Loss of epithelial p53 and αv integrin cooperate through Akt to induce squamous cell carcinoma yet prevent remodeling of the tumor microenvironment

A. Savar, S. Acin, C. L. Gonzalez, T. El-Sawy, O. Mejia, Z. Li, B. Esmaeli, A. Lacy-Hulbert, A. K. El-Naggar, J. H. McCarty, C. Caulin

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

Most of the squamous cell carcinomas (SCCs) of the skin and head and neck contain p53 mutations. The presence of p53 mutations in premalignant lesions suggests that they represent early events during tumor progression and additional alterations may be required for SCC development. Here we show that codeletion of the p53 and αv integrin genes in mouse stratified epithelia induced SCCs in 100% of the mice, more frequently and with much shorter latency than deletion of either gene alone. The SCCs that lacked p53 and αv in the epithelial tumor cells exhibited high Akt activity, lacked multiple types of infiltrating immune cells, contained a defective vasculature and grew slower than tumors that expressed p53 or αv. These results reveal that loss of αv in epithelial cells that lack p53 promotes SCC development, but also prevents remodeling of the tumor microenvironment and delays tumor growth. We observed that Akt inactivation in SCC cells that lack p53 and αv promoted anoikis. Thus, tumors may arise in these mice as a result of the increased cell survival induced by Akt activation triggered by loss of αv and p53, and by the defective recruitment of immune cells to these tumors, which may allow immune evasion. However, the defective vasculature and lack of a supportive stroma create a restrictive microenvironment in these SCCs that slows their growth. These mechanisms may underlie the rapid onset and slow growth of SCCs that lack p53 and αv.

Original languageEnglish (US)
Pages (from-to)516-524
Number of pages9
JournalOncogene
Volume34
Issue number4
DOIs
StatePublished - Jan 22 2015
Externally publishedYes

Keywords

  • integrins
  • mouse model
  • p53
  • squamous cell carcinoma
  • tumor microenvironment

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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