Lymph Liquid Biopsy for Detection of Cancer Stem Cells

Abstract

Collection of a blood sample defined by the term “blood liquid biopsy” is commonly used to detect diagnostic, prognostic, and therapeutic decision‐making markers of metastatic tumors including circulating tumor cells (CTCs). Many tumors also release CTCs and other markers into lymph fluid, but the utility of lymphatic markers largely remains unexplored. Here, we introduce lymph liquid biopsy through collection of peripheral (afferent) and central (thoracic duct [TD]) lymph samples and demonstrates its feasibility for detection of stem‐like CTCs potentially responsible for metastasis development and tumor relapse. Stemness of lymphatic CTCs (L‐CTCs) was determined by spheroid‐forming assay in vitro. Simultaneously, we tested blood CTCs by conventional blood liquid biopsy, and monitored the primary tumor size, early metastasis in a sentinel lymph node (SLN) and distant metastasis in lungs. Using a mouse model at early melanoma stage with no distant metastasis, we identified stem‐like L‐CTCs in lymph samples from afferent lymphatic vessels. Since these vessels transport cells from the primary tumor to SLN, our finding emphasizes the significance of the lymphatic pathway in development of SLN metastasis. Surprisingly, in pre‐metastatic disease, stem‐like L‐CTCs were detected in lymph samples from the TD, which directly empties lymph into blood circulation. This suggests a new contribution of the lymphatic system to initiation of distant metastasis. Integration of lymph and blood liquid biopsies demonstrated that all mice with early melanoma had stem‐like CTCs in at least one of three samples (afferent lymph, TD lymph, and blood). At the stage of distant metastasis, spheroid‐forming L‐CTCs were detected in TD lymph, but not in afferent lymph. Altogether, our results demonstrated that lymph liquid biopsy and testing L‐CTCs holds promise for diagnosis and prognosis of early metastasis. © 2020 International Society for Advancement of Cytometry

Nomogram for Predicting Distant Metastasis of Pancreatic Ductal Adenocarcinoma: A SEER-Based Population Study

“…Some tumor cells infiltrate into the lymphatic vessels and then colonize distant organs or tissues through the lymphatic circulation and continue to grow into metastases [ 32 ]. Han et al [ 33 ] detected stem-like lymphatic circulating tumor cells from the thoracic duct that empties lymph directly into the circulation, suggesting a key role for the lymphatic system in mediating distant metastasis of cancer. The relationship between lymph node and distant metastasis has also been demonstrated in mouse cancer models by injecting tumor cells directly into lymphatic vessels and using photoswitchable tumor cell models [ 34 , 35 ].…”

Endogenous Mobilization of Mesenchymal Stromal Cells: A Pathway for Interorgan Communication?

“…Other studies indicate that systemically infused MSCs can be found in secondary lymphoid organs [e.g., mesenteric lymph nodes after intracardiac infusion (Li et al, 2012), lymph nodes, Peyer patches, spleen (Schwarz et al, 2014)]. Interestingly, Han et al (2020) very recently reported the presence of lots of circulating cells able to form spheroids in the thoracic duct of a mouse model of melanoma, though distant metastases were not developed. Altogether, those data suggest that as cancer cells do, MSCs may exploit several bodily fluid systems as natural transportation routes (Follain et al, 2020; Figure 1).…”

Rationale for Early Detection of EWSR1 Translocation-Associated Sarcoma Biomarkers in Liquid Biopsy

“…While tissue biopsies remain the gold standard for the diagnosis of tumours, liquid biopsy offers the advantages of a non-invasive procedure that can be performed repeatedly during and after the course of treatment [1,2]. The most common source of liquid biopsy is the blood, which need only be collected in small volumes (~10mL), but the downstream analyses are usually compatible with fluid or cells collected from the more invasive bone marrow aspirates [3], fluid collected from ascites [4] or lymphatic vessels [5], urine [6], lavages [7], or cerebrospinal fluid [8], if necessary.…”