Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 38
Filtrar
Filtros adicionais











Intervalo de ano
1.
Aging (Albany NY) ; 11(9): 2874-2888, 2019 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-31076561

RESUMO

Certain dietary interventions might improve the therapeutic index of cancer treatments. An alternative to the "drug plus diet" approach is the pharmacological reproduction of the metabolic traits of such diets. Here we explored the impact of adding metformin to an established therapeutic regimen on the systemic host metabolism of cancer patients. A panel of 11 serum metabolites including markers of mitochondrial function and intermediates/products of folate-dependent one-carbon metabolism were measured in paired baseline and post-treatment sera obtained from HER2-positive breast cancer patients randomized to receive either metformin combined with neoadjuvant chemotherapy and trastuzumab or an equivalent regimen without metformin. Metabolite profiles revealed a significant increase of the ketone body ß-hydroxybutyrate and of the TCA intermediate α-ketoglutarate in the metformin-containing arm. A significant relationship was found between the follow-up levels of homocysteine and the ability of treatment arms to achieve a pathological complete response (pCR). In the metformin-containing arm, patients with significant elevations of homocysteine tended to have a higher probability of pCR. The addition of metformin to an established anti-cancer therapeutic regimen causes a fasting-mimicking modification of systemic host metabolism. Circulating homocysteine could be explored as a clinical pharmacodynamic biomarker linking the antifolate-like activity of metformin and biological tumor response.

2.
Oncotarget ; 9(86): 35687-35704, 2018 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-30479698

RESUMO

The METTEN study assessed the efficacy, tolerability, and safety of adding metformin to neoadjuvant chemotherapy plus trastuzumab in early HER2-positive breast cancer (BC). Women with primary, non-metastatic HER2-positive BC were randomized (1:1) to receive metformin (850 mg twice-daily) for 24 weeks concurrently with 12 cycles of weekly paclitaxel plus trastuzumab, followed by four cycles of 3-weekly FE75C plus trastuzumab (arm A), or equivalent regimen without metformin (arm B), followed by surgery. Primary endpoint was the rate of pathological complete response (pCR) in the per-protocol efficacy population. pCR rate was numerically higher in the metformin-containing arm A (19 of 29 patients [65.5%, 95% CI: 47.3-80.1]) than in arm B (17 of 29 patients [58.6%, 95% CI: 40.7-74.5]; OR 1.34 [95% CI: 0.46-3.89], P = 0.589). The rate of breast-conserving surgery was 79.3% and 58.6% in arm A and B (P = 0.089), respectively. Blood metformin concentrations (6.2 µmol/L, 95% CI: 3.6-8.8) were within the therapeutic range. Seventy-six percent of patients completed the metformin-containing regimen; 13% of patients in arm A dropped out because of metformin-related gastrointestinal symptoms. The most common adverse events (AEs) of grade ≥3 were neutropenia in both arms and diarrhea in arm A. None of the serious AEs was deemed to be metformin-related. Addition of anti-diabetic doses of metformin to a complex neoadjuvant regimen was well tolerated and safe. Because the study was underpowered relative to its primary endpoint, the efficacy data should be interpreted with caution.

3.
Aging (Albany NY) ; 8(7): 1330-52, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27295498

RESUMO

Our understanding on how selective mitochondrial autophagy, or mitophagy, can sustain the archetypal properties of stem cells is incomplete. PTEN-induced putative kinase 1 (PINK1) plays a key role in the maintenance of mitochondrial morphology and function and in the selective degradation of damaged mitochondria by mitophagy. Here, using embryonic fibroblasts fromPINK1 gene-knockout (KO) mice, we evaluated whether mitophagy is a causal mechanism for the control of cell-fate plasticity and maintenance of pluripotency. Loss of PINK1-dependent mitophagy was sufficient to dramatically decrease the speed and efficiency of induced pluripotent stem cell (iPSC) reprogramming. Mitophagy-deficient iPSC colonies, which were characterized by a mixture of mature and immature mitochondria, seemed unstable, with a strong tendency to spontaneously differentiate and form heterogeneous populations of cells. Although mitophagy-deficient iPSC colonies normally expressed pluripotent markers, functional monitoring of cellular bioenergetics revealed an attenuated glycolysis in mitophagy-deficient iPSC cells. Targeted metabolomics showed a notable alteration in numerous glycolysis- and TCA-related metabolites in mitophagy-deficient iPSC cells, including a significant decrease in the intracellular levels of α-ketoglutarate -a key suppressor of the differentiation path in stem cells. Mitophagy-deficient iPSC colonies exhibited a notably reduced teratoma-initiating capacity, but fully retained their pluripotency and multi-germ layer differentiation capacity in vivo. PINK1-dependent mitophagy pathway is an important mitochondrial switch that determines the efficiency and quality of somatic reprogramming. Mitophagy-driven mitochondrial rejuvenation might contribute to the ability of iPSCs to suppress differentiation by directing bioenergetic transition and metabolome remodeling traits. These findings provide new insights into how mitophagy might influence the stem cell decisions to retain pluripotency or differentiate in tissue regeneration and aging, tumor growth, and regenerative medicine.


