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[This corrects the article DOI: 10.1186/s13148-015-0167-0.].
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Background. Increased oxidative stress is a well described feature of patients in hemodialysis. Their need for multiple blood transfusions and supplemental iron causes a significant iron overload that has recently been associated with increased oxidation of polyunsaturated lipids and accelerated aging due to DNA damage caused by telomere shortening. Methods. A total of 70 patients were evaluated concomitantly, 35 volunteers with ferritin levels below 500 ng/mL (Group A) and 35 volunteers with ferritin levels higher than 500 ng/mL (Group B). A sample of venous blood was taken to extract DNA from leukocytes and to measure relative telomere length by real-time PCR. Results. Patients in Group B had significantly higher plasma TBARS (p = 0.008), carbonyls (p = 0.0004), and urea (p = 0.02) compared with those in Group A. Telomeres were significantly shorter in Group B, 0.66 (SD, 0.051), compared with 0.75 (SD, 0.155) in Group A (p = 0.0017). We observed a statistically significant association between relative telomere length and ferritin levels (r = -0.37, p = 0.001). Relative telomere length was inversely related to time on hemodialysis (r = -0.27, p = 0.02). Conclusions. Our findings demonstrate that iron overload was associated with increased levels of oxidative stress and shorter relative telomere length.
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Sobrecarga de Ferro/etiologia , Falência Renal Crônica/complicações , Estresse Oxidativo , Adulto , Senilidade Prematura , Ecocardiografia , Feminino , Ferritinas/análise , Humanos , Sobrecarga de Ferro/metabolismo , Falência Renal Crônica/metabolismo , Falência Renal Crônica/patologia , Leucócitos/citologia , Leucócitos/metabolismo , Masculino , Malondialdeído/sangue , Pessoa de Meia-Idade , Carbonilação Proteica , Reação em Cadeia da Polimerase em Tempo Real , Diálise Renal , Telômero/genética , Encurtamento do Telômero , Ureia/sangueRESUMO
OBJECTIVE: To correlate image parameters in contrast-enhanced digital mammography (CEDM) with blood and lymphatic microvessel density (MVD). METHODS: 18 Breast Imaging-Reporting and Data System (BI-RADS)-4 to BI-RADS-5 patients were subjected to CEDM. Craniocaudal views were acquired, two views (low and high energy) before iodine contrast medium (CM) injection and four views (high energy) 1-5 min afterwards. Processing included registration and two subtraction modalities, traditional single-energy temporal (high-energy) and "dual-energy temporal with a matrix", proposed to improve lesion conspicuity. Images were calibrated into iodine thickness, and iodine uptake, contrast, time-intensity and time-contrast kinetic curves were quantified. Image indicators were compared with MVD evaluated by anti-CD105 and anti-podoplanin (D2-40) immunohistochemistry. RESULTS: 11 lesions were cancerous and 7 were benign. CEDM subtraction strongly increased conspicuity of lesions enhanced by iodine uptake. A strong correlation was observed between lymphatic vessels and blood vessels; all benign lesions had <30 blood microvessels per field, and all cancers had more than this value. MVD showed no correlation with iodine uptake, nor with contrast. The most frequent curve was early uptake followed by plateau for uptake and contrast in benign and malignant lesions. The positive-predictive value of uptake dynamics was 73% and that of contrast was 64%. CONCLUSION: CEDM increased lesion visibility and showed additional features compared with conventional mammography. Lack of correlation between image parameters and MVD is probably due to tumour tissue heterogeneity, mammography projective nature and/or dependence of extracellular iodine irrigation on tissue composition. ADVANCES IN KNOWLEDGE: Quantitative analysis of CEDM images was performed. Image parameters and MVD showed no correlation. Probably, this is indication of the complex dependence of CM perfusion on tumour microenvironment.
