TRAIL-coated leukocytes to kill circulating tumor cells in the flowing blood from prostate cancer patients

Nerymar Ortiz-Otero,Jean Joseph,Antonio Glenn,Deepak M Sahasrabudhe,Jocelyn R Marshall,Michael R King,Jubin Matloubieh,Edward M Messing

doi:10.1186/s12885-021-08589-8

Nerymar Ortiz-Otero, Jean Joseph + Show 6 more

Open Access

https://doi.org/10.1186/s12885-021-08589-8

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Abstract

BackgroundRadical surgery is the first line treatment for localized prostate cancer (PC), however, several studies have demonstrated that surgical procedures induce tumor cell mobilization from the primary tumor into the bloodstream.MethodsThe number and temporal fluctuations of circulating tumor cells (CTC), cancer associated fibroblasts (CAF) and CTC cluster present in each blood sample was determined.ResultsThe results show that both CTC and CTC cluster levels significantly increased immediately following primary tumor resection, but returned to baseline within 2 weeks post-surgery. In contrast, the CAF level decreased over time. In patients who experienced PC recurrence within months after resection, CTC, CAF, and cluster levels all increased over time. Based on this observation, we tested the efficacy of an experimental TNF-related apoptosis-inducing ligand (TRAIL)-based liposomal therapy ex-vivo to induce apoptosis in CTC in blood. The TRAIL-based therapy killed approximately 75% of single CTCs and CTC in cluster form.ConclusionCollectively, these data indicate that CTC cluster and CAF levels can be used as a predictive biomarker for cancer recurrence. Moreover, for the first time, we demonstrate the efficacy of our TRAIL-based liposomal therapy to target and kill prostate CTC in primary patient blood samples, suggesting a potential new adjuvant therapy to use in combination with surgery.

Highlights

Radical surgery is the first line treatment for localized prostate cancer (PC), several studies have demonstrated that surgical procedures induce tumor cell mobilization from the primary tumor into the bloodstream
circulating tumor cells (CTC) release by primary tumor surgical resection in PC patients To investigate CTC mobilization induced by surgical resection of the primary PC tumor, 7.5 mL of blood was collected from 15 patients diagnosed with prostate adenocarcinoma at four time points throughout the cancer treatment process (Additional file 1 and Table 1)
We found that PC patients exhibit mostly small CTC clusters composed of less than 15 cells per cluster at the time of diagnosis, whereas after the surgical resection of the primary tumor, PC patient blood contains an over two-fold greater number of small CTC clusters along with larger CTC clusters that included up to 40 cells per cluster

Summary

Introduction

Radical surgery is the first line treatment for localized prostate cancer (PC), several studies have demonstrated that surgical procedures induce tumor cell mobilization from the primary tumor into the bloodstream. The estimated 5-year survival rate of PC is approximately 98.9%, cancer recurrence, metastatic progression, and the inevitable emergence of resistance to hormonal therapy makes PC the second leading cause of cancer death in men in western countries and the fifth. These cancer treatments prolong patient life expectancy, ~ 50% of patients will experience cancer recurrence [5, 6]. Ortiz-Otero et al BMC Cancer (2021) 21:898 studies suggest that tumor cells may migrate from the primary tumor as CTC clusters containing up to 40 cells per cluster These CTC clusters can contain a heterogeneous group of cells including immune cells, CAF, epithelial cells, and platelets. Recent studies have found that CAF level and number of CTCCAF clusters in the circulation can predict cancer prognosis, with elevated levels correlating with worse prognoses in breast, colorectal cancer and PC [19, 20]

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