Assuntos
Linhagem da Célula/fisiologia , Mitocôndrias/metabolismo , Degradação Mitocondrial/fisiologia , Células-Tronco/metabolismo , Animais , Reprogramação Celular/fisiologia , Metabolismo Energético , Fibroblastos/citologia , Fibroblastos/metabolismo , Metabolômica , Camundongos , Camundongos Knockout , Proteínas Quinases/genética , Proteínas Quinases/metabolismo , Células-Tronco/citologia
4.
Oncotarget ; 6(32): 32317-38, 2015 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-26474458

RESUMO

Clinically HER2+ (cHER2+) breast cancer (BC) can no longer be considered a single BC disease entity in terms of trastuzumab responsiveness. Here we propose a framework for predicting the response of cHER2+ to trastuzumab that integrates the molecular distinctions of intrinsic BC subtypes with recent knowledge on cancer stem cell (CSC) biology. First, we consider that two interchangeable populations of epithelial-like, aldehyde dehydrogenase (ALDH)-expressing and mesenchymal-like, CD44+CD24-/low CSCs can be found in significantly different proportions across all intrinsic BC subtypes. Second, we overlap all the intrinsic subtypes across cHER2+ BC to obtain a continuum of mixed phenotypes in which one extreme exhibits a high identity with ALDH+ CSCs and the other extreme exhibits a high preponderance of CD44+CD24-/low CSCs. The differential enrichment of trastuzumab-responsive ALDH+ CSCs versus trastuzumab-refractory CD44+CD24-/low CSCs can explain both the clinical behavior and the primary efficacy of trastuzumab in each molecular subtype of cHER2+ (i.e., HER2-enriched/cHER2+, luminal A/cHER2+, luminal B/cHER2+, basal/cHER2+, and claudin-low/cHER2+). The intrinsic plasticity determining the epigenetic ability of cHER2+ tumors to switch between epithelial and mesenchymal CSC states will vary across the continuum of mixed phenotypes, thus dictating their intratumoral heterogeneity and, hence, their evolutionary response to trastuzumab. Because CD44+CD24-/low mesenchymal-like CSCs distinctively possess a highly endocytic activity, the otherwise irrelevant HER2 can open the door to a type of "Trojan horse" approach by employing antibody-drug conjugates such as T-DM1, which will allow a rapid and CSC-targeted delivery of cytotoxic drugs to therapeutically manage trastuzumab-unresponsive basal/cHER2+ BC. Contrary to the current dichotomous model used clinically, our model proposes that a reclassification of cHER2+ tumors based on the spectrum of molecular BC subtypes might inform on their CSC-determined sensitivity to trastuzumab, thus providing a better delineation of the predictive value of cHER2+ in BC by incorporating CSCs-driven intra-tumor heterogeneity into clinical decisions.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Células-Tronco Neoplásicas/efeitos dos fármacos , Receptor ErbB-2/antagonistas & inibidores , Trastuzumab/uso terapêutico , Aldeído Desidrogenase/metabolismo , Antineoplásicos/imunologia , Antineoplásicos/uso terapêutico , Neoplasias da Mama/classificação , Neoplasias da Mama/metabolismo , Epigênese Genética , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transição Epitelial-Mesenquimal/genética , Feminino , Humanos , Receptores de Hialuronatos/metabolismo , Modelos Biológicos , Células-Tronco Neoplásicas/metabolismo , Fenótipo , Receptor ErbB-2/imunologia , Receptor ErbB-2/metabolismo , Trastuzumab/imunologia , Resultado do Tratamento
5.
Oncotarget ; 6(9): 7104-22, 2015 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-25742793

RESUMO

There is an urgent need to refine the prognostic taxonomy of HER2+ breast carcinomas and develop easy-to-use, clinic-based prediction algorithms to distinguish between good- and poor- responders to trastuzumab-based therapy. Building on earlier studies suggesting that HER2+ tumors enriched with molecular and morpho-immunohistochemical features classically ascribed to basal-like tumors are highly aggressive and refractory to trastuzumab, we investigated the prognostic and predictive value of the basal-HER2+ phenotype in HER2-overexpressing tumors. Our retrospective cohort study of a consecutive series of 152 HER2+ primary invasive ductal breast carcinomas first confirmed the existence of a distinct subgroup co-expressing HER2 protein and basal cytokeratin markers CK5/6, the so-called basal-HER2+ phenotype. Basal-HER2+ phenotype (≥10% of cells showing positive CK5/6 staining), but not estrogen receptor status, was significantly associated with inferior overall survival by univariate analysis and predicted worsened disease free survival after accounting for strong prognostic variables such as tumor size at diagnosis in stepwise multivariate analysis. In the sub-cohort of HER2+ patients treated with trastuzumab-based adjuvant/neoadjuvant therapy, basal-HER2+ phenotype was found to be the sole independent prognostic marker for a significantly inferior time to treatment failure in multivariate analysis. A CK5/6-based immunohistochemical fingerprint may provide a simple, rapid, and accurate method for re-classifying women diagnosed with HER2+ breast cancer in a manner that can improve prognosis and therapeutic planning in patients with clinically aggressive basal-HER2+ tumors who are not likely to benefit from trastuzumab-based therapy.


Assuntos
Neoplasias da Mama/metabolismo , Carcinoma Ductal de Mama/metabolismo , Resistencia a Medicamentos Antineoplásicos , Queratina-5/metabolismo , Queratina-6/metabolismo , Receptor ErbB-2/metabolismo , Trastuzumab/química , Adulto , Idoso , Algoritmos , Neoplasias da Mama/tratamento farmacológico , Carcinoma Ductal de Mama/tratamento farmacológico , Intervalo Livre de Doença , Feminino , Humanos , Imunofenotipagem , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Fenótipo , Valor Preditivo dos Testes , Prognóstico , Estudos Prospectivos , Estudos Retrospectivos , Resultado do Tratamento
6.
Sci Rep ; 4: 5743, 2014 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-25034150

RESUMO

The one-step nucleic acid amplification (OSNA) assay is a molecular procedure that can identify deposits of breast cancer (BC) cells in the sentinel lymph node (SLN). We examined the consistency of the OSNA assay with a classic hematoxylin-eosin (H&E)-based immunohistochemistry (IHC) study and evaluated how OSNA-based axillary staging might impact the therapeutic management of BC patients. SLN biopsy results were considered to be positive in 60 patients (40%) in the OSNA group (N = 148) and in 43 (28%) patients in the IHC cohort (N = 153, p = 0.023). There was no difference in the macrometastasis (22% for OSNA, 15% for H&E, p = 0.139) or micrometastasis (19% for OSNA, 13% for H&E, p = 0.166) rates, but we found statistically significant differences in the number of isolated tumor cells (1% for OSNA, 11% for H&E, p < 0.001). There were no differences in the administration rate of adjuvant systemic therapy between the OSNA (66% in the SLN(+) patients) and the H&E (74% in the SLN(+) patients) groups (p = 0.159). The OSNA assay allows for the detection of SLN metastases more precisely than conventional pathologic methods but does not alter the therapeutic management of SLN(+) BC patients.


