RESUMEN

The primary reason for high mortality rates among cancer patients is metastasis, where tumor cells migrate through the bloodstream from the original site to other parts of the body. Recent advancements in technology have significantly enhanced our comprehension of the mechanisms behind the bloodborne spread of circulating tumor cells (CTCs). One critical process, DNA methylation, regulates gene expression and chromosome stability, thus maintaining dynamic equilibrium in the body. Global hypomethylation and locus-specific hypermethylation are examples of changes in DNA methylation patterns that are pivotal to carcinogenesis. This comprehensive review first provides an overview of the various processes that contribute to the formation of CTCs, including epithelial-mesenchymal transition (EMT), immune surveillance, and colonization. We then conduct an in-depth analysis of how modifications in DNA methylation within CTCs impact each of these critical stages during CTC dissemination. Furthermore, we explored potential clinical implications of changes in DNA methylation in CTCs for patients with cancer. By understanding these epigenetic modifications, we can gain insights into the metastatic process and identify new biomarkers for early detection, prognosis, and targeted therapies. This review aims to bridge the gap between basic research and clinical application, highlighting the significance of DNA methylation in the context of cancer metastasis and offering new avenues for improving patient outcomes.

Asunto(s)

Metilación de ADN , Transición Epitelial-Mesenquimal , Neoplasias , Células Neoplásicas Circulantes , Células Neoplásicas Circulantes/patología , Células Neoplásicas Circulantes/metabolismo , Humanos , Metilación de ADN/genética , Transición Epitelial-Mesenquimal/genética , Neoplasias/genética , Neoplasias/patología , Biomarcadores de Tumor/genética , Metástasis de la Neoplasia , Epigénesis Genética/genética

RESUMEN

The current constraints associated with cancer diagnosis and molecular profiling, which rely on invasive tissue biopsies or clinical imaging, have spurred the emergence of the liquid biopsy field. Liquid biopsy involves the extraction of circulating tumor cells (CTCs), circulating free or circulating tumor DNA (cfDNA or ctDNA), circulating cell-free RNA (cfRNA), extracellular vesicles (EVs), and tumor-educated platelets (TEPs) from bodily fluid samples. Subsequently, these components undergo molecular characterization to identify biomarkers that are critical for early cancer detection, prognosis, therapeutic assessment, and post-treatment monitoring. These innovative biosources exhibit characteristics analogous to those of the primary tumor from which they originate or interact. This review comprehensively explores the diverse technologies and methodologies employed for processing these biosources, along with their principal clinical applications.

Asunto(s)

Biomarcadores de Tumor , Neoplasias , Células Neoplásicas Circulantes , Humanos , Biopsia Líquida/métodos , Neoplasias/patología , Neoplasias/diagnóstico , Neoplasias/metabolismo , Neoplasias/genética , Células Neoplásicas Circulantes/metabolismo , Células Neoplásicas Circulantes/patología , Biomarcadores de Tumor/metabolismo , Vesículas Extracelulares/metabolismo , ADN Tumoral Circulante , Ácidos Nucleicos Libres de Células/genética

RESUMEN

Chromosomal Instability (CIN) is a common and evolving feature in breast cancer. Large-scale Transitions (LSTs), defined as chromosomal breakages leading to gains or losses of at least 10 Mb, have recently emerged as a metric of CIN due to their standardized definition across platforms. Herein, we report the feasibility of using low-pass Whole Genome Sequencing to assess LSTs, copy number alterations (CNAs) and their relationship in individual circulating tumor cells (CTCs) of triple-negative breast cancer (TNBC) patients. Initial assessment of LSTs in breast cancer cell lines consistently showed wide-ranging values (median 22, range 4-33, mean 21), indicating heterogeneous CIN. Subsequent analysis of CTCs revealed LST values (median 3, range 0-18, mean 5), particularly low during treatment, suggesting temporal changes in CIN levels. CNAs averaged 30 (range 5-49), with loss being predominant. As expected, CTCs with higher LSTs values exhibited increased CNAs. A CNA-based classifier of individual patient-derived CTCs, developed using machine learning, identified genes associated with both DNA proliferation and repair, such as RB1, MYC, and EXO1, as significant predictors of CIN. The model demonstrated a high predictive accuracy with an Area Under the Curve (AUC) of 0.89. Overall, these findings suggest that sequencing CTCs holds the potential to facilitate CIN evaluation and provide insights into its dynamic nature over time, with potential implications for monitoring TNBC progression through iterative assessments.

