RESUMEN
Angiomotin (Amot) is a newly discovered, multifunctional protein that is involved in cell migration and angiogenesis. However, the role of its isoform, AmotP130, in the regulation of cytoskeleton and metastasis of breast cancer, is unclear. The aim of this study was to investigate the role of AmotP130 in the reorganization of the actin cytoskeleton and the changes of morphology in breast cancer cells through the Rho pathway that influences the invasion and migration of cells. The results suggested that AmotP130 suppressed the invasion ability through remodelling the cytoskeleton of breast cancer cells, including the actin fibre organization and focal adhesion protein turnover. Global transcriptome changes in breast cancer cells following knockdown of AmotP130 identified pathways related with the cytoskeleton and cell motility that involved the Rho GTPase family. From database analyses, changes in the Rho GTPase family of proteins were identified as possible prognostic factors in patients with breast cancer. We have been suggested that AmotP130 suppressed the invasion ability through remodelling of the cytoskeleton of breast cancer cells, involving regulation of the Rho pathway. The cytoskeleton-related pathway components may provide novel, clinically therapeutic targets for breast cancer treatment.
Asunto(s)
Actinas/genética , Neoplasias de la Mama/genética , Péptidos y Proteínas de Señalización Intercelular/genética , Proteínas de la Membrana/genética , Proteínas de Unión al GTP rho/genética , Angiomotinas , Neoplasias de la Mama/patología , Adhesión Celular/genética , Línea Celular Tumoral , Movimiento Celular/genética , Citoesqueleto/genética , Femenino , Adhesiones Focales/genética , Adhesiones Focales/patología , Regulación Neoplásica de la Expresión Génica , Humanos , Proteínas de Microfilamentos , Isoformas de Proteínas/genética , Transducción de Señal , Proteína de Unión al GTP rhoA/genéticaRESUMEN
ALK-positive NSCLC patients demonstrate initial responses to ALK tyrosine kinase inhibitor (TKI) treatments, but eventually develop resistance, causing rapid tumor relapse and poor survival rates. Growing evidence suggests that the combination of drug and immune therapies greatly improves patient survival; however, due to the low immunogenicity of the tumors, ALK-positive patients do not respond to currently available immunotherapies. Tumor-associated macrophages (TAMs) play a crucial role in facilitating lung cancer growth by suppressing tumoricidal immune activation and absorbing chemotherapeutics. However, they can also be programmed toward a pro-inflammatory tumor suppressive phenotype, which represents a highly active area of therapy development. Iron loading of TAMs can achieve such reprogramming correlating with an improved prognosis in lung cancer patients. We previously showed that superparamagnetic iron oxide nanoparticles containing core-cross-linked polymer micelles (SPION-CCPMs) target macrophages and stimulate pro-inflammatory activation. Here, we show that SPION-CCPMs stimulate TAMs to secrete reactive nitrogen species and cytokines that exert tumoricidal activity. We further show that SPION-CCPMs reshape the immunosuppressive Eml4-Alk lung tumor microenvironment (TME) toward a cytotoxic profile hallmarked by the recruitment of CD8+ T cells, suggesting a multifactorial benefit of SPION-CCPM application. When intratracheally instilled into lung cancer-bearing mice, SPION-CCPMs delay tumor growth and, after first line therapy with a TKI, halt the regrowth of relapsing tumors. These findings identify SPIONs-CCPMs as an adjuvant therapy, which remodels the TME, resulting in a delay in the appearance of resistant tumors.
Asunto(s)
Crizotinib , Neoplasias Pulmonares , Nanopartículas Magnéticas de Óxido de Hierro , Microambiente Tumoral , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Microambiente Tumoral/efectos de los fármacos , Animales , Nanopartículas Magnéticas de Óxido de Hierro/química , Humanos , Ratones , Crizotinib/farmacología , Crizotinib/química , Antineoplásicos/farmacología , Antineoplásicos/química , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/química , Línea Celular Tumoral , Macrófagos Asociados a Tumores/efectos de los fármacos , Macrófagos Asociados a Tumores/metabolismo , Proliferación Celular/efectos de los fármacos , FemeninoRESUMEN
OBJECTIVE: Hyperferremia and hyperferritinemia are observed in patients and disease models of type 2 diabetes mellitus (T2DM). Likewise, patients with genetic iron overload diseases develop diabetes, suggesting a tight link between iron metabolism and diabetes. The liver controls systemic iron homeostasis and is a central organ for T2DM. Here, we investigate how the control of iron metabolism in hepatocytes is affected by T2DM. METHODS: Perls Prussian blue staining was applied to analyze iron distribution in liver biopsies of T2DM patients. To identify molecular mechanisms underlying hepatocyte iron accumulation we established cellular models of insulin resistance by treatment with palmitate and insulin. RESULTS: We show that a subset of T2DM patients accumulates iron in hepatocytes, a finding mirrored in a hepatocyte model of insulin resistance. Iron accumulation can be explained by the repression of the iron exporter ferroportin upon palmitate and/or insulin treatment. While during palmitate treatment the activation of the iron regulatory hormone hepcidin may contribute to reducing ferroportin protein levels in a cell-autonomous manner, insulin treatment decreases ferroportin transcription via the PI3K/AKT and Ras/Raf/MEK/ERK signaling pathways. CONCLUSION: Repression of ferroportin at the transcriptional and post-transcriptional level may contribute to iron accumulation in hepatocytes observed in a subset of patients with T2DM.
