Dynamics of CXCR4 positive circulating tumor cells in prostate cancer patients during radiotherapy

Abstract

Ablative radiotherapy is a highly efficient treatment modality for patients with metastatic prostate cancer (PCa). However, a subset of patients does not respond. Currently, this subgroup with bad prognosis cannot be identified before disease progression. We hypothesize that markers indicative of radioresistance, stemness and/or bone tropism may have a prognostic potential to identify patients profiting from metastases‐directed radiotherapy. Therefore, circulating tumor cells (CTCs) were analyzed in patients with metastatic PCa (n = 24) during radiotherapy with CellSearch, multicolor flow cytometry and imaging cytometry. Analysis of copy‐number alteration indicates a polyclonal CTC population that changes after radiotherapy. CTCs were found in 8 out of 24 patients (33.3%) and were associated with a shorter time to biochemical progression after radiotherapy. Whereas the total CTC count dropped after radiotherapy, a chemokine receptor CXCR4‐expressing subpopulation representing 28.6% of the total CTC population remained stable up to 3 months. At once, we observed higher chemokine CCL2 plasma concentrations and proinflammatory monocytes. Additional functional analyses demonstrated key roles of CXCR4 and CCL2 for cellular radiosensitivity, tumorigenicity and stem‐like potential in vitro and in vivo. Moreover, a high CXCR4 and CCL2 expression was found in bone metastasis biopsies of PCa patients. In summary, panCK+CXCR4+ CTCs may have a prognostic potential in patients with metastatic PCa treated with metastasis‐directed radiotherapy.

ALDH1A1 drives prostate cancer metastases and radioresistance by interplay with AR- and RAR-dependent transcription

“…To further investigate the role of ALDH genes in metastasis, we measured the expression of ALDH1A1 and ALDH1A3 genes in the PC3-derived cell lines originating from different metastatic sites 45 . For this analysis, PC3 cells were first subcutaneously injected into immunodeficient NSG mice, and small pieces of surgically excised xenograft primary tumors (PT), as well as spontaneous lung (L) and bone marrow (BM) metastases were used for in vitro propagation of sublines PC3-PT, PC3-L, and PC-BM, respectively (Figure 4 J) 9 , 45 , 46 . These sublines were then re-injected subcutaneously into the secondary recipient NSD mice, and the entire procedure was repeated four times.…”

Comprehensive Analysis of CXCR4, JUNB, and PD-L1 Expression in Circulating Tumor Cells (CTCs) from Prostate Cancer Patients

“…CXCR4 is normally involved in homeostatic processes in the bloodstream, such as leukocyte transport and hematopoiesis [22]. On the other hand, it may also be involved in carcinogenesis and metastasis in various cancers, including prostate cancer [22][23][24]. This is confirmed by a meta-analysis showing that increased CXCR4 expression in prostate cancer samples correlates to metastases [25].…”

Combined use of NK cells and radiotherapy in the treatment of solid tumors

“…Importantly, with no pharmaceutical strategies clinically available, radiotherapy seems to be the most cost-effective strategy to drive the expression of these chemokine receptors or their ligands. Specifically, expression of CXCR4 and its ligand CXCL12 were found to be increased after radiotherapy in patients with metastatic prostate cancer ( 75 ), rectal cancer ( 76 ), or nasopharyngeal carcinoma ( 77 ). When exploring tumor-infiltrating lymphocytes (TILs) after radiotherapy in patients with prostate cancer, researchers observed a higher number of CCR7 + TILs in tumor biopsies post-radiotherapy ( 78 ).…”