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1.
Nature ; 514(7520): 54-8, 2014 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-25079331

RESUMO

Cancers arise through a process of somatic evolution that can result in substantial sub-clonal heterogeneity within tumours. The mechanisms responsible for the coexistence of distinct sub-clones and the biological consequences of this coexistence remain poorly understood. Here we used a mouse xenograft model to investigate the impact of sub-clonal heterogeneity on tumour phenotypes and the competitive expansion of individual clones. We found that tumour growth can be driven by a minor cell subpopulation, which enhances the proliferation of all cells within a tumour by overcoming environmental constraints and yet can be outcompeted by faster proliferating competitors, resulting in tumour collapse. We developed a mathematical modelling framework to identify the rules underlying the generation of intra-tumour clonal heterogeneity. We found that non-cell-autonomous driving of tumour growth, together with clonal interference, stabilizes sub-clonal heterogeneity, thereby enabling inter-clonal interactions that can lead to new phenotypic traits.


Assuntos
Células Clonais/metabolismo , Células Clonais/patologia , Neoplasias/genética , Neoplasias/patologia , Animais , Linhagem Celular Tumoral , Proliferação de Células , Epigênese Genética/genética , Feminino , Interleucina-11/metabolismo , Camundongos , Modelos Biológicos , Metástase Neoplásica , Neoplasias/metabolismo , Fenótipo , Microambiente Tumoral
2.
Breast Cancer Res ; 20(1): 65, 2018 07 04.
Artigo em Inglês | MEDLINE | ID: mdl-29973218

RESUMO

BACKGROUND: The microenvironment and stress factors like glucocorticoids have a strong influence on breast cancer progression but their role in the first stages of breast cancer and, particularly, in myoepithelial cell regulation remains unclear. Consequently, we investigated the role of glucocorticoids in ductal carcinoma in situ (DCIS) in breast cancer, focusing specially on myoepithelial cells. METHODS: To clarify the role of glucocorticoids at breast cancer onset, we evaluated the effects of cortisol and corticosterone on epithelial and myoepithelial cells using 2D and 3D in vitro and in vivo approaches and human samples. RESULTS: Glucocorticoids induce a reduction in laminin levels and favour the disruption of the basement membrane by promotion of myoepithelial cell apoptosis in vitro. In an in vivo stress murine model, increased corticosterone levels fostered the transition from DCIS to invasive ductal carcinoma (IDC) via myoepithelial cell apoptosis and disappearance of the basement membrane. RU486 is able to partially block the effects of cortisol in vitro and in vivo. We found that myoepithelial cell apoptosis is more frequent in patients with DCIS+IDC than in patients with DCIS. CONCLUSIONS: Our findings show that physiological stress, through increased glucocorticoid blood levels, promotes the transition from DCIS to IDC, particularly by inducing myoepithelial cell apoptosis. Since this would be a prerequisite for invasive features in patients with DCIS breast cancer, its clinical management could help to prevent breast cancer progression to IDC.


Assuntos
Biomarcadores Tumorais/sangue , Carcinoma Ductal de Mama/sangue , Carcinoma Intraductal não Infiltrante/sangue , Glucocorticoides/sangue , Animais , Apoptose/genética , Biomarcadores Tumorais/genética , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/patologia , Carcinoma Intraductal não Infiltrante/genética , Carcinoma Intraductal não Infiltrante/patologia , Linhagem Celular Tumoral , Progressão da Doença , Feminino , Xenoenxertos , Humanos , Laminina/genética , Camundongos , Mioepitelioma/sangue , Mioepitelioma/genética , Mioepitelioma/patologia , Microambiente Tumoral/genética
3.
Proc Natl Acad Sci U S A ; 107(21): 9742-6, 2010 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-20453196

RESUMO

The 8q24 gene desert contains risk loci for multiple epithelial cancers, including colon, breast, and prostate. Recent evidence suggests these risk loci contain enhancers. In this study, data are presented showing that each risk locus bears epigenetic marks consistent with enhancer elements and forms a long-range chromatin loop with the MYC proto-oncogene located several hundred kilobases telomeric and that these interactions are tissue-specific. We therefore propose that the 8q24 risk loci operate through a common mechanism-as tissue-specific enhancers of MYC.


