Clinical and morphological features of large-cell neuroendocrine carcinomas and small-cell lung carcinomas expressing the DLL3 and ASCL1 oncoproteins

Author(s)

T.G. Prieto ^[1] ; C.M. Baldavira ^[2] ; J. Machado-Rugolo ; E.H.R. Olivieri ^[4] ; E.C.A. da Silva ^[5] ; V.G. Silva ^[6] ; A.M. Ab'Saber ; T.Y. Takagaki ^[8] ; V.L. Capelozzi ^[9]

Affiliation

^[1] Universidade de São Paulo. Departamento de Patologia, Faculdade de Medicina. Laboratório de Genômica e Histomorfometria - Brasil

^[2] Universidade de São Paulo. Departamento de Patologia, Faculdade de Medicina. Laboratório de Genômica e Histomorfometria - Brasil

^[4] AC Camargo Cancer Center. Centro Internacional de Pesquisa - Brasil

^[5] Hospital de Câncer de Barretos. Centro de Pesquisa em Oncologia Molecular - Brasil

^[6] Fundação Oncocentro do Estado de São Paulo - Brasil

^[8] Instituto do Coração, Faculdade de Medicina, Universidade de São Paulo. Divisão de Pneumologia - Brasil

^[9] Universidade de São Paulo. Departamento de Patologia, Faculdade de Medicina. Laboratório de Genômica e Histomorfometria - Brasil

• Document type: Journal article
• Source: Brazilian Journal of Medical and Biological Research; v. 56, 2023-12-22.

Abstract

Abstract Intratumoral similarities and differences between large-cell neuroendocrine carcinomas (LCNECs) and small-cell lung carcinomas (SCLCs) are determined partially by the Notch signaling pathway, which controls the switch from neuroendocrine to slight/non-neuroendocrine cell fate. LCNECs are divided into two subgroups according to genomic alterations: type I LCNECs exhibit a neuroendocrine profile characterized by achaete‐scute homolog 1 (ASCL1)high/delta-like protein 3 (DLL3)high/NOTCHlow and type II LCNECs show the pattern ASCL1low/DLL3low/NOTCHhigh. Here, we used immunohistochemistry, transmission electron microscopy, and digital analysis to examine the role of the Notch ligand DLL3 as an immunomarker of the neuroendocrine state and ASCL1 as a regulator of cell-cell interactions in SCLCs and LCNECs. High DLL3 and ASCL1 expression was associated with atypical submicroscopic characteristics involving nuclear size, chromatin arrangement, Golgi apparatus, and endoplasmic reticulum, and was characteristic of type I LCNECs with similarity to SCLCs, whereas low DLL3 and ASCL1 expression was found in both SCLCs and type II LCNECs. In patients diagnosed at an early stage who did not have metastasis and who underwent chemotherapy, DLL3high and ASCL1high SCLCs and type I LCNECs were associated with a better prognosis and a lower risk of death. The present findings suggested that DLL3/ASCL1 are potential therapeutic targets and prognostic indicators in patients with SCLCs or LCNECs. (AU)

• FAPESP's process: 19/12151-0 - Evaluation of the protein expression of DLL-3 and ASCL-1 as a new perspective in biomarkers for the early diagnosis of small cell lung carcinomas
• Grantee: Tabatha Gutierrez Prieto Martins Rocha
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 18/20403-6 - Biomolecular markers of proliferation and remodeling in acute and chronic respiratory diseases: promising therapeutic targets
• Grantee: Vera Luiza Capelozzi
• Support Opportunities: Research Projects - Thematic Grants