Inactivation of Tp53 and Pten drives rapid development of pleural and peritoneal malignant mesotheliomas

Our plain-English summary of Inactivation of Tp53 and Pten drives rapid development of pleural and peritoneal malignant mesotheliomas, by E. Sementino, C.W. Menges, Y. Kadariya, et al (Journal of Cellular Physiology, 2018).

The study

• Authors: E. Sementino, C.W. Menges, Y. Kadariya, S. Peri, J. Xu, Z. Liu, R.G. Wilkes, K.Q. Cai, F.J. Rauscher, A.J. Klein-Szanto, J.R. Testa
• Journal: Journal of Cellular Physiology
• Published: 2018;233(11):8952-8961
• Cited by: 24 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant mesothelioma (MM) is a therapy-resistant cancer arising primarily from the lining of the pleural and peritoneal cavities. The most frequently altered genes in human MM are cyclin-dependent kinase inhibitor 2A (CDKN2A), which encodes components of the p53 (p14ARF) and RB (p16INK4A) pathways, BRCA1-associated protein 1 (BAP1), and neurofibromatosis 2 (NF2). Furthermore, the p53 gene (TP53) itself is mutated in ~15% of MMs. In many MMs, the PI3K-PTEN-AKT-mTOR signaling node is hyperactivated, which contributes to tumor cell survival and therapeutic resistance. Here, we demonstrate that the inactivation of both Tp53 and Pten in the mouse mesothelium is sufficient to rapidly drive aggressive MMs. PtenL/L ;Tp53L/L mice injected intraperitoneally or intrapleurally with adenovirus-expressing Cre recombinase developed high rates of peritoneal and pleural MMs (92% of mice with a median latency of 9.4 weeks and 56% of mice with a median latency of 19.3 weeks, respectively). MM cells from these mice showed consistent activation of Akt-mTor signaling, chromosome breakage or aneuploidy, and upregulation of Myc; occasional downregulation of Bap1 was also observed. Collectively, these findings suggest that when Pten and Tp53 are lost in combination in mesothelial cells, DNA damage is not adequately repaired and genomic instability is widespread, whereas the activation of Akt due to Pten loss protects genomically damaged cells from apoptosis, thereby increasing the likelihood of tumor formation. Additionally, the mining of an online dataset (The Cancer Genome Atlas) revealed codeletions of PTEN and TP53 and/or CDKN2A/p14ARF in ~25% of human MMs, indicating that cooperative losses of these genes contribute to the development of a significant proportion of these aggressive neoplasms and suggesting key target pathways for therapeutic intervention.

© 2018 Wiley Periodicals, Inc.

In plain English

This laboratory study used conditional knockout mice to test whether losing both Pten and Tp53 in the mesothelium causes malignant mesothelioma (MM) without asbestos. In a pilot, 15 PtenL/L mice given adeno-Cre intrathoracically produced MM in only 1/15 (7%), at 12 months. In PtenL/L;Tp53L/L mice, 23/25 (92%) injected intraperitoneally with adeno-Cre developed MM with a median latency of 9.4 weeks, and 19/34 (56%) injected intrathoracically developed pleural MM with a median latency of 19.3 weeks; none of eight adeno-LacZ controls (by 33 weeks) and none of 12 Tp53L/L mice given adeno-Cre (by 14 weeks) developed tumors. Some mice died of other tumor types. Most MMs were sarcomatoid (54% pleural, 67% peritoneal), the rest biphasic. All 12 tumor cell lines lost Pten and p53 and showed raised P-Akt, P-S6 and Myc; Bap1 was reduced in 4/12 (33%). All five cell lines examined showed genomic instability. Mining of 87 human MMs in The Cancer Genome Atlas found codeletion or inactivation of PTEN with TP53 and/or p14ARF in 23/87 (26%).