Assuntos
Neoplasias da Mama/genética , Cromossomos Humanos Par 8 , Neoplasias do Colo/genética , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Proteínas Proto-Oncogênicas c-myc/genética , Linhagem Celular Tumoral , Loci Gênicos , Genoma Humano , Humanos , Especificidade de Órgãos , Proto-Oncogene Mas , Fatores de Risco
4.
Cancer Res ; 83(2): 264-284, 2023 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-36409824

RESUMO

Inflammatory breast cancer (IBC) is a difficult-to-treat disease with poor clinical outcomes due to high risk of metastasis and resistance to treatment. In breast cancer, CD44+CD24- cells possess stem cell-like features and contribute to disease progression, and we previously described a CD44+CD24-pSTAT3+ breast cancer cell subpopulation that is dependent on JAK2/STAT3 signaling. Here we report that CD44+CD24- cells are the most frequent cell type in IBC and are commonly pSTAT3+. Combination of JAK2/STAT3 inhibition with paclitaxel decreased IBC xenograft growth more than either agent alone. IBC cell lines resistant to paclitaxel and doxorubicin were developed and characterized to mimic therapeutic resistance in patients. Multi-omic profiling of parental and resistant cells revealed enrichment of genes associated with lineage identity and inflammation in chemotherapy-resistant derivatives. Integrated pSTAT3 chromatin immunoprecipitation sequencing and RNA sequencing (RNA-seq) analyses showed pSTAT3 regulates genes related to inflammation and epithelial-to-mesenchymal transition (EMT) in resistant cells, as well as PDE4A, a cAMP-specific phosphodiesterase. Metabolomic characterization identified elevated cAMP signaling and CREB as a candidate therapeutic target in IBC. Investigation of cellular dynamics and heterogeneity at the single cell level during chemotherapy and acquired resistance by CyTOF and single cell RNA-seq identified mechanisms of resistance including a shift from luminal to basal/mesenchymal cell states through selection for rare preexisting subpopulations or an acquired change. Finally, combination treatment with paclitaxel and JAK2/STAT3 inhibition prevented the emergence of the mesenchymal chemo-resistant subpopulation. These results provide mechanistic rational for combination of chemotherapy with inhibition of JAK2/STAT3 signaling as a more effective therapeutic strategy in IBC. SIGNIFICANCE: Chemotherapy resistance in inflammatory breast cancer is driven by the JAK2/STAT3 pathway, in part via cAMP/PKA signaling and a cell state switch, which can be overcome using paclitaxel combined with JAK2 inhibitors.


Assuntos
Neoplasias da Mama , Neoplasias Inflamatórias Mamárias , Humanos , Feminino , Neoplasias Inflamatórias Mamárias/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Transdução de Sinais , Paclitaxel/farmacologia , Paclitaxel/uso terapêutico , Células-Tronco/metabolismo , Fator de Transcrição STAT3/metabolismo
5.
Biochim Biophys Acta ; 1816(2): 105-18, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21616127

RESUMO

Nerve fibers accompany blood and lymphatic vessels all over the body. An extensive amount of knowledge has been obtained with regard to tumor angiogenesis and tumor lymphangiogenesis, yet little is known about the potential biological effects of "neoneurogenesis". Cancer cells can exploit the advantage of the factors released by the nerve fibers to generate a positive microenvironment for cell survival and proliferation. At the same time, they can stimulate the formation of neurites by secreting neurotrophic factors and axon guidance molecules. The neuronal influence on the biology of a neoplasm was initially described several decades ago. Since then, an increasing amount of experimental evidence strongly suggests the existence of reciprocal interactions between cancer cells and nerves in humans. Moreover, researchers have been able to demonstrate a crosstalk between cancer cells and nerve fibers as a strategy for survival. Despite all these evidence, a lot remains to be done in order to clarify the role of neurotransmitters, neuropeptides, and their associated receptor-initiated signaling pathways in the development and progression of cancer, and response to therapy. A global-wide characterization of the neurotransmitters or neuropeptides present in the tumor microenvironment would provide insights into the real biological influences of the neuronal tissue on tumor progression. This review is intended to discuss our current understanding of neurosignaling in cancer and its potential implications on cancer prevention and therapy. The review will focus on the soluble factors released by cancer cells and nerve endings, their biological effects and their potential relevance in the treatment of cancer.