Asunto(s)

Inestabilidad Cromosómica , Variaciones en el Número de Copia de ADN , Células Neoplásicas Circulantes , Neoplasias de la Mama Triple Negativas , Secuenciación Completa del Genoma , Humanos , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/patología , Neoplasias de la Mama Triple Negativas/sangre , Células Neoplásicas Circulantes/metabolismo , Células Neoplásicas Circulantes/patología , Femenino , Secuenciación Completa del Genoma/métodos , Línea Celular Tumoral

RESUMEN

BACKGROUND: Circulating tumor cells (CTCs) are pivotal in tumor metastasis across cancers, yet their specific role in renal cancer remains unclear. METHODS: This study investigated C-C motif chemokine ligand 5 (CCL5)'s tumorigenic impact on renal cancer cells and CTCs using bioinformatics, in vivo, and in vitro experiments. It also assessed renal cancer patients' CTCs prognostic value through Lasso regression and Kaplan-Meier survival curves. RESULTS: Bioinformatics analysis revealed differential genes focusing on cellular adhesion and migration between CTCs and tumor cells. CCL5 exhibited high expression in various CTCs, correlating with poor prognosis in renal cancer. In 786-O-CTCs, CCL5 enhanced malignancy, while in renal cell carcinoma cell line CAKI-2 and 786-O, it promoted epithelial-mesenchymal transition (EMT) via smad2/3, influencing cellular characteristics. The nude mouse model suggested CCL5 increased CTCs and intensified EMT, enhancing lung metastasis. Clinical results shown varying prognostic values for different EMT-typed CTCs, with mesenchymal CTCs having the highest value. CONCLUSIONS: In summary, CCL5 promoted EMT in renal cancer cells and CTCs through smad2/3, enhancing the malignant phenotype and facilitating lung metastasis. Mesenchymal-type CTC-related factors can construct a risk model for renal cancer patients, allowing personalized treatment based on metastatic risk prediction.

Asunto(s)

Quimiocina CCL5 , Transición Epitelial-Mesenquimal , Neoplasias Renales , Ratones Desnudos , Células Neoplásicas Circulantes , Transición Epitelial-Mesenquimal/genética , Quimiocina CCL5/metabolismo , Humanos , Células Neoplásicas Circulantes/patología , Células Neoplásicas Circulantes/metabolismo , Animales , Línea Celular Tumoral , Neoplasias Renales/patología , Neoplasias Renales/sangre , Neoplasias Renales/genética , Pronóstico , Masculino , Regulación Neoplásica de la Expresión Génica , Femenino , Estimación de Kaplan-Meier , Ratones , Movimiento Celular , Persona de Mediana Edad

RESUMEN

Approaches to brain tumour diagnosis and detecting recurrence after treatment are costly and significantly invasive. Developing peripheral-sample liquid biopsy tools is the key to enhancing our ability to prognosticate brain tumour subtypes and molecular heterogeneity. The present scoping review was designed to discuss current updates in liquid biopsy tools for diagnosis and guiding clinical management of brain tumours; we evaluated the literature within the context of low-and-middle-income country challenges. Circulating tumour cells (CTCs), circulating tumour DNA (ctDNA), cell-free DNA (cfDNA), extracellular vesicle-associated biomarkers, protein biomarkers, microRNAs, and serum metabolites are discussed with the collation of current data supporting their utility in liquid biopsy. Further challenges to implanting liquid biopsy tools at a systematic level are highlighted.