Assuntos
Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/secundário , Linfonodos/patologia , Adulto , Idoso , Axila , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Carcinoma Ductal de Mama/tratamento farmacológico , Carcinoma Ductal de Mama/genética , Quimioterapia Adjuvante , Feminino , Humanos , Metástase Linfática , Pessoa de Meia-Idade , Técnicas de Diagnóstico Molecular , Estadiamento de Neoplasias/métodos , Técnicas de Amplificação de Ácido Nucleico , Melhoria de Qualidade
7.
Oncotarget ; 5(7): 1942-54, 2014 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-24722433

RESUMO

This study aimed to improve gastric cancer (GC) diagnosis by identifying and validating an INflammatory PROtein-driven GAstric cancer Signature (hereafter INPROGAS) using low-cost affinity proteomics. The detection of 120 cytokines, 43 angiogenic factors, 41 growth factors, 40 inflammatory factors and 10 metalloproteinases was performed using commercially available human antibody microarray-based arrays. We identified 21 inflammation-related proteins (INPROGAS) with significant differences in expression between GC tissues and normal gastric mucosa in a discovery cohort of matched pairs (n=10) of tumor/normal gastric tissues. Ingenuity pathway analysis confirmed the "inflammatory response", "cellular movement" and "immune cell trafficking" as the most overrepresented biofunctions within INPROGAS. Using an expanded independent validation cohort (n = 22), INPROGAS classified gastric samples as "GC" or "non-GC" with a sensitivity of 82% (95% CI 59-94) and a specificity of 73% (95% CI 49-89). The positive predictive value and negative predictive value in this validation cohort were 75% (95% CI 53-90) and 80% (95% CI 56-94), respectively. The positive predictive value and negative predictive value in this validation cohort were 75% (95% CI 53-90) and 80% (95% CI 56-94), respectively. Antibody microarray analyses of the GC-associated inflammatory proteome identified a 21-protein INPROGAS that accurately discriminated GC from noncancerous gastric mucosa.


Assuntos
Indutores da Angiogênese/metabolismo , Biomarcadores Tumorais/metabolismo , Citocinas/metabolismo , Mucosa Gástrica/metabolismo , Metaloproteases/metabolismo , Neoplasias Gástricas/metabolismo , Movimento Celular , Reações Falso-Negativas , Reações Falso-Positivas , Feminino , Humanos , Imunidade Celular , Inflamação/metabolismo , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Análise Serial de Proteínas , Proteômica , Neoplasias Gástricas/diagnóstico
8.
Cell Cycle ; 13(3): 358-70, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24406535

RESUMO

In the science-fiction thriller film Minority Report, a specialized police department called "PreCrime" apprehends criminals identified in advance based on foreknowledge provided by 3 genetically altered humans called "PreCogs". We propose that Yamanaka stem cell technology can be similarly used to (epi)genetically reprogram tumor cells obtained directly from cancer patients and create self-evolving personalized translational platforms to foresee the evolutionary trajectory of individual tumors. This strategy yields a large stem cell population and captures the cancer genome of an affected individual, i.e., the PreCog-induced pluripotent stem (iPS) cancer cells, which are immediately available for experimental manipulation, including pharmacological screening for personalized "stemotoxic" cancer drugs. The PreCog-iPS cancer cells will re-differentiate upon orthotopic injection into the corresponding target tissues of immunodeficient mice (i.e., the PreCrime-iPS mouse avatars), and this in vivo model will run through specific cancer stages to directly explore their biological properties for drug screening, diagnosis, and personalized treatment in individual patients. The PreCog/PreCrime-iPS approach can perform sets of comparisons to directly observe changes in the cancer-iPS cell line vs. a normal iPS cell line derived from the same human genetic background. Genome editing of PreCog-iPS cells could create translational platforms to directly investigate the link between genomic expression changes and cellular malignization that is largely free from genetic and epigenetic noise and provide proof-of-principle evidence for cutting-edge "chromosome therapies" aimed against cancer aneuploidy. We might infer the epigenetic marks that correct the tumorigenic nature of the reprogrammed cancer cell population and normalize the malignant phenotype in vivo. Genetically engineered models of conditionally reprogrammable mice to transiently express the Yamanaka stemness factors following the activation of phenotypic copies of specific cancer diseases might crucially evaluate a "reprogramming cure" for cancer. A new era of xenopatients 2.0 generated via nuclear reprogramming of the epigenetic landscapes of patient-derived cancer genomes might revolutionize the current personalized translational platforms in cancer research.


Assuntos
Reprogramação Celular/genética , Epigênese Genética , Genoma , Neoplasias/genética , Células-Tronco Neoplásicas/patologia , Células-Tronco Pluripotentes/patologia , Animais , Carcinogênese/genética , Carcinogênese/patologia , Diferenciação Celular/genética , Linhagem Celular Tumoral , Genoma Humano , Humanos , Camundongos , Neoplasias/patologia , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Pluripotentes/metabolismo , Medicina de Precisão , Pesquisa Médica Translacional
9.
Cell Cycle ; 12(22): 3471-7, 2013 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-24107627