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Neoplasias da Mama/diagnóstico por imagem , Vasos Linfáticos/patologia , Mamografia/métodos , Microvasos/patologia , Adulto , Idoso , Neoplasias da Mama/irrigação sanguínea , Neoplasias da Mama/patologia , Meios de Contraste , Feminino , Humanos , Pessoa de Meia-IdadeRESUMO
Maintenance of telomere length is one function of human telomerase that is crucial for the survival of cancer cells and cancer progression. Both telomeres and telomerase have been proposed as possible biomarkers of cancer risk and cancer invasiveness; however, their clinical relevance is still under discussion. In order to improve our understanding of the relationship between telomere length and telomerase activity with cancer invasiveness, we studied telomere length as well as telomerase levels, activity, and intracellular localization in breast cancer cell lines with diverse invasive phenotypes. We found an apparently paradoxical coincidence of short telomeres and enhanced telomerase activity in the most invasive breast cancer cell lines. We also observed that hTERT intracellular localization could be correlated with its level of activity. There was no association between human telomerase reverse transcriptase (hTERT) protein expression levels and invasiveness. We propose that simultaneous evaluation of these two biomarkers-telomere length and telomerase activity-could be useful for the assessment of the invasive capacity and aggressiveness of tumor cells from breast cancer patients.
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Biomarcadores Tumorais/metabolismo , Telomerase/metabolismo , Encurtamento do Telômero , Telômero/genética , Animais , Western Blotting , Neoplasias da Mama/enzimologia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Células HeLa , Humanos , Células MCF-7 , Metaloproteinases da Matriz/metabolismo , Camundongos , Microscopia de Fluorescência , Células NIH 3T3 , Invasividade Neoplásica , Fenótipo , Reação em Cadeia da Polimerase/métodos , Proteína Supressora de Tumor p53/metabolismoRESUMO
BACKGROUND: Retinoblastoma is a malignant tumor of the retina in children <5 years of age and occurs after two mutations in the RB1 gene. The first mutation (M1) is germinal and confers predisposition to the hereditary type, which is transmitted as an autosomal dominant highly penetrant trait, so 90 % of carriers develop retinoblastoma; however, 10 % of carriers either do not develop the tumor or develop it unilaterally. Most mutations are point mutations. Inactivation of the RB1 gene is usually caused by mutations affecting the coding region. Silencing by methylation of the RB1 promoter has been observed in retinoblastoma tumors as a second mutation (M2) and is classified as somatic epimutation. Germline methylation of the RB1 gene promoter was studied in a particular pedigree of six generations from the paternal side, with incomplete penetrance and bias towards healthy male carriers and those affected with unilateral retinoblastoma. RESULTS: The methylation status of the 27 CpGs dinucleotides that constitute the core of the RB1 gene promoter, analyzed by cloning and genomic sequencing after DNA sodium bisulfite conversion, demonstrated a monoallelic methylation pattern which coincides with a c. [-187T > G; -188T > G] sequence variant that is found in peripheral blood lymphocytes and tumor DNA. Unexpectedly, it was the mother who transmitted this variant to two more generations. Microsatellite markers of D chromosome showed a biparental contribution of both D13 chromosomes to the retinoblastoma phenotype, conferring double heterozygosity in the affected cases. CONCLUSIONS: The monoallelic genetic-epigenetic finding, the sequence variant, and methylation suggest a constitutive epimutation and probably a genetic-epigenetic hereditary predisposition for retinoblastoma in this family.
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Metilação de DNA/genética , Epigênese Genética/genética , Regiões Promotoras Genéticas/genética , Neoplasias da Retina/genética , Proteína do Retinoblastoma/genética , Retinoblastoma/genética , Alelos , Pré-Escolar , Feminino , Predisposição Genética para Doença , Células Germinativas/metabolismo , Células Germinativas/microbiologia , Heterozigoto , Humanos , Lactente , Masculino , Repetições de Microssatélites/genética , Linhagem , Mutação PuntualRESUMO
A common causative agent for uterine cervical cancer is the human papillomavirus type 18 (HPV-18) which has three phylogenic variants: Asian-Amerindian, European, and African. Each variant shows significant molecular differences in the E6 gene. E6 oncoprotein is a negative regulator of tumor suppressor protein p53, hence, this oncoprotein indirectly regulates the expression of tumor-suppressor p14(ARF) . p14(ARF) and p16(INK4A) genes are overexpressed in--and have been proposed as markers for--HPV-related cervical cancer. In order to dissect the role of E6 on the regulation of p14(ARF) expression, separating it from that of other intervening factors, transfection of E6 variants to MCF-7 cells was performed, assessing cDNA transcript levels by RT-PCR, whereas p14(ARF) and p53 expression were evaluated by immunocytochemistry and Western blot. E6 transfected cells differentially expressed transcripts of two molecular forms: E6 and E6*. The ratio of these two forms varied with the transfected E6 variant. With the Asian-Amerindian variant, the ratio was E6 > E6*, whereas with the European and the African the ratio was E6* > E6. As expected with the E6* construct, E6* transcripts were solely observed. In addition, when E6 > E6* and p53 expression was low, p14(ARF) was high and when E6* > E6 and p53 expression was high, p14(ARF) was low. In conclusion, each E6 variant distinctively affects p53 levels and consequently p14(ARF) expression, finding that could be related with the differences in oncogenic effect of infection with the diverse high-risk HPV variants.
