Crucial roles of circulating tumor cells in the metastatic cascade and tumor immune escape: biology and clinical translation

Abstract

Cancer-related deaths are mainly caused by metastatic spread of tumor cells from the primary lesion to distant sites via the blood circulation. Understanding the mechanisms of blood-borne tumor cell dissemination by the detection and molecular characterization of circulating tumor cells (CTCs) in the blood of patients with cancer has opened a new avenue in cancer research. Recent technical advances have enabled a comprehensive analysis of the CTCs at the genome, transcriptome and protein level as well as first functional studies using patient-derived CTC cell lines. In this review, we describe and discuss how research on CTCs has yielded important insights into the biology of cancer metastasis and the response of patients with cancer to therapies directed against metastatic cells. Future investigations will show whether CTCs leaving their primary site are more vulnerable to attacks by immune effector cells and whether cancer cell dissemination might be the ‘Achilles heel’ of metastatic progression. Here, we focus on the lessons learned from CTC research on the biology of cancer metastasis in patients with particular emphasis on the interactions of CTCs with the immune system. Moreover, we describe and discuss briefly the potential and challenges for implementing CTCs into clinical decision-making including detection of minimal residual disease, monitoring efficacies of systemic therapies and identification of therapeutic targets and resistance mechanisms.

Microfluidic-SERS Technologies for CTC: A Perspective on Clinical Translation

“…Understanding the phenotypic changes in CTCs provides insights into the mechanisms that cancer employs to evade treatment and can guide future therapeutic development. This is particularly crucial given the impracticality of obtaining biopsies from patients’ metastatic sites. , …”

“…This is particularly crucial given the impracticality of obtaining biopsies from patients' metastatic sites. 100,101 CTCs also act as independent prognostic factors, and their presence in the blood post treatment is associated with a poor prognosis in various cancer types. During disease surveillance, their increased counts are correlated to a higher likelihood of metastasis and cancer aggressiveness.…”

Immunosurveillance in clinical cancer management

“…1 In the third phase, malignant cells fully escape from immune control to a point at which they become clinically detectable and become able to infiltrate adjacent tissues and ultimately generate distant metastases. 17,18 The three Es are also reflected in the means by which we intervene against cancer. Elimination may be achieved by prophylactic immunization, 19 as exemplified by the ability of human papillomavirus vaccination to protect against cervical carcinoma.…”

“…In this setting, cancer cells that acquire the ability to avoid immune recognition or that weaken immune effectors selectively expand within the tumor 1 . In the third phase, malignant cells fully escape from immune control to a point at which they become clinically detectable and become able to infiltrate adjacent tissues and ultimately generate distant metastases 17,18 …”

Detection and Molecular Characterization of Circulating Tumour Cells: Challenges for the Clinical Setting

“…Up to now, most CTC studies were performed in patients with advanced-stage cancer, where CTC numbers are usually much higher than in early stage. The next goal for CTC analysis is the detection and characterization of minimal residual disease (MRD) [ 12 ], since a number of clinical studies have shown that CTC detection in the peripheral blood of patients who lack any clinical or radiological signs of metastasis is related to recurrence [ 13 ] ( Figure 1 ). Towards this goal, the molecular characterization of CTC provides critical information for the presence of therapeutic targets and resistance mechanisms that is paramount for the management of cancer patients [ 14 ].…”