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1.
medRxiv ; 2024 Aug 16.
Artículo en Inglés | MEDLINE | ID: mdl-39185534

RESUMEN

Progression from pre-cancers like ductal carcinoma in situ (DCIS) to invasive disease (cancer) is driven by somatic evolution and is altered by clinical interventions. We hypothesized that genetic and/or phenotypic intra-tumor heterogeneity would predict clinical outcomes for DCIS since it serves as the substrate for natural selection among cells. We profiled two samples from two geographically distinct foci from each DCIS in both cross-sectional (N = 119) and longitudinal cohorts (N = 224), with whole exome sequencing, low-pass whole genome sequencing, and a panel of immunohistochemical markers. In the longitudinal cohorts, the only statistically significant predictors of time to non-invasive DCIS recurrence were the combination of treatment (lumpectomy only vs mastectomy or lumpectomy with radiation, HR = 12.13, p = 0.003, Wald test with FDR correction), ER status (HR = 0.16 for ER+ compared to ER-, p = 0.0045), and divergence in SNVs between the two samples (HR = 1.33 per 10% divergence, p = 0.018). SNV divergence also distinguished between pure DCIS and DCIS synchronous with invasive disease in the cross-sectional cohort. In contrast, the only statistically significant predictors of time to progression to invasive disease were the combination of the width of the surgical margin (HR = 0.67 per mm, p = 0.043) and the number of mutations that were detectable at high allele frequencies (HR = 1.30 per 10 SNVs, p = 0.02). These results imply that recurrence with DCIS is a clinical and biological process different from invasive progression.

2.
PLoS One ; 18(6): e0287901, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37384647

RESUMEN

Chimerism is a widespread phenomenon across the tree of life. It is defined as a multicellular organism composed of cells from other genetically distinct entities. This ability to 'tolerate' non-self cells may be linked to susceptibility to diseases like cancer. Here we test whether chimerism is associated with cancers across obligately multicellular organisms in the tree of life. We classified 12 obligately multicellular taxa from lowest to highest chimerism levels based on the existing literature on the presence of chimerism in these species. We then tested for associations of chimerism with tumour invasiveness, neoplasia (benign or malignant) prevalence and malignancy prevalence in 11 terrestrial mammalian species. We found that taxa with higher levels of chimerism have higher tumour invasiveness, though there was no association between malignancy or neoplasia and chimerism among mammals. This suggests that there may be an important biological relationship between chimerism and susceptibility to tissue invasion by cancerous cells. Studying chimerism might help us identify mechanisms underlying invasive cancers and also could provide insights into the detection and management of emerging transmissible cancers.


Asunto(s)
Quimerismo , Neoplasias , Animales , Neoplasias/genética , Mamíferos
3.
Nat Genet ; 54(6): 850-860, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-35681052

RESUMEN

Ductal carcinoma in situ (DCIS) is the most common form of preinvasive breast cancer and, despite treatment, a small fraction (5-10%) of DCIS patients develop subsequent invasive disease. A fundamental biologic question is whether the invasive disease arises from tumor cells in the initial DCIS or represents new unrelated disease. To address this question, we performed genomic analyses on the initial DCIS lesion and paired invasive recurrent tumors in 95 patients together with single-cell DNA sequencing in a subset of cases. Our data show that in 75% of cases the invasive recurrence was clonally related to the initial DCIS, suggesting that tumor cells were not eliminated during the initial treatment. Surprisingly, however, 18% were clonally unrelated to the DCIS, representing new independent lineages and 7% of cases were ambiguous. This knowledge is essential for accurate risk evaluation of DCIS, treatment de-escalation strategies and the identification of predictive biomarkers.


Asunto(s)
Neoplasias de la Mama , Carcinoma Ductal de Mama , Carcinoma Intraductal no Infiltrante , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/genética , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Carcinoma Ductal de Mama/genética , Carcinoma Intraductal no Infiltrante/genética , Carcinoma Intraductal no Infiltrante/patología , Femenino , Genómica , Humanos , Recurrencia Local de Neoplasia/genética
4.
PLoS Biol ; 19(11): e3001471, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-34788294

RESUMEN

Trichoplax adhaerens is the simplest multicellular animal with tissue differentiation and somatic cell turnover. Like all other multicellular organisms, it should be vulnerable to cancer, yet there have been no reports of cancer in T. adhaerens or any other placozoan. We investigated the cancer resistance of T. adhaerens, discovering that they are able to tolerate high levels of radiation damage (218.6 Gy). To investigate how T. adhaerens survive levels of radiation that are lethal to other animals, we examined gene expression after the X-ray exposure, finding overexpression of genes involved in DNA repair and apoptosis including the MDM2 gene. We also discovered that T. adhaerens extrudes clusters of inviable cells after X-ray exposure. T. adhaerens is a valuable model organism for studying the molecular, genetic, and tissue-level mechanisms underlying cancer suppression.