Asunto(s)
Diabetes Mellitus Tipo 2 , Resistencia a la Insulina , Insulinas , Sobrecarga de Hierro , Humanos , Hierro/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Sobrecarga de Hierro/metabolismo , Hepatocitos/metabolismo , Palmitatos/metabolismo , Insulinas/metabolismoRESUMEN
OBJECTIVE: The molecular pathogenesis of late complications associated with type 2 diabetes mellitus (T2DM) is not yet fully understood. While high glucose levels indicated by increased HbA1c only poorly explain disease progression and late complications, a pro-inflammatory status, oxidative stress, and reactive metabolites generated by metabolic processes were postulated to be involved. Individuals with metabolic syndrome (MetS) frequently progress to T2DM, whereby 70% of patients with T2DM show non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of MetS, and insulin resistance (IR). Epidemiological studies have shown that T2DM and steatosis are associated with alterations in iron metabolism and hepatic iron accumulation. Excess free iron triggers oxidative stress and a switch towards a macrophage pro-inflammatory status. However, so far it remains unclear whether hepatic iron accumulation plays a causative role in the generation of IR and T2DM or whether it is merely a manifestation of altered hepatic metabolism. To address this open question, we generated and characterized a mouse model of T2DM with IR, steatosis, and iron overload. METHODS: Leprdb/db mice hallmarked by T2DM, IR and steatosis were crossed with Fpnwt/C326S mice with systemic iron overload to generate Leprdb/db/Fpnwt/C326S mice. The resulting progeny was characterized for major diabetic and iron-related parameters. RESULTS: We demonstrated that features associated with T2DM in Leprdb/db mice, such as obesity, steatosis, or IR, reduce the degree of tissue iron overload in Fpnwt/C326S mice, suggesting an 'iron resistance' phenotype. Conversely, we observed increased serum iron levels that strongly exceeded those in the iron-overloaded Fpnwt/C326S mice. Increased hepatic iron levels induced oxidative stress and lipid peroxidation and aggravated IR, as indicated by diminished IRS1 phosphorylation and AKT activation. Additionally, in the liver, we observed gene response patterns indicative of de novo lipogenesis and increased gluconeogenesis as well as elevated free glucose levels. Finally, we showed that iron overload in Leprdb/db/Fpnwt/C326S mice enhances microvascular complications observed in retinopathy, suggesting that iron accumulation can enhance diabetic late complications associated with the liver and the eye. CONCLUSION: Taken together, our data show that iron causes the worsening of symptoms associated with the MetS and T2DM. These findings imply that iron depletion strategies together with anti-diabetic drugs may ameliorate IR and diabetic late complications.
Asunto(s)
Diabetes Mellitus Tipo 2/metabolismo , Resistencia a la Insulina , Sobrecarga de Hierro/metabolismo , Hierro/metabolismo , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Animales , Glucemia/análisis , Glucemia/metabolismo , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/genética , Modelos Animales de Enfermedad , Humanos , Hierro/sangre , Sobrecarga de Hierro/sangre , Sobrecarga de Hierro/genética , Peroxidación de Lípido , Hígado/metabolismo , Hígado/patología , Masculino , Ratones , Ratones Transgénicos , Enfermedad del Hígado Graso no Alcohólico/sangre , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/patología , Estrés Oxidativo , Receptores de Leptina/genéticaRESUMEN
PURPOSE: Numerous previous studies have reported inconsistent results about the differences between synchronous contralateral breast cancer (sCBC) and metachronous contralateral breast cancer (mCBC). This study aimed to compare the clinical characteristics and outcomes between sCBC and mCBC and determine predictive factors for the survival of sCBC and mCBC patients. METHODS: Using the Surveillance, Epidemiology, and End Results Program database, we identified sCBC or mCBC patients from 2000 to 2010. The Kaplan-Meier method and Cox proportional hazards regression analysis were used to analyze overall survival and breast cancer-specific survival (BCSS) rates of sCBCs and mCBCs, respectively. RESULTS: Overall, 14,057 sCBC (n = 8,139, 57.9%) and mCBC (n = 5,918, 42.1%) patients were included. The first tumors of sCBC were more likely to have higher stage and more lymph and distant metastases, whereas those of mCBC were more often infiltrating ductal carcinoma (IDC), had localized stage, were estrogen receptor (ER) and progesterone receptor (PR) negative, and had less axillary nodal involvement. The second tumors of mCBC tended to be IDC and have higher grade, adverse stage, ER and PR-negativity; and more axillary nodal involvement, compared to the second tumors of sCBC. mCBC patients had significantly favorable 5-year BCSS but worse long-term BCSS compared with sCBC patients. Moreover, subgroup analysis revealed no significant difference of BCSS between sCBC and mCBC among patients aged 18-60 years. Multivariate analysis indicated that age, grade, and stage of 2 tumors; surgery for second tumor; and ER status of the second tumor were independent prognostic factors for BCSS of contralateral breast cancer (CBC). CONCLUSION: The characteristics and outcomes of sCBCs and mCBCs were substantially different. sCBC and mCBC patients may have different prognosis, and the prognosis of CBC depends on the first and second tumors.
RESUMEN
Triple-negative breast cancers (TNBCs) have poor prognosis, and chemotherapy remains the mainstay of therapy because of lack of discovered possible target. MYC were found overexpressed in TNBCs compared with other subtypes and especially in those resistant to chemotherapy, but the inhibition has been challenging to achieve. Recently, the cooperation of PIM1 and MYC was identified involved in cell proliferation, migration and apoptosis of TNBCs, which has been reported in hematological malignancy and prostatic cancer. Inhibition of PIM1 can promote the apoptosis of tumor cells and enhance sensitivity to chemotherapy. Notably, PIM1-null mice develop normally and are fertile, suggesting the side effects can be tolerated. Thus, PIM1 may be a promising target in TNBCs and further investigation, both in vivo and in vitro, needs to be carried out.