RESUMO

The restoration of pluripotency circuits by the reactivation of endogenous stemness factors, such as SOX2, may provide a new paradigm in cancer development. The tumoral stem cell reprogramming hypothesis, i.e., the ability of stemness factors to redirect normal and differentiated tumor cells toward a less-differentiated and stem-like state, adds new layers of complexity to cancer biology, because the effects of such reprogramming may remain dormant until engaged later in response to (epi)genetic and/or (micro)environmental events. To test this hypothesis, we utilized an in vitro model of a SOX2-overexpressing cancer stem cell (CSC)-like cellular state that was recently developed in our laboratory by employing Yamanaka's nuclear reprogramming technology in the estrogen receptor α (ERα)-positive MCF-7 breast cancer cell line. Despite the acquisition of distinct molecular features that were compatible with a breast CSC-like cellular state, such as strong aldehyde dehydrogenase activity, as detected by ALDEFLUOR, and overexpression of the SSEA-4 and CD44 breast CSC markers, the tumor growth-initiating ability of SOX2-overexpressing CSC-like MCF-7 cells solely occurred in female nude mice supplemented with estradiol when compared with MCF-7 parental cells. Ser118 phosphorylation of estrogen receptor α (ERα), which is a pivotal integrator of the genomic and nongenomic E 2/ERα signaling pathways, drastically accumulated in nuclear speckles in the interphase nuclei of SOX2-driven CSC-like cell populations. Moreover, SOX2-positive CSC-like cells accumulated significantly higher numbers of actively dividing cells, and the highest levels of phospho-Ser118-ERα occurred when chromosomes lined up on a metaphase plate. The previously unrecognized link between E 2/ERα signaling and SOX2-driven stem cell circuitry may significantly impact our current understanding of breast cancer initiation and progression, i.e., SOX2 can promote non-genomic E 2 signaling that leads to nuclear phospho-Ser118-ERα, which ultimately exacerbates genomic ER signaling in response to E 2. Because E 2 stimulation has been recently shown to enhance breast tumor-initiating cell survival by downregulating miR-140, which targets SOX2, the establishment of a bidirectional cross-talk interaction between the stem cell self-renewal regulator, SOX2, and the local and systemic ability of E 2 to increase breast CSC activity may have profound implications for the development of new CSC-directed strategies for breast cancer prevention and therapy.


Assuntos
Neoplasias da Mama/metabolismo , Reprogramação Celular , Estradiol/fisiologia , Estrogênios/fisiologia , Células-Tronco Neoplásicas/fisiologia , Fatores de Transcrição SOXB1/metabolismo , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Estradiol/farmacologia , Receptor alfa de Estrogênio/metabolismo , Estrogênios/farmacologia , Feminino , Humanos , Células MCF-7 , Camundongos , Camundongos Nus , Fosforilação , Receptores de Progesterona/metabolismo , Fatores de Transcrição SOXB1/genética , Transdução de Sinais
10.
Sci Rep ; 3: 2469, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23965851

RESUMO

Autophagy may control the de novo refractoriness of HER2 gene-amplified breast carcinomas to the monoclonal antibody trastuzumab (Herceptin). Tumor cells originally obtained from a patient who rapidly progressed on trastuzumab ab initio display increased cellular levels of the LC3-II protein--a finding that correlates with increased numbers of autophagosomes--and decreased levels of the autophagy receptor p62/SQSTM1, a protein selectively degraded by autophagy. Trastuzumab-refractory cells are in a state of "autophagy addiction" because genetic ablation of autophagy-specific genes (ATG8, ATG5, ATG12) notably reduces intrinsic refractoriness to trastuzumab. When the anti-malarial lysosomotropic drug chloroquine impedes autophagic resolution of the accumulation of autophagolysosomes formed in the presence of trastuzumab, cells commit to die by apoptosis. Accordingly, combination treatment with trastuzumab and chloroquine radically suppresses tumor growth by > 90% in a tumor xenograft completely refractory to trastuzumab. Adding chloroquine to trastuzumab-based regimens may therefore improve outcomes among women with autophagy-addicted HER2-positive breast cancer.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Cloroquina/farmacologia , Resistencia a Medicamentos Antineoplásicos , Receptor ErbB-2/genética , Animais , Antimaláricos/farmacologia , Autofagia/efeitos dos fármacos , Autofagia/genética , Neoplasias da Mama/patologia , Caspase 3/metabolismo , Linhagem Celular Tumoral , Modelos Animais de Doenças , Ativação Enzimática/efeitos dos fármacos , Feminino , Humanos , Camundongos , Fagossomos/metabolismo , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/metabolismo , Trastuzumab , Carga Tumoral/efeitos dos fármacos , Carga Tumoral/genética , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Oncotarget ; 4(9): 1484-95, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23986086

RESUMO

Cancer cells expressing constitutively active phosphatidylinositol-3 kinase (PI3K) are proliferative regardless of the absence of insulin, and they form dietary restriction (DR)-resistant tumors in vivo. Because the binding of insulin to its receptors activates the PI3K/AKT/mammalian target of rapamycin (mTOR) signaling cascade, activating mutations in the PIK3CA oncogene may determine tumor response to DR-like pharmacological strategies targeting the insulin and mTOR pathways. The anti-diabetic drug metformin is a stereotypical DR mimetic that exerts its anti-cancer activity through a dual mechanism involving insulin-related (systemic) and mTOR-related (cell-autonomous) effects. However, it remains unclear whether PIK3CA-activating mutations might preclude the anti-cancer activity of metformin in vivo. To model the oncogenic PIK3CA-driven early stages of cancer, we used the clonal breast cancer cell line MCF10DCIS.com, which harbors the gain-of-function H1047R hot-spot mutation in the catalytic domain of the PI3KCA gene and has been shown to form DR-refractory xenotumors. To model PIK3CA-activating mutations in late stages of cancer, we took advantage of the isogenic conversion of a PIK3CA-wild-type tumor into a PIK3CA H1047R-mutated tumor using the highly metastatic colorectal cancer cell line SW48. MCF10DCIS.com xenotumors, although only modestly affected by treatment with oral metformin (approximately 40% tumor growth inhibition), were highly sensitive to the intraperitoneal (i.p.) administration of metformin, the anti-cancer activity of which increased in a time-dependent manner and reached >80% tumor growth inhibition by the end of the treatment. Metformin treatment via the i.p. route significantly reduced the proliferation factor mitotic activity index (MAI) and decreased tumor cellularity in MCF10DCIS.com cancer tissues. Whereas SW48-wild-type (PIK3CA+/+) cells rapidly formed metformin-refractory xenotumors in mice, ad libitum access to water containing metformin significantly reduced the growth of SW48-mutated (PIK3CAH1047R/+) xenotumors by approximately 50%. Thus, metformin can no longer be considered as a bona fide DR mimetic, at least in terms of anti-cancer activity, because tumors harboring the insulin-unresponsive, DR-resistant, PIK3CA-activating mutation H1047R remain sensitive to the anti-tumoral effects of the drug. Given the high prevalence of PIK3CA mutations in human carcinomas and the emerging role of PIK3CA mutation status in the treatment selection process, these findings might have a significant impact on the design of future trials evaluating the potential of combining metformin with targeted therapy.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Metformina/farmacologia , Fosfatidilinositol 3-Quinases/genética , Animais , Neoplasias da Mama/enzimologia , Neoplasias da Mama/patologia , Processos de Crescimento Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Classe I de Fosfatidilinositol 3-Quinases , Dieta , Feminino , Humanos , Camundongos , Camundongos Nus , Fosfatidilinositol 3-Quinases/metabolismo , Distribuição Aleatória , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Cell Cycle ; 12(18): 3109-24, 2013 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-23974095