Asunto(s)
Reparación del ADN/genética , Placozoa/genética , Tolerancia a Radiación/genética , Regulación hacia Arriba/genética , Animales , Daño del ADN/genética , Daño del ADN/efectos de la radiación , Reparación del ADN/efectos de la radiación , Regulación de la Expresión Génica/efectos de la radiación , Placozoa/anatomía & histología , Placozoa/efectos de la radiación , Exposición a la Radiación , Análisis de Secuencia de ADN , Regulación hacia Arriba/efectos de la radiación , Secuenciación Completa del Genoma , Rayos X
5.
Brief Bioinform ; 22(6)2021 11 05.
Artículo en Inglés | MEDLINE | ID: mdl-34117742

RESUMEN

Most tissue collections of neoplasms are composed of formalin-fixed and paraffin-embedded (FFPE) excised tumor samples used for routine diagnostics. DNA sequencing is becoming increasingly important in cancer research and clinical management; however it is difficult to accurately sequence DNA from FFPE samples. We developed and validated a new bioinformatic pipeline to use existing variant-calling strategies to robustly identify somatic single nucleotide variants (SNVs) from whole exome sequencing using small amounts of DNA extracted from archival FFPE samples of breast cancers. We optimized this strategy using 28 pairs of technical replicates. After optimization, the mean similarity between replicates increased 5-fold, reaching 88% (range 0-100%), with a mean of 21.4 SNVs (range 1-68) per sample, representing a markedly superior performance to existing tools. We found that the SNV-identification accuracy declined when there was less than 40 ng of DNA available and that insertion-deletion variant calls are less reliable than single base substitutions. As the first application of the new algorithm, we compared samples of ductal carcinoma in situ of the breast to their adjacent invasive ductal carcinoma samples. We observed an increased number of mutations (paired-samples sign test, P < 0.05), and a higher genetic divergence in the invasive samples (paired-samples sign test, P < 0.01). Our method provides a significant improvement in detecting SNVs in FFPE samples over previous approaches.


Asunto(s)
Biomarcadores de Tumor , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/genética , Biología Computacional/métodos , Polimorfismo de Nucleótido Simple , ADN de Neoplasias , Femenino , Heterogeneidad Genética , Pruebas Genéticas/métodos , Pruebas Genéticas/normas , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Mutación , Flujo de Trabajo
6.
Cell Oncol (Dordr) ; 40(4): 367-378, 2017 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-28593575

RESUMEN

PURPOSE: The transition of cells from the epithelial to the mesenchymal state (EMT) plays an important role in tumor progression. EMT allows cells to acquire mobility, stem-like behavior and resistance to apoptosis and drug treatment. These features turn EMT into a central process in tumor biology. Ion channels are attractive targets for the treatment of cancer since they play critical roles in controlling a wide range of physiological processes that are frequently deregulated in cancer. Here, we investigated the role of ether-a-go-go-related 1 (hERG1) ion channels in the EMT of colorectal cancer cells. METHODS: We studied the epithelial-mesenchymal profile of different colorectal cancer-derived cell lines and the expression of hERG1 potassium channels in these cell lines using real-time PCR. Next, we knocked down hERG1 expression in HCT116 cells using lentivirus mediated RNA interference and characterized the hERG1 silenced cells in vitro and in vivo. Finally, we investigated the capacity of riluzole, an ion channel-modulating drug used in humans to treat amyotrophic lateral sclerosis, to reduce the resistance of the respective colorectal cancer cells to the chemotherapeutic drug cisplatin. RESULTS: We found that of the colorectal cancer-derived cell lines tested, HCT116 showed the highest mesenchymal profile and a high hERG1 expression. Subsequent hERG1 expression knockdown induced a change in cell morphology, which was accompanied by a reduction in the proliferative and tumorigenic capacities of the cells. Notably, we found that hERG1expression knockdown elicited a reversion of the EMT profile in HCT116 cells with a reacquisition of the epithelial-like profile. We also found that riluzole increased the sensitivity of HCT116 cisplatin-resistant cells to cisplatin. CONCLUSIONS: Our data indicate that hERG1 plays a role in the EMT of colorectal cancer cells and that its knockdown reduces the proliferative and tumorigenic capacities of these cells. In addition, we conclude that riluzole may be used in combination with cisplatin to reduce chemo-resistance in colorectal cancer cells.