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Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Regulação da Expressão Gênica , Interações Hospedeiro-Patógeno , Papillomavirus Humano 18/fisiologia , Proteínas Oncogênicas Virais/genética , Proteínas Oncogênicas Virais/metabolismo , Proteína Supressora de Tumor p14ARF/biossíntese , Proteína Supressora de Tumor p53/biossíntese , Western Blotting , Linhagem Celular , Feminino , Perfilação da Expressão Gênica , Humanos , Imuno-Histoquímica , Reação em Cadeia da Polimerase em Tempo RealRESUMO
The female reproductive system (FRS) has a great capacity for regeneration. The existence of somatic stem cells (SSC) that are likely to reside in distinct tissue compartments of the FRS is anticipated. Normal SSC are capable of regenerating themselves, produce a progeny of cells that differentiate and maintain tissue architecture and functional characteristics, and respond to homeostatic controls. Among those SSC of the FRS that have been identified are: a) undifferentiated cells capable of differentiating into thecal cells and synthesizing hormones upon transplantation, b) ovarian surface epithelium stem cells, mitotically responsive to ovulation, c) uterine endometrial and myometrial cells, as clonogenic epithelial and stromal cells, and d) epithelial and mesenchymal cells with self-renewal capacity and multipotential from cervical tissues. Importantly, these cells are believed to significantly contribute to the development of different pathologies and tumors of the FRS.It is now widely accepted that cancer stem cells (CSC) are at the origin of many tumors. They are capable of regenerating themselves, produce a progeny that will differentiate aberrantly and do not respond adequately to homeostatic controls. Several cell surface antigens such as CD44, CD117, CD133 and MYD88 have been used to isolate ovarian cancer stem cells. Clonogenic epithelial and stromal endometrial and myometrial cells have been found in normal and cancer tissues, as side population, label-retaining cells, and CD146/PDGF-R beta-positive cells with stem-like features. In summary, here we describe a number of studies supporting the existence of somatic stem cells in the normal tissues and cancer stem cells in tumors of the human female reproductive system.
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Neoplasias dos Genitais Femininos/patologia , Genitália Feminina/citologia , Células-Tronco Neoplásicas/patologia , Células-Tronco/citologia , Biomarcadores/metabolismo , Biomarcadores Tumorais/metabolismo , Diferenciação Celular , Proliferação de Células , Feminino , Neoplasias dos Genitais Femininos/metabolismo , Genitália Feminina/metabolismo , Humanos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco/metabolismoRESUMO
BACKGROUND: Increased telomere shortening has been demonstrated in several diseases including type 2 diabetes. However, it is not known whether telomere length changes during the course of type 2 diabetes. OBJECTIVE: To determine telomere length at different stages of type 2 diabetes, including early and late stages. METHODS: A total of 93 males with type 2 diabetes and 10 years or more since original diagnosis; 96 males with less than one year of diagnosis; 98 age matched healthy males. Telomere length was estimated by means of real-time polymerase chain reaction. Fasting venous blood samples were obtained for measurement of lipid peroxidation and inflammation markers. RESULTS: We found a greater telomere shortening in group (A) with type 2 diabetes of 10 years or more since original diagnosis, compared with the control group (C) of healthy males (5.4 vs 9.6 Kb) (p = 0.04) and with group B (5.4 vs 8.7 kb) (p = 0.05). With regard to inflammatory markers TNF-α, malondialdehyde peroxidation and adiponectin we found significant differences. CONCLUSION: Telomere shortening increases with the duration of diabetes. The time of exhibition suggests in parallel that the progressive increase of inflammation and/or oxidative stress plays a direct role in telomere shortening.
