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1.
Med Sci Monit ; 26: e921040, 2020 Mar 22.
Artículo en Inglés | MEDLINE | ID: mdl-32200389

RESUMEN

Circulating tumor DNA (ctDNA) describes the fragmented DNA released from tumor cells into the blood. The ctDNA may have the same genetic changes as the primary tumor. Currently, ctDNA has become a popular biomarker for diagnosis, treatment, real-time clinical response monitoring, and prognosis, for solid tumors. Detection of ctDNA is minimally invasive, and repeat sampling can easily be performed. However, due to its low quality and short DNA fragment length, ctDNA detection still faces challenges and requires highly sensitive analytical techniques. Recently, liquid biopsies for the analysis of circulating tumor cells (CTCs) and circulating tumor-derived exosomes have been studied, and nanotechnology techniques have rapidly developed. Compared to traditional analytical methods, these nanotechnology-based platforms have the advantages of sensitivity, multiplex detection, simplicity, miniaturization, and automation, which support their potential use in clinical practice. This review aims to discuss the recent nanotechnological strategies for ctDNA analysis and the design of reliable techniques for ctDNA detection and to identify the potential clinical applications.


Asunto(s)
ADN Tumoral Circulante/sangre , ADN de Neoplasias/genética , Nanotecnología/métodos , Neoplasias/genética , Células Neoplásicas Circulantes/metabolismo , Biomarcadores de Tumor/sangre , ADN Tumoral Circulante/genética , ADN de Neoplasias/sangre , Detección Precóz del Cáncer/métodos , Humanos , Biopsia Líquida , Neoplasias/sangre , Neoplasias/diagnóstico
2.
Crit Rev Oncol Hematol ; 146: 102879, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-32005411

RESUMEN

Cell-free circulating tumor DNA (ct-DNA) reflecting the whole tumor spatial and temporal heterogeneity currently represents the most promising candidate for liquid biopsy strategy in glioma. Unlike other solid tumors, it is now widely accepted that the best source of ct-DNA for glioma patients is the cerebrospinal fluid, since blood levels are usually low and detectable only in few cases. A cerebrospinal fluid ct-DNA liquid biopsy approach may virtually support all the stages of glioma management, from facilitating molecular diagnosis when surgery is not feasible, to monitoring tumor response, identifying early recurrence, tracking longitudinal genomic evolution, providing a new molecular characterization at recurrence and allowing patient selection for targeted therapies. This review traces the history of ct-DNA liquid biopsy in the field of diffuse malignant gliomas, describes its current status and analyzes what are the future perspectives and pitfalls of this potentially revolutionary molecular tool.


Asunto(s)
Biomarcadores de Tumor/metabolismo , Neoplasias Encefálicas/líquido cefalorraquídeo , ADN Tumoral Circulante/líquido cefalorraquídeo , ADN de Neoplasias/metabolismo , Glioma/líquido cefalorraquídeo , Biopsia Líquida/métodos , Células Neoplásicas Circulantes/metabolismo , Biomarcadores de Tumor/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , ADN de Neoplasias/genética , Genes Relacionados con las Neoplasias/genética , Glioblastoma/líquido cefalorraquídeo , Glioblastoma/genética , Glioblastoma/patología , Glioma/genética , Glioma/patología , Humanos , Mutación , Clasificación del Tumor , Recurrencia Local de Neoplasia/diagnóstico , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/metabolismo , Células Neoplásicas Circulantes/patología
3.
Medicine (Baltimore) ; 99(8): e19097, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-32080083

