Head and neck squamous cell carcinomas (HNSCC), including cancers of the upper aerodigestive tract, are oneof the most common cancers worldwide, with an estimated 52,000 new cases in the United States in 20111.While treatment of early-stage HNSCC with radiation therapy and/or surgery is often successful in treatingprimary tumors, many patients develop second primary tumors (SPT) or experience recurrence, resulting in a5-year survival rate of approximately 50%, a rate which has remained constant for decades2. To date, all-transretinoic acid (RA) and its isoforms are perhaps the most thoroughly studied agents in the treatment andprevention of SPT and HNSCC recurrence. The rate-limiting enzyme in endogenous RA synthesis from retinol(vitamin A), aldehyde dehydrogenase 1a2 (ALDH1a2), has recently been shown to act as a tumor suppressor inhuman prostate cancer20. Moreover, ALDH1a2 transcript levels were dramatically reduced in RNA data setsfrom over 500 human HNSCC samples.
We aim to investigate the role of ALDH1a2 as an inhibitor of HNSCCtumorigenesis. We hypothesize that ALDH1a2 expression inhibits the development of HNSCC by increasingendogenous RA production and signaling. To test this hypothesis, I will conduct a multi-faceted projectexamining the effect of ALDH1a2 expression on HNSCC both in vitro and in vivo.
In Aim 1, I will determine ifALDH1a2 expression alters the tumorigenic phenotype of several human HNSCC lines by infecting them with aretroviral ALDH1a2 expression vector. My preliminary results indicate that ALDH1a2 expression significantlyinhibits HNSCC cell growth and clonogenicity in vitro.
In Aim 2 I will create transgenic mice that inducibly (viatetracycline regulation) express ALDH1a2 in the oral mucosa, and then determine whether this inductionreduces the incidence and/or severity of oral cavity carcinogenesis in our carcinogen-induced murine model ofhuman oral carcinogenesis. Furthermore, in both aims I will compare the effects of endogenous ALDH1a2expression to those of treatment with exogenous RA. By completing these aims I will determine if ectopicALDH1a2 expression can inhibit the malignant phenotype and onset of oral cavity cancer, and ascertainwhether enhanced production of endogenous RA is more inhibitory with respect to oral cavity carcinogenesisthan addition of exogenous RA. This research will not only further our understanding of retinoid signaling andchemoprevention in HNSCC, but may also provide the first evidence for ALDH1a2 as an inhibitor of tumordevelopment in HNSCC.
The proposed research will significantly advance our knowledge of retinoids as chemopreventative agents in head and neck cancer (HNSCC). Investigating the potential of endogenous retinoid synthesis (via: ALDH1a2) in inhibiting oral cavity carcinogenesis will reveal new and more effective strategies of retinoid therapy for treating HNSCC; one of the most common forms of cancer worldwide.