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Animal experiment using conditional knockout mice (adenovirus-Cre induced gene deletion), with cell-line analyses and secondary mining of a public human genomic dataset
• Who was studied: Mice of 129S6/svEv background (PtenL/L, Tp53L/L and PtenL/L;Tp53L/L), both sexes, 10-12 weeks old at injection, at Fox Chase Cancer Center; plus a human cohort of 87 mesotheliomas from The Cancer Genome Atlas
• Exposure: Genetic: Cre-mediated inactivation of Pten and/or Tp53 by intrapleural or intraperitoneal adenovirus-Cre injection; no asbestos or other fiber exposure was used
• Main results:
  • Pten deletion alone: 1 of 15 PtenL/L mice injected intrathoracically with adeno-Cre developed MM, 12 months after injection
  • Peritoneal MM in PtenL/L;Tp53L/L mice given adeno-Cre intraperitoneally: 23/25 (92%), median latency 9.4 weeks
  • Pleural MM in PtenL/L;Tp53L/L mice given adeno-Cre intrathoracically: 19/34 (56%), median latency 19.3 weeks
  • Controls: no MM in 8 PtenL/L;Tp53L/L mice given adeno-LacZ intraperitoneally by 33 weeks, and no tumors in 12 Tp53L/L mice given adeno-Cre intraperitoneally by 14 weeks
  • Histology of the mesotheliomas (not of all tumors) in the PtenL/L;Tp53L/L mice: mostly sarcomatoid, remainder biphasic; some mice died of other tumor types
  • All 12 primary MM cell lines from intraperitoneally injected PtenL/L;Tp53L/L mice lost Pten and p53 and had elevated P-Akt and P-S6; Bap1 was downregulated in 4/12 (33%)
  • Cytogenetics of five peritoneal MM cell lines: all showed genomic instability; trisomy 15 was the most frequent recurring change (4 of 5 lines)
  • In the 87 human MMs from TCGA, 32% had TP53 and 31% had PTEN deletions; 13/87 (15%) had PTEN and TP53 codeletion (or in one case PTEN deletion with a TP53 truncating mutation); 23/87 (26%) overall had loss or inactivation of PTEN with TP53 and/or p14ARF
• The authors' conclusion: The authors concluded that their in vivo data show combined loss or inactivation of Tp53 and Pten is sufficient to drive aggressive pleural and peritoneal mesotheliomas with high penetrance and short latency, and that these pathways may be therapeutic targets in human MM
• Limitations the authors state:
  • The authors state the model cannot be used to test compounds that restore p53 function, because Tp53 is lost in both alleles
  • The authors state the model does not reproduce somatic changes in other tumor suppressor genes commonly involved in human MM
  • The authors note the mouse deletions are biallelic whereas human PTEN and TP53 deletions are generally monoallelic

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Malignant Mesothelioma, CDKN2A, BAP1, Mesothelium, Latency, Mesothelial Cells, Apoptosis, Neoplasm.

Related studies

• The function, mechanisms, and role of the genes PTEN and TP53 and the effects of asbestos in the development of malignant mesothelioma: a review focused on the genes' molecular mechanisms — L.V. de Assis, M.C. Isoldi (2014)
• Germline mutation of Bap1 accelerates development of asbestos-induced malignant mesothelioma — J. Xu, Y. Kadariya, et al. (2014)
• First case report of malignant peritoneal mesothelioma and oral verrucous carcinoma in a patient with a germline PTEN mutation: a combination of extremely rare diseases with probable further implications — M.W. Löffler, J. Steinhilber, et al. (2018)
• Caveolin-1 regulates lung cancer stem-like cell induction and p53 inactivation in carbon nanotube-driven tumorigenesis — S. Luanpitpong, L. Wang, et al. (2014)
• Exploratory analysis of activation of PTEN-PI3K pathway and downstream proteins in malignant pleural mesothelioma (MPM) — S. Cedrés, M.A. Montero, et al. (2012)
• Bap1 Is a Bona Fide Tumor Suppressor: Genetic Evidence from Mouse Models Carrying Heterozygous Germline Bap1 Mutations — Y. Kadariya, M. Cheung, et al. (2016)

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