Assuntos
Neoplasias/etiologia , Neurônios/fisiologia , Progressão da Doença , Humanos , Neuropeptídeos/fisiologia , Neurotransmissores/fisiologia
6.
J Cell Physiol ; 227(4): 1358-66, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21604273

RESUMO

NK1 is a tachykinin receptor highly relevant to tumorigenesis and metastasis development in breast cancer and other carcinomas. Despite the substantial efforts done to develop potent NK1 receptor antagonists, none of these antagonists had shown good antitumor activity in clinical trials. Now, we have tested the effect of inhibition of the neuropeptide Substance P (SP), a NK1 ligand, as a potential therapeutic approach in cancer. We found that the inhibition of SP with antibodies strongly inhibit cell growth and induce apoptosis in breast, colon, and prostate cancer cell lines. These effects were accompained by a decrease in the mitogen-activated kinase singaling pathway. Interestingly, in some cell lines SP abrogation decreased the steady state of Her2 and EGFR, suggesting that SP-mediated signaling is important for the basal activity of these ErbB receptors. In consequence, we observed a blockade of the cell cycle progression and the inhibition of several cell cycle-related proteins including mTOR. SP inhibition also induced cell death in cell lines resistant to Lapatinib and Trastuzumab that have increased levels of active Her2, suggesting that this therapeutic approach could be also effective for those cancers resistant to current anti-ErbB therapies. Thus, we propose a new therapeutic strategy for those cancers that express NK1 receptor and/or other tachykinin receptors, based in the immuno-blockade of the neuropeptide SP.


Assuntos
Receptores ErbB/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Receptor ErbB-2/metabolismo , Substância P/antagonistas & inibidores , Anticorpos/farmacologia , Anticorpos Monoclonais Humanizados/farmacologia , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Lapatinib , Ligantes , Masculino , Neoplasias/patologia , Antagonistas dos Receptores de Neurocinina-1 , Piperidinas/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Quinazolinas/farmacologia , Receptores da Neurocinina-1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Substância P/imunologia , Trastuzumab
7.
Mol Cancer ; 9: 161, 2010 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-20573240

RESUMO

BACKGROUND: CD95 is a death receptor controlling not only apoptotic pathways but also activating mechanisms promoting tumor growth. During the acquisition of chemoresistance to oxaliplatin there is a progressive loss of CD95 expression in colon cancer cells and a decreased ability of this receptor to induce cell death. The aim of this study was to characterize some key cellular responses controlled by CD95 signaling in oxaliplatin-resistant colon cancer cells. RESULTS: We show that CD95 triggering results in an increased metastatic ability in resistant cells. Moreover, oxaliplatin treatment itself stimulates cell migration and decreases cell adhesion through CD95 activation, since CD95 expression inhibition by siRNA blocks the promigratory effects of oxaliplatin. These promigratory effects are related to the epithelia-to-mesenchymal transition (EMT) phenomenon, as evidenced by the up-regulation of some transcription factors and mesenchymal markers both in vitro and in vivo. CONCLUSIONS: We conclude that oxaliplatin treatment in cells that have acquired resistance to oxaliplatin-induced apoptosis results in tumor-promoting effects through the activation of CD95 signaling and by inducing EMT, all these events jointly contributing to a metastatic phenotype.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Transdução de Sinais , Receptor fas/metabolismo , Antineoplásicos/farmacologia , Sequência de Bases , Western Blotting , Ciclo Celular , Linhagem Celular Tumoral , Transição Epitelial-Mesenquimal , Citometria de Fluxo , Imunofluorescência , Humanos , Compostos Organoplatínicos/farmacologia , Oxaliplatina , Reação em Cadeia da Polimerase , RNA Interferente Pequeno
8.
Cancer Res ; 67(13): 6512-9, 2007 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-17616713

RESUMO

Implantation of the Yoshida AH-130 ascites hepatoma to rats resulted in a decrease in muscle weight 7 days after the inoculation of the tumor. These changes were associated with increases in the mRNA content for both peroxisome proliferator-activated receptor (PPAR) gamma and PPAR delta in skeletal muscle. The increase in gene expression for these transcription factors was related to increases in the expression of several genes involved in fatty acid transport, activation, and oxidation. Tumor burden also resulted in increases in PPAR gamma coactivator-1 alpha gene expression and pyruvate dehydrogenase kinase 4. All these changes in lipid metabolism genes suggest that a metabolic shift occurs in skeletal muscle of tumor-bearing rats toward a more oxidative phenotype. Formoterol treatment to tumor-bearing rats resulted in an amelioration of all the changes observed as a result of tumor burden. Administration of this beta(2)-adrenergic agonist also resulted in a decrease in mRNA content of muscle PPAR alpha, PPAR delta, and PPAR gamma, as well as in mRNA levels of many of the genes involved in both lipid and mitochondrial metabolism. All these results suggest an involvement of the different PPARs as transcription factors related with muscle wasting and also indicate that a possible mode of action of the anticachectic compound formoterol may involve a normalization of the levels of these transcription factors.


