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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.

The cancer stem-cell hypothesis : its emerging role in lung cancer biology and its relevance for future therapy

TGF-β-induced factor homeobox 2 (TGIF2) is a transcription regulator that plays essential roles in the regulation of development and cell fate decisions. Aberrant expression of TGIF family proteins has been observed in several cancers, including ovarian, esophageal, and colorectal cancers. Here, we report that TGIF2 mediates the EGFR–RAS–ERK signaling pathway to enhance the stemness of lung adenocarcinoma (LUAD) cells and, therefore, promote the progression and metastasis of LUAD. We found that high TGIF2 expression was closely correlated with tumor growth, lymph node metastasis, and survival of patients with LUAD. Mice bearing TGIF2-silenced H1299 xenografts developed smaller tumors and fewer lung metastases. Importantly, silencing TGIF2 decreased the cancer stem cell (CSC)-like properties in A549 and H1299 cells. Furthermore, we identified that TGIF2 binding to the OCT4 promoter promotes its expression. In both LUAD cells and in vivo LUAD mouse models, we revealed that EGFR–RAS–ERK signaling phosphorylated TGIF2 and increased its stability, which was important for TGIF2-promoted LUAD stemness since phosphorylation-deficient TGIF2 mutants lost these functions. Thus, our study revealed that an important factor, TGIF2, bridges EGFR signaling to the CSC characteristics of LUAD cells, which can be utilized as an effective target for LUAD therapy.

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TGIF2 promotes the progression of lung adenocarcinoma by bridging EGFR/RAS/ERK signaling to cancer cell stemness

Expression of the essential regulator genes, SOX2, NANOG, and OCT4, so-called as stemness factors, is prerequisite for the tumorigenic capability of cancer stem cells (CSCs) and their potential role in the formation and progression of various human cancers. In this study, the expression levels of SOX2, NANOG, and OCT4 were quantified by a qRT-PCR method in 100 gastric cancer tumor tissues vs the paired adjacent normal tissues. Then, the relationship between the expression of the three genes in gastric cancer tumor tissues and the clinicopathological characteristics and overall survival of patients was investigated. Higher expression levels of SOX2, NANOG, and OCT4 were found in gastric cancer tumor tissues compared with those in paired adjacent normal tissues (P = 0.0001). Overexpression of the mentioned genes in gastric cancer tumor tissues was resolved to be significantly associated with tumor size (P < 0.05), TNM stage (P = 0.001), tumor grade (P < 0.01), and shortened overall survival time (P = 0.0001). These findings indicted that the stemness factors SOX2, NANOG, and OCT4 are significantly overexpressed in gastric cancer and may serve as potential biomarkers of gastric cancer progression and prognosis.

Association of High Expression Levels of SOX2, NANOG, and OCT4 in Gastric Cancer Tumor Tissues with Progression and Poor Prognosis

Despite the successful application of immune checkpoint therapy, no response or recurrence is typical in lung cancer. Cancer stem cells (CSCs) have been identified as a crucial player in immunotherapy-related resistance. Ferroptosis, a form of cell death driven by iron-dependent lipid peroxidation, is highly regulated by cellular metabolism remolding and has been shown to have synergistic effects when combined with immunotherapy. Metabolic adaption of CSCs drives tumor resistance, yet the mechanisms of their ferroptosis defense in tumor immune evasion remain elusive. Here, through metabolomics, transcriptomics, a lung epithelial-specific Cpt1a-knockout mouse model, and clinical analysis, we demonstrate that CPT1A, a key rate-limiting enzyme of fatty acid oxidation, acts with L-carnitine, derived from tumor-associated macrophages to drive ferroptosis-resistance and CD8+ T cells inactivation in lung cancer. Mechanistically, CPT1A restrains ubiquitination and degradation of c-Myc, while c-Myc transcriptionally activates CPT1A expression. The CPT1A/c-Myc positive feedback loop further enhances the cellular antioxidant capacity by activating the NRF2/GPX4 system and reduces the amount of phospholipid polyunsaturated fatty acids through ACSL4 downregulating, thereby suppressing ferroptosis in CSCs. Significantly, targeting CPT1A enhances immune checkpoint blockade-induced anti-tumor immunity and tumoral ferroptosis in tumor-bearing mice. The results illustrate the potential of a mechanism-guided therapeutic strategy by targeting a metabolic vulnerability in the ferroptosis of CSCs to improve the efficacy of lung cancer immunotherapy. 

Targeting carnitine palmitoyl transferase 1A (CPT1A) induces ferroptosis and synergizes with immunotherapy in lung cancer

In this review, we analyse the impact of oncogenic Ras mutations in mediating cancer drug resistance, and progress made in the abrogation of this resistance, through pharmacological targeting. At a physiological level, Ras is implicated in many cellular proliferation and survival pathways. However, mutations within this small GTPase can be responsible for the initiation of cancer, therapeutic resistance and failure and ultimately disease relapse. Often termed 'undruggable', Ras is notoriously difficult to target directly, due to its structure and intrinsic activity. Thus, Ras-mediated drug resistance remains a considerable pharmacological problem. However, with advances in both analytical techniques and novel drug classes, the therapeutic landscape against Ras is changing. Allele-specific, direct Ras-targeting agents have reached clinical trials for the first time, indicating there may, at last, be hope of targeting such an elusive but significant protein for better more effective cancer therapy.

https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1111/bph.15420

The importance of Ras in drug resistance in cancer.

ICAM3 mediates inflammatory signaling to promote cancer cell stemness.

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TGIF2 promotes the progression of lung adenocarcinoma by bridging EGFR/RAS/ERK signaling to cancer cell stemness

ICAM3 mediates inflammatory signaling to promote cancer cell stemness.