Abstract
Cancer stem cells represent the putative tumor-driving subpopulation thought to account for drug resistance, relapse, and metastatic spread of epithelial and other cancer types. Accordingly, cell surface markers for therapeutic delivery to cancer stem cells are subject of intense research. Somatostatin receptor 2 and nucleolin are known to be overexpressed by various cancer types, which have elicited comprehensive efforts to explore their therapeutic utilization. Here, we evaluated somatostatin receptor 2 targeting and nucleolin targeting for therapeutic delivery to cancer stem cells from lung cancer. Nucleolin is expressed highly but not selectively, while somatostatin receptor 2 is expressed selectively but not highly by cancer cells. The non-small cell lung cancer cell lines A549 and H1299, displayed average levels of both surface molecules as judged based on analysis of a larger cell line panel. H1299 compared to A549 cells showed significantly elevated sphere-forming capacity, indicating higher cancer stem cell content, thus qualifying as suitable test system. Nucleolin-targeting 57Co-DOTA-AS1411 aptamer showed efficient internalization by cancer cells and, remarkably, at even higher efficiency by cancer stem cells. In contrast, somatostatin receptor 2 expression levels were not sufficiently high in H1299 cells to confer efficient uptake by either non-cancer stem cells or cancer stem cells. The data provides indication that the nucleolin-targeting AS1411 aptamer might be used for therapeutic delivery to non-small cell lung cancer stem cells.
Highlights
Lung cancer is the most common cause of cancer death in industrialized countries, with nonsmall cell lung cancer (NSCLC) as the most common form accounting for about 80% of the cases [1, 2]
In order to evaluate if Somatostatin receptor 2 (SSTR2) and NCL can potentially be used for therapeutic delivery in NSCLC cells, we initially determined the relative mRNA expression levels by real-time PCR in the two NSCLC cell lines A549 and H1299 and in a panel of other cancer cell lines (Fig 1)
Four cancer cell lines had elevated mRNA levels compared to normal epithelial cells, including the breast cancer cell line HCC1500 and the NSCLC cell line H1299 with about 2- to 3-fold increase
Summary
Lung cancer is the most common cause of cancer death in industrialized countries, with nonsmall cell lung cancer (NSCLC) as the most common form accounting for about 80% of the cases [1, 2]. Cancer stem cells (CSCs) represent a small subpopulation of the cancer cells with stemlike properties such as ability for self-renewal and asymmetric division, that enables them to restore heterogeneous tumors [3,4,5] After their initial discovery in breast cancer, CSCs were subsequently found in various other solid cancer types, including NSCLC [4,5,6,7]. A common property across cancer types is the ability to form tumor spheres under non-adherent culture conditions, in the presence of defined growth factors This has advanced to a standard assay for determining the CSC numbers [5,6,7]
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