RESUMEN

Liquid biopsy is an emerging technique for noninvasive detection of various cancers. Majority of liquid biopsy tests still, however, use solitary type of biomarkers with unsatisfactory sensitivity and specificity. To this end, a combined approach of circulating tumor cells (CTCs) and salivary mRNA biomarkers was evaluated for discriminating non-small-cell lung cancer (NSCLC) from healthy controls.Our study included a discovery phase to find multiple biomarkers, and an independent validation phase to confirm the applicability of the selected biomarkers. In the discovery phase, CTC level in blood and 5 mRNA biomarkers in saliva (i.e., CCNI, Epidermal growth factor receptor [EGFR], FGF19, FRS2, and GREB1) were measured for 140 NSCLC patients and 140 healthy controls, followed by developing a predictive model. Next, this panel of biomarkers was applied to another patient cohort consisted of 60 patients with NSCLC and 60 healthy controls in the validation phase.We found that our novel biomarker panel could differentiate patients with NSCLC from healthy controls with high sensitivity (92.1%) and high specificity (92.9%) in the discovery phase. In the validation phase, we achieved sensitivity of 88.3% and specificity of 90.0%.To our best knowledge, it is the first time that a combined use of CTC and salivary mRNA biomarkers were applied for noninvasive detection of NSCLC.


Asunto(s)
Biomarcadores de Tumor/sangre , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Células Neoplásicas Circulantes/metabolismo , ARN Mensajero/metabolismo , Saliva/metabolismo , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Adulto , Anciano , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Ciclina I/metabolismo , Receptores ErbB/metabolismo , Femenino , Factores de Crecimiento de Fibroblastos/metabolismo , Humanos , Biopsia Líquida/métodos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Masculino , Proteínas de la Membrana/metabolismo , Persona de Mediana Edad , Proteínas de Neoplasias/metabolismo , Células Neoplásicas Circulantes/patología , Valor Predictivo de las Pruebas , Sensibilidad y Especificidad
4.
Cancer Sci ; 111(2): 441-450, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31821662

RESUMEN

Regorafenib has improved the survival of patients with refractory metastatic colorectal cancer (mCRC), yet the mechanisms of inherited or acquired resistance are not well understood. A total of 50 patients with refractory mCRC were enrolled. Circulating tumor cell (CTC) enumeration was carried out at baseline, day 21 after initiation of regorafenib, and at the time of progression of disease (PD) using the CellSearch System (Veridex LLC, NJ, USA). Poly(A) mRNA was extracted from CTCs, and gene expression of epithelial and epithelial-mesenchymal transition markers was analyzed by a multiplex-PCR based DNA Chip. Patients with fewer than 3 CTCs at baseline and day 21 had a longer progression-free survival than those with 3 or more CTCs (3.3 vs 2.0 months, P = .008 and 3.3 vs 2.0 months, P = .004, respectively). Patients with fewer than 3 CTCs at baseline and day 21 had a longer overall survival (OS) than those with 3 or more CTCs (10.0 vs 4.6 months, P < .001 and 8.7 vs 3.8 months, P = .003, respectively). In multivariable analysis, CTC counts remained significantly associated with OS at baseline and day 21 (P = .019 and P = .028). Circulating tumor cell EGFR gene expression was upregulated at day 21 and/or PD in 64% of patients. Patients had significantly increased EGFR expression at PD compared to baseline (P = .041) and at day 21 and/or PD compared to baseline (P = .004). Our findings suggest that CTC count and EGFR expression could be useful markers of regorafenib efficacy and outcomes. Upregulation of CTC EGFR expression might be a molecular escape mechanism under regorafenib therapy.


Asunto(s)
Neoplasias Colorrectales/tratamiento farmacológico , Células Neoplásicas Circulantes/efectos de los fármacos , Compuestos de Fenilurea/administración & dosificación , Piridinas/administración & dosificación , Regulación hacia Arriba , Adulto , Anciano , Recuento de Células , Neoplasias Colorrectales/genética , Progresión de la Enfermedad , Resistencia a Antineoplásicos , Transición Epitelial-Mesenquimal , Receptores ErbB/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Células Neoplásicas Circulantes/metabolismo , Compuestos de Fenilurea/farmacología , Pronóstico , Estudios Prospectivos , Piridinas/farmacología , Estudios Retrospectivos , Resultado del Tratamiento
5.
Recent Results Cancer Res ; 215: 3-24, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-31605221

RESUMEN

The traditional model of metastatic progression postulates that the ability to form distant metastases is driven by random mutations in cells of the primary tumor.


