Early Dissemination of Circulating Tumor Cells: Biological and Clinical Insights

Abstract

Circulating tumor cells (CTCs) play a causal role in the development of metastasis, the major cause of cancer-associated mortality worldwide. In the past decade, the development of powerful cellular and molecular technologies has led to a better understanding of the molecular characteristics and timing of dissemination of CTCs during cancer progression. For instance, genotypic and phenotypic characterization of CTCs, at the single cell level, has shown that CTCs are heterogenous, disseminate early and could represent only a minor subpopulation of the primary tumor responsible for disease relapse. While the impact of molecular profiling of CTCs has not yet been translated to the clinic, CTC enumeration has been widely used as a prognostic biomarker to monitor treatment response and to predict disease relapse. However, previous studies have revealed a major challenge: the low abundance of CTCs in the bloodstream of patients with cancer, especially in early stage disease where the identification and characterization of subsequently “lethal” cells has potentially the greatest clinical relevance. The CTC field is rapidly evolving with development of new technologies to improve the sensitivity of CTC detection, enumeration, isolation, and molecular profiling. Here we examine the technical and analytical validity of CTC technologies, we summarize current data on the biology of CTCs that disseminate early and review CTC-based clinical applications.

Microfluidic-Based Technologies for CTC Isolation: A Review of 10 Years of Intense Efforts towards Liquid Biopsy

“…The study of CTCs may overcome these limitations and become complementary to tissue biopsies. CTCs are released into the bloodstream from primary and metastatic tumors; in addition, besides playing an important role in cancer metastasis [4], they offer a promising clinical potential for cancer diagnosis and prognosis. The isolation of CTCs directly from a blood test, referred to as "liquid biopsy", has therefore raised strong interest in recent years.…”

Therapeutic Targeting of Minimal Residual Disease to Prevent Late Recurrence in Hormone-Receptor Positive Breast Cancer: Challenges and New Approaches

“…In either case, dissemination of microscopic disease that is not removed by locoregional treatment (surgery and radiation) is a necessary prerequisite. Circulating tumor cells (CTCs) in the blood are implicated in early dissemination ( 10 ). The existence of, and ability to detect disseminated tumor cells (DTCs) in the bone marrow of patients diagnosed with breast cancer has been well-recognized and studied for several decades.…”

“…The technologies underlying each of these approaches (recently reviewed elsewhere ( 14 , 15 )) depend on the identification of tumor specific features not normally present in blood samples. For CTCs, this includes immunophenotypic characteristics of circulating cells such as EpCAM (Epithelial Cell Adhesion Molecule) and cytokeratin (together with absence of leukocyte markers) that mark their tumor origin ( 10 ), whereas for ctDNA, the presence of somatic alterations (point mutations, copy number alterations) or methylation patterns can distinguish ctDNA from other cell free DNA (cfDNA) released by normal cells.…”

Therapeutische Behandlung der minimalen Resterkrankung zur Verhinderung von Spätrezidiven bei Hormonrezeptor-positivem Brustkrebs: Herausforderungen und neue Ansätze

“…In beiden Fällen ist die Verbreitung mikroskopischer Erkrankungen, die nicht durch eine lokoregionale Behandlung (Operation und Bestrahlung) entfernt werden, eine notwendige Voraussetzung. Im Blut zirkulierende Tumorzellen (CTCs) sind an der frühen Verbreitung beteiligt [10]. Das Vorhandensein und die Fähigkeit, verbreitete Tumorzellen (DTCs) im Knochenmark von Patientinnen mit diagnostiziertem Brustkrebs nachzuweisen, ist seit mehreren Jahrzehnten bekannt und wurde bereits ebenso lange untersucht.…”