Assuntos
Agonistas Adrenérgicos beta/farmacologia , Regulação Neoplásica da Expressão Gênica , Músculo Esquelético/metabolismo , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Animais , Peso Corporal , Caquexia , Ácidos Graxos/metabolismo , Metabolismo dos Lipídeos , Masculino , Músculo Esquelético/patologia , Atrofia Muscular , Neoplasias Experimentais , Ratos , Ratos Wistar , Transcrição Gênica
9.
Biochim Biophys Acta ; 1770(7): 1028-36, 2007 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-17442496

RESUMO

Calcineurin has been proposed to regulate skeletal muscle hypertrophy, while its relevance to the pathogenesis of muscle atrophy is unknown. The present study was aimed to investigate if perturbations of the calcineurin pathway may be involved in causing skeletal muscle atrophy in two different experimental conditions: cancer cachexia (rats bearing the AH-130 hepatoma), and hyperglycemia (rats treated with streptozotocin). Calcineurin expression in the gastrocnemius was comparable between tumor hosts and controls. By contrast, besides unchanged calcineurin mRNA levels, those of protein were lower in diabetic animals than in controls. The DNA-binding activity of the transcription factors NF-AT and MEF-2 was analysed as an indirect measure of calcineurin activity in vivo. The nuclear translocation of both factors was similar in tumor hosts and controls. Consistently with the reduced calcineurin protein levels, NF-AT DNA-binding activity significantly decreased in the gastrocnemius of diabetic rats compared to controls. Finally, muscle wasting correction afforded in the AH-130 hosts by pentoxifylline or interleukin-15 was not paralleled by changes of calcineurin mRNA levels, while treatment of diabetic animals with dehydroepiandrosterone partially prevented calcineurin down-regulation. These results suggest that modulations of calcineurin activity may be involved in the pathogenesis of muscle wasting in diabetes though not in cancer cachexia.


Assuntos
Calcineurina/metabolismo , DNA/metabolismo , Músculo Esquelético/metabolismo , Atrofia Muscular/metabolismo , Fatores de Transcrição NFATC/metabolismo , Animais , Western Blotting , Caquexia/metabolismo , Carcinoma Hepatocelular/metabolismo , Primers do DNA , Ensaio de Desvio de Mobilidade Eletroforética , Hiperglicemia/metabolismo , Insulina/sangue , Interleucina-15 , Masculino , Óxido Nítrico/sangue , Pentoxifilina , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase Via Transcriptase Reversa
10.
Cancer Lett ; 424: 70-83, 2018 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-29548821

RESUMO

Histamine receptor 1 (HRH1) belongs to the rhodopsin-like G-protein-coupled receptor family. Its activation by histamine triggers cell proliferation, embryonic development, and tumor growth. We recently established that HRH1 is up-regulated in basal and human epidermal growth factor receptor 2 (HER2)-enriched human breast tumors and that its expression correlates with a worse prognosis. Nevertheless, the functional role of HRH1 in basal and HER2-targeted therapy-resistant breast cancer (BC) progression has not yet been addressed. Using terfenadine, a selective chemical inhibitor of HRH1, we showed that the inhibition of HRH1 activity in basal BC cells leads to sub-G0 cell accumulation, suppresses proliferation, promotes cell motility and triggers the activation of extracellular signal-regulated kinase (ERK) signaling, initiating the mitochondrial apoptotic pathway. Furthermore, HER2-targeted therapy-resistant cells express higher levels of HRH1 and are more sensitive to terfenadine treatment. Moreover, in vivo experiments showed that terfenadine therapy reduced the tumor growth of basal and trastuzumab-resistant BC cells. In conclusion, our results suggest that targeting HRH1 is a promising new clinical approach to consider that could enhance the effectiveness of current therapeutic treatment in patients with basal and BC tumors resistant to HER2-targeted therapies.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Antagonistas não Sedativos dos Receptores H1 da Histamina/administração & dosagem , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Receptores Histamínicos H1/metabolismo , Terfenadina/administração & dosagem , Trastuzumab/administração & dosagem , Animais , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Sinergismo Farmacológico , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Antagonistas não Sedativos dos Receptores H1 da Histamina/farmacologia , Humanos , Células MCF-7 , Camundongos , Neoplasia de Células Basais/tratamento farmacológico , Neoplasia de Células Basais/metabolismo , Receptor ErbB-2/metabolismo , Terfenadina/farmacologia , Trastuzumab/farmacologia , Regulação para Cima/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Mol Oncol ; 12(11): 1838-1855, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30133130