Asunto(s)

Biomarcadores de Tumor , Neoplasias Encefálicas , ADN Tumoral Circulante , Países en Desarrollo , Células Neoplásicas Circulantes , Humanos , Biopsia Líquida/métodos , Neoplasias Encefálicas/sangre , Neoplasias Encefálicas/diagnóstico , Biomarcadores de Tumor/sangre , Células Neoplásicas Circulantes/patología , ADN Tumoral Circulante/sangre , Ácidos Nucleicos Libres de Células/sangre , Vesículas Extracelulares/metabolismo , MicroARNs/sangre

RESUMEN

OBJECTIVE: This case demonstrated the possibility of using GATA3-positive circulating tumor cells (CTCs) to detect early-stage breast cancer (BrC). CASE REPORT: The 86 years old female patient received a mammographic examination with no evidence of malignancy (Breast Imaging Reporting and Data System, (BI-RADS category 2). However, CTC testing on the same day revealed four GATA3-positive CTCs in 4 ml of peripheral blood. Core needle biopsy was performed in the suspicious area even with no evidence of malignant image on breast ultrasound. Pathologic examination showed invasive carcinoma of no special type of the breast. The patient then received an oncoplastic partial mastectomy of right breast and sentinel lymph node biopsy. The surgical staging was cT1N0M0. Post-operation follow-up examination showed absence of GATA3-positive CTCs and the presence of HER2/ER positive CTCs. CONCLUSION: The role of GATA3-positive CTCs as a potential biomarker for early-stage BrC should be explored.

Asunto(s)

Neoplasias de la Mama , Factor de Transcripción GATA3 , Estadificación de Neoplasias , Células Neoplásicas Circulantes , Humanos , Femenino , Factor de Transcripción GATA3/análisis , Factor de Transcripción GATA3/metabolismo , Neoplasias de la Mama/patología , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/sangre , Células Neoplásicas Circulantes/patología , Células Neoplásicas Circulantes/metabolismo , Anciano de 80 o más Años , Biomarcadores de Tumor/sangre , Biopsia del Ganglio Linfático Centinela , Biopsia con Aguja Gruesa , Mastectomía Segmentaria , Detección Precoz del Cáncer/métodos

RESUMEN

This study aimed to explore the potential of liquid biopsy as a diagnostic tool by integrating two key biomarkers, Circulating Tumor Cells (CTCs) and Circulating Tumor DNA (ctDNA), and to enhance the detection fidelity of prostate cancer. A dual biomarker analysis approach was employed to synergize the sensitivities of CTCs and ctDNA. Various genetic mutations of ctDNA and tissues were scrutinized, investigating their prevalence, co-existence, and mutual exclusivity. The findings uncovered a more intricate mutation landscape than previously anticipated, indicating a complex interplay between cellular and genetic aberrations in prostate cancer. Through harnessing the combined power of CTCs and ctDNA, our dual biomarker approach provides a more comprehensive understanding of prostate cancer genetics. This has the potential to revolutionize early detection and guide personalized therapeutic interventions.

Asunto(s)

Biomarcadores de Tumor , ADN Tumoral Circulante , Mutación , Células Neoplásicas Circulantes , Neoplasias de la Próstata , Humanos , Masculino , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/sangre , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/diagnóstico , Células Neoplásicas Circulantes/patología , Células Neoplásicas Circulantes/metabolismo , Biopsia Líquida/métodos , ADN Tumoral Circulante/sangre , ADN Tumoral Circulante/genética , Biomarcadores de Tumor/sangre , Biomarcadores de Tumor/genética

RESUMEN

Existing clinical biomarkers do not reliably predict treatment response or disease progression in patients with advanced intrahepatic cholangiocarcinoma (ICC). Circulating neoplastic-immune hybrid cells (CHCs) have great promise as a blood-based biomarker for patients with advanced ICC. Peripheral blood specimens were longitudinally collected from patients with advanced ICC enrolled in the HELIX-1 phase II clinical trial (NCT04251715). CHCs were identified by co-expression of pan-cytokeratin (CK) and CD45, and levels were correlated to patient clinical disease course. Unsupervised machine learning was then performed to extract their morphological features to compare them across disease courses. Five patients were included in this study, with a median of nine specimens collected per patient. A median of 13.5 CHCs per 50,000 peripheral blood mononuclear cells were identified at baseline, and levels decreased to zero following the initiation of treatment in all patients. Counts remained undetectable in three patients who demonstrated end-of-trial clinical treatment response and conversely increased in two patients with evidence of therapeutic resistance. In the post-trial surveillance period, interval counts increased prior to or at the time of clinical progression in three patients and remain undetectable in one patient with continued long-term disease stability. Using our machine learning platform, treatment-resistant CHCs exhibited upregulation of CK and downregulation of CD45 relative to treatment-responsive CHCs. CHCs represent a promising blood-based biomarker to supplement traditional radiographic and biochemical measures.

