Targeting PLK1 as a novel chemopreventive approach to eradicate preneoplastic mucosal changes in the head and neck.

D Vicky De Boer,Elisabeth Bloemena,Ralf Dietrich,Marijke Buijze,Ruud H Brakenhoff,C René Leemans,Victor W Van Beusechem,Boudewijn J.M Braakhuis,Marijke Stigter-Van Walsum,Sanne R Martens-De Kemp

doi:10.18632/oncotarget.17880

D Vicky De Boer, Elisabeth Bloemena + Show 8 more

Open Access

https://doi.org/10.18632/oncotarget.17880

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Abstract

Head and neck squamous cell carcinomas (HNSCC) and local relapses thereof develop in preneoplastic fields in the mucosal linings of the upper aerodigestive tract. These fields are characterized by tumor-associated genetic changes, are frequently dysplastic and occasionally macroscopically visible. Currently, no adequate treatment options exist to prevent tumor development. Array-based screening with a panel of tumor-lethal small interfering RNAs (siRNAs) identified Polo-like kinase 1 (PLK1) as essential for survival of preneoplastic cells. Inhibition of PLK1 caused cell death of preneoplastic and HNSCC cells, while primary cells were hardly affected. Both siRNAs and small molecule inhibitors caused a strong G2/M cell cycle arrest accompanied by formation of monopolar spindles. In a xenografted mouse model PLK1 caused a significant tumor growth delay and cures, while chemoradiation had no effect. Thus, PLK1 seems to be a promising target for chemopreventive treatment of preneoplastic cells, and could be applied to prevent HNSCC and local relapses.

Highlights

Worldwide around 600,000 cases of head and neck squamous cell carcinoma (HNSCC) arise each year, forming about 5% of all cancer cases [1]
Head and neck squamous cell carcinomas (HNSCC) and local relapses thereof develop in preneoplastic fields in the mucosal linings of the upper aerodigestive tract
Array-based small interfering RNAs (siRNAs) screening with a ‘tumor-lethal’ library reveals genes essential for preneoplastic cells

Summary

Introduction

Worldwide around 600,000 cases of head and neck squamous cell carcinoma (HNSCC) arise each year, forming about 5% of all cancer cases [1]. An important phase in HNSCC development is the formation of genetically altered precancerous fields. These fields develop in several steps, starting when a mucosal stem cell undergoes mutations and other (epi)genetic alterations. These mutations are subsequently transferred to the daughter transit-amplifying and differentiating cells, forming a genetically altered clonal unit (‘patch’) in the mucosal linings. Despite the cancer-related genetic alterations in these cells, such as TP53 mutations www.impactjournals.com/oncotarget and losses of the chromosomal arms 3p, 9p and 17p, these preneoplastic fields are not yet invasive [2]

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