RESUMO

Energy metabolism plasticity enables stemness programs during the reprogramming of somatic cells to an induced pluripotent stem cell (iPSC) state. This relationship may introduce a new era in the understanding of Warburg's theory on the metabolic origin of cancer at the level of cancer stem cells (CSCs). Here, we used Yamanaka's stem cell technology in an attempt to create stable CSC research lines in which to dissect the transcriptional control of mTOR--the master switch of cellular catabolism and anabolism--in CSC-like states. The rare colonies with iPSC-like morphology, obtained following the viral transduction of the Oct4, Sox2, Klf4, and c-Myc (OSKM) stemness factors into MCF-7 luminal-like breast cancer cells (MCF-7/Rep), demonstrated an intermediate state between cancer cells and bona fide iPSCs. MCF-7/Rep cells notably overexpressed SOX2 and stage-specific embryonic antigen (SSEA)-4 proteins; however, other stemness-related markers (OCT4, NANOG, SSEA-1, TRA-1-60, and TRA-1-81) were found at low to moderate levels. The transcriptional analyses of OSKM factors confirmed the strong but unique reactivation of the endogenous Sox2 stemness gene accompanied by the silencing of the exogenous Sox2 transgene in MCF-7/Rep cells. Some but not all MCF-7/Rep cells acquired strong alkaline phosphatase (AP) activity compared with MCF-7 parental cells. SOX2-overexpressing MCF-7/Rep cells contained drastically higher percentages of CD44(+) and ALDEFLUOR-stained ALDH(bright) cells than MCF-7 parental cells. The overlap between differentially expressed mTOR signaling-related genes in 3 different SOX2-overexpressing CSC-like cell lines revealed a notable downregulation of 3 genes, PRKAA1 (which codes for the catalytic α 1 subunit of AMPK), DDIT4/REDD1 (a stress response gene that operates as a negative regulator of mTOR), and DEPTOR (a naturally occurring endogenous inhibitor of mTOR activity). The insulin-receptor gene (INSR) was differentially upregulated in MCF-7/Rep cells. Consistent with the downregulation of AMPK expression, immunoblotting procedures confirmed upregulation of p70S6K and increased phosphorylation of mTOR in Sox2-overexpressing CSC-like cell populations. Using an in vitro model of the de novo generation of CSC-like states through the nuclear reprogramming of an established breast cancer cell line, we reveal that the transcriptional suppression of mTOR repressors is an intrinsic process occurring during the acquisition of CSC-like properties by differentiated populations of luminal-like breast cancer cells. This approach may provide a new path for obtaining information about preventing the appearance of CSCs through the modulation of the AMPK/mTOR pathway.


Assuntos
Reprogramação Celular , Células-Tronco Neoplásicas/citologia , Fatores de Transcrição SOXB1/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Neoplasias da Mama , Regulação para Baixo , Ácido Graxo Sintase Tipo I/metabolismo , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Cinesina/genética , Cinesina/metabolismo , Células MCF-7 , Células-Tronco Neoplásicas/metabolismo , Fator 3 de Transcrição de Octâmero/genética , Fator 3 de Transcrição de Octâmero/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Receptor de Insulina/genética , Receptor de Insulina/metabolismo , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Fatores de Transcrição SOXB1/antagonistas & inibidores , Fatores de Transcrição SOXB1/genética , Serina-Treonina Quinases TOR/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Ativação Transcricional , Regulação para Cima
13.
Cell Cycle ; 12(8): 1166-79, 2013 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-23549172

RESUMO

When fighting cancer, knowledge on metabolism has always been important. Today, it matters more than ever. The restricted cataloging of cancer genomes is quite unlikely to achieve the task of curing cancer, unless it is integrated into metabolic networks that respond to and influence the constantly evolving cancer stem cell (CSC) cellular states. Once the genomic era of carcinogenesis had pushed the 1920s Otto Warburg's metabolic cancer hypothesis into obscurity for decades, the most recent studies begin to support a new developing paradigm, in which the molecular logic behind the conversion of non-CSCs into CSCs can be better understood in terms of the "metabolic facilitators" and "metabolic impediments" that operate as proximate openings and roadblocks, respectively, for the transcriptional events and signal transduction programs that ultimately orchestrate the intrinsic and/or microenvironmental paths to CSC cellular states. Here we propose that a profound understanding of how human carcinomas install a proper "Warburg effect version 2.0" allowing them to "run" the CSCs' "software" programs should guide a new era of metabolo-genomic-personalized cancer medicine. By viewing metabolic reprogramming of CSCs as an essential characteristic that allows dynamic, multidimensional and evolving cancer populations to compete successfully for their expansion on the organism, we now argue that CSCs bioenergetics might be another cancer hallmark. A definitive understanding of metabolic reprogramming in CSCs may complement or to some extent replace, the 30-y-old paradigm of targeting oncogenes to treat human carcinomas, because it can be possible to metabolically create non-permissive or "hostile" metabotypes to prevent the occurrence of CSC cellular states with tumor- and metastasis-initiating capacity.