Asunto(s)

Neoplasias de los Conductos Biliares , Biomarcadores de Tumor , Colangiocarcinoma , Células Neoplásicas Circulantes , Humanos , Colangiocarcinoma/sangre , Colangiocarcinoma/patología , Biomarcadores de Tumor/sangre , Masculino , Neoplasias de los Conductos Biliares/patología , Neoplasias de los Conductos Biliares/sangre , Neoplasias de los Conductos Biliares/diagnóstico , Neoplasias de los Conductos Biliares/metabolismo , Femenino , Persona de Mediana Edad , Pronóstico , Células Neoplásicas Circulantes/metabolismo , Células Neoplásicas Circulantes/patología , Anciano , Antígenos Comunes de Leucocito/metabolismo , Queratinas/metabolismo

RESUMEN

Most cancer-related deaths are due to the spread of tumour cells throughout the body-a process known as metastasis. While in the vasculature, these cells are referred to as circulating tumour cells (CTCs) and can be found as either single cells or clusters of cells (often including platelets), with the latter having the highest metastatic potential. However, the biology of CTC clusters is poorly understood, and there are no therapies that specifically target them. We previously developed an in vitro model system for CTC clusters and proposed a new extravasation model that involves cluster dissociation, adherence, and single-cell invasion in response to TGF-ß1 released by platelets. Here, we investigated TGF-ß1-induced gene expression changes in this model, focusing on genes for which targeted drugs are available. In addition to the upregulation of the TGF-ß1 signalling pathway, we found that (i) genes in the EGF/EGFR pathway, including those coding for EGFR and several EGFR ligands, were also induced, and (ii) Erlotinib and Osimertinib, two therapeutic EGFR/tyrosine kinase inhibitors, decreased the TGF-ß1-induced adherence and invasion of the CTC cluster-like line despite the line expressing wild-type EGFR. Overall, we suggest that EGFR inhibitors have the potential to decrease the dispersal of CTC clusters that respond to TGF-ß1 and overexpress EGFR (irrespective of its status) and thus could improve patient survival.

Asunto(s)

Receptores ErbB , Células Neoplásicas Circulantes , Factor de Crecimiento Transformador beta1 , Receptores ErbB/metabolismo , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/genética , Humanos , Células Neoplásicas Circulantes/metabolismo , Células Neoplásicas Circulantes/efectos de los fármacos , Células Neoplásicas Circulantes/patología , Factor de Crecimiento Transformador beta1/metabolismo , Línea Celular Tumoral , Inhibidores de Proteínas Quinasas/farmacología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Clorhidrato de Erlotinib/farmacología , Transducción de Señal/efectos de los fármacos , Acrilamidas , Compuestos de Anilina , Indoles , Pirimidinas

Asunto(s)

5'-Nucleotidasa , Adenosina Trifosfato , Adenosina , Apirasa , Plaquetas , Células Neoplásicas Circulantes , Humanos , 5'-Nucleotidasa/metabolismo , Adenosina/metabolismo , Adenosina/análogos & derivados , Plaquetas/metabolismo , Células Neoplásicas Circulantes/patología , Células Neoplásicas Circulantes/metabolismo , Apirasa/metabolismo , Adenosina Trifosfato/metabolismo , Transducción de Señal , Antígenos CD/metabolismo , Proteínas Ligadas a GPI/metabolismo