Asunto(s)
Metástasis de la Neoplasia/genética , Células Neoplásicas Circulantes/metabolismo , Células Neoplásicas Circulantes/patología , Progresión de la Enfermedad , Humanos , Mutación
6.
Recent Results Cancer Res ; 215: 57-76, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-31605223

RESUMEN

The classification of human cancers has traditionally relied on the tissue of origin, the histologic appearance and anatomical extent of disease, otherwise referred to as grade and stage. However, this system fails to explain the highly variable clinical behaviour seen for any one cancer. Molecular characterization through techniques such as next-generation sequencing (NGS) has led to an appreciation of the extreme genetic heterogeneity that underlies most human cancers. Because of the difficulties associated with fresh tissue biopsy, interest has increased in using circulating tumour material, such as circulating tumour cells (CTCs), as a non-invasive way to access tumour tissue. CTC enumeration has been demonstrated to have prognostic value in metastatic breast, colon and prostate cancers. Recent studies have also shown that CTCs are suitable material for molecular characterization, using techniques such as reverse transcription-polymerase chain reaction (RT-PCR), fluorescence in situ hybridization (FISH), array comparative genomic hybridization (aCGH) and NGS. Furthermore, genetic analysis of CTCs may be more suitable to study tumour heterogeneity and clonal evolution than fresh tissue biopsy. Whether blood-based biopsy techniques will be accepted as a replacement to fresh tissue biopsies remains to be seen, but there is reason for optimism. While significant barriers to this acceptance exist, blood-based biopsy techniques appear to be reliable and representative alternatives to fresh tissue biopsy.


Asunto(s)
Análisis Mutacional de ADN , Neoplasias/genética , Neoplasias/patología , Células Neoplásicas Circulantes , Hibridación Genómica Comparativa , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Hibridación Fluorescente in Situ , Neoplasias/sangre , Células Neoplásicas Circulantes/metabolismo , Pronóstico
7.
Recent Results Cancer Res ; 215: 89-104, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-31605225

RESUMEN

Circulating tumor cells (CTCs) represent novel biomarkers, since they are obtainable through a simple and noninvasive blood draw or liquid biopsy. Here, we review the high-definition single-cell analysis (HD-SCA) workflow, which brings together modern methods of immunofluorescence with more sophisticated image processing to rapidly and accurately detect rare tumor cells among the milieu of platelets, erythrocytes, and leukocytes in the peripheral blood. In particular, we discuss progress in methods to measure CTC morphology and subcellular protein expression, and we highlight some initial applications that lead to fundamental new insights about the hematogenous phase of cancer, as well as its performance in early-stage diagnosis and treatment monitoring. We end with an outlook on how to further probe CTCs and the unique advantages of the HD-SCA workflow for improving the precision of cancer care.


Asunto(s)
Biología Computacional , Neoplasias/patología , Células Neoplásicas Circulantes/metabolismo , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/genética , Ensayos Analíticos de Alto Rendimiento , Humanos , Neoplasias/diagnóstico , Neoplasias/terapia , Células Neoplásicas Circulantes/patología , Análisis de la Célula Individual
8.
Recent Results Cancer Res ; 215: 105-125, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-31605226

RESUMEN

Circulating tumour cells (CTCs) constitute a potential tumour surrogate that could serve as "liquid biopsy" with the advantage to be a minimally invasive approach compared to traditional tissue biopsies. As CTCs are thought to be the source of metastatic lesions, their analysis represents a potential means of tracking cancer cells from the primary tumour en route to distant sites, thus providing valuable insights into the metastatic process. However, several problems, such as their rarity in the peripheral blood, the technical limitations of single-cell downstream analysis and their phenotypic variability, make CTC detection and molecular characterisation very challenging. Nevertheless, in the last decade, there has been an exponential increase of interest in the development of powerful cellular and molecular methodologies applied to CTCs. In this chapter, we focus on the recent advances of functional studies and molecular profiling of CTCs. We will also highlight the clinical relevance of CTC detection and enumeration, and discuss their potential as tumour biomarkers with special focus on lung cancer.