RESUMO

Targeted therapy for patients with HER2-positive (HER2+) breast cancer has improved overall survival, but many patients still suffer relapse and death from the disease. Intratumor heterogeneity of both estrogen receptor (ER) and HER2 expression has been proposed to play a key role in treatment failure, but little work has been done to comprehensively study this heterogeneity at the single-cell level. In this study, we explored the clinical impact of intratumor heterogeneity of ER protein expression, HER2 protein expression, and HER2 gene copy number alterations. Using combined immunofluorescence and in situ hybridization on tissue sections followed by a validated computational approach, we analyzed more than 13 000 single tumor cells across 37 HER2+ breast tumors. The samples were taken both before and after neoadjuvant chemotherapy plus HER2-targeted treatment, enabling us to study tumor evolution as well. We found that intratumor heterogeneity for HER2 copy number varied substantially between patient samples. Highly heterogeneous tumors were associated with significantly shorter disease-free survival and fewer long-term survivors. Patients for which HER2 characteristics did not change during treatment had a significantly worse outcome. This work shows the impact of intratumor heterogeneity in molecular diagnostics for treatment selection in HER2+ breast cancer patients and the power of computational scoring methods to evaluate in situ molecular markers in tissue biopsies.


Assuntos
Neoplasias da Mama , Resistencia a Medicamentos Antineoplásicos , Dosagem de Genes , Terapia Neoadjuvante , Receptor ErbB-2 , Idoso , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/mortalidade , Neoplasias da Mama/terapia , Intervalo Livre de Doença , Feminino , Humanos , Pessoa de Meia-Idade , Receptor ErbB-2/biossíntese , Receptor ErbB-2/genética , Taxa de Sobrevida
12.
Biochim Biophys Acta ; 1760(11): 1613-7, 2006 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17056184

RESUMO

Previous studies have demonstrated that interleukin-15 (IL-15) has important anabolic effects on muscle protein metabolism. In the present investigation we have analysed the effects of IL-15 on glucose metabolism in skeletal muscle. Administration of a single dose of the cytokine (100 microg/kg body weight) resulted in a 32% increase on glucose uptake (as measured by the uptake of 2-deoxyglucose) in skeletal muscle. The effects observed on glucose uptake were direct since in vitro incubations of rat EDL muscles in the presence of the cytokine resulted in a 30% increase in glucose uptake. Similarly, IL-15 increased glucose uptake in C2C12 cell cultures, this being related with an increase in both glucose oxidation to CO2 and the incorporation into muscle lipid. The effects of the cytokine were associated with an increase in GLUT-4 mRNA, suggesting a higher effect in insulin sensitivity. In conclusion, the data presented here indicate that IL-15 facilitates glucose metabolism in skeletal muscle and, therefore, a possible role of the cytokine as an antidiabetogenic drug merits future investigations.


Assuntos
Glucose/metabolismo , Hipoglicemiantes/farmacologia , Interleucina-15/farmacologia , Músculo Esquelético/metabolismo , Animais , Células Cultivadas , Masculino , Músculo Esquelético/efeitos dos fármacos , Ratos , Ratos Wistar , Fatores de Tempo
13.
Biochim Biophys Acta ; 1761(1): 37-42, 2006 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-16458591

RESUMO

Interleukin 15 (IL-15) has previously been shown to have important effects on lipid metabolism in adipose tissue, particularly influencing the rate of the de novo fatty acid synthesis. The results presented here show that chronic administration to rats (100 microg/kg body weight) has important effects on the metabolic fate of an exogenous [(14)C]-triolein load, decreasing the incorporation of lipid into adipose tissue and significantly increasing the total (14)CO(2) formation from [(14)C]-triolein. Skeletal muscle and possibly liver seem to be the main organs involved in the action of IL-15 on lipid oxidation, since the presence of the cytokine in incubated EDL muscle with [(14)C]-palmitic acid increased (14)CO(2) formation by 39%. Concerning the mechanism, the results suggest that the transport of fatty acids into mitochondria could be involved in the action of IL-15 since the cytokine clearly increases the presence of L-CPT-I and CPT-II in liver tissue. In addition, IL-15 treatment resulted in a significant increment in the gene expression of PPARdelta, a transcription factor clearly related with lipid catabolism in many tissues. Altogether, the results presented here suggest that IL-15 alters exogenous lipid partitioning, limiting adipose tissue uptake and favouring oxidation.


