Date

July 2008

Document Type

Dissertation

Degree Name

Ph.D.

Department

Dept. of Cell and Developmental Biology

Institution

Oregon Health & Science University

Abstract

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer in the United States. However, the prognosis of HNSCC has not improved in the past 20 years. While many molecular changes have been uncovered, few are known to play a causal role in HNSCC carcinogenesis. During my PhD thesis study, we found that Smad4 was frequently lost in preneoplastic and cancer lesions of HNSCC. When we deleted Smad4 in mouse head and neck epithelia (HN-Smad4-/-), HN-Smad4-/- mice developed spontaneous HNSCC. Interestingly, HN-Smad4-/- head and neck tissue and HNSCCs exhibited increased genomic instability evidenced by increased centrosome numbers and chromosomal aberrations, which correlated with downregulated gene expression of genes in the Fanconi anemia/Brca (Fanc/Brca) pathway. Further analysis revealed a causal role for Smad4 loss in downregulation of the Fanc/Brca pathway in both human and mouse HNSCC cells. Additionally, HN-Smad4-/- head and neck tissue and HNSCCs exhibited severe inflammation, which was associated with increased TGFβ1 and activated Smad3. Additionally, inflammatory cytokines and chemokines, such as MCP-1, MCP-2, MMP2, and MIP-2, which have been shown to be upregulated by TGFβ1, were overexpressed in HN-Smad4-/- mucosa and HNSCCs in comparison with HN-Smad4+/+ controls. Lastly, Smad4 loss in keratinocyte stem cells led to aberrant stem cell proliferation and retention of multipotency. Taken together, both the accumulation of genetic insults in epithelia and increased stromal inflammation appeared to contribute to Smad4 loss-initiated HNSCC carcinogenesis.

Identifier

doi:10.6083/M4862DDG

School

School of Medicine

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