Microenvironment-Modulated Metastatic CD133+/CXCR4+/EpCAM− Lung Cancer–Initiating Cells Sustain Tumor Dissemination and Correlate with Poor Prognosis

Abstract

Metastasis is the main reason for lung cancer-related mortality, but little is known about specific determinants of successful dissemination from primary tumors and metastasis initiation. Here, we show that CD133þ cancer-initiating cells (CIC) directly isolated from patient-derived xenografts (PDX) of non-small cell lung cancer are endowed with superior ability to seed and initiate metastasis at distant organs. We additionally report that CXCR4 inhibition successfully prevents the increase of cisplatin-resistant CD133 ), which also shows the greatest in vitro invasive potential. We next prove that recovered disseminated cells from lungs of PDX-bearing miceþ /EpCAM À CICs are highly tumorigenic and metastatic. Importantly, microenvironment stimuli eliciting epithelial-to-mesenchymal transition, including signals from cancer-associated fibroblasts, are able to increase the dissemination potential of lung cancer cells through the generation of the CD133set. These findings also have correlates in patient samples where disseminating CICs are enriched in metastatic lymph nodes (20-fold, P ¼ 0.006) and their detection in primary tumors is correlated with poor clinical outcome (diseasefree survival: P ¼ 0.03; overall survival: P ¼ 0.05). Overall, these results highlight the importance of specific cellular subsets in the metastatic process, the need for in-depth characterization of disseminating tumor cells, and the potential of therapeutic strategies targeting both primary tumor and tumor-microenvironment interactions.

Altered CXCL12 expression reveals a dual role of CXCR4 in osteosarcoma primary tumor growth and metastasis

“…These findings are in line with the results obtained from analyses of human OS primary tumor tissue and lung metastases that also showed higher expression of CXCR4 in lung metastases than in primary tumors (Oda et al 2006;Namlos et al 2012). These observations suggest that the expression of CXCR4 in OS cells settling in the lung is likely induced by regulatory molecules released from the lung microenvironment as recently proposed in studies of colon (Zeelenberg et al 2003) and lung cancers (Bertolini et al 2015).…”

Metabolic Evaluation of Non–Small Cell Lung Cancer Patient–Derived Xenograft Models Using 18F-FDG PET: A Potential Tool for Early Therapy Response

“…In fact, in that study CD1331 cells could be imaged only by using a specific 64 Cu-conjugated antibody-based tracer. However, we observed a tendency for tumors with a higher SUV max to have a greater relative disseminating-CSC content (CD133/CXCR4/ EpCAM2), which we recently identified as being modulated by microenvironmental cues and related to a bad clinical outcome in NSCLC patients (12). This could indicate a propensity for tumors with high glycolytic activity to induce selective enrichment of CSCs with disseminating ability, possibly providing a link between high SUV max and worst prognosis.…”

“…Measurement of CD1331 and CD1331/CXCR41/EpCAM− Cells on PDXs CD1331 CSCs and the disseminating CD1331/CXCR41/EpCAM2 subset were detected using previously described procedures (10,12).…”

“…Development of agents targeting critical steps in CSCderegulated pathways (i.e., Wnt, Notch, and Hedgehog) holds promise as an innovative therapeutic approach (11). In this context, we have previously shown that in lung cancer, CD1331 cells endowed with stemlike properties are resistant to cisplatin treatment (10), and we recently identified CD1331/CXCR41/EpCAM2 cells as metastasis-initiating (12).…”

The Clinical Significance of Cancer Stem Cell Markers ALDH1A1 and CD133 in Lung Adenocarcinoma

“…CD133 is involved in diverse cellular processes, including the uptake of glucose and transferrin, autophagy, membrane-membrane interaction, and matrix metalloproteinase functions (21). The expression of CD133 on the cell surface was shown to be a specific marker for CSCs in a number of malignancies, including lung cancer (6,22). Although several landmark studies have revealed that isolated CD133-positive lung cancer cells exhibited in vitro CSC-like features and in vivo tumorigenicity, subsequent studies showed similar tumorigenic potential of both CD133-positive and CD133-negative lung cancer cells both in vitro and in vivo (6,23).…”