Assuntos
Interleucina-15/farmacologia , Trioleína/metabolismo , Animais , Interleucina-15/genética , Masculino , Especificidade de Órgãos , Oxirredução , Receptores Ativados por Proliferador de Peroxissomo/genética , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase Via Transcriptase Reversa
14.
Front Biosci ; 12: 3024-51, 2007 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-17485280

RESUMO

Cancer cachexia is a syndrome characterized by a marked weight loss, anorexia, asthenia and anemia. The degree of cachexia is inversely correlated with the survival time of the patient and it always implies a poor prognosis. Lean body mass depletion is one of the main features of cachexia and it involves not only skeletal muscle but also affects cardiac protein. The cachectic state is invariably associated with the presence and growth of the tumour and leads to a malnutrition status due to the induction of anorexia or decreased food intake. In addition, the competition for nutrients between the tumour and the host leads to an accelerated starvation state which promotes severe metabolic disturbances in the host, including hypermetabolism which leads to an increased energetic inefficiency. Unfortunately, at the clinical level, cachexia is not treated until the patient suffers from a considerable weight loss and wasting. Therefore, it is of great interest to analyze possible early markers of the syndrome. In the present review both metabolic and hormonal markers are described. Although the search for the cachectic factor(s) started a long time ago, and although many scientific and economic efforts have been devoted to its discovery, we are still a long way from fully understanding the underlying basis for this syndrome. The suggested mediators (associated with both depletion of fat stores and muscular tissue) can be divided into two categories: of tumour origin (produced and released by the neoplasm) and humoural factors (mainly cytokines). One of the aims of the present review is to summarize and evaluate the different catabolic mediators (both humoural and tumoural) involved in cancer cachexia, since they may represent targets for clinical investigations. Additionally, an overview of the main therapeutic approaches for the treatment of the cachectic syndrome is presented.


Assuntos
Oncologia , Neoplasias/metabolismo , Caquexia/dietoterapia , Caquexia/tratamento farmacológico , Caquexia/metabolismo , Humanos , Neoplasias/complicações , Neoplasias/fisiopatologia
15.
Int J Oncol ; 30(5): 1239-45, 2007 May.
Artigo em Inglês | MEDLINE | ID: mdl-17390027

RESUMO

Daily treatment of rats bearing the cachectic Yoshida AH-130 ascites hepatoma with the double inhibitor of NF-kappaB and AP-1 SP100030 at a dose of 1 mg/kg of body weight resulted in a clear amelioration of the cachectic effect, especially at the level of skeletal muscle. Thus, tumour-bearing rats treated with SP100030 showed a significant recovery in the weights of gastrocnemius, EDL, tibialis and cardiac muscles. In addition, treatment with the inhibitor affected both liver and kidney weights. The amelioration in muscle weight was accompanied by an increase in MyoD gene expression, the main transcription factor of muscle tissue involved in muscle differentiation, in gastrocnemius muscle. At the dose used in this study, SP100030 was an effective inhibitor of AP-1; however, the NF-kappaB transcription factor was not affected. The effects of the inhibitor seem to be at the level of proteolysis since lower total proteolytic rates were found when incubating isolated rat muscles in the presence of SP100030. The inhibitor influenced the gene expression of the ubiquitin-conjugating enzyme E214K in skeletal muscle of tumour-bearing rats; this enzyme seems to be the main regulator of the activity of the main proteolytic system involved during cancer cachexia, the ubiquitin-proteasome system. In conclusion, treatment of cachectic tumour-bearing rats with SP100030 results in an amelioration of the muscle wasting effect, suggesting that the AP-1 signaling cascade plays an important role in the signaling of muscle wasting associated with disease.


Assuntos
Caquexia/tratamento farmacológico , Regulação Neoplásica da Expressão Gênica , Atrofia Muscular/tratamento farmacológico , NF-kappa B/biossíntese , Neoplasias Experimentais/tratamento farmacológico , Fator de Transcrição AP-1/antagonistas & inibidores , Animais , Antineoplásicos/farmacologia , Humanos , Imunossupressores/farmacologia , Masculino , Músculos/patologia , Atrofia Muscular/metabolismo , NF-kappa B/química , Neoplasias Experimentais/complicações , Compostos Orgânicos/farmacologia , Ratos , Ratos Wistar
16.
Clin Nutr ; 26(5): 658-61, 2007 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17904252