RESUMEN

Circulating tumor cells (CTCs) are recognized as promising targets for liquid biopsy, which play an important role in early diagnosis and efficacy monitoring of cancer. However, due to the extreme scarcity of CTCs and partial size overlap between CTCs and white blood cells (WBCs), the separation and detection of CTCs from blood remain a big challenge. To address this issue, we fabricated a microfluidic chip by integrating a passive contraction-expansion array (CEA) inertial sorting zone and an active magnetophoresis zone with the trapezoidal groove and online coupled it with inductively coupled plasma mass spectrometry (ICP-MS) for rapid separation and precise detection of MCF-7 cells (as a model CTC) in blood samples. In the integrated microfluidic chip, most of the small-sized WBCs can be rapidly removed in the circular CEA inertial sorter, while the rest of the magnetically labeled WBCs can be further captured in the trapezoidal groove under the magnetic field. As a result, the rapid separation of MCF-7 cells from blood samples was achieved with an average recovery of 91.6% at a sample flow rate of 200 µL min-1. The developed online integrated inertial-magnetophoresis microfluidic chip-ICP-MS system has been applied for the detection of CTCs in real clinical blood samples with a fast analysis speed (5 min per 1 mL blood). CTCs were detected in all 24 blood samples from patients with different types of cancer, exhibiting excellent application potential in clinical diagnosis.

Asunto(s)

Separación Celular , Dispositivos Laboratorio en un Chip , Espectrometría de Masas , Células Neoplásicas Circulantes , Humanos , Células Neoplásicas Circulantes/patología , Células MCF-7 , Separación Celular/instrumentación , Separación Celular/métodos , Técnicas Analíticas Microfluídicas/instrumentación

RESUMEN

This Special Issue, 'Circulating Tumor Cells: Pathological, Molecular and Functional Characteristics 1 [...].

Asunto(s)

Neoplasias , Células Neoplásicas Circulantes , Humanos , Células Neoplásicas Circulantes/patología , Células Neoplásicas Circulantes/metabolismo , Neoplasias/patología , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/sangre , Biomarcadores de Tumor

RESUMEN

Previous research has revealed that platelets promote tumor metastasis by binding to circulating tumor cells (CTCs). However, the role of platelets in epithelial-mesenchymal transition (EMT) of cancer cells at the primary tumor site, the crucial initial step of tumor metastasis, remains to be elucidated. Here, we found that platelet releasate enhanced EMT and motility of hepatocellular carcinoma (HCC) cells via AMPK/mTOR-induced autophagy. RNA-seq indicated that platelet releasate altered TGF-ß signaling pathway of cancer cells. Inhibiting TGFBR or deleting platelet TGF-ß1 suppressed AMPK/mTOR pathway activation and autophagy induced by platelet releasate. Compared with Pf4cre-; Tgfb1fl/fl mice, HCC orthotopic models established on Pf4cre+; Tgfb1fl/fl mice showed reduced TGF-ß1 in primary tumors, which corresponded with decreased cancer cell EMT, autophagy, migration ability and tumor metastasis. Inhibition of autophagy via Atg5 knockdown in cancer cells negated EMT and metastasis induced by platelet-released TGF-ß1. Clinically, higher platelet count correlated with increased TGF-ß1, LC3 and N-cad expression in primary tumors of HCC patients, suggesting a link between platelets and HCC progression. Our study indicates that platelets promote cancer cell EMT in the primary tumor and HCC metastasis through TGF-ß1-induced HCC cell autophagy via the AMPK/mTOR pathway. These findings offer novel insights into the role of platelets in HCC metastasis and the potential therapeutic targets for HCC metastasis.

Asunto(s)

Autofagia , Plaquetas , Carcinoma Hepatocelular , Transición Epitelial-Mesenquimal , Neoplasias Hepáticas , Transducción de Señal , Factor de Crecimiento Transformador beta1 , Animales , Humanos , Masculino , Ratones , Proteínas Quinasas Activadas por AMP/metabolismo , Proteína 5 Relacionada con la Autofagia/genética , Proteína 5 Relacionada con la Autofagia/metabolismo , Plaquetas/metabolismo , Plaquetas/patología , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Línea Celular Tumoral , Movimiento Celular , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/genética , Metástasis de la Neoplasia , Células Neoplásicas Circulantes/metabolismo , Células Neoplásicas Circulantes/patología , Serina-Treonina Quinasas TOR/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Factor de Crecimiento Transformador beta1/genética