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Senilidade Prematura/fisiopatologia , Diabetes Mellitus Tipo 2/fisiopatologia , Encurtamento do Telômero/fisiologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/genética , Progressão da Doença , Humanos , Interleucina-6/sangue , Peroxidação de Lipídeos , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Estresse Oxidativo/fisiologia , Síndrome , Homeostase do Telômero/fisiologia , Fator de Necrose Tumoral alfa/sangueRESUMO
BACKGROUND: Interleukin 1 beta (IL-1beta) and other inflammatory cytokines are reported to induce phenotypic changes in epithelial breast cancer tumor cells related to increased invasiveness. Mechanisms involved in the process are not well understood. METHODS: The noninvasive breast cancer epithelial cell line MCF-7 was used to investigate the IL-1beta-induced phenotype. Live cells expressing EGFP-actin were monitored for cell morphology changes and actin cytoskeleton dynamics by time-lapse video microscopy in the presence of IL-1beta and specific inhibitors of actin signaling pathways. Chemotaxis, invasion of Matrigel, MMP activity and expression of S100A4 in cells treated with IL-1beta were assessed by migration assays, zymograms and immunoblots. RESULTS: Exposure to IL-1beta specifically induced a change in MCF-7 cells from a typical epithelial morphology into elongated cells, showing numerous dynamic actin-rich lamellae and peripheral ruffles characteristic of fibroblasts. These cells could scatter from compact cell colonies and respond to chemoattractants such as the homing-associated chemokine CXCL-12. Pharmacological blockage of actin signaling pathways and negative mutants of RhoGTPases revealed that actin reorganization and enhanced motility are regulated via PI3K/Rac 1 activation. IL-1beta-stimulated cells expressed the metastasis promoter S100A4, increased secretion of active MMP-9 and MMP-2 and invasion of extracellular matrix proteins. CONCLUSIONS: IL-1beta induces a PI3K/Rac 1-regulated reorganization of the actin cytoskeleton of MCF-7 cells that is required for cell scattering, elongation and migration. The enhanced motility is accompanied by expression of protein markers correlated with invasive behavior.
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Actinas/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Interleucina-1beta/farmacologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Forma Celular/efeitos dos fármacos , Citoesqueleto/efeitos dos fármacos , Citoesqueleto/metabolismo , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Feminino , Humanos , Interleucina-1beta/metabolismo , Mesoderma/efeitos dos fármacos , Mesoderma/metabolismo , Mesoderma/patologia , Microscopia de Vídeo , Invasividade Neoplásica/patologia , Fenótipo , Fosfatidilinositol 3-Quinases/metabolismo , Receptores CXCR4/metabolismo , Receptores Tipo I de Interleucina-1/metabolismo , Proteínas Recombinantes/farmacologia , Transdução de Sinais , Proteínas rac1 de Ligação ao GTP/metabolismoRESUMO
During carcinogenesis it is known that growth factors and cytokines from stromal and inflammatory cells from the microenvironment promote angiogenesis and lymphangiogenesis. However, the participation of macrophages and mast cells in these processes is not well understood. The aim of this study was to evaluate the relationship between mast cell and macrophage density with blood and lymphatic vessels in various stages of carcinoma of the uterine cervix. Tissue sections from archival paraffin-embedded samples from cases with cervical intraepithelial neoplasias (CIN) 1, 2, 3, carcinoma in situ, and invasive carcinoma were used. Immunohistochemical staining was done using the following antibodies: anti-LYVE-1; anti-CD31; anti-CD68, and anti-tryptase. Our results showed a significant increase in the number of macrophages in carcinoma in situ, a correlation between lymphatic vessels and macrophages in premalignant lesions CIN 2, and a correlation between mast cells and blood vessels in both CIN 2 and carcinoma in situ. In conclusion, our data underscore the importance of the recruitment of macrophages and mast cells in the development of tumor-associated blood and lymphatic capillaries.
