Non-epithelial Circulating Tumor Cells Enhance Disease Progression in High-risk Prostate Cancer through EMT and COL1A1 Expression

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Introduction: Circulating tumor cells (CTCs) are important prognostic indicators for malignancies.However, a reliable positive/negative cutoff value of non-epithelial (NE + : hybrid and mesenchymal) CTCs phenotype in prostate cancer (PCa) patients has not been established.Here, we aimed to determine the cutoff value and the prognostic value of NE + CTCs in high-risk prostate cancer (HRPC) patients after radical prostatectomy (RP).Methods: The cutoff value of NE + CTCs was established in spiking experiments, and CTCs were detected in 208 HRPC patients using the CanPatrol TM platform.The expression and function of COL1A1 in PCa were examined via qRT-PCR, Western blot, wound healing assay, Transwell assay, and immunohistochemistry (IHC).Results: The cutoff value of NE + CTCs was determined to be 45% by spiking experiments.In 208 HRPC patients, the NE + CTCs positive group had higher prostate-specific antigen (PSA) levels, more advanced pathological tumor stage, and lymph node stage (P < 0.001, P = 0.002 and 0.002, respectively).Besides, patients with NE + CTCs ≥ 45% had a shorter median progression-free survival (PFS) than those with NE + CTCs < 45% (44.5 vs. 51.0months, hazard ratio = 3.31, P < 0.05).Moreover, we identified that COL1A1 was associated with a high proportion of NE + CTCs in HRPC patients via an EMT mechanism.Conclusion: Our findings suggest that NE + CTCs represent a reliable prognostic indicator for HRPC patients and that targeting COL1A1 may prevent the formation of NE + CTCs.

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