RESUMEN

Cancer metastasis and therapy resistance are intricately linked with the dynamics of Epithelial-Mesenchymal Transition (EMT) and Circulating Tumor Cells (CTCs). EMT hybrid cells, characterized by a blend of epithelial and mesenchymal traits, have emerged as pivotal in metastasis and demonstrate remarkable plasticity, enabling transitions across cellular states crucial for intravasation, survival in circulation, and extravasation at distal sites. Concurrently, CTCs, which are detached from primary tumors and travel through the bloodstream, are crucial as potential biomarkers for cancer prognosis and therapeutic response. There is a significant interplay between EMT hybrid cells and CTCs, revealing a complex, bidirectional relationship that significantly influences metastatic progression and has a critical role in cancer drug resistance. This resistance is further influenced by the tumor microenvironment, with factors such as tumor-associated macrophages, cancer-associated fibroblasts, and hypoxic conditions driving EMT and contributing to therapeutic resistance. It is important to understand the molecular mechanisms of EMT, characteristics of EMT hybrid cells and CTCs, and their roles in both metastasis and drug resistance. This comprehensive understanding sheds light on the complexities of cancer metastasis and opens avenues for novel diagnostic approaches and targeted therapies and has significant advancements in combating cancer metastasis and overcoming drug resistance.

Asunto(s)

Resistencia a Antineoplásicos , Transición Epitelial-Mesenquimal , Metástasis de la Neoplasia , Neoplasias , Células Neoplásicas Circulantes , Microambiente Tumoral , Humanos , Células Neoplásicas Circulantes/efectos de los fármacos , Células Neoplásicas Circulantes/patología , Células Neoplásicas Circulantes/metabolismo , Transición Epitelial-Mesenquimal/efectos de los fármacos , Microambiente Tumoral/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Animales , Biomarcadores de Tumor/metabolismo , Células M

RESUMEN

The combination of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) with endocrine therapy (ET) is the standard-of-care for estrogen receptor (ER)-positive, HER2-negative (ER+/HER2- advanced/metastatic breast cancer (mBC). However, the impact of CDK4/6i on circulating immune cells and circulating tumor cells (CTCs) in patients receiving CDK4/6i and ET (CDK4/6i+ET) remains poorly understood. This was a prospective cohort study including 44 patients with ER+/HER2- mBC treated with CDK4/6i+ET in either first or second line. Peripheral blood samples were collected before (baseline) and 3 months (t2) after therapy. Immune cell's subsets were quantified by flow cytometry, and microfluidic-captured CTCs were counted and classified according to the expression of cytokeratin and/or vimentin. Patients were categorized according to response as responders (progression-free survival [PFS] ≥ 6.0 months; 79.1%) and non-responders (PFS < 6.0 months; 20.9%). CDK4/6i+ET resulted in significant changes in the hematological parameters, including decreased hemoglobin levels and increased mean corpuscular volume, as well as reductions in neutrophil, eosinophil, and basophil counts. Specific immune cell subsets, such as early-stage myeloid-derived suppressor cells, central memory CD4+ T cells, and Vδ2+ T cells expressing NKG2D, decreased 3 months after CDK4/6i+ET. Additionally, correlations between the presence of CTCs and immune cell populations were observed, highlighting the interplay between immune dysfunction and tumor dissemination. This study provides insights into the immunomodulatory effects of CDK4/6i+ET, underscoring the importance of considering immune dynamics in the management of ER+/HER2- mBC.

Asunto(s)

Neoplasias de la Mama , Quinasa 4 Dependiente de la Ciclina , Quinasa 6 Dependiente de la Ciclina , Células Neoplásicas Circulantes , Inhibidores de Proteínas Quinasas , Humanos , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/sangre , Femenino , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 4 Dependiente de la Ciclina/metabolismo , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/metabolismo , Células Neoplásicas Circulantes/patología , Células Neoplásicas Circulantes/efectos de los fármacos , Células Neoplásicas Circulantes/metabolismo , Persona de Mediana Edad , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacología , Anciano , Metástasis de la Neoplasia , Adulto , Estudios Prospectivos