RESUMO

BACKGROUND & AIMS: In rodents and humans, inactivity or starvation leads to atrophy of skeletal muscle including a decrease in the number and size of muscle cells and in the myofibrillar protein content. It has previously been described that in overwintering bears the inactivity does not provoke any loss of skeletal muscle cell number or size. Taking all these into account, the aim of this study is to test if hibernating bear plasma has any antiproteolytic effect on incubated rat skeletal muscle. METHODS: Rat skeletal extensor digitorum longus (EDL) muscles were incubated in the presence of hibernating, non-hibernating and control bear plasma. After that, proteolytic rate was evaluated as levels of tyrosine released to the medium and muscle mRNA content for different proteolytic systems were measured by Northern blot. RESULTS: Rat skeletal EDL muscles incubation in the presence of hibernating bear plasma resulted in a 40% decrease of the net proteolytic rate. This inhibition of proteolysis was accompanied by decreases in the expression of both lysosomal (cathepsin B) and ubiquitin-dependent (ubiquitin) proteolytic systems. CONCLUSIONS: The results suggest that during hibernation the bear is able to produce a powerful proteolytic inhibitor which is released to the circulation and blocks muscle wasting associated with immobilization.


Assuntos
Hibernação/fisiologia , Músculo Esquelético/metabolismo , Atrofia Muscular/tratamento farmacológico , Plasma/fisiologia , Ursidae/sangue , Animais , Humanos , Masculino , Proteínas Musculares/metabolismo , Músculo Esquelético/efeitos dos fármacos , Ratos , Ratos Wistar , Ursidae/fisiologia
17.
Cancer Res ; 64(18): 6725-31, 2004 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-15374990

RESUMO

In cancer cachexia both cardiac and skeletal muscle suffer an important protein mobilization as a result of increased proteolysis. Administration of the beta2-agonist formoterol to both rats and mice bearing highly cachectic tumors resulted in an important reversal of the muscle-wasting process. The anti-wasting effects of the drug were based on both an activation of the rate of protein synthesis and an inhibition of the rate of muscle proteolysis. Northern blot analysis revealed that formoterol treatment resulted in a decrease in the mRNA content of ubiquitin and proteasome subunits in gastrocnemius muscles; this, together with the decreased proteasome activity observed, suggest that the main anti-proteolytic action of the drug may be based on an inhibition of the ATP-ubiquitin-dependent proteolytic system. Interestingly, the beta2-agonist was also able to diminish the increased rate of muscle apoptosis (measured as DNA laddering as well as caspase-3 activity) present in tumor-bearing animals. The present results indicate that formoterol exerted a selective, powerful protective action on heart and skeletal muscle by antagonizing the enhanced protein degradation that characterizes cancer cachexia, and it could be revealed as a potential therapeutic tool in pathologic states wherein muscle protein hypercatabolism is a critical feature such as cancer cachexia or other wasting diseases.


Assuntos
Agonistas Adrenérgicos beta/farmacologia , Caquexia/tratamento farmacológico , Etanolaminas/farmacologia , Músculo Esquelético/patologia , Neoplasias Experimentais/metabolismo , Animais , Caquexia/metabolismo , Caquexia/patologia , Carcinoma Pulmonar de Lewis/metabolismo , Carcinoma Pulmonar de Lewis/patologia , Modelos Animais de Doenças , Ingestão de Alimentos/efeitos dos fármacos , Fumarato de Formoterol , Neoplasias Hepáticas Experimentais/metabolismo , Neoplasias Hepáticas Experimentais/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Musculares/metabolismo , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Neoplasias Experimentais/patologia , Ratos , Ratos Wistar , Sarcoma de Yoshida/metabolismo , Sarcoma de Yoshida/patologia
18.
Oncotarget ; 7(5): 5313-26, 2016 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-26673618

RESUMO

The nervous system is now recognized to be a relevant component of the tumor microenvironment. Receptors for neuropeptides and neurotransmitters have been identified in breast cancer. However, very little is known about the role of neurogenes in regulating breast cancer progression. Our purpose was to identify neurogenes associated with breast cancer tumorigenesis with a potential to be used as biomarker and/or targets for treatment. We used three databases of human genes: GeneGo, GeneCards and Eugenes to generate a list of 1266 relevant neurogenes. Then we used bioinformatics tools to interrogate two published breast cancer databases SAGE and MicMa (n=96) and generated a list of 7 neurogenes that are differentially express among breast cancer subtypes. The clinical potential was further investigated using the GOBO database (n=1881). We identified 6 neurogenes that are differentially expressed among breast cancer subtypes and whose expression correlates with prognosis. Histamine receptor1 (HRH1), neuropilin2 (NRP2), ephrin-B1 (EFNB1), neural growth factor receptor (NGFR) and amyloid precursor protein (APP) were differentially overexpressed in basal and HER2-enriched tumor samples and syntaxin 1A (STX1A) was overexpressed in HER2-enriched and luminal B tumors. Analysis of HRH1, NRP2, and STX1A expression using the GOBO database showed that their expression significantly correlated with a shorter overall survival (p < 0.0001) and distant metastasis-free survival (p < 0.0001). In contrast, elevated co-expression of NGFR, EFNB1 and APP was associated with longer overall (p < 0.0001) and metastasis-free survival (p < 0.0001). We propose that HRH1, NRP2, and STX1A can be used as prognostic biomarkers and therapeutic targets for basal and HER2-enriched breast cancer subtypes.


