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Journal of Molecular and Clinical Medicine   2019, Vol. 2 Issue (2): 41-53    DOI: 10.31083/j.jmcm.2019.02.151
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The role of developmental signaling pathways in non-small cell lung carcinoma
Darko Durovski1, 2, Ornella Randazzo1, 5, Godefridus J. Peters1, 3, Elisa Giovannetti1, 4, *()
1 Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, VU University, Amsterdam 1081HV, The Netherlands
2 Amsterdam University College, Amsterdam 1098XG, The Netherlands
3 Department of Biochemistry, Medical University of Gdansk, Gdansk 80-4161, Poland
4 Cancer Pharmacology Lab, AIRC Start Up Unit, Fondazione Pisana per la Scienza, Pisa 56017, Italy
5 Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo 90123, Italy
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On a global scale, lung cancer is the most widespread and deadly type of cancer and the non-small cell lung cancer histological subtype, contributes to a significant proportion of this mortality. It has been recently proposed that the main drivers of cancer progression and chemoresistance are cancer stem cells which can be identified through numerous biomarkers or through the overactivation of developmental signaling pathways which are essential for embryonic development but are normally suppressed in adulthood. The primary aim of this review was to compile experimental findings about mediators of three signaling pathways, namely Sonic Hedgehog, Notch and Wingless Integrated, in the prognosis and targeting of three non-small cell lung carcinoma histological types, namely adenocarcinoma, squamous cell carcinoma and large cell neuroendocrine lung carcinoma. Some mediators of all three signaling pathways can be used as biomarkers and overactivation is associated with shorter overall and disease-free survival of patients accompanied by metastasis, epithelial-to-mesenchymal transition and the acquisition of chemoresistance and radioresistance. Additionally, using antagonists to block overexpressed pathway mediators has yielded promising results in vitro with significant apoptotic and anti-tumor activity. Finally, numerous novel mediators of the three pathways have been identified and their pharmacological targeting has resulted in promising pre-clinical findings. The first in-human clinical trials of several drugs are currently being conducted. The current review supports further exploration of the three developmental signaling pathways in the prognosis and targeted treatment of non-small cell lung carcinoma with the aim of enhancing current treatment guidelines with the implementation of targeted therapies.

Key words:  Non-small cell lung carcinoma      developmental signaling pathways      Notch      Sonic hedgehog      Wingless Integrated     
Published:  20 April 2019     
*Corresponding Author(s):  Elisa Giovannetti     E-mail:

Cite this article: 

Darko Durovski, Ornella Randazzo, Godefridus J. Peters, Elisa Giovannetti. The role of developmental signaling pathways in non-small cell lung carcinoma. Journal of Molecular and Clinical Medicine , 2019, 2(2): 41-53.

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Figure 1.  Shown are the mediators involved in Sonic Hedgehog signaling in the inactivated state of the pathway (a) and the activated state (b). Legend: Shh - Sonic Hedgehog ligand, HHIP - Hedgehog interacting protein, Smo - Smoothened, SUFU - suppressor of fused homolog, GSK3 - glycogen synthase kinase 3, Gli - glioma-associated oncogene.

Figure 2.  Shown are the mediators involved in canonical Notch signaling in the inactivated state of the pathway. Legend: DLL - Delta-like ligand, JAG - Jagged, NICD - Notch intracellular domain.

Table 1  Association of Notch ligands with OS
Ligand Outcome
JAG1 Higher OS [62], lower OS [67]
JAG2 Lower OS [60]
DLL1 Higher OS [62]
DLL3 No predictive value [60]
DLL4 Higher OS [60]
Table 2  The association of Notch pathway mediators with NSCLC outcomes
Signaling mediator Role in Notch signaling Outcome of targeting
Histone deacetylase 6 (HDAC6) [84] Deacetylation of HSP90; link for TGF-β1-induced activation of Notch1 Prevented HEY-1, HES-1 upregulation
Forkhead box J2 (FOXJ2) [85] Inhibits TGF-β1-mediated EMT; lower expression in cancer Increased Notch1 and NICD1 levels
Zinc-finger RNA (ZFR) binding protein [86] Increases Notch1 levels Reduced cell migration potential
lncRNA-Low Expression in Tumor (LET) [87] Reduces NICD1 levels Downregulation led to higher TNM stage, low OS
Rnd3/RhoE (Rho GTPase) [88] Downregulated; associated with higher NICD expression Forced regulation led to an inhibition of Notch-regulated proliferation
miR-129-5p [89] Inhibits DLL1 homologue in A549 and H460 cells Diminished stemness markers, reduced resistance
miR-223 [90] Upregulated; leads to overactivation of Notch Reduced CD44+ subpopulation of CSCs, improved response to erlotinib
Rumi, protein-O-glucosyltransferase [91] Two to three-fold higher expression in NSCLC Knockdown led to decreased Hes1, Hey1, cell proliferation and migration
Figure 3.  Shown are the mediators involved in canonical Wnt signaling in the inactivated state of the pathway (left) and the activated state (right). Legend: Frizzled - Fz, LRP6 - lipoprotein receptor 6, Dishevelled - DVL, GSK3 - glycogen synthase kinase, CK1 - casein kinase 1.

Table 3  Antagonist families in the Wnt signaling pathway and their corresponding members
Antagonist family Members
Secreted frizzled related protein (SFRP) [98] SFRP1, SFRP2, SFRP3, SFRP4, SFRP5
Wnt inhibitory factors (WIF) [98, 99] WIF-1
Dickkopf (Dkk) [100]
Dvl antagonists [100] Idax, human homolog of Dapper (HDPR1)
Miscellaneous Cerberus, [100] Disabled-2, [100] Wnt-7a, [101] Frizzled-9 [101]
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