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.
Highlights
Differentiation therapy is a novel strategy for treating cancers, which is based on the concept that cancer cells arise from tissue stem cells and share the stemness and plasticity with normal stem cells.[5,6,7]
As cancer cells arise from stem cells, the degree of differentiation and malignancy of the cells mainly depend on the differentiating stage of origin stem cells at which the maturation arrest and oncogenic mutations occur
We have investigated the stemness, tumorigenicity, and plasticity for inducing differentiations of the Small cell lung cancer (SCLC) NCI-H446 cells and explored the preliminary mechanisms of inducing differentiation and death of these cancer cells, such as regulatory effects of Sirtuin1/2 on osteogenic differentiation of the cancer cells and the cross-talking between autophagy and apoptosis during the differentiation processes
Summary
Differentiation therapy is a novel strategy for treating cancers, which is based on the concept that cancer cells arise from tissue stem cells and share the stemness and plasticity with normal stem cells.[5,6,7] When the normal stem cells were arrested at an immature or less-differentiated state and suffered from oncogenic damages, they could transform into cancer cells. Differentiation therapy aims to induce the cancer cells to differentiate and maturate continuously by treatment with differentiation-inducing agents.[8,9] most differentiation agents could not destroy the cancer cells directly, they could inhibit their proliferation and induce them to terminally differentiate and undergo apoptosis.[10,11,12,13] Differentiation therapy may drive a critical clinical and biological transition from a fatal cancer into one more amenable to treatment using conventional therapeutic approaches, which will improve the prognosis of patients with less-differentiated and highly aggressive tumor.[14] Exploring the cellular origin, stemness, and plasticity of cancers in different organs will be helpful for inventing the inducing agents and methods to induce differentiation and apoptosis of the cancer cells. As cancer cells arise from stem cells, the degree of differentiation and malignancy of the cells mainly depend on the differentiating stage of origin stem cells at which the maturation arrest and oncogenic mutations occur. If maturation arrest of origin stem cells occurs early in the differentiating into multilineages, the cancer cells will be poorly differentiated and highly malignant. We have investigated the stemness, tumorigenicity, and plasticity for inducing differentiations of the SCLC NCI-H446 cells and explored the preliminary mechanisms of inducing differentiation and death of these cancer cells, such as regulatory effects of Sirtuin1/2 on osteogenic differentiation of the cancer cells and the cross-talking between autophagy and apoptosis during the differentiation processes
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