Asunto(s)
Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Células Neoplásicas Circulantes/metabolismo , Biomarcadores de Tumor/análisis , Humanos , Células Neoplásicas Circulantes/patología
9.
Recent Results Cancer Res ; 215: 127-145, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-31605227

RESUMEN

With active screening for early detection and advancements in treatment, there has been a significant decrease in mortality from breast cancer. However, a significant proportion of patients with non-metastatic breast cancer at time of diagnosis will relapse. Therefore, it is suggested that the dissemination of bloodstream tumor cells (circulating tumor cells, CTCs) undetectable by currently available diagnostic tools occurs during the early stages of breast cancer progression, and may be the potential source of micrometastases responsible for treatment failures. Here, we review the clinical significance of CTCs, as detected by the FDA-approved CellSearch® System, in both metastatic and non-metastatic breast cancer patients. Studies so far suggest that CTCs are prognostic of poorer outcomes in breast cancer patients; however, there is currently insufficient data to support use of CTC data to guide treatment. Therefore, there are ongoing studies to evaluate the utility of assessing CTC phenotypes to develop personalized breast cancer treatment, which will be reviewed in this chapter.


Asunto(s)
Neoplasias de la Mama/patología , Células Neoplásicas Circulantes/metabolismo , Biomarcadores de Tumor/análisis , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/terapia , Progresión de la Enfermedad , Humanos , Células Neoplásicas Circulantes/patología , Medicina de Precisión , Pronóstico
10.
Iran Biomed J ; 24(1): 47-53, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31454863

RESUMEN

Background: The analysis of the gene copy number alterations in tumor samples are increasingly used for diagnostic and prognostic purposes in patients with gastric cancer (GC). However, these procedures are not always applicable due to their invasive nature. In this study, we have analyzed the copy number alterations of five genes (HER2, MDM2, c-MYC, c-MET, and TP53) with a fixed relevance for GC in the circulating tumor cells (CTCs) of GC patients, and, accordingly, as a potential approach, evaluated their usage to complete primary tumor biopsy. Methods: We analyzed the status of the copy number alterations of the selected genes in CTCs and matched biopsy tissues from 37 GC patients using fluorescence in situ hybridization. Results: HER2 amplification was observed in 2 (5.41%) samples. HER2 gene status in CTCs showed a strong agreement with its status in 36 out of 37 patients' matched tissue samples (correlation: 97.29%; Kappa: 0.65; p < 0.001). MDM2 amplification was found only in 1 (2.70%) sample; however, the amplification of this gene was not detectable in the CTCs isolated from this patient. c-MYC amplification was observed in 3 (8.11%) samples, and the status of its amplification in the CTCs indicated a complete agreement with its status in the matched tissue samples (correlation: 100%; Kappa: 1.0). Conclusion: Our work suggests that the amplification of HER2 and c-MYC is in concordance with the CTCs and achieved biopsies, and, consequently, CTCs may act as a non-invasive alternative for recording the amplification of these genes among GC patients.


Asunto(s)
Variaciones en el Número de Copia de ADN/genética , Proteínas de Neoplasias/genética , Células Neoplásicas Circulantes/metabolismo , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proyectos Piloto
11.
Recent Results Cancer Res ; 215: 77-88, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-31605224

RESUMEN

Circulating tumor cells (CTCs) provide valuable information about the molecular evolution of cancers, as they may initially respond and ultimately progress on therapy. As intact tumor cells isolated from the bloodstream, CTCs also enable assessment of heterogeneous subpopulations, and their analysis may include DNA, RNA, and protein biomarkers. New microfluidic cell isolation strategies greatly facilitate the challenge of enriching viable tumor cells from the billions of hematopoietic cells within a standard blood specimen. While counting and characterization of enriched CTCs have primarily relied on immunostaining for tumor cell-specific antigens, new RNA-based analytic platforms are providing new insight into the identity of CTCs and providing new tools for clinical applications. Single-cell RNA sequencing of CTCs reveals a high degree of heterogeneity among cancer cells from a single individual, while new digital RNA-based amplification platforms may now allow high-sensitivity and high-throughput quantitative scoring of CTCs for clinical applications. Here, we focus on transcriptomic analysis of CTCs and its relevance in understanding metastatic cancer progression and in developing diagnostic assays to monitor cancer.


