Metastasis initiating cells in primary prostate cancer tissues from transurethral resection of the prostate (TURP) predicts castration-resistant progression and survival of prostate cancer patients

Abstract

BACKGROUND We previouslyreported that the activation of RANK and c-Met signaling components in both experimental mouse models and human prostate cancer (PC) specimens predicts bone metastatic potential and PC patient survival. This study addresses whether a population of metastasis-initiating cells (MICs) known to express a stronger RANKL, phosphorylated c-Met (p-c-Met), and neuropilin-1 (NRP1) signaling network than bystander or dormant cells (BDCs) can be detected in PC tissues from patients subjected to transurethral resection of the prostate (TURP) for urinary obstruction prior to the diagnosis of PC with or without prior hormonal manipulation, and whether the relative abundance of MICs over BDCs could predict castration-resistant progression and PC patient survival. METHODS We employed a multiplexed quantum-dot labeling (mQDL) protocol to detect and quantify MICs and BDCs at the single cell level in TURP tissues obtained from 44 PC patients with documented overall survival and castration resistance status. RESULTS PC tissues with a higher number of MICs and an activated RANK signaling network, including increased expression of RANKL, p-c-Met, and NRP1 compared to BDCs, were found to correlate with the development of castration resistance and overall survival. CONCLUSIONS The assessment of PC cells with MIC and BDC phenotypes in primary PC tissues from hormone-naïve patients can predict the progression to castration resistance and the overall survival of PC patients.

Regulatory signaling network in the tumor microenvironment of prostate cancer bone and visceral organ metastases and the development of novel therapeutics

“…To validate the MICs phenotype in clinical PCa specimens, we developed a multiplexing quantum dot technology to stain MIC gene profiles at the single cell level. These studies identified MIC-expressing cells in PCa tissues collected from patients and also confirmed that the relative abundance of these cells in pathologic tissue specimens can predict progression to castration resistance and the overall survival of PCa patients [36] , [37] . In support of the MIC concept, we characterized two naturally occurring MICs (nMICs) derived from ex vivo culture of the ascites fluid of a bone metastatic PCa patient.…”

Keratin 13 expression reprograms bone and brain metastases of human prostate cancer cells

“…Our laboratory has established an immunohistochemical method using a quantum dot labeling (QDL) technique in which prostate cancer cell biomarker staining is more sensitive and the immunoreactivity can be quantified [ 19 , 20 ]. Employing prostate cancer cell QDL in a cohort of well-defined primary prostate cancer tissue specimens collected from 44 hormone-naïve patients [ 21 ], we demonstrated that KRT13 expression, at a single cell level, correlates with the overall survival of prostate cancer patients (Figure 2B ). Increased KRT13 expression also correlates significantly with castration resistance (Figure 2C ), bone metastasis (Figure 2D ), and Gleason grade (Figure 2E ) of prostate cancer patients.…”

Exosomes from bulk and stem cells from human prostate cancer have a differential microRNA content that contributes cooperatively over local and pre-metastatic niche

“…However, RANKL also plays a role at the primary tumor niche. RANKL is overexpressed by PCa cells increasing its level in the tissue [ 38 ], favoring progression by enhancing cancer cells migration and by modulating the immune response [ 39 , 40 ]. According to our results, expression of RANKL in fibroblasts is increased by miRNAs from PCa exosomes, augmenting local levels of RANKL and making a favorable microenvironment for tumor progression.…”