RESUMEN

This study aims to evaluate the prognostic utility of Activity-dependent neuroprotective protein (ADNP) expression in Circulating Tumor Cells (CTCs) inpatients with Non-muscle-invasive Bladder Cancer (NMIBC) undergoing Transurethral Resection of Bladder Tumor (TURBT). A prospective cohort of 74 bladder cancer patients and 22 non-cancer controls were enrolled. The expression of ADNP mRNA was detected by immunomagnetic beads-droplet digital PCR. The ADNP mRNA expression was evaluated in patients with high-risk NMIBC and those with indeterminate invasion depth post 2nd TURBT. Primary cultured bladder cancer cells and PBMCs from healthy donors were immunofluorescence stained. Our findings suggest that baseline ADNP mRNA level in CTCs shows potential as a prognostic marker for NMIBC with a sensitivity of 83.33% and a specificity of 73.58%. In comparison to baseline, ADNP mRNA expression increased post 2nd TURBT in 5 patients, where 2 experienced recurrence. Meanwhile, among the 12 patients with decreased levels, only one patient relapsed. A considerable limitation of this study entails the small sample size. The Immuno-magnetic beads-ddPCR technique provided a viable method for ADNP mRNA detection in CTCs from bladder cancer patients. The preoperative ADNP mRNA level in CTCs was identified as a prognostic indicator for NMIBC. Longitudinal monitoring of ADNP mRNA in CTCs of bladder cancer patients shows promise in evaluating treatment responses and predicting prognosis.

Asunto(s)

Biomarcadores de Tumor , Células Neoplásicas Circulantes , Neoplasias Vesicales sin Invasión Muscular , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/sangre , Invasividad Neoplásica , Células Neoplásicas Circulantes/metabolismo , Células Neoplásicas Circulantes/patología , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Neoplasias Vesicales sin Invasión Muscular/sangre , Neoplasias Vesicales sin Invasión Muscular/diagnóstico , Neoplasias Vesicales sin Invasión Muscular/genética , Neoplasias Vesicales sin Invasión Muscular/patología , Pronóstico , Estudios Prospectivos , ARN Mensajero/genética , ARN Mensajero/metabolismo

RESUMEN

INTRODUCTION: Small-cell lung cancer (SCLC) accounts for 15% of lung cancers and has a dismal prognosis due to early dissemination and acquired chemoresistance. The initial good response to chemotherapy is followed by refractory relapses within 1-2 years. Mechanisms leading to chemoresistance are not clear and progress is poor. AREAS COVERED: This article reviews the current evidence of the resistance of SCLCs at the cellular level including alteration of key proteins and the possible presence of cancer stem cells (CSCs). Without compelling evidence for cellular mechanisms and clinical failures of novel approaches, the study of SCLC has advanced to the role of 3D tumor cell aggregates in chemoresistance. EXPERT OPINION: The scarcity of viable tumor specimen from relapsed SCLC patients has hampered the investigations of acquired chemoresistance but a panel of nine SCLC circulating tumor cell (CTC) cell lines have revealed characteristics of SCLC in the advanced refractory states. The chemoresistance of relapsed SCLC seems to be linked to the spontaneous formation of large spheroids, termed tumorospheres, which contain resistant quiescent and hypoxic cells shielded by a physical barrier. So far, drugs to tackle large tumor spheroids are in preclinical and early clinical development.

Asunto(s)

Antineoplásicos , Resistencia a Antineoplásicos , Neoplasias Pulmonares , Células Madre Neoplásicas , Carcinoma Pulmonar de Células Pequeñas , Humanos , Carcinoma Pulmonar de Células Pequeñas/patología , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Antineoplásicos/uso terapéutico , Células Madre Neoplásicas/patología , Células Madre Neoplásicas/efectos de los fármacos , Recurrencia Local de Neoplasia , Células Neoplásicas Circulantes/patología , Esferoides Celulares , Animales , Pronóstico

