Stemness and inducing differentiation of small cell lung cancer NCI-H446 cells

Abstract

Small cell lung cancer (SCLC) accounts for nearly 15% of human lung cancers and is one of the most aggressive solid tumors. The SCLC cells are thought to derive from self-renewing pulmonary neuroendocrine cells by oncogenic transformation. However, whether the SCLC cells possess stemness and plasticity for differentiation as normal stem cells has not been well understood thus far. In this study, we investigated the expressions of multilineage stem cell markers in the cancer cells of SCLC cell line (NCI-H446) and analyzed their clonogenicity, tumorigenicity, and plasticity for inducing differentiation. It has been found that most cancer cells of the cell line expressed multilineage stem cell markers under the routine culture conditions and generated single-cell clones in anchorage-dependent or -independent conditions. These cancer cells could form subcutaneous xenograft tumors and orthotopic lung xenograft tumors in BALB/C-nude mice. Most cells in xenograft tumors expressed stem cell markers and proliferation cell nuclear antigen Ki67, suggesting that these cancer cells remained stemness and highly proliferative ability in vivo. Intriguingly, the cancer cells could be induced to differentiate into neurons, adipocytes, and osteocytes, respectively, in vitro. During the processes of cellular phenotype-conversions, autophagy and apoptosis were two main metabolic events. There is cross-talking between autophagy and apoptosis in the differentiated cancer cells. In addition, the effects of the inhibitor and agonist for Sirtuin1/2 on the inducing osteogenic differentiation indicated that Sirtuin1/2 had an important role in this process. Taken together, these results indicate that most cancer cells of NCI-H446 cell line possess stemness and plasticity for multilineage differentiation. These findings have potentially some translational applications in treatments of SCLC with inducing differentiation therapy.

A DNA Hypomethylation Signature Predicts Antitumor Activity of LSD1 Inhibitors in SCLC

“…SCLC is neuroendocrine in origin, expresses molecular features associated with neuroendocrine cells (Park et al, 2011), has been characterized as a tumor type that is poorly differentiated, and retains stem cell markers such as CD133, Oct4, and Sal4 (Zhang et al, 2013;Sarvi et al, 2014). LSD1 is implicated in differentiation in both normal hematopoiesis and in AML, raising the possibility that efficacy in SCLC is also the result of inducing differentiation.…”

Phase I, Open-Label, Dose-Escalation Study of the Safety, Pharmacokinetics, Pharmacodynamics, and Efficacy of GSK2879552 in Relapsed/Refractory SCLC

“…16,17 Furthermore, inhibition of KDM1A provided an antileukemic effect in secondary engraftment models, indicating an effect on the leukemiainitiating cell population and further suggesting a role for KDM1A in the self-renewal of cancer stem cells. 18 Both SCLC and AML are poorly differentiated tumors 19,20 ; thus, inhibition of KDM1A may invoke a similar differentiation mechanism in SCLC.…”

Stem cell-like ALDHbrightcellular states in EGFR-mutant non-small cell lung cancer: A novel mechanism of acquired resistance to erlotinib targetable with the natural polyphenol silibinin

“…[18][19][20][21][22][23][24][25][26][27][28][29] The generation of CSC-like features through aberrant activation of the EMT genetic program [30][31][32][33][34][35][36][37][38][39][40] and increases in the CSC-like cell population are well known to be potential causes of the highly malignant activity and drug-refractoriness of SCLC in comparison with NSCLC. [41][42][43][44][45] However, studies addressing the possibility that subpopulations of NSCLC cells enriched with tumorigenic capacity and characterized by a specific stem cell-associated gene expression signature could explain the mechanism by which EGFR-mutant NSCLCs eventually stop responding to erlotinib have not yet been reported. In this scenario, we envision that: (1) the enrichment of CSC-like cellular states might play a causative role in the generalized progression of EGFR-mutant NSCLC after an initial response to erlotinib; and (2) novel treatments could be designed to eliminate erlotinib-refractory CSCs by inhibiting the maintenance of the stem-cell state.…”