Ablating all three retinoblastoma family members in mouse lung leads to neuroendocrine tumor formation

Lung cancer is a deadly disease with increasing cases diagnosed worldwide and still a very poor prognosis. While mutations in the retinoblastoma (RB1) tumor suppressor have been reported in lung cancer, mainly in small cell lung carcinoma, the tumor suppressive role of its relatives p107 and p130 is...

Full description

Saved in:
Bibliographic Details
Published in:Oncotarget 2017-01, Vol.8 (3), p.4373-4386
Main Authors: Lázaro, Sara, Pérez-Crespo, Miriam, Enguita, Ana Belén, Hernández, Pilar, Martínez-Palacio, Jesús, Oteo, Marta, Sage, Julien, Paramio, Jesús M, Santos, Mirentxu
Format: Article
Language:English
Subjects:
Animals
Cell Transformation, Neoplastic - genetics
Lung Neoplasms - chemically induced
Lung Neoplasms - genetics
Lung Neoplasms - pathology
Mice
Mice, Knockout
Neoplasms, Experimental - chemically induced
Neoplasms, Experimental - genetics
Neoplasms, Experimental - pathology
Neuroendocrine Tumors - chemically induced
Neuroendocrine Tumors - genetics
Neuroendocrine Tumors - pathology
Nitrosamines - adverse effects
Research Paper
Retinoblastoma Protein - genetics
Retinoblastoma-Like Protein p107 - genetics
Retinoblastoma-Like Protein p130 - genetics
Signal Transduction
Urethane - adverse effects
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Lung cancer is a deadly disease with increasing cases diagnosed worldwide and still a very poor prognosis. While mutations in the retinoblastoma (RB1) tumor suppressor have been reported in lung cancer, mainly in small cell lung carcinoma, the tumor suppressive role of its relatives p107 and p130 is still a matter of debate. To begin to investigate the role of these two Rb family proteins in lung tumorigenesis, we have generated a conditional triple knockout mouse model (TKO) in which the three Rb family members can be inactivated in adult mice. We found that ablation of all three family members in the lung of mice induces tumorlets, benign neuroendocrine tumors that are remarkably similar to their human counterparts. Upon chemical carcinogenesis, DHPN and urethane accelerate tumor development; the TKO model displays increased sensitivity to DHPN, and urethane increases malignancy of tumors. All the tumors developing in TKO mice (spontaneous and chemically induced) have neuroendocrine features but do not progress to fully malignant tumors. Thus, loss of Rb and its family members confers partial tumor susceptibility in neuroendocrine lineages in the lungs of mice. Our data also imply the requirement of other oncogenic signaling pathways to achieve full transformation in neuroendocrine lung lesions mutant for the Rb family.
ISSN:1949-2553
1949-2553
DOI:10.18632/oncotarget.13875