Asunto(s)
Cisplatino/farmacología , Neoplasias Colorrectales/tratamiento farmacológico , Resistencia a Antineoplásicos/efectos de los fármacos , Transición Epitelial-Mesenquimal/efectos de los fármacos , Canales de Potasio Éter-A-Go-Go/genética , Riluzol/farmacología , Animales , Anticonvulsivantes/farmacología , Antineoplásicos/farmacología , Células CACO-2 , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/genética , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Resistencia a Antineoplásicos/genética , Sinergismo Farmacológico , Transición Epitelial-Mesenquimal/genética , Canales de Potasio Éter-A-Go-Go/metabolismo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Células HCT116 , Células HT29 , Humanos , Ratones Desnudos , Interferencia de ARN , Ensayos Antitumor por Modelo de Xenoinjerto
7.
Artículo en Inglés | MEDLINE | ID: mdl-28148564

RESUMEN

Evolution by natural selection is the conceptual foundation for nearly every branch of biology and increasingly also for biomedicine and medical research. In cancer biology, evolution explains how populations of cells in tumors change over time. It is a fundamental question whether this evolutionary process is driven primarily by natural selection and adaptation or by other evolutionary processes such as founder effects and drift. In cancer biology, as in organismal evolutionary biology, there is controversy about this question and also about the use of adaptation through natural selection as a guiding framework for research. In this review, we discuss the differences and similarities between evolution among somatic cells versus evolution among organisms. We review what is known about the parameters and rate of evolution in neoplasms, as well as evidence for adaptation. We conclude that adaptation is a useful framework that accurately explains the defining characteristics of cancer. Further, convergent evolution through natural selection provides the only satisfying explanation both for how a group of diverse pathologies have enough in common to usefully share the descriptive label of "cancer" and for why this convergent condition becomes life-threatening.


Asunto(s)
Adaptación Fisiológica , Neoplasias/genética , Selección Genética , Humanos , Mutación , Fenotipo
8.
Bioessays ; 37(10): 1106-18, 2015 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-26316378

RESUMEN

The presence of fetal cells has been associated with both positive and negative effects on maternal health. These paradoxical effects may be due to the fact that maternal and offspring fitness interests are aligned in certain domains and conflicting in others, which may have led to the evolution of fetal microchimeric phenotypes that can manipulate maternal tissues. We use cooperation and conflict theory to generate testable predictions about domains in which fetal microchimerism may enhance maternal health and those in which it may be detrimental. This framework suggests that fetal cells may function both to contribute to maternal somatic maintenance (e.g. wound healing) and to manipulate maternal physiology to enhance resource transmission to offspring (e.g. enhancing milk production). In this review, we use an evolutionary framework to make testable predictions about the role of fetal microchimerism in lactation, thyroid function, autoimmune disease, cancer and maternal emotional, and psychological health. Also watch the Video Abstract.


Asunto(s)
Quimerismo , Feto/citología , Salud Materna , Animales , Quimerismo/embriología , Femenino , Feto/metabolismo , Humanos , Intercambio Materno-Fetal/genética , Parto/fisiología , Placenta/citología , Embarazo
9.
Front Oncol ; 3: 285, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-24312898

RESUMEN

OBJECTIVE: The aim of the present study was to define the role of luteinizing hormone receptor (LH-R) expression in endometrial cancer (EC), using preclinical mouse models, to further transfer these data to the clinical setting. MATERIALS AND METHODS: The role of LH-R over-expression was studied using EC cells (Hec1A, e.g., cells with low endogenous LH-R expression) transfected with the LH-R (Hec1A-LH-R). In vitro cell proliferation was measured through the WST-1 assay, whereas cell invasion was measured trough the matrigel assay. The effects of LH-R over-expression in vivo were analyzed in an appropriately developed preclinical mouse model of EC, which mimicked postmenopausal conditions. The model consisted in an orthotopic xenograft of Hec1A cells into immunodeficient mice treated daily with recombinant LH, to assure high levels of LH. RESULTS: In vitro data indicated that LH-R over-expression increased Hec1A invasiveness. In vivo results showed that tumors arising from Hec1A-LH-R cells injection displayed a higher local invasion and a higher number of distant metastases, mainly in the lung, compared to tumors obtained from the injection of Hec1A cells. LH withdrawal strongly inhibited local and distant metastatic spread of tumors, especially those arising from Hec1A-LH-R cells. CONCLUSION: The over-expression of the LH-R increases the ability of EC cells to undergo local invasion and metastatic spread. This occurs in the presence of high LH serum concentrations.