Assuntos
Transformação Celular Neoplásica/metabolismo , Descoberta de Drogas/tendências , Metabolismo Energético/fisiologia , Oncologia/tendências , Redes e Vias Metabólicas/fisiologia , Modelos Biológicos , Células-Tronco Neoplásicas/metabolismo , Respiração Celular/fisiologia , Glicólise , Humanos
14.
Oncol Lett ; 5(2): 459-462, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23419985

RESUMO

Neuroendocrine tumors (NETs) are frequently associated with second primary malignancies (SPMs). Earlier studies have demonstrated that NETs are highly associated with synchronous or metachronous gastrointestinal and genitourinary SPMs. We report, for the first time, a case of pure NE breast carcinoma (NEBC) exhibiting all of the World Health Organization (WHO)-categorized morphological and phenotypic NE features (i.e., round solid nests of spindle cells, plasmacytoid cells, large clear or mucinous signet-ring cells with a peripheral palisading tendency and immunohistochemical positivity for the NE markers synaptophysin and chromogranin in more than 50% of the tumor cell population) along with synchronous abdominal non-Hodgkin's lymphoma. In the present study, we review the diagnosis, clinicopathological features and histogenetic profiling of NEBC and discuss the literature relevant to the clinical and anatomopathological management of this case. This previously unreported case of synchronous solid NEBC and abdominal lymphoma, together with earlier studies showing that primary symptoms are caused by SPMs in a significant subgroup of NET patients, strongly supports the notion that NETs should be cautiously considered to be index tumors. Therefore, risk-adapted clinicopathological follow-up with systematic investigation is strongly recommended.

15.
Cell Cycle ; 12(4): 555-78, 2013 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-23370395

RESUMO

Aging can be viewed as a quasi-programmed phenomenon driven by the overactivation of the nutrient-sensing mTOR gerogene. mTOR-driven aging can be triggered or accelerated by a decline or loss of responsiveness to activation of the energy-sensing protein AMPK, a critical gerosuppressor of mTOR. The occurrence of age-related diseases, therefore, reflects the synergistic interaction between our evolutionary path to sedentarism, which chronically increases a number of mTOR activating gero-promoters (e.g., food, growth factors, cytokines and insulin) and the "defective design" of central metabolic integrators such as mTOR and AMPK. Our laboratories at the Bioactive Food Component Platform in Spain have initiated a systematic approach to molecularly elucidate and clinically explore whether the "xenohormesis hypothesis," which states that stress-induced synthesis of plant polyphenols and many other phytochemicals provides an environmental chemical signature that upregulates stress-resistance pathways in plant consumers, can be explained in terms of the reactivity of the AMPK/mTOR-axis to so-called xenohormetins. Here, we explore the AMPK/mTOR-xenohormetic nature of complex polyphenols naturally present in extra virgin olive oil (EVOO), a pivotal component of the Mediterranean style diet that has been repeatedly associated with a reduction in age-related morbid conditions and longer life expectancy. Using crude EVOO phenolic extracts highly enriched in the secoiridoids oleuropein aglycon and decarboxymethyl oleuropein aglycon, we show for the first time that (1) the anticancer activity of EVOO secoiridoids is related to the activation of anti-aging/cellular stress-like gene signatures, including endoplasmic reticulum (ER) stress and the unfolded protein response, spermidine and polyamine metabolism, sirtuin-1 (SIRT1) and NRF2 signaling; (2) EVOO secoiridoids activate AMPK and suppress crucial genes involved in the Warburg effect and the self-renewal capacity of "immortal" cancer stem cells; (3) EVOO secoiridoids prevent age-related changes in the cell size, morphological heterogeneity, arrayed cell arrangement and senescence-associated ß-galactosidase staining of normal diploid human fibroblasts at the end of their proliferative lifespans. EVOO secoiridoids, which provide an effective defense against plant attack by herbivores and pathogens, are bona fide xenohormetins that are able to activate the gerosuppressor AMPK and trigger numerous resveratrol-like anti-aging transcriptomic signatures. As such, EVOO secoiridoids constitute a new family of plant-produced gerosuppressant agents that molecularly "repair" the aimless (and harmful) AMPK/mTOR-driven quasi-program that leads to aging and aging-related diseases, including cancer.


Assuntos
Envelhecimento/efeitos dos fármacos , Transformação Celular Neoplásica/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Iridoides/farmacologia , Longevidade/efeitos dos fármacos , Óleos Vegetais/química , Polifenóis/farmacologia , Envelhecimento/genética , Animais , Transformação Celular Neoplásica/genética , Dieta Mediterrânea , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Hormese , Humanos , Iridoides/isolamento & purificação , Longevidade/genética , Azeite de Oliva , Polifenóis/isolamento & purificação , Proteínas Quinases/genética , Proteínas Quinases/metabolismo , Sirtuína 1/genética , Sirtuína 1/metabolismo , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Resposta a Proteínas não Dobradas/efeitos dos fármacos , beta-Galactosidase/genética , beta-Galactosidase/metabolismo
16.
Cell Cycle ; 12(2): 225-45, 2013 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-23255137