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Carcinoma in Situ/imunologia , Linfangiogênese/imunologia , Macrófagos/imunologia , Mastócitos/imunologia , Neovascularização Patológica/imunologia , Displasia do Colo do Útero/imunologia , Neoplasias do Colo do Útero/imunologia , Neoplasias do Colo do Útero/patologia , Antígenos CD , Antígenos de Diferenciação Mielomonocítica , Carcinoma in Situ/patologia , Estudos de Casos e Controles , Feminino , Humanos , Macrófagos/metabolismo , Mastócitos/metabolismo , Neoplasias do Colo do Útero/irrigação sanguínea , Displasia do Colo do Útero/patologiaAssuntos
Medula Óssea , Diabetes Mellitus Experimental/terapia , Transplante das Ilhotas Pancreáticas/métodos , Animais , Glicemia , Sobrevivência de Enxerto , Imuno-Histoquímica , Ilhotas Pancreáticas/anatomia & histologia , Ilhotas Pancreáticas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Transplante HomólogoRESUMO
Small RNAs belong to a newly discovered strain of molecules. These molecules are composed of double strand RNA comprised by just about 19-31 nucleotides. They have two main characteristics that make them unique. Firstly, they are noncoding for proteins and second they interfere post-transcriptional with mRNA. This interfering action is the distinguishing hallmark, therefore known as interfering RNA or RNAi. There are three main subclasses of which micro-RNA and siRNA are the most widely studied. Interference RNAs participate in a myriad of cellular functions mainly through modulation of genetic expression. Due to these capabilities it has been used as therapeutic weapon in a number of diseases including cancer. It is known that both miRNA and siRNA participate in carcinogenesis, either inhibiting suppressor genes, or stimulating oncogenes. It has been demonstrated that manipulating small interfering RNAs in cell lines and animal models, the malignant and metastatic phenotype can be reversed. Up to now a few clinical trials using RNAi as a therapeutic agent have demonstrated some success and feasibility. It is forseeable that in the near future cancer treatment with small RNAs will be widely applicable, once the many constrains for its systemic application are surpassed.
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Regulação Neoplásica da Expressão Gênica/genética , Terapia Genética/métodos , MicroRNAs/genética , Neoplasias/genética , Interferência de RNA , RNA Mensageiro/genética , RNA Interferente Pequeno/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Linhagem Celular Tumoral/efeitos dos fármacos , Linhagem Celular Tumoral/patologia , Transformação Celular Neoplásica/genética , Ensaios Clínicos como Assunto , Sistemas de Liberação de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Estudos de Viabilidade , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Genes Supressores de Tumor , Vetores Genéticos/uso terapêutico , Humanos , Masculino , MicroRNAs/biossíntese , Neoplasias/tratamento farmacológico , Neoplasias/terapia , Neoplasias/virologia , Oncogenes , RNA Mensageiro/antagonistas & inibidores , RNA Neoplásico/antagonistas & inibidores , RNA Neoplásico/biossíntese , RNA Neoplásico/genética , RNA Interferente Pequeno/genéticaRESUMO
The Papanicolaou test (Pap) has been responsible for a significant reduction of cervical cancer-related morbimortality. In order to increase its sensitivity and specificity new markers have been studied and incorporated to cytological and histological methods for diagnosis for cervical cancer, such as p16INK4A that has been considered the immunocytochemical marker of choice for detection of HPV related cancers. We considered that p14ARF could be a complementary marker in order to improve the accuracy of cytological diagnosis because its genetic proximity to p16INK4A. We performed a systematic analysis of several putative cervical cancer markers in order to evaluate their performance in the detection of malignancy, in comparison with p16INK4A and p14ARF, using immunocytochemistry (ICC), immunofluorescence (IF) and Western blot analyses. Most markers were non-specific and could not discriminate HPV infected cancer cell lines from other non HPV malignant. In contrast, nuclear co-expression of p16INK4A and p14ARF was observed only in HPV-transformed cancer cell lines. Notably, in C-33A cervical cancer cells (HPV negative), p14ARF was present in the nucleoli, but p16INK4A was conspicuously absent from the nuclei of these cells. We conclude that both markers; p16INK4A and p14ARF are complementary and should be evaluated jointly in order to improve the accuracy of cytological diagnosis of cervical cancer.
