New syngeneic inflammatory‐related lung cancer metastatic model harboring double KRAS/WWOX alterations. Issue 11 (28th January 2014)

• Record Type: Journal Article
• Authors: Bleau, Anne‐Marie; Freire, Javier; Pajares, María José; Zudaire, Isabel; Anton, Iker; Nistal‐Villán, Estanislao; Redrado, Miriam; Zandueta, Caroli na; Garmendia, Irati; Ajona, Daniel; Blanco, David; Pio, Ruben; Lecanda, Fernando; Calvo, Alfonso; Montuenga, Luis M.
• Is Part Of: International journal of cancer. Volume 135:Issue 11(2014:Dec. 01)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2014-01-28
• Subjects: Cancer -- Periodicals; Cancer -- Prevention -- Periodicals; 616.994
• DOI: 10.1002/ijc.28574
• Languages: English
• ISSNs: 0020-7136

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <p>New mouse models with specific drivers of genetic alterations are needed for preclinical studies. Herein, we created and characterized at the genetic level a new syngeneic model for lung cancer and metastasis in Balb‐c mice. Tumor cell lines were obtained from a silica‐mediated airway chronic inflammation that promotes tumorigenesis when combined with low doses of <italic>N</italic>‐nitrosodimethylamine, a tobacco smoke carcinogen. Orthotopic transplantation of these cells induced lung adenocarcinomas, and their intracardiac injection led to prominent colonization of various organs (bone, lung, liver and brain). Driver gene alterations included a mutation in the codon 12 of KRAS (G–A transition), accompanied by a homozygous deletion of the <italic>WW domain‐containing oxidoreductase</italic> (<italic>WWOX</italic>) gene. The mutant form of <italic>WWOX</italic> lacked exons 5–8 and displayed reduced protein expression level and activity. <italic>WWOX</italic> gene restoration decreased the <italic>in vitro</italic> and <italic>in vivo</italic> tumorigenicity, confirming the tumor suppressor function of this gene in this particular model. Interestingly, we found that cells displayed remarkable sphere formation ability with expression of specific lung cancer stem cell markers. Study of non‐small‐cell lung cancer patient cohorts demonstrated a deletion of <italic>WWOX</italic> in 30% of cases, with significant reduction in protein levels as compared to normal tissues. Overall, our new syngeneic mouse model provides a most valuable tool to study lung cancer metastasis in balb‐c mice background and highlights the importance of <italic>WWOX</italic> deletion in lung carcinogenesis.</p> </abstract>