Assuntos
Neoplasias da Mama/genética , Neurogênese/genética , Neuropeptídeos/genética , Feminino , Expressão Gênica/genética , Humanos , Prognóstico , Fatores de Risco , Microambiente Tumoral
19.
Cancer Res ; 76(7): 1926-34, 2016 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-26941287

RESUMO

The frequency and proliferative activity of tissue-specific stem and progenitor cells are suggested to correlate with cancer risk. In this study, we investigated the association between breast cancer risk and the frequency of mammary epithelial cells expressing p27, estrogen receptor (ER), and Ki67 in normal breast tissue. We performed a nested case-control study of 302 women (69 breast cancer cases, 233 controls) who had been initially diagnosed with benign breast disease according to the Nurses' Health Studies. Immunofluorescence for p27, ER, and Ki67 was performed on tissue microarrays constructed from benign biopsies containing normal mammary epithelium and scored by computational image analysis. We found that the frequency of Ki67(+) cells was positively associated with breast cancer risk among premenopausal women [OR = 10.1, 95% confidence interval (CI) = 2.12-48.0]. Conversely, the frequency of ER(+) or p27(+) cells was inversely, but not significantly, associated with subsequent breast cancer risk (ER(+): OR = 0.70, 95% CI, 0.33-1.50; p27(+): OR = 0.89, 95% CI, 0.45-1.75). Notably, high Ki67(+)/low p27(+) and high Ki67(+)/low ER(+) cell frequencies were significantly associated with a 5-fold higher risk of breast cancer compared with low Ki67(+)/low p27(+) and low Ki67(+)/low ER(+) cell frequencies, respectively, among premenopausal women (Ki67(hi)/p27(lo): OR = 5.08, 95% CI, 1.43-18.1; Ki67(hi)/ER(lo): OR = 4.68, 95% CI, 1.63-13.5). Taken together, our data suggest that the fraction of actively cycling cells in normal breast tissue may represent a marker for breast cancer risk assessment, which may therefore impact the frequency of screening procedures in at-risk women. Cancer Res; 76(7); 1926-34. ©2016 AACR.


Assuntos
Neoplasias da Mama/etiologia , Células Epiteliais/patologia , Glândulas Mamárias Humanas/patologia , Adulto , Neoplasias da Mama/patologia , Estudos de Casos e Controles , Feminino , Humanos , Pré-Menopausa
20.
FEBS Lett ; 579(3): 717-22, 2005 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-15670834

RESUMO

Implantation of a fast growing tumour to mice (Lewis lung carcinoma) resulted in a clear cachectic state characterized by a profound muscle wasting. This was accompanied by a significant increase in both UCP2 and UCP3 gene expression in skeletal muscle and heart. Interestingly, this increase in gene expression was not linked to a rise in circulating fatty acids or in a decrease in food intake, as previously reported in other pathophysiological states. These results question the concept that hyperlipaemia is the only factor controlling UCP gene expression in different pathophysiological conditions. In addition, the present work suggests that UCPs might participate in a counter-regulatory mechanism to lower the production of ROS.


Assuntos
Caquexia/metabolismo , Proteínas de Transporte/genética , Ingestão de Energia , Ácidos Graxos/sangue , Regulação da Expressão Gênica , Proteínas de Membrana Transportadoras/genética , Proteínas Mitocondriais/genética , Músculo Esquelético/metabolismo , Neoplasias Experimentais/metabolismo , Espécies Reativas de Oxigênio , Animais , Sequência de Bases , Northern Blotting , Western Blotting , Caquexia/genética , Caquexia/patologia , Primers do DNA , Modelos Animais de Doenças , Canais Iônicos , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias Experimentais/genética , Neoplasias Experimentais/patologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteína Desacopladora 2 , Proteína Desacopladora 3
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