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

Abstract

Background Radical 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. Methods The number and temporal fluctuations of circulating tumor cells (CTC), cancer associated fibroblasts (CAF) and CTC cluster present in each blood sample was determined. Results The 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. Conclusion Collectively, 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.

Circulating tumor cell-blood cell crosstalk: Biology and clinical relevance

“…However, to our knowledge, the largest prospective-retrospective study on 594 metastatic breast cancer patients indicated that it is the number of CTCs, regardless of ''cluster status,'' that causes the dismal prognosis (Paoletti et al, 2019). Furthermore, certain treatment regimens can cause a release of CTC clusters without causing an increase in metastases formation (Mohme et al, 2017;Ortiz-Otero et al, 2021). Nevertheless, CTC clusters may additionally have other negative consequences for patient outcome by causing cerebral infarctions and lung emboli (Feinauer et al, 2021;Hong et al, 2016).…”

A narrative review of circulating tumor cells clusters: A key morphology of cancer cells in circulation promote hematogenous metastasis

“…In a word, CAFs can protect CTC clusters through various mechanisms ( 121 ). More importantly, studies have shown that the level of CTC clusters and CAFs can be used as bio–markers to predict cancer recurrence ( 122 ). This shows that targeting CAF–CTC clusters has certain clinical significance.…”

Insights into Circulating Tumor Cell Clusters: A Barometer for Treatment Effects and Prognosis for Prostate Cancer Patients

“…They observed that 2/15 patients experienced cancer recurrence within 2 months after primary tumor resection, and levels of individual CTCs and CTC clusters were increased in these patients at the time of surgery or after surgery. Moreover, the levels did not normalize after 2 weeks, suggesting levels of individual CTCs and CTC clusters vary considerably in PCa progression [ 22 ]. Additionally, combining CTC clusters with routine single CTC detection exhibited independent predictive value in improving prognostic stratification in mCRPC patients [ 127 ].…”

“…CTCs are generally referred to as either single CTCs or CTC clusters, with the latter considered to have a 23- to 50-fold greater metastatic potential [ 12 , 19 ]. Studies suggest that a CTC cluster contains at least 2 tumor cells (and up to 100) and several non-malignant cells including but not limited to a heterogeneous group of cells, for example, tumor-associated macrophages (TAMs), cancer-associated fibroblasts (CAFs), white blood cells, epithelial cells and platelets [ 20 , 21 , 22 , 23 , 24 , 25 ]. In contrast to single CTCs, CTC clusters show distinctive phenotypes, gene expression, and metastasis patterns, indicating unique biological properties in neoplasm metastasis.…”

“…In contrast to single CTCs, CTC clusters show distinctive phenotypes, gene expression, and metastasis patterns, indicating unique biological properties in neoplasm metastasis. CTC clusters can be detected in men with either localized PCa or metastatic PCa, and there is a larger enumeration of CTC clusters in men with advanced PCa during multiple stages of cancer recurrence and metastasis [ 22 , 26 , 27 , 28 , 29 ]. Moreover, CTC clusters have also been detected in prostate cancer patient-derived xenograft (PDX) models.…”