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Núcleo Celular/metabolismo , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Papillomaviridae/metabolismo , Proteína Supressora de Tumor p14ARF/metabolismo , Neoplasias do Colo do Útero/metabolismo , Catepsinas/metabolismo , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Inibidor p16 de Quinase Dependente de Ciclina/genética , Fator de Transcrição E2F1/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Células HeLa , Humanos , Metaloproteinases da Matriz/metabolismo , Proteínas Oncogênicas Virais/genética , Proteínas Oncogênicas Virais/metabolismo , Papillomaviridae/genética , Proteína do Retinoblastoma/genética , Proteína do Retinoblastoma/metabolismo , Proteína Supressora de Tumor p14ARF/genética , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/virologiaRESUMO
When the first preventive HPV vaccine became available in 2006, it drew both enthusiasm and multiple ethical problems. In the case of HPV vaccination, there is a clear conflict between the scientific data that claim a definitive advantage for preventing HPV infection in the exposed population and the ethical and moral issues resulting from a compulsory program. Despite the evident success of routine and compulsory vaccination in young women, there is increasing concern about safety, efficacy, and equity of the vaccine and to close the knowledge "gaps" about HPV infection and consequent health outcomes. Some of these fears are expressed particularly in conservative groups that link these arguments to those of religious and moral issues contending that HPV vaccination is an indirect license for liberal sexual activity in youths, resulting in promiscuity and/or less participation in cervical cancer screening. It has been well demonstrated that HPV infection can lead to harm through the induction of premalignant and cancerous lesions. Therefore, any proven method for preventing infection, such as HPV vaccines, should be used in persons at risk. These policies, however, should be strictly linked to cervical cancer screening programs.
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Vacinas contra Papillomavirus/imunologia , Vacinação/ética , Adolescente , Criança , Feminino , Humanos , Neoplasias do Colo do Útero/prevenção & controle , Vacinação/métodosRESUMO
Invasion and metastasis are the most important events in cancer progression. In these two phases, several molecules are implicated and have been long associated with several forms of cancer. Proteases play a critical role not only in tumor cell invasion, but also in the earliest stages of carcinogenesis and its associated changes: angiogenesis and metastasis. Aside from their ability to degrade the extracellular matrix, facilitate invasion and metastasis, proteases target a great variety of substrates that favor or inhibit cancer progression: b-FGF, HGF, VEGF, cell death receptors, cistatin-C, galectin, procollagen, and other proteases. Proteases are also signaling molecules that modulate other molecules by underlying pathways in addition to their degradative role. Proteases form interconnected cascades, circuits and networks that bring about the tumor's potential for malignancy. Although, proteases are regulated by diverse molecules, it is known that tumoral and stromal cells secrete several biological molecules, including cytokines and chemokines that directly or indirectly regulate the protease-expression within the tumor's microenvironment. The present review briefly summarizes some of the major aspects associated with the role of proteases in cancer progression.
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Neoplasias/enzimologia , Peptídeo Hidrolases/fisiologia , Animais , Membrana Basal/fisiologia , Matriz Extracelular/fisiologia , Humanos , Neovascularização PatológicaRESUMO
La invasión y la metástasis son los eventos más importantes en la progresión del cáncer, en los cuales están implicadas muchas moléculas, entre ellas, las proteasas. Éstas desempeñan un papel importante en etapas tempranas de la carcinogénesis, en la invasión, en fenómenos asociados como la angiogénesis y en la metástasis, principalmente por su capacidad para degradar componentes de la matriz extracelular, aunque sus sustratos son de naturaleza diversa: citocinas, quimiocinas, factores de crecimiento (b- FGF, HGF, VEGF) y de muerte celular, cistatina-C, galectina, procolágena y otras proteasas, que pueden favorecer o inhibir la progresión neoplásica. Las proteasas son también moléculas de señalización que modulan a otras moléculas; forman cascadas, circuitos e incluso redes, que en conjunto determinan parte del potencial maligno. Se sabe que tanto la célula tumoral como las del estroma secretan diversos factores que regulan directa e indirectamente la expresión de proteasas en el microambiente tumoral. Esta revisión proporciona un panorama breve y actualizado sobre la participación de las proteasas en la progresión neoplásica.