10.
Sci Rep ; 3: 3308, 2013 Nov 25.
Artículo en Inglés | MEDLINE | ID: mdl-24270902

RESUMEN

Angiogenesis is a potential target for cancer therapy. We identified a novel signaling pathway that sustains angiogenesis and progression in colorectal cancer (CRC). This pathway is triggered by ß1 integrin-mediated adhesion and leads to VEGF-A secretion. The effect is modulated by the human ether-à-go-go related gene 1 (hERG1) K(+) channel. hERG1 recruits and activates PI3K and Akt. This in turn increases the Hypoxia Inducible Factor (HIF)-dependent transcription of VEGF-A and other tumour progression genes. This signaling pathway has novel features in that the integrin- and hERG1-dependent activation of HIF (i) is triggered in normoxia, especially after CRC cells have experienced a hypoxic stage, (ii) involves NF-kB and (iii) is counteracted by an active p53. Blocking hERG1 switches this pathway off also in vivo, by inhibiting cell growth, angiogenesis and metastatic spread. This suggests that non-cardiotoxic anti-hERG1 drugs might be a fruitful therapeutic strategy to prevent the failure of anti-VEGF therapy.


Asunto(s)
Neoplasias Colorrectales/patología , Canales de Potasio Éter-A-Go-Go/metabolismo , Integrina beta1/metabolismo , Neovascularización Patológica/patología , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Hipoxia de la Célula , Línea Celular Tumoral , Neoplasias Colorrectales/metabolismo , Modelos Animales de Enfermedad , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Canales de Potasio Éter-A-Go-Go/genética , Células HCT116 , Células HT29 , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Masculino , Ratones , Ratones Desnudos , FN-kappa B/antagonistas & inhibidores , FN-kappa B/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3 , Fosforilación/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Interferencia de ARN , ARN Interferente Pequeño/metabolismo , Transducción de Señal/efectos de los fármacos , Trasplante Heterólogo , Proteína p53 Supresora de Tumor/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo
11.
Diagn Mol Pathol ; 22(4): 215-21, 2013 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-24193004

RESUMEN

Cancer molecular investigation revealed a huge molecular heterogeneity between different types of cancers as well as among cancer patients affected by the same cancer type. This implies the necessity of a personalized approach for cancer diagnosis and therapy, on the basis of the development of standardized protocols to facilitate the application of molecular techniques in the clinical decision-making process. Ion channels encoding genes are acquiring increasing relevance in oncological translational studies, representing new candidates for molecular diagnostic and therapeutic purposes. Hence, the development of molecular protocols for the quantification of ion channels encoding genes in tumor specimens may have relevance for diagnostic and prognostic investigation. Two main hindrances must be overcome for these purposes: the use of formalin-fixed and paraffin-embedded samples for gene expression analysis and the physiological expression of ion channels in excitable cells, potentially present in the tumor sample. We here propose a method for hERG1 gene quantification in colorectal cancer samples in both cryopreserved and formalin-fixed and paraffin-embedded samples. An analytical method was developed to estimate hERG1 gene expression exclusively in epithelial cancer cells. Indeed, we found that the hERG1 gene was expressed at significant levels by myofibroblasts present in the tumor stroma. This method was based on the normalization on a smooth muscle-myofibroblast-specific gene, MYH11, with no need of microdissection. By applying this method, hERG1 expression turned out to correlate with VEGF-A expression, confirming previous immunohistochemical data.


