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Molecular Biology of Liquid Biopsy in Cancer

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (10 September 2024) | Viewed by 6713

Special Issue Editor


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Guest Editor
Department of Radiological, Oncological and Pathological Sciences, Sapienza-University of Rome, 00161 Rome, Italy
Interests: precision medicine; liquid biopsy; CTC; ctDNA; breast cancer; personalized treatment
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Special Issue Information

Dear Colleagues,

Liquid biopsy has evolved into a comprehensive tool, moving beyond the mere enumeration of circulating tumor cells (CTCs) to delving into their phenotypic intricacies.  This shift has given rise to novel biomarker strategies, spotlighting the prognostic significance of diverse CTC phenotypes.  Classification based on traits like nuclear size, content, and cytokeratin intensities has become a pivotal focus.  Beyond traditional CTCs, EpCAM+/CK+ objects and fusion hybrids of neoplastic cells with leukocytes offer added prognostic insights.  The enumeration and characterization of micro-sized tumor fragments and tumor-derived extracellular vesicles (tdEVs) serve as prognostic indicators in metastatic cancers.  Exploring CTCs with attenuated CK expression and clusters reveals clinical relevance, associated with shorter progression-free survival (PFS) and worse OS.  The observed CK expression variability underscores the importance of investigating the role of epithelial–mesenchymal transition in therapy resistance and metastasis.  Moving forward, crucial attention is needed to characterize phenotypic heterogeneity at the single CTC level, providing insights into malignant progression and resistance biomarker identification.

Moreover, liquid biopsy emerges as a promising, non-invasive alternative for real-time tumor evolution assessment.  Overcoming the limitations of spatial heterogeneity, clonal dynamics, and therapeutic pressure on biomarker analysis, liquid biopsy offers timely and repeatable tumor information.  Various compounds, including nucleic acids, CTCs, extracellular vesicles, soluble factors, and tumor-educated platelets, present clinical utility in early diagnosis, minimal residual disease detection, prognosis, and treatment response.  Extracellular vesicles play roles in angiogenesis, immune suppression, tumor microenvironment modulation, metastasis, and treatment resistance.  Innovations in avoiding extracellular vesicle effects hold potential for advancing cancer treatments.

We welcome submissions to this Special Issue that explore a wide range of topics related to molecular research into liquid biopsy in cancer, including, but not limited to, the following:

  • Identification of molecular biomarkers for early diagnosis, risk classification, and prognosis;
  • Utility of liquid biopsy in detecting minimal residual disease and predicting treatment response;
  • Elucidation of molecular mechanisms influenced by extracellular vesicles and the development of targeted therapeutic strategies;
  • Investigation of tumor-related circulating cells and their implications in cancer progression;
  • Application of artificial intelligence for the analysis of liquid biopsy data;
  • Exploration of clonal hematopoiesis and its impact on liquid biopsy results;
  • Standardization of methodologies associated with liquid biopsy procedures;
  • Development of innovative techniques for analyzing tumor components in liquid biopsy samples.

Dr. Valentina Magri
Guest Editor

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Keywords

  • liquid biopsy
  • Exosomes
  • Non-coding RNA
  • cancer
  • molecular biology
  • early diagnosis
  • minimal residual disease
  • treatment response prediction
  • extracellular vesicles
  • targeted therapeutic strategies
  • circulating tumor cells
  • clonal hematopoiesis

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Published Papers (3 papers)