Asunto(s)
Separación Celular/métodos , Neoplasias/genética , Neoplasias/patología , Células Neoplásicas Circulantes , ARN Neoplásico/análisis , Progresión de la Enfermedad , Humanos , Neoplasias/diagnóstico , Células Neoplásicas Circulantes/metabolismo , ARN Neoplásico/genética
12.
Ann Hematol ; 98(12): 2769-2780, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31748925

RESUMEN

Difficulty in regularly analyzing marrow myeloma cells (MMCs) and low frequency of circulating myeloma cells (CMCs) in blood presents challenges for monitoring minimal residual disease (MRD) in multiple myeloma (MM). We have developed a set of method for enrichment of CMCs by immunomagetic beads (IMB) combined with flow cytometry (IMB-FCM) based on CD38-APC/CD138-APC antibodies in U266-spiked samples and in 122 patient samples. U266 cell capture efficiency of CD38/CD138-IMB-FCM (6.960, 2.574) was 6- and 2-fold higher than that of FCM (1.032), and the sensitivity of FCM and IMB-FCM was 0.01% and 0.001%, respectively. In MM cohort, the positive rate of CMCs by IMB-FCM increased from 60.5~70.0 to 85~87.2% in newly diagnosed/relapsed and partial remission (PR) patients compared with by FCM (P < 0.05). Two complete remission (CR) patients contain certain amounts of CMCs by IMB-FCM while no CMCs and MMCs were detectable by FCM. Patients exhibiting PR and CR upon therapy had much lower CMC and MMC counts than newly diagnosed/relapsed patients (P < 0.005). Based on MRD measurement in BM and PB samples, all FCM-negative BM samples were also paired with FCM/IMB-FCM-negative PB samples among newly diagnosed, relapsed, and PR patients, and FCM-positive BM samples were accompanied by IMB-FCM-positive results in 88% of corresponding PB samples. CMCs strongly associated with other clinical biomarkers of disease burden, including elevated MMCs, ß2-MG, sCrea, and DS and ISS stages, and more serious anemia, bone destruction, and renal impairment (P < 0.05). Logistic regression analysis revealed that elevated ß2-MG and moderate-to-more anemia were significant risk factors for the presence of CMCs (P < 0.05). As a noninvasive "liquid biopsy" of monitoring MRD, the potential of IMB-FCM for CMC detection may complement or minimize bone marrow aspiration in future treatment of MM patients.


Asunto(s)
Citometría de Flujo , Separación Inmunomagnética , Mieloma Múltiple/sangre , Células Neoplásicas Circulantes/metabolismo , Adulto , Línea Celular Tumoral , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mieloma Múltiple/patología , Mieloma Múltiple/terapia , Neoplasia Residual , Células Neoplásicas Circulantes/patología
13.
Int J Mol Sci ; 20(19)2019 Oct 02.
Artículo en Inglés | MEDLINE | ID: mdl-31581693

RESUMEN

The aim of this study was to identify genes with higher expression in solid tumor cells by comparing human tumor biopsies with healthy blood samples using both in silico statistical analysis and experimental validations. This approach resulted in a novel panel of 80 RNA biomarkers with high discrimination power to detect circulating tumor cells in blood samples. To identify the 80 RNA biomarkers, Affymetrix HG-U133 plus 2.0 microarrays datasets were used to compare breast tumor tissue biopsies and breast cancer cell lines with blood samples from patients with conditions other than cancer. A total of 859 samples were analyzed at the discovery stage, consisting of 417 mammary tumors, 41 breast lines, and 401 control samples. To confirm this discovery, external datasets of eight types of tumors were used, and experimental validation studies (NanoString n-counter gene expression assay) were performed, totaling 5028 samples analyzed. In these analyses, the 80 biomarkers showed higher expression in all solid tumors analyzed relative to healthy blood samples. Experimental validation studies using NanoString assay confirmed the results were not dependent of the gene expression platform. A panel of 80 RNA biomarkers was described here, with the potential to detect solid tumor cells present in the blood of multiple tumor types.