RESUMEN

Activating the cGAS-STING pathway of circulating tumor cell clusters (CTC clusters) represents a promising strategy to mitigate metastases. To fully exploit the potential of cholesterol-regulating agents in activating CTCs' STING levels, we developed a nanoparticle (NP) composed of metal complex lipid (MCL). This design includes MCL-miriplatin to increase NP stiffness and loads lomitapide (lomi) modulating cholesterol levels, resulting in the creation of PLTs@Pt-lipid@lomi NPs. MCL-miriplatin not only enhances lomi's eliciting efficacy on STING pathway but also increases NPs' stiffness, thus a vital factor affecting the penetration into CTC clusters to further boost lomi's ability. Demonstrated by cy5 tracking experiments, PLTs@Pt-lipid@lomi NPs quickly attach to cancer cell via platelet membrane anchorage, penetrate deep into the spheres, and reach the subcellular endoplasmic reticulum where lomi regulates cholesterol. Additionally, these NPs have been shown to track CTCs in the bloodstream, a capability not demonstrated by the free drug. PLTs@Pt-lipid@lomi NPs more efficiently activate the STING pathway and reduce CTC stemness compared to free lomi. Ultimately, PLTs@Pt-lipid@lomi NPs reduce metastasis in a post-surgery animal model. While cholesterol-regulating agents are limited in efficacy when being repositioned as immunomodulatory agents, this MCL-composing NP strategy demonstrates the potential to effectively deliver these agents to target CTC clusters.

Asunto(s)

Lípidos , Proteínas de la Membrana , Nanopartículas , Células Neoplásicas Circulantes , Animales , Humanos , Nanopartículas/química , Ratones , Células Neoplásicas Circulantes/efectos de los fármacos , Proteínas de la Membrana/metabolismo , Lípidos/química , Línea Celular Tumoral , Femenino , Ratones Endogámicos BALB C , Evasión Inmune/efectos de los fármacos , Colesterol/química

RESUMEN

Circulating tumor cells (CTCs) enumeration and molecular profiling hold promise in revolutionizing the management of solid tumors. Their understanding has evolved significantly over the past two decades, encompassing pivotal biological discoveries and clinical studies across various malignancies. While for some tumor types, such as breast, prostate, and colorectal cancer, CTCs are ready to enter clinical practice, for others, additional research is required. CTCs serve as versatile biomarkers, offering insights into tumor biology, metastatic progression, and treatment response. This review summarizes the latest advancements in CTC research and highlights future directions of investigation. Special attention is given to concurrent evaluations of CTCs and other circulating biomarkers, particularly circulating tumor DNA. Multi-analyte assessment holds the potential to unlock the full clinical capabilities of liquid biopsy. In conclusion, CTCs represent a transformative biomarker in precision oncology, offering extraordinary opportunities to translate scientific discoveries into tangible improvements in patient care.

Asunto(s)

Biomarcadores de Tumor , Neoplasias , Células Neoplásicas Circulantes , Células Neoplásicas Circulantes/patología , Células Neoplásicas Circulantes/metabolismo , Humanos , Biomarcadores de Tumor/sangre , Neoplasias/patología , Neoplasias/diagnóstico , Neoplasias/sangre , Neoplasias/terapia , Biopsia Líquida/métodos , ADN Tumoral Circulante/sangre , ADN Tumoral Circulante/genética

RESUMEN

Hepatocellular carcinoma (HCC) is a leading contributor to cancer-related deaths worldwide and presents significant challenges in diagnosis and treatment due to its heterogeneous nature. The discovery of biomarkers has become crucial in addressing these challenges, promising early detection, precise diagnosis, and personalized treatment plans. Key biomarkers, such as alpha fetoprotein (AFP) glypican 3 (GPC3) and des gamma carboxy prothrombin (DCP) have shown potential in improving clinical results. Progress in proteomic technologies, including next-generation sequencing (NGS), mass spectrometry, and liquid biopsies detecting circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA), has deepened our understanding of HCC's molecular landscape. Immunological markers, like PD-L1 expression and tumor-infiltrating lymphocytes (TILs), also play a crucial role in guiding immunotherapy decisions. Despite these advancements, challenges remain in biomarker validation, standardization, integration into clinical practice, and cost-related barriers. Emerging technologies like single-cell sequencing and machine learning offer promising avenues for further exploration. Continued investment in research and collaboration among researchers, healthcare providers, and policymakers is vital to harness the potential of biomarkers fully, ultimately revolutionizing HCC management and improving patient outcomes through personalized treatment approaches.

Asunto(s)

Biomarcadores de Tumor , Carcinoma Hepatocelular , Neoplasias Hepáticas , Medicina de Precisión , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/terapia , Humanos , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/terapia , Medicina de Precisión/métodos , Pronóstico , Células Neoplásicas Circulantes/patología , Glipicanos , Proteómica/métodos