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. 2014 May;12(5):654-9.
doi: 10.1158/1541-7786.MCR-13-0554. Epub 2014 Jan 30.

PTEN Is a Potent Suppressor of Small Cell Lung Cancer

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Free PMC article

PTEN Is a Potent Suppressor of Small Cell Lung Cancer

Min Cui et al. Mol Cancer Res. .
Free PMC article

Abstract

Small cell lung carcinoma (SCLC) is a highly metastatic tumor type with neuroendocrine features and a dismal prognosis. PTEN mutations and PIK3CA activating mutations have been reported in SCLC but the functional relevance of this pathway is unknown. The PTEN/PIK3CA pathway was interrogated using an AdenoCre-driven mouse model of SCLC harboring inactivated Rb and p53. Inactivation of one allele of PTEN in Rb/p53-deleted mice led to accelerated SCLC with frequent metastasis to the liver. In contrast with the high mutation burden reported in human SCLC, exome analyses revealed a low number of protein-altering mutations in mouse SCLC. Inactivation of both alleles of PTEN in the Rb/p53-deleted system led to nonmetastatic adenocarcinoma with neuroendocrine differentiation. This study reveals a critical role for the PTEN/PI3K pathway in both SCLC and lung adenocarcinoma and provides an ideal system to test the phosphoinositide 3-kinase (PI3K) pathway inhibitors as targeted therapy for subsets of patients with SCLC.

Implications: The ability of PTEN inactivation to accelerate SCLC in a genetic mouse model suggests that targeting the PTEN pathway is a therapeutic option for a subset of human patients with SCLC. VISUAL OVERVIEW: http://mcr.aacrjournals.org/content/early/2014/04/28/1541-7786.MCR-13-0554/F1.large.jpg.

Conflict of interest statement

The authors declare that no conflicts of interest exist.

Figures

Figure 1
Figure 1. Inactivation of Pten accelerates Rb/p53 mutant lung tumors
A) Kaplan-Meier curves showing time to morbidity following AdCre delivery to Rblox/lox/p53lox/lox, Rblox/lox;p53lox/lox;Ptenlox/+ and Rblox/lox;p53lox/lox;Ptenlox/lox mice B) Hematoxylin and eosin (H+E) stain of murine SCLC (arrow) from AdCre Rblox/lox;p53lox/lox mouse at 15 months post AdCre with inset showing immunostaining for the neuroendocrine marker CGRP. Lymph node metastasis is indicated (LN). C) H+E of advanced SCLC in lymph node (LN) and lung (arrow) with CGRP immunostaining (inset) of Rblox/lox;p53lox/lox;Ptenlox/+ lung at 9 months post AdCre. Heterogeneity in CGRP staining across tumor nodules is apparent. D) High magnification (100X) image of H+E stained SCLC from Rblox/lox;p53lox/lox;Ptenlox/+ model. Scale bar for A: 2mm, D: 13 microns.
Figure 2
Figure 2. HomozygousPten inactivation in Rb/p53 mutant lung
A) Hematoxylin and eosin (H+E) stain showing tumor filled lung from Rblox/lox;p53lox/lox;Ptenlox/lox mouse 3 months 20 days post AdCre (left panels). CGRP immunostaining of adjacent section showing neuroendocrine character of many tumor nodules (right panels). Boxed region shows magnified view of adenocarcinoma with neuroendocrine differentiation (Ac-NE) along with adenocarcinoma negative for CGRP (asterix). B) High-magnification (100x) view of adenocarcinoma histology C) Synaptophysin (SYP) and CK19 immunostaining of adenocarcinoma. Adjacent lesions both exhibit CK19 positivity but only tumor area to left is synaptophysin positive D) Synaptophysin (SYP) positivity and absence of CK19 immunostaining in hyperplastic neuroendocrine cells along the airway (NEC-HP). Scale bars for A (upper): 2mm; A (lower): 400 microns; B: 13 microns; C, D: 80 microns.
Figure 3
Figure 3. Analyses of murine lung neuroendocrine tumors
A) Western blot analyses of normal lung and SCLCs from the indicated genotypes showing PTEN, Phospho Akt S473, pan-AKT and actin loading control. B) Number of protein-altering mutations in murine lung neuroendocrine tumors of the indicated genotypes. Metastatic samples are indicated (*). Rblox/lox;p53lox/lox : 8 tumors from 3 animals, Rblox/lox;p53lox/lox;Ptenlox/+ : 13 tumors from 6 animals, Rblox/lox;p53lox/lox;Ptenlox/lox : 6 tumors from 3 animals. C) Patterns of transitions and transversions in primary murine SCLC.

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