Invasion and metastasis are the most important events in cancer progression. In these two phases, several molecules are implicated and have been long associated with several forms of cancer. Proteases play a critical role not only in tumor cell invasion, but also in the earliest stages of carcinogenesis and its associated changes: angiogenesis and metastasis. Aside from their ability to degrade the extracellular matrix, facilitate invasion and metastasis, proteases target a great variety of substrates that favor or inhibit cancer progression: b-FGF, HGF, VEGF, cell death receptors, cistatin-C, galectin, procollagen, and other proteases. Proteases are also signaling molecules that modulate other molecules by underlying pathways in addition to their degradative role. Proteases form interconnected cascades, circuits and networks that bring about the tumor's potential for malignancy. Although, proteases are regulated by diverse molecules, it is known that tumoral and stromal cells secrete several biological molecules, including cytokines and chemokines that directly or indirectly regulate the protease-expression within the tumor's microenvironment. The present review briefly summarizes some of the major aspects associated with the role of proteases in cancer progression.
Assuntos
Humanos , Animais , Neoplasias/enzimologia , Peptídeo Hidrolases/fisiologia , Matriz Extracelular/fisiologia , Membrana Basal/fisiologia , Neovascularização PatológicaRESUMO
It is well-known that there are different tumor-type-dependent metastatic patterns. For example, in carcinomas metastatic spread is preferentially via the lymphatic system by which they reach regional lymph nodes through pre-existent afferent lymph vessels and/or newly formed lymph capillaries; while in sarcomas the favored pathway is through bloodvessels. These metastatic patterns have been used for many years by clinicians and surgeons for staging and tumor resection, particularly in the case of breast cancer. Recently this knowledge has been applied to detection and resection of sentinel lymph nodes. The lymphatic system drains the interstitial fluid from tissues and reincorporates it into the blood flow; in addition, it forms part of the host's immune defense and in pathological conditions, induces different types of lymph edema and participates in tumor invasion and metastasis. Although, the study of lymphangiogenesis was stagnated for several decades, it was not until a few years ago that biomolecular mechanisms were discovered and many specific markers are now in use to study the process of tumor dissemination and metastasis. There is a tendency to utilize molecular knowledge in clinical settings for grading and estimating prognostic significance of tumors as well as to develop specific therapeutic strategies.
Assuntos
Metástase Linfática , Neoplasias/patologia , Humanos , Sistema Linfático/anatomia & histologia , Sistema Linfático/fisiologiaRESUMO
Es bien sabido que existen diferentes patrones de metástasis dependiendo del tipo tumoral. Por ejemplo, la diseminación metastásica de los carcinomas es vía linfática preferencialmente, las células neoplásicas llegan a los ganglios linfáticos regionales a través de vasos linfáticos aferentes preexistentes o capilares linfáticos de nueva formación; en cambio, en los sarcomas la vía principal es a través de los vasos sanguíneos. Estos patrones metastásicos han sido utilizados durante muchos años por los clínicos y cirujanos para la etapificación y resección tumoral, particularmente en cáncer de mama. Recientemente este conocimiento ha sido aplicado para la detección y resección del ganglio centinela. El sistema linfático drena el líquido intersticial de los tejidos y lo reincorpora al sistema sanguíneo; además, forma parte de la defensa inmune del huésped y en condiciones patológicas induce diferentes tipos de linfedema y participa en la invasión y metástasis. El estudio de la linfangiogénesis permaneció aletargado por muchas décadas y no es sino hasta los últimos años que se han descrito mecanismos biomoleculares y marcadores específicos, los cuales actualmente se están utilizando para estudiar el proceso de diseminación tumoral y metástasis. Existe una tendencia hacia la aplicación clínica de este conocimiento molecular en la clínica para estimar el significado pronóstico de los tumores, así como para desarrollar estrategias terapéuticas específicas.