RESUMO

High rates of inherent primary resistance to the humanized monoclonal antibody trastuzumab (Herceptin) are frequent among HER2 gene-amplified breast carcinomas in both metastatic and adjuvant settings. The clinical efficacy of trastuzumab is highly correlated with its ability to specifically and efficiently target HER2-driven populations of breast cancer stem cells (CSCs). Intriguingly, many of the possible mechanisms by which cancer cells escape trastuzumab involve many of the same biomarkers that have been implicated in the biology of CS-like tumor-initiating cells. In the traditional, one-way hierarchy of CSCs in which all cancer cells descend from special self-renewing CSCs, HER2-positive CSCs can occur solely by self-renewal. Therefore, by targeting CSC self-renewal and resistance, trastuzumab is expected to induce tumor shrinkage and further reduce breast cancer recurrence rates when used alongside traditional therapies. In a new, alternate model, more differentiated non-stem cancer cells can revert to trastuzumab-refractory, CS-like cells via the activation of intrinsic or microenvironmental paths-to-stemness, such as the epithelial-to-mesenchymal transition (EMT). Alternatively, stochastic transitions of trastuzumab-responsive CSCs might also give rise to non-CSC cellular states that lack major attributes of CSCs and, therefore, can remain "hidden" from trastuzumab activity. Here, we hypothesize that a better understanding of the CSC/non-CSC social structure within HER2-overexpressing breast carcinomas is critical for trastuzumab-based treatment decisions in the clinic. First, we decipher the biological significance of CSC features and the EMT on the molecular effects and efficacy of trastuzumab in HER2-positive breast cancer cells. Second, we reinterpret the genetic heterogeneity that differentiates trastuzumab-responders from non-responders in terms of CSC cellular states. Finally, we propose that novel predictive approaches aimed at better forecasting early tumor responses to trastuzumab should identify biological determinants that causally underlie the intrinsic flexibility of HER2-positive CSCs to "enter" into or "exit" from trastuzumab-sensitive states. An accurate integration of CSC cellular states and EMT-related biomarkers with the currently available breast cancer molecular taxonomy may significantly improve our ability to make a priori decisions about whether patients belonging to HER2 subtypes differentially enriched with a "mesenchymal transition signature" (e.g., luminal/HER2 vs. basal/HER2) would distinctly benefit from trastuzumab-based therapy ab initio.


Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Neoplasias da Mama/tratamento farmacológico , Carcinoma Basocelular/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/fisiologia , Transição Epitelial-Mesenquimal/fisiologia , Regulação Neoplásica da Expressão Gênica/fisiologia , Células-Tronco Neoplásicas/fisiologia , Receptor ErbB-2/metabolismo , Anticorpos Monoclonais Humanizados/uso terapêutico , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Carcinoma Basocelular/genética , Carcinoma Basocelular/metabolismo , Linhagem Celular Tumoral , Biologia Computacional , Feminino , Humanos , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Análise Serial de Proteínas , Trastuzumab
17.
Sci Rep ; 2: 964, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23236586

RESUMO

The antidiabetic drug metformin efficiently circumvents the dilemma that in reducing the tumourigenicity of stem cells, their essence, specifically their pluripotency, must also be sacrificed. Metformin prevents the occurrence or drastically reduces the size and weight of teratoma-like masses after the transplantation of induced pluripotent stem (iPS) cells into immunodeficient mice. Yet, iPS cells implanted into metformin-treated mice retain full pluripotency, as they produce the same number of distinct tissue types derived from the three embryonic germ layers that is observed in untreated mice. Mechanistically, metformin appears to suppress the Oct4-driven compartment of malignant stem cells responsible for teratocarcinoma growth while safeguarding an intact, Oct4-independent competency to generate terminally differentiated tissues. Metformin's ability to efficiently and specifically control the tumourigenic fate of teratoma-initiating iPS cells without interfering with their pluripotency not only has implications for the clinical use of iPS cells but also in stem cell biology, cancer and ageing.


Assuntos
Transformação Celular Neoplásica/efeitos dos fármacos , Hipoglicemiantes/farmacologia , Células-Tronco Pluripotentes Induzidas/citologia , Metformina/farmacologia , Animais , Diferenciação Celular , Linhagem Celular , Células-Tronco Pluripotentes Induzidas/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Nus , Fator 3 de Transcrição de Octâmero/metabolismo , Teratoma/metabolismo , Teratoma/patologia
18.
Cell Cycle ; 11(22): 4211-21, 2012 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-23095638

RESUMO

Energy- and nutrient-sensing proteins such as AMPK, mTOR and S6K1 are now recognized as novel regulators of mitotic completion in proliferating cells. We investigated the cellular distribution of the Ser2481 autophosphorylation of mTOR, which directly monitors mTORC-specific catalytic activity, during mammalian cell mitosis and cytokinesis. Automated immunofluorescence experiments in human carcinoma cell lines revealed that phospho-mTOR (Ser2481) exhibited profound spatial and temporal dynamics during cell division. Phospho-mTOR (Ser2481) was strikingly enriched in mitotic cells, and in prophase, bright phospho-mTOR (Ser2481) staining could be clearly observed among condensed chromosomes. Phospho-mTOR (Ser2481) then redistributes from diffuse cytosolic staining that partially colocalizes with the mitotic spindle during the early phases of mitosis to the furrow at the onset of cytokinesis. Like the bona fide chromosomal passenger proteins (CPPs) INCENP and Aurora B, phospho-mTOR (Ser2481) displayed noteworthy accumulation in the central spindle midzone and the midbody regions, which persisted during the furrowing process. Accordingly, double-staining experiments confirmed that phospho-mTOR (Ser2481) largely colocalized with CCPs in the midbodies. The CPP-like mitotic localization of phospho-mTOR (Ser2481) was fully prevented by the microtubule-depolymerizing drug nocodazole; mitotic traveling of phospho-mTOR (Ser2481) to the midbody during telophase and cytokinesis, where it appears to be integrated into the CPP-driven cytokinetic machinery, may therefore require dynamic microtubules. Although the Ser2448-phosphorylated form of mTOR was also found at high levels during M-phase in human cancer cells, we failed to observe a significant association of phospho-mTOR (Ser2448) with CCP-positive mitotic and cytokinetic structures. Our findings add phospho-mTOR (Ser2481) to the growing list of phospho-active forms of proteins belonging to the AMPK/mTOR/S6K1 signaling axis that reside at the mitotic and cytokinetic apparatus. Future studies should elucidate how the specific ability of phospho-mTOR (Ser2481) to spatially and temporally couple to the cleavage furrow and midbody region as a CPP-like protein can signal to or from adjacent signaling complexes and/or with the basic machinery of cell abscission.


