Abstract
The molecular mechanisms that contribute to the initiation and progression of head and neck squamous cell carcinoma (HNSCC) have not been completely delineated. Our observations indicate that defects in the transforming growth factor-β and PI3K/Akt signaling pathways are common in human HNSCCs. Conditional activation of the PI3K/Akt pathway due to Pten deletion in the mouse head and neck epithelia gives rise to hyperproliferation, but only a few lesions progress to HNSCC. However, Pten-deficient mice developed full-penetrance HNSCC in combination with type I TGF-β receptor (Tgfbr1) deletion. Molecular analysis revealed enhanced cell proliferation, decreased apoptosis, and increased expression of CCND1 in the basal layer of the head and neck epithelia, as well as in the tumors of Tgfbr1/Pten double conditional knockout (2cKO) mice. Furthermore, neoplastic transformation involves senescence evasion, and is associated with an increased number of putative cancer stem cells. In addition, the nuclear factor-κB pathway activation, myeloid-derived suppressor cell infiltration, angiogenesis and immune suppression in the tumor microenvironment, all of which are characteristics of human HNSCCs, contribute significantly to head and neck carcinogenesis in 2cKO mice. These tumors display pathology and multiple molecular alterations resembling human HNSCCs. This suggests that the Tgfbr1/Pten 2cKO mouse model is suitable for preclinical intervention, and that it has significant implications in the development of diagnostic cancer biomarkers and effective strategies for prevention and treatment of HNSCCs.
Highlights
Head and neck squamous cell carcinoma (HNSCC) is one of the most common types of human cancer (Jemal et al, 2010)
Loss of TGFBR1 and PTEN is a common event in human HNSCCs To determine whether deletion in the Transforming growth factor-b (TGF-b) and PTEN/ PI3K/Akt signaling pathways often occur together in a TGF-b and PTEN defects promote HNSCC Y Bian et al 3323 subset of human HNSCCs, we examined TGFBR1 mRNA expression in 10 human HNSCC cell lines
The quantitative real-time PCR results revealed that the mRNA expression levels of TGFBR1 was reduced in all the 10 HNSCC cell lines compared with human oral keratinocyte cells, and in 6/10 (60%) of the cell lines the reduction was more than 50% (Figure 1a)
Summary
Head and neck squamous cell carcinoma (HNSCC) is one of the most common types of human cancer (Jemal et al, 2010). Alcohol consumption and human papillomavirus are the major risk factors associated with the development of HNSCC (Licitra et al, 2006; Curado and Hashibe, 2009). These risk factors, together with genetic susceptibility, result in the accumulation of multiple genetic and epigenetic alterations in a multistep process of cancer development (Deshpande and Wong, 2008). Transforming growth factor-b (TGF-b) and PTEN/PI3K/Akt/mTOR pathways are among the most frequently altered signaling routes Both pathways have central roles in numerous cellular processes, including metabolism, cell growth, apoptosis (programmed cell death), survival and differentiation, which contribute to HNSCC progression (Molinolo et al, 2009)
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