It is well-known that there are different tumor-type-dependent metastatic patterns. For example, in carcinomas metastatic spread is preferentially via the lymphatic system by which they reach regional lymph nodes through pre-existent afferent lymph vessels and/or newly formed lymph capillaries; while in sarcomas the favored pathway is through bloodvessels. These metastatic patterns have been used for many years by clinicians and surgeons for staging and tumor resection, particularly in the case of breast cancer. Recently this knowledge has been applied to detection and resection of sentinel lymph nodes. The lymphatic system drains the interstitial fluid from tissues and reincorporates it into the blood flow; in addition, it forms part of the host's immune defense and in pathological conditions, induces different types of lymph edema and participates in tumor invasion and metastasis. Although, the study of lymphangiogenesis was stagnated for several decades, it was not until a few years ago that biomolecular mechanisms were discovered and many specific markers are now in use to study the process of tumor dissemination and metastasis. There is a tendency to utilize molecular knowledge in clinical settings for grading and estimating prognostic significance of tumors as well as to develop specific therapeutic strategies.
Assuntos
Humanos , Metástase Linfática , Neoplasias/patologia , Sistema Linfático/anatomia & histologia , Sistema Linfático/fisiologiaRESUMO
Expression of estrogen receptors (ER) is clinically relevant in designing therapeutic strategies. The relative importance of the two types of estrogen receptors (ER-alpha and ER-beta) in human breast cancers in pre- and post-menopausal women has not been properly defined. To determine the possible association between the expression of estrogen receptor and serum estradiol levels in pre- and post-menopausal women with breast cancer. 44 patients with invasive ductal carcinoma of the breast were studied and a breast tissue biopsy was taken. ER-alpha and ER-beta were detected by immunocytochemistry. Serum levels of estradiol and estrone were measured by radioimmunoassay and FSH was measured using IRMA. We studied 21 pre- and 23 post-menopausal women with breast carcinoma. Examining the number of cases with tumors positive for ER, we found no differences in the frequency of ER-alpha between pre- and post-menopausal women, but ER-beta decreased marginally after menopause (p < 0.051). In cases with tumors positive for ER, the proportion of cells positive for ER-alpha was similar post-menopausally (53.95%) and pre-menopausally (57.21%), but for ER-beta the number of positive cells decreased significantly after menopause (p < 0.051). In pre-menopausal women there was a correlation between serum estradiol levels and ER-beta; in post-menopausal women there was a correlation between serum FSH levels and ER-alpha. These results indicate that estradiol levels in women with mammary carcinoma are related to ER-beta expression in the breast tumor tissue.
Assuntos
Neoplasias da Mama/metabolismo , Carcinoma Ductal de Mama/metabolismo , Receptor alfa de Estrogênio/biossíntese , Receptor beta de Estrogênio/biossíntese , Pós-Menopausa/metabolismo , Pré-Menopausa/metabolismo , Adulto , Estradiol/sangue , Feminino , Hormônio Foliculoestimulante/sangue , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , RadioimunoensaioRESUMO
BACKGROUND: The liver is the current site for pancreatic islet transplantation, but presents important technical complications and limitations. We asked whether pancreatic islets could be engrafted in the bone marrow, an easily accessible and widely distributed transplant site that may lack the limitations seen in the liver. METHODS: We implanted pancreatic islet isografts (Lewis islets to Lewis rats), allografts (Wistar Furth islets to Sprague Dawley rats), and xenografts (Tilapia islets to Sprague Dawley rats) into the bone marrow of nondiabetic recipients and assessed survival by histology and immunocytochemistry. No immunosuppression was used. RESULTS: Isografts and allografts showed positive staining for insulin and glucagon and no evidence of allograft rejection up to 21 days posttransplant. Xenografts were acutely rejected. CONCLUSIONS: The bone marrow may be an attractive alternative site for pancreatic islet transplantation. The acceptance of allografts and isografts but rejection of xenografts suggests a selective phenomenon for the inflammatory process.