Abstract
Circulating tumor microemboli (CTM) aggregated by ≥ 2 circulating tumor cells (CTCs) are more migratory than single CTCs. Aside from the plasticity in their molecular characteristics, which have been considered tumor migration, CTM also possesses high size heterogeneity. This study, therefore, systematically investigated the heterogeneous sizes of CTM and their involvement in therapeutic resistance in 114 patients with advanced gastric cancer (GC) using a pre-established surface molecule-independent subtraction enrichment (SE)-iFISH strategy. CTM, which was pre-therapeutically detected in 33.3% of GC patients, can further form in another 34.78% of patients following chemo-/targeted therapies. The presence of CTM is relevant to liver metastasis as well as higher CTC levels (≥ 5/6 mL). Further size-based profiling of GC-CTM revealed that CTM with 2 CTCs (CTM2) was the dominant subtype, accounting for 50.0% of all detected GC-CTMs. However, CTM with 3–4 CTCs (CTM3–4) specifically associates with chemo-/targeted therapeutic resistance and inferior prognosis. Patients with ≥ 1 CTM3–4/6 mL have shorter median progression-free survival and median overall survival. Unlike CTM2 and CTM3–4, which are detectable in pre-therapy and post-therapy, larger aggregated CTM≥5 (CTM with ≥ 5 CTCs) was only intra-therapeutically detected in four HER2+ GC patients, of which three experienced liver metastases. Obtained results suggested that the cluster size of GC-CTM should be dynamically profiled beyond pre-therapeutic whole CTM enumeration in terms of chemo-/targeted resistance or metastasis monitoring. GC-CTM3–4 could be a potential indicator of therapeutic resistance, while the dynamic presence of GC-CTM≥5 implies liver metastasis in HER2+ GC patients.
Highlights
Circulating tumor microemboli (CTM) are clusters of two or more circulating tumor cells (CTCs), which always coexist with isolated CTCs in peripheral blood during tumor dissemination and metastasis [1]
The CTM positivity rate was significantly higher in patients who had liver metastasis or had higher CTC levels (≥ 5/6 mL), indicating that the formation of CTM, which positively correlates with the elevation of CTC number in CTM-negative subjects
CTM2 is the dominant subtype in gastric cancer (GC)-CTM, CTM3–4 is the specific subtype that is involved in therapeutic resistance and correlates with prognosis
Summary
Circulating tumor microemboli (CTM) are clusters of two or more circulating tumor cells (CTCs), which always coexist with isolated CTCs in peripheral blood during tumor dissemination and metastasis [1]. Different numbers of aggregated cells confer a highly heterogeneous cluster size to CTM [4, 9,10,11]. An in vitro study on the physical behaviors of breast cancer cell lines showed that cell clusters containing ≥ 20 cells could traverse capillaries by automatic dissociation into individual cells, which can be substantially reorganized to promote their resistance to fluid shear stress [15]. Observations from clinical studies suggest that CTM aggregated by 2 − 5 cells, rather than the larger ones, were dominant in breast cancer patients [10], implying much more intricate aggregate behaviors of CTM during their transportation and dissemination
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