Asunto(s)
Neoplasias Colorrectales/patología , Canales de Potasio Éter-A-Go-Go/biosíntesis , Perfilación de la Expresión Génica/métodos , Expresión Génica , Patología Molecular/métodos , Canales de Potasio Éter-A-Go-Go/genética , Humanos , Manejo de Especímenes/métodos , Fijación del Tejido/métodos , Factor A de Crecimiento Endotelial Vascular/biosíntesis , Factor A de Crecimiento Endotelial Vascular/genética
12.
Cancer Med ; 2(5): 583-94, 2013 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-24403225

RESUMEN

The human ether-à-go-go-related gene (hERG)1 K(+) channel is upregulated in human colorectal cancer cells and primary samples. In this study, we examined the role of hERG1 in colorectal carcinogenesis using two mouse models: adenomatous polyposis coli (Apc(min/+) ) and azoxymethane (AOM)-treated mice. Colonic polyps of Apc(min/+) mice overexpressed mERG1 and their formation was reverted by the hERG1 blocker E4031. AOM was applied to either hERG1-transgenic (TG) mice, which overexpress hERG1 in the mucosa of the large intestine, or wild-type mice. A significant increase of both mucin-depleted foci and polyps in the colon of hERG1-TG mice was detected. Both the intestine of TG mice and colonic polyps of Apc(min/+) showed an upregulation of phospho-Protein Kinase B (pAkt)/vascular endothelial growth factor (VEGF-A) and an increased angiogenesis, which were reverted by treatment with E4031. On the whole, this article assigns a relevant role to hERG1 in the process of in vivo colorectal carcinogenesis.


Asunto(s)
Carcinogénesis/metabolismo , Neoplasias Colorrectales/metabolismo , Canales de Potasio Éter-A-Go-Go/fisiología , Poliposis Adenomatosa del Colon/irrigación sanguínea , Poliposis Adenomatosa del Colon/metabolismo , Animales , Azoximetano , Carcinógenos , Neoplasias Colorrectales/irrigación sanguínea , Neoplasias Colorrectales/inducido químicamente , Modelos Animales de Enfermedad , Canal de Potasio ERG1 , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Canales de Potasio Éter-A-Go-Go/biosíntesis , Canales de Potasio Éter-A-Go-Go/genética , Regulación Neoplásica de la Expresión Génica , Humanos , Mucosa Intestinal/metabolismo , Intestino Grueso/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Proteínas de Neoplasias/biosíntesis , Proteínas de Neoplasias/genética , Neovascularización Patológica/metabolismo , Neovascularización Patológica/patología , Piperidinas/farmacología , Proteínas Proto-Oncogénicas c-akt/biosíntesis , Piridinas/farmacología , Factor A de Crecimiento Endotelial Vascular/biosíntesis
13.
Genome Biol ; 7(1): R4, 2006.
Artículo en Inglés | MEDLINE | ID: mdl-16507136

RESUMEN

BACKGROUND: Genome-wide RNA interference (RNAi) screening is a very powerful tool for analyzing gene function in vivo in Caenorhabditis elegans. The effectiveness of RNAi varies from gene to gene, however, and neuronally expressed genes are largely refractive to RNAi in wild-type worms. RESULTS: We found that C. elegans strains carrying mutations in lin-35, the worm ortholog of the tumor suppressor gene p105Rb, or a subset of the genetically related synMuv B family of chromatin-modifying genes, show increased strength and penetrance for many germline, embryonic, and post-embryonic RNAi phenotypes, including neuronal RNAi phenotypes. Mutations in these same genes also enhance somatic transgene silencing via an RNAi-dependent mechanism. Two genes, mes-4 and zfp-1, are required both for the vulval lineage defects resulting from mutations in synMuv B genes and for RNAi, suggesting a common mechanism for the function of synMuv B genes in vulval development and in regulating RNAi. Enhanced RNAi in the germline of lin-35 worms suggests that misexpression of germline genes in somatic cells cannot alone account for the enhanced RNAi observed in this strain. CONCLUSION: A worm strain with a null mutation in lin-35 is more sensitive to RNAi than any other previously described single mutant strain, and so will prove very useful for future genome-wide RNAi screens, particularly for identifying genes with neuronal functions. As lin-35 is the worm ortholog of the mammalian tumor suppressor gene p105Rb, misregulation of RNAi may be important during human oncogenesis.


Asunto(s)
Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Interferencia de ARN , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Proteína de Retinoblastoma/química , Animales , Caenorhabditis elegans/anatomía & histología , Proteínas de Caenorhabditis elegans/química , Linaje de la Célula , Silenciador del Gen , Genes de Helminto , Modelos Genéticos , Mutación/genética , Sistema Nervioso/metabolismo , Fenotipo , Proteínas Represoras/química , Supresión Genética
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