Asunto(s)
Biomarcadores de Tumor , Neoplasias/genética , Transcriptoma , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Células Neoplásicas Circulantes/metabolismo , Reproducibilidad de los Resultados
14.
J Cancer Res Clin Oncol ; 145(12): 2911-2920, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31646374

RESUMEN

OBJECTIVE: To investigate the presence of vimentin expression in CTCs and its clinical relevance in patients with advanced lung cancer. METHODS: Peripheral blood was obtained from 61 treatment-naive patients with advanced lung cancer. Subtraction enrichment and immunostaining-fluorescence in situ hybridization (SE-iFISH) platform was applied to identify, enumerate and characterize CTCs based on cell size, aneuploidy of chromosome 8 (Chr8) and vimentin expression. Quantification and analysis of CTCs were performed on patients before chemotherapy administration and after two cycles of therapy. RESULTS: Before treatment, CTCs were detected in 60 (98.4%) patients, small cell CTCs (≤ 5 µm of WBCs) accounted for 52.8% of the absolute CTCs number, while 12 (19.7%) of the included patients had detectable vimentin-positive CTCs (vim+ CTCs). Liver metastases were reported in 7 (11.5%) patients and were significantly correlated to the presence of Vim+ CTCs (p = 0.002), with a high positivity rate of 71.4% (5/7). Vim+ CTCs were mostly in small cell size and Chr8 aneuploidy (77.0% and 82.05%, respectively). Baseline small cell CTCs ≥ 2/6 ml, triploid CTCs ≥ 2/6 ml, Vim+ CTCs ≥ 1/6 ml were found to significantly correlate with poor progression-free survival (PFS) (p = 0.017, p = 0.009 and p = 0.001, respectively). After adjusting for clinically significant factors, baseline Vim+ CTCs ≥ 1/6 ml was the only independent predictor of poor PFS [hazard ratio (HR):2.756, 95% confidence interval (CI): 1.239-6.131; p = 0.013]. CONCLUSIONS: This study demonstrates an important morphologic, karyotypic and phenotypic CTCs heterogeneity in advanced lung cancer patients. The majority of Vim+ CTCs are in small size and Chr8 aneuploidy. Baseline presence of Vim+ CTCs is correlated with liver metastases and may help predict poor PFS.


Asunto(s)
Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Células Neoplásicas Circulantes/metabolismo , Vimentina/metabolismo , Cromosomas Humanos Par 8/genética , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Supervivencia sin Progresión , Estudios Prospectivos
15.
Breast Cancer Res ; 21(1): 101, 2019 09 03.
Artículo en Inglés | MEDLINE | ID: mdl-31481116

RESUMEN

BACKGROUND: The incidence of brain metastases in breast cancer (BCBM) patients is increasing. These patients have a very poor prognosis, and therefore, identification of blood-based biomarkers, such as circulating tumor cells (CTCs), and understanding the genomic heterogeneity could help to personalize treatment options. METHODS: Both EpCAM-dependent (CellSearch® System) and EpCAM-independent Ficoll-based density centrifugation methods were used to detect CTCs from 57 BCBM patients. DNA from individual CTCs and corresponding primary tumors and brain metastases were analyzed by next-generation sequencing (NGS) in order to evaluate copy number aberrations and single nucleotide variations (SNVs). RESULTS: CTCs were detected after EpCAM-dependent enrichment in 47.7% of the patients (≥ 5 CTCs/7.5 ml blood in 20.5%). The CTC count was associated with ERBB2 status (p = 0.029) of the primary tumor as well as with the prevalence of bone metastases (p = 0.021). EpCAM-independent enrichment revealed CTCs in 32.6% of the patients, especially among triple-negative breast cancer (TNBC) patients (70.0%). A positive CTC status after enrichment of either method was significantly associated with decreased overall survival time (p < 0.05). Combining the results of both enrichment methods, 63.6% of the patients were classified as CTC positive. In three patients, the matched tumor tissue and single CTCs were analyzed by NGS showing chromosomal aberrations with a high genomic clonality and mutations in pathways potentially important in brain metastasis formation. CONCLUSION: The detection of CTCs, regardless of the enrichment method, is of prognostic relevance in BCBM patients and in combination with molecular analysis of CTCs can help defining patients with higher risk of early relapse and suitability for targeted treatment.


