypothesis, which states that the increased immune surveillance after the immune hyper-responsiveness can inhibit or exert a protective effect against the development of cancer. Similarly, the prophylaxis hypothesis suggests that the physical effects of allergy symptoms can prevent cancer by removing potential carcinogens. In contrast, the opposing hypothesis propose that there is a deviation of the immune response toward Th2, which favors the development of cancer, or that the process of chronic inflammation favors the generation of mutations, and therefore the development of cancer. With the purpose of understanding more about these two hypotheses, the main soluble and cellular factors of allergic diseases that could be playing a key role in the development or inhibition of cancer were considered in this review.

Diminished expression of CRHR2 in human colon cancer promotes tumor growth and EMT via persistent IL-6/Stat3 signaling.

BACKGROUND & AIMS: Chronic inflammation promotes development and progression of colorectal cancer (CRC). We explored the distribution of Corticotropin-Releasing-Hormone (CRH)-family of receptors and ligands in CRC and their contribution in tumor growth and oncogenic EMT. METHODS: mRNA expression of CRH-family members was analyzed in CRC (N=56) and control (N=46) samples, 7 CRC cell lines and normal NCM460 cells. Immunohistochemical detection of CRHR2 was performed in 20 CRC and 5 normal tissues. Cell proliferation, migration and invasion were compared between Urocortin-2 (Ucn2)-stimulated parental and CRHR2-overexpressing (CRHR2+) cells in absence or presence of IL-6. CRHR2/Ucn2-targeted effects on tumor growth and EMT were validated in SW620-xenograft mouse models. RESULTS: CRC tissues and cell lines showed decreased mRNA and protein CRHR2 expression compared to controls and NCM460, respectively. The opposite trend was shown for Ucn2. CRHR2/Ucn2 signaling inhibited cell proliferation, migration, invasion and colony formation in CRC-CRHR2+ cells. In vivo, SW620-CRHR2+ xenografts showed decreased growth, reduced expression of EMT-inducers and elevated levels of EMT-suppressors. IL-1b, IL-6 and IL-6R mRNAs where diminished in CRC-CRHR2+ cells, while CRHR2/Ucn2 signaling inhibited IL-6-mediated Stat3 activation, invasion, migration and expression of downstream targets acting as cell cycle- and EMT-inducers. Expression of cell cycle- and EMT-suppressors was augmented in IL-6/Ucn2-stimulated CRHR2+ cells. In patients, CRHR2 mRNA expression was inversely correlated with IL-6R and vimentin levels and metastasis occurrence, while positively associated with E-cadherin expression and overall survival. CONCLUSIONS: CRHR2 downregulation in CRC supports tumor expansion and spread through maintaining persistent inflammation and constitutive Stat3 activation. CRHR2low CRC phenotypes are associated with higher risk for distant metastases and poor clinical outcomes.

Inhibition of tumor progression during allergic airway inflammation in a murine model: significant role of TGF-ß.

INTRODUCTION: TGF-ß is an important mediator of pulmonary allergic inflammation, and it has been recently reported to be a potential inhibitor of lung tumor progression. The correlation between cancer and allergic inflammatory diseases remains controversial. Thus, the aim of the present study was to evaluate the effects of pulmonary allergic inflammation and in particular the role of TGF-ß on cancer progression. METHODS: Cancer cells were implanted in a BALB/c mice model of allergic airway inflammation, and tumor growth was measured. Apoptosis was evaluated by TUNEL assay, and TGF-ß was measured by ELISA. Expression of proliferating cell nuclear antigen, TGF-ß, TGF-ß receptors I and II, phospho-Smad2 and phospho-Smad4 was evaluated by immunohistochemistry and quantified using digital pathology. The effect of a TGF-ß activity inhibitor and recombinant TGF-ß on tumor growth was analyzed. The effect of exogenous TGF-ß on cell proliferation and apoptosis was evaluated in vitro. RESULTS: Mice with allergic airway inflammation exhibited decreased tumor volumes due to cell proliferation inhibition and increased apoptosis. TGF-ß was increased in the sera and tumor tissues of allergic mice. TGF-ß activity inhibition increased tumor progression in allergic mice by enhancing proliferation and decreasing apoptosis of tumor cells. The administration of TGF-ß resulted in reduced tumor growth. CONCLUSION: This study is the first to establish an inverse relationship between allergic airway inflammation and tumor progression. This effect appears to be mediated by TGF-ß, which is overexpressed in tumor cells during pulmonary allergic inflammation. This study indicates that TGF-ß is a potential target for antitumor therapy.

TGF- ß: an important mediator of allergic disease and a molecule with dual activity in cancer development.

The transforming growth factor- ß (TGF- ß ) superfamily is a family of structurally related proteins that includes TGF- ß , activins/inhibins, and bone morphogenic proteins (BMPs). Members of the TGF- ß superfamily regulate cellular functions such as proliferation, apoptosis, differentiation, and migration and thus play key roles in organismal development. TGF- ß is involved in several human diseases, including autoimmune disorders and vascular diseases. Activation of the TGF- ß receptor induces phosphorylation of serine/threonine residues and triggers phosphorylation of intracellular effectors (Smads). Once activated, Smad proteins translocate to the nucleus and induce transcription of their target genes, regulating various processes and cellular functions. Recently, there has been an attempt to correlate the effect of TGF- ß with various pathological entities such as allergic diseases and cancer, yielding a new area of research known as "allergooncology," which investigates the mechanisms by which allergic diseases may influence the progression of certain cancers. This knowledge could generate new therapeutic strategies aimed at correcting the pathologies in which TGF- ß is involved. Here, we review recent studies that suggest an important role for TGF- ß in both allergic disease and cancer progression.