The Cancer Stem-Cell Hypothesis: Its Emerging Role in Lung Cancer Biology and Its Relevance for Future Therapy

Abstract

The cancer stem-cell (CSC) hypothesis suggests that there is a small subset of cancer cells that are responsible for tumor initiation and growth, possessing properties such as indefinite self-renewal, slow replication, intrinsic resistance to chemotherapy and radiotherapy, and an ability to give rise to differentiated progeny. Through the use of xenotransplantation assays, putative CSCs have been identified in many cancers, often identified by markers usually expressed in normal stem cells. This is also the case in lung cancer, and the accumulated data on side population cells, CD133, CD166, CD44 and ALDH1 are beginning to clarify the true phenotype of the lung cancer stem cell. Furthermore, it is now clear that many of the pathways of normal stem cells, which guide cellular proliferation, differentiation, and apoptosis are also prominent in CSCs; the Hedgehog (Hh), Notch, and Wnt signaling pathways being notable examples. The CSC hypothesis suggests that there is a small reservoir of cells within the tumor, which are resistant to many standard therapies, and can give rise to new tumors in the form of metastases or relapses after apparent tumor regression. Therapeutic interventions that target CSC pathways are still in their infancy and clinical data of their efficacy remain limited. However Smoothened inhibitors, gamma-secretase inhibitors, anti-DLL4 antagonists, Wnt antagonists, and CBP/β-catenin inhibitors have all shown promising anticancer effects in early studies. The evidence to support the emerging picture of a lung cancer CSC phenotype and the development of novel therapeutic strategies to target CSCs are described in this review.

CD133+ Cancer Stem-like Cells in Small Cell Lung Cancer Are Highly Tumorigenic and Chemoresistant but Sensitive to a Novel Neuropeptide Antagonist

“…In SCLC cells and other cell types, CD133 expression is localized to plasma membrane protrusions and its function may be associated with plasma membrane remodeling and may effect cell migration (54) and communication with extracellular matrix proteins that can influence resistance to chemotherapy. The current strategies to target CSCs have focussed primarily on pathways that regulate normal stem cell growth and differentiation such as the Hedgehog (Hh), Notch, and Wnt signaling pathways, and there is emerging evidence that targeting these pathways may show some benefit (55). However, these pathways have not been extensively studied in SCLC.…”

Afatinib Enhances the Efficacy of Conventional Chemotherapeutic Agents by Eradicating Cancer Stem–like Cells

“…Importantly, the multidrug resistance (MDR) phenotype of CSCs is responsible for chemotherapeutic failure (31,32). The most common cause of MDR is the increased drug efflux from cancer cells mediated by ATP-binding cassette (ABC) transporters including ABCG2 and ABCB1 (P-gp).…”

Elacridar, a third-generation ABCB1 inhibitor, overcomes resistance to docetaxel in non-small cell lung cancer

“…Cancer stem cell (CSC) features also contribute to this drug resistance (26,27). CSCs drive both continued expansion of malignant cells and resistance to chemotherapy (28)(29)(30). However, CSCs in lung cancer remain a subject of ongoing research, and specific markers have not yet been identified.…”