Assuntos
Proteínas Cromossômicas não Histona/metabolismo , Cromossomos/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Antineoplásicos/farmacologia , Aurora Quinase B , Aurora Quinases , Divisão Celular , Linhagem Celular Tumoral , Citocinese/efeitos dos fármacos , Células HeLa , Humanos , Células MCF-7 , Microtúbulos/química , Microtúbulos/metabolismo , Nocodazol/farmacologia , Fosforilação/efeitos dos fármacos , Transdução de Sinais , Sirolimo/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Telófase/efeitos dos fármacos
19.
Cell Cycle ; 11(21): 4020-32, 2012 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-22992620

RESUMO

The rate of inherent resistance to single-agent trastuzumab in HER2-overexpressing metastatic breast carcinomas is impressive at above 70%. Unfortunately, little is known regarding the distinctive genetic signatures that could predict trastuzumab refractoriness ab initio. The epithelial-to-mesenchymal transition (EMT) molecular features, HER2 expression status and primary responses to trastuzumab were explored in the public Lawrence Berkeley Laboratory (LBL) Breast Cancer Collection. Lentivirus-delivered small hairpin RNAs were employed to reduce specifically and stably the expression of EMT transcription factors in trastuzumab-refractory basal/HER2+ cells. Cell proliferation assays and pre-clinical nude mice xenograft-based studies were performed to assess the contribution of specific EMT transcription factors to inherent trastuzumab resistance. Primary sensitivity to trastuzumab was restricted to the SLUG/SNAIL2-negative subset of luminal/HER2+ cell lines, whereas all of the SLUG/SNAIL2-positive basal/HER2+ cell lines exhibited an inherent resistance to trastuzumab. The specific knockdown of SLUG/SNAIL2 suppressed the stem-related CD44+CD24(-/low) mesenchymal immunophenotype by transcriptionally upregulating the luminal epithelial marker CD24 in basal/HER2+ cells. Basal/HER2+ cells gained sensitivity to the growth-inhibitory effects of trastuzumab following SLUG/SNAIL2 gene depletion, which induced the expression of the mesenchymal-to-epithelial transition (MET) genes involved in promoting an epithelial phenotype. The isolation of CD44+CD24(-/low) mesenchymal cells by magnetic-activated cell sorting (MACS) confirmed their intrinsic unresponsiveness to trastuzumab. A reduction in tumor growth and dramatic gain in sensitivity to trastuzumab in vivo were confirmed when the SLUG/SNAIL2 knockdown basal/HER2+ cells were injected into nude mice. HER2 overexpression in a basal, rather than in a luminal molecular background, results in a basal/HER2+ breast cancer subtype that is intrinsically resistant to trastuzumab. EMT transcription factors might induce an enhanced phenotypic plasticity that would allow basal/HER2+ breast cancer cells to "enter" into and "exit" dynamically from trastuzumab-responsive stem cell-like states. The systematic determination of SLUG/SNAIL2 as a stem/CD44+CD24(-/low) cell-associated protein may improve the therapeutic management of HER2+ breast carcinomas.


Assuntos
Anticorpos Monoclonais Humanizados/toxicidade , Antineoplásicos/toxicidade , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Animais , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Antígeno CD24/metabolismo , Linhagem Celular Tumoral , Transição Epitelial-Mesenquimal , Feminino , Humanos , Receptores de Hialuronatos/metabolismo , Imunofenotipagem , Camundongos , Camundongos Nus , Receptor ErbB-2/metabolismo , Fatores de Transcrição da Família Snail , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Transplante Heterólogo , Trastuzumab
20.
Int J Oncol ; 39(6): 1455-79, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21833472

RESUMO

KRAS mutation status is being used as the sole biomarker to predict therapeutic efficacy of cetuximab in metastatic colorectal cancer (mCRC). A significant number of mCRC patients with KRAS wild-type (WT) tumors, however, do not benefit from cetuximab. We are also lacking efficacy predictors in head and neck squamous cell carcinomas with an intact KRAS signaling and in non-small cell lung cancer in which KRAS mutations do not predict cetuximab efficacy. We recently established pre-clinical models of EGFR gene-amplified KRAS WT A431 squamous carcinoma cells chronically adapted to grow in the presence of cetuximab. We employed the ingenuity pathway analysis software to functionally interpret data from Agilent's whole human genome arrays in the context of biological processes, networks, and pathways. Cetuximab-induced activation of the interferon (IFN)/STAT1 appeared to switch from 'growth inhibitory' in acutely-treated cells to 'pro-survival' in chronically-adapted cells. Cetuximab treatment appeared to negatively select initially dominant IFN-sensitive clones and promoted selection of IFN- and cetuximab-refractory tumor clones constitutively bearing an up-regulated IFN/STAT1 signaling. High-levels of mRNAs coding for the EGFR ligands amphiregulin (AREG), epiregulin (EREG), and neuregulin-1/heregulin (NRG1) predicted for acute cetuximab's functioning. Chronic cetuximab, however, appeared to negatively select initially dominant AREG/EREG/NRG1-positive clones to promote selection of cetuximab-refractory clones exhibiting a knocked-down neuregulin signaling. Our current evolutionary mapping of the transcriptomic changes that occur during cetuximab-induced chronic blockade of EGFR/KRAS WT signaling strongly suggests that mRNAs coding for IFN/STAT1- and EGFR ligands-related genes can be evaluated as novel predictors of efficacy in KRAS WT squamous cancer patients being treated with cetuximab.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Interferons/farmacologia , Neurregulinas/metabolismo , Proteínas Proto-Oncogênicas/genética , Fator de Transcrição STAT1/metabolismo , Proteínas ras/genética , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais Humanizados , Antineoplásicos/farmacologia , Biomarcadores/metabolismo , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Linhagem Celular Tumoral , Cetuximab , Receptores ErbB/antagonistas & inibidores , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Genoma Humano , Estudo de Associação Genômica Ampla , Humanos , Modelos Biológicos , Análise de Sequência com Séries de Oligonucleotídeos , Proteínas Proto-Oncogênicas p21(ras) , Transdução de Sinais/efeitos dos fármacos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA