Blood‐based biopsies—clinical utility beyond circulating tumor cells

Abstract

Circulating tumor cells (CTCs), epithelial–mesenchymal transition (EMT) cells, as well as a number of circulating cancer stromal cells (CStCs) are known to shed into the blood of cancer patients. Individually, and together, these cells provide biological and clinical information about the cancers. Filtration is a method used to isolate all of these cells, while eliminating red and white blood cells from whole peripheral blood. We have previously shown that accurate identification of these cell types is paramount to proper clinical assessment by describing the overlapping phenotypes of CTCs to one such CStC, the cancer‐associated macrophage‐like cell (CAML). We report that CAMLs possess a number of parallel applications to CTCs but have a broader range of clinical utility, including cancer screening, companion diagnostics, diagnosis, prognosis, monitoring of treatment response, and detection of recurrence. © 2018 The Authors. Cytometry Part A published by Wiley Periodicals, Inc. on behalf of ISAC.

Tumor-Cell–Macrophage Fusion Cells as Liquid Biomarkers and Tumor Enhancers in Cancer

“…Other groups refer to these likely identical cells as tumor-macrophage fusion cells (TMFs), macrophage-tumor cell fusion cells (MTFs), or cancer-associated macrophage-like (CAMLs) cells [8,[27][28][29]73]. While some investigators attributed these cells with equivalent and similar features to be cellular fusion products between tumor cells and macrophages (MTFs), other groups described these large cells in a rather broader way as CAMLs, not clearly hypothesizing on the cellular fusion events but rather describing giant macrophages that contain phagocytosed tumor debris [15,21,22,27,29,73,75,76]. Based on the multiple studies that are discussed in this review, the authors believe that these cells are all identical and are actually a product of tumor cell and macrophage fusion events.…”

“…Metastatic breast cancer patients with macrophage/tumor cell fusions in the blood have higher cancer stages and worse clinical outcomes, when measured in terms of progression-free and overall survival [79]. In a cohort of 269 patients with solid cancers of different origins (breast, prostate, pancreatic, lung, kidney, and esophagus) and clinical stages, an association with poor survival was shown if ≥6 fusion cells were present in 7.5 mL of whole blood or if fusion cells were ≥50 µm in size [76]. Importantly, in a study of the same group, a high prevalence of fusion cells in the blood of early-stage cancer patients was observed, making them a potential liquid biomarker for early cancer detection in screening settings [29,73].…”

“…These interesting findings on the negative impact of tumor cell/macrophage fusion cells on cancer patients' outcome suggest a highly-informative correlation of fusion cells with aggressive tumor biology in humans. [76] Abbreviations: IHC-immunohistochemistry; IF-immunofluorescence; PCR-polymerase chain reaction; FISH-fluorescence in situ hybridization; FC-flow cytometry.…”

Cytopathological Heterogeneity of Circulating Tumor Cells in Non-metastatic Esophageal Adenocarcinoma

“…Although the CAMLs are thought not to be cancer cells, we listed them next to the CTCs, considering that they originate from the tumor site and are believed to interact with the CTCs (17). The detection of CAMLs is of significance, since there is evidence of high prevalence in different cancer types even in early stages (20). Moreover, increased size of these cells and higher count of CAMLs have been found to be associated with worse progressionfree and overall survival in patients with breast cancer (19,20).…”

“…It is hypothesized that CAMLs originate from the local tumor-associated macrophages (TAMs) and have spread into the blood circulation (17,18). The increased CAML size and higher levels of CAML is correlated with shorter progression-free survival and worse OS in untreated breast cancer patients (19,20).…”