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Research

21 pages, 4544 KiB  
Article
miRNAs-Set of Plasmatic Extracellular Vesicles as Novel Biomarkers for Hepatocellular Carcinoma Diagnosis Across Tumor Stage and Etiologies
by Francisco A. Molina-Pelayo, David Zarate-Lopez, Rosendo García-Carrillo, César Rodríguez-Beas, Ramón Íñiguez-Palomares, José L. Rodríguez-Mejía, Adriana Soto-Guzmán, Gabriela Velasco-Loyden, Mónica Sierra-Martínez, Adolfo Virgen-Ortiz, Enrique Sánchez-Pastor, Nancy E. Magaña-Vergara, Rafael Baltiérrez-Hoyos, Javier Alamilla, Victoria Chagoya de Sánchez, Adán Dagnino-Acosta, Enrique Chávez and Luis Castro-Sánchez
Int. J. Mol. Sci. 2025, 26(6), 2563; https://doi.org/10.3390/ijms26062563 - 12 Mar 2025
Cited by 1 | Viewed by 2531
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver cancer, often diagnosed at advanced stages due to insufficient early screening and monitoring. MicroRNAs (miRNAs) are key regulators of gene expression and potential biomarkers for cancer diagnosis. This study investigated the diagnostic potential of [...] Read more.
Hepatocellular carcinoma (HCC) is the most common primary liver cancer, often diagnosed at advanced stages due to insufficient early screening and monitoring. MicroRNAs (miRNAs) are key regulators of gene expression and potential biomarkers for cancer diagnosis. This study investigated the diagnostic potential of miRNAs in Extracellular Vesicles (EVs) from HCC. miRNA expression in EVs was analyzed using HCC cell lines, circulating EVs from a Diethylnitrosamine (DEN)-induced liver tumor rat model, and plasma samples from HCC patients. Receiver Operating Characteristics (ROCs) were applied to evaluate the diagnostic accuracy of circulating EV miRNAs in patients. Five miRNAs (miR-183-5p, miR-19a-3p, miR-148b-3p, miR-34a-5p, and miR-215-5p) were consistently up-regulated in EVs across in vitro and in vivo HCC models. These miRNAs showed statistically significant differences in HCC patients stratified by TNM staging and Edmondson–Steiner grading compared to healthy controls. They also differentiated HCC patients with various etiologies from the control group and distinguished HCC patients, with or without liver cirrhosis, from cirrhotic and healthy individuals. Individually and as a panel, they demonstrated high sensitivity, specificity, and accuracy in identifying HCC patients. Their consistent upregulation across models and clinical samples highlights their robustness as biomarkers for HCC diagnosis, offering the potential for early disease management and prognosis. Full article
(This article belongs to the Special Issue Molecular Biology of Liquid Biopsy in Cancer)
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14 pages, 4215 KiB  
Article
Exploratory Analyses of Circulating Neoplastic-Immune Hybrid Cells as Prognostic Biomarkers in Advanced Intrahepatic Cholangiocarcinoma
by Ranish K. Patel, Michael S. Parappilly, Brett S. Walker, Robert T. Heussner, Alice Fung, Young Hwan Chang, Adel Kardosh, Charles D. Lopez, Skye C. Mayo and Melissa H. Wong
Int. J. Mol. Sci. 2024, 25(17), 9198; https://doi.org/10.3390/ijms25179198 - 24 Aug 2024
Cited by 2 | Viewed by 1709
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Molecular Biology of Liquid Biopsy in Cancer)
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10 pages, 1297 KiB  
Article
Circulating Cancer-Associated Macrophage-like Cells as a Blood-Based Biomarker of Response to Immune Checkpoint Inhibitors
by Valentina Magri, Gianluigi De Renzi, Luca Marino, Michela De Meo, Marco Siringo, Alain Gelibter, Roberta Gareri, Chiara Cataldi, Giuseppe Giannini, Daniele Santini, Chiara Nicolazzo and Paola Gazzaniga
Int. J. Mol. Sci. 2024, 25(7), 3752; https://doi.org/10.3390/ijms25073752 - 28 Mar 2024
Cited by 1 | Viewed by 1928
Abstract
Evidence has been provided that circulating cancer-associated macrophage-like cell (CAM-L) numbers increase in response to chemotherapy, with an inverse trend compared to circulating tumor cells (CTCs). In the era of evolving cancer immunotherapy, whether CAM-Ls might have a potential role as predictive biomarkers [...] Read more.
Evidence has been provided that circulating cancer-associated macrophage-like cell (CAM-L) numbers increase in response to chemotherapy, with an inverse trend compared to circulating tumor cells (CTCs). In the era of evolving cancer immunotherapy, whether CAM-Ls might have a potential role as predictive biomarkers of response has been unexplored. We evaluated whether a serial blood evaluation of CTC to CAM-L ratio might predict response to immune checkpoint inhibitors in a cohort of non-small-cell lung cancer patients. At baseline, CTCs, CAM-Ls, and the CTC/CAM-L ratio significantly correlate with both progression-free survival (PFS) and overall survival (OS). The baseline CTC/CAM-L ratio was significantly different in early progressors (4.28 ± 3.21) compared to long responders (0.42 ± 0.47) (p = 0.001). In patients treated with immune checkpoint inhibitors, a CTC/CAM-L ratio ≤ 0.25 at baseline is associated with better PFS and OS. A baseline CTC/CAM-L ratio ≤ 0.25 is statistically significant to discriminate early progressions from durable response. The results of the present pilot study suggest that CAM-Ls together with CTCs could play an important role in evaluating patients treated with cancer immunotherapy. Full article
(This article belongs to the Special Issue Molecular Biology of Liquid Biopsy in Cancer)
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