Asunto(s)
Neoplasias Encefálicas/sangre , Neoplasias Encefálicas/secundario , Neoplasias de la Mama/sangre , Neoplasias de la Mama/patología , Células Neoplásicas Circulantes/patología , Biomarcadores de Tumor/sangre , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Recuento de Células , Aberraciones Cromosómicas , Variaciones en el Número de Copia de ADN , Molécula de Adhesión Celular Epitelial/metabolismo , Femenino , Humanos , Mutación , Células Neoplásicas Circulantes/metabolismo , Pronóstico , Análisis de Supervivencia
16.
Anticancer Res ; 39(9): 4711-4720, 2019 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-31519570

RESUMEN

BACKGROUND/AIM: Dynamics of circulating tumor cells (CTCs) after molecular targeting therapy remain unclear. MATERIALS AND METHODS: We examined changes in CTC numbers and morphology early after targeting therapy in EGFR-mutated PC-9 human lung cancer and HER2-gene amplified GLM-1 gastric cancer mouse CTC models using a cytology-based semi-automated CTC detection platform. RESULTS: Erlotinib and T-DM1 inhibited cell growth mainly by induction of apoptosis in vitro. The number of CTCs detected 5-10 days after targeting therapy in mice was significantly increased compared to CTC numbers before therapy. The increased CTCs after therapy consisted of apoptotic CTCs and viable CTCs. This heterogeneous population of CTCs reflects well the cell population of the primary tumor disrupted by therapy. CONCLUSION: CTCs can be mobilized from the primary tumor due to tissue disruption in acute response to targeting therapy, suggesting potential usefulness of CTC monitoring as a predictor of therapeutic response in the clinical settings.


Asunto(s)
Amplificación de Genes , Mutación , Células Neoplásicas Circulantes/metabolismo , Receptor ErbB-2/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología , Animales , Antineoplásicos/farmacología , Biomarcadores , Biomarcadores de Tumor , Línea Celular Tumoral , Modelos Animales de Enfermedad , Receptores ErbB/genética , Clorhidrato de Erlotinib/farmacología , Xenoinjertos , Humanos , Inmunohistoquímica , Ratones , Células Neoplásicas Circulantes/patología , Neoplasias Gástricas/tratamiento farmacológico
17.
BMC Complement Altern Med ; 19(1): 204, 2019 Aug 07.
Artículo en Inglés | MEDLINE | ID: mdl-31391058

RESUMEN

BACKGROUND: Metastasis is the main cause of lung cancer death. As a seed of metastasis, circulating tumor cells are an important target for metastasis intervention. The traditional Chinese medicine, Jinfukang, has been clinically available for the treatment of non-small cell lung cancer (NSCLC). In this study, we investigated the action and underlying mechanisms of Jinfukang against circulating lung tumor cells. METHODS: The cell counting kit-8 (CCK-8), colony formation and cell cycle assays were used to study the cell proliferation ability. Flow cytometry was used to detect the apoptosis and the expression level of ROS and Caspase-3. Comet and TUNEL assays were used to detect DNA damage. DNA damage related pathway protein was detected by western blot. RESULTS: Jinfukang significantly inhibits the proliferation of CTC-TJH-01 cells by inducing G1 phase arrest and inhibits their colony formation in a dose-dependent manner. Moreover, Jinfukang induces apoptosis in CTC-TJH-01 cells through the ROS-mediated ATM/ATR-p53 pathway and DNA damage. CONCLUSIONS: Our findings suggest that Jinfukang may be a potential drug for lung cancer metastasis.


Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Carcinoma de Pulmón de Células no Pequeñas/genética , Daño del ADN/efectos de los fármacos , Medicamentos Herbarios Chinos/farmacología , Células Neoplásicas Circulantes/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Apoptosis/efectos de los fármacos , Proteínas de la Ataxia Telangiectasia Mutada/genética , Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/fisiopatología , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Humanos , Células Neoplásicas Circulantes/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo
19.
Int J Mol Sci ; 20(15)2019 Aug 05.
Artículo en Inglés | MEDLINE | ID: mdl-31387281

RESUMEN

Utilization of liquid biopsy in the management of cancerous diseases is becoming more attractive. This method can overcome typical limitations of tissue biopsies, especially invasiveness, no repeatability, and the inability to monitor responses to medication during treatment as well as condition during follow-up. Liquid biopsy also provides greater possibility of early prediction of cancer presence. Corpus uteri mesenchymal tumors are comprised of benign variants, which are mostly leiomyomas, but also a heterogenous group of malignant sarcomas. Pre-surgical differentiation between these tumors is very difficult and the final description of tumor characteristics usually requires excision and histological examination. The leiomyomas and malignant leiomyosarcomas are especially difficult to distinguish and can, therefore, be easily misdiagnosed. Because of the very aggressive character of sarcomas, liquid biopsy based on early diagnosis and differentiation of these tumors would be extremely helpful. Moreover, after excision of the tumor, liquid biopsy can contribute to an increased knowledge of sarcoma behavior at the molecular level, especially on the formation of metastases which is still not well understood. In this review, we summarize the most important knowledge of mesenchymal uterine tumors, the possibilities and benefits of liquid biopsy utilization, the types of molecules and cells that can be analyzed with this approach, and the possibility of their isolation and capture. Finally, we review the typical abnormalities of leiomyomas and sarcomas that can be searched and analyzed in liquid biopsy samples with the final aim to pre-surgically differentiate between benign and malignant mesenchymal tumors.


Asunto(s)
Biomarcadores de Tumor , Leiomioma/diagnóstico , Sarcoma/diagnóstico , Neoplasias Uterinas/diagnóstico , Micropartículas Derivadas de Células , Aberraciones Cromosómicas , ADN Tumoral Circulante , Metilación de ADN , Diagnóstico Diferencial , Femenino , Humanos , Leiomioma/genética , Leiomioma/metabolismo , Biopsia Líquida , MicroARNs/sangre , Mutación , Estadificación de Neoplasias , Células Neoplásicas Circulantes/metabolismo , Células Neoplásicas Circulantes/patología , Sarcoma/genética , Sarcoma/metabolismo , Neoplasias Uterinas/genética , Neoplasias Uterinas/metabolismo
20.
Life Sci Alliance ; 2(4)2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-31416894

RESUMEN

GRP78 conducts protein folding and quality control in the ER and shows elevated expression and cell surface translocation in advanced tumors. However, the underlying mechanisms enabling GRP78 to exert novel signaling functions at cell surface are just emerging. CD44 is a transmembrane protein and an important regulator of cancer metastasis, and isoform switch of CD44 through incorporating additional variable exons to the extracellular juxtamembrane region is frequently observed during cancer progression. Using super-resolution dual-color single-particle tracking, we report that GRP78 interacts with CD44v in plasma membrane nanodomains of breast cancer cells. We further show that targeting cell surface GRP78 by the antibodies can effectively reduce cell surface expression of CD44v and cell spreading of tamoxifen-resistant breast cancer cells. Our results uncover new functions of GRP78 as an interacting partner of CD44v and as a regulator of CD44v membrane homeostasis and cell spreading. This study also provides new insights into anti-CD44 therapy in tamoxifen-resistant breast cancer.


Asunto(s)
Neoplasias de la Mama/metabolismo , Resistencia a Antineoplásicos , Proteínas de Choque Térmico/metabolismo , Receptores de Hialuranos/metabolismo , Actinas/metabolismo , Membrana Celular/metabolismo , Femenino , Regulación Neoplásica de la Expresión Génica , Homeostasis , Humanos , Receptores de Hialuranos/química , Células MCF-7 , Células Neoplásicas Circulantes/metabolismo , Transducción de Señal , Tamoxifeno
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