Non-small-cell lung carcinoma: role of the Notch signaling pathway

Abstract

Notch signaling plays a pivotal role during embryogenesis. It regulates three fundamental processes: lateral inhibition, boundary formation, and lineage specification. During post-natal life, Notch receptors and ligands control critical cell fate decisions both in compartments that are undergoing differentiation and in pluripotent progenitor cells. First recognized as a potent oncogene in certain lymphoblastic leukemias and mesothelium-derived tissue, the role of Notch signaling in epithelial, solid tumors has been far more controversial. The overall consequence of Notch signaling and which form of the Notch receptor drives malignancy in humans is deeply debated. Most likely, this is due to the high degree of context-dependent effects of Notch signaling. More recently, it has been discovered that Notch (especially Notch-1) can exert different, even opposite effects in the same tissue under differing microenvironmental conditions. Further complicating the understanding of Notch receptors is the recently discovered role for non-canonical Notch signaling. Additionally, the most frequent Notch signaling antagonists used in biological systems have been inhibitors of the transmembrane protease complex γ-secretase, which itself processes a plethora of class one transmembrane proteins and thus cannot be considered a Notch-specific upstream regulator. Here we review the available empirical evidence gathered in recent years concerning Notch receptors and ligands in non-small-cell lung carcinoma (NSCLC). Although an overview of the field reveals seemingly contradicting results, we propose that Notch signaling can be exploited as a therapeutic target in NSCLC and represents a promising complement to the current arsenal utilized to combat this malignancy, particularly in targeting NSCLC tissues under specific environmental conditions, such as hypoxia.

Notch Signaling Components

“… 37 , 38 Specifically, Notch1 inhibits lung tumor formation and JAG2 mediates ADC epithelial-mesenchymal transition and metastasis in mice. 24 , 26 DLL4 is involved in angiogenesis in NSCLC. 29 Notch1 and Notch3 have been extensively studied in lung cancer.…”

“…Little is known about the role of Notch2, Notch4, or Notch ligands in NSCLC. 18 , 24 The present study introduces Notch receptors and ligands as candidate biomarkers for prognosis of NSCLC.…”

“…Compelling evidence indicates Notch receptors and ligands could be variously tumor-suppressive or oncogenic in different neoplasms including NSCLC. 24 , 25 Some studies found that inactivation of Notch1 in mouse models of NSCLC abrogated tumorigenesis and inhibited cell growth, 26 , 27 whereas others showed that NICD1 or Notch1 inhibited NSCLC cell and xenograft tumor growth. 28 , 29 Similarly, several studies have shown that high Notch1 or low DLL4 expression is a negative prognostic indicator 30 , 31 ; however, another study indicated that higher Notch1 predicts better survival.…”