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FIGURE 7.1 Genetic progression model for HNSCC. Genetic chromosomal aberrations during the progressive development of head and neck tumors have been determined by analysis of various premalignant and malignant HNSCC lesions. Adapted from Califano et al., Cancer Res. 56, 2488-2492 (1996).

Benign or premalignant lesions

FIGURE 7.1 Genetic progression model for HNSCC. Genetic chromosomal aberrations during the progressive development of head and neck tumors have been determined by analysis of various premalignant and malignant HNSCC lesions. Adapted from Califano et al., Cancer Res. 56, 2488-2492 (1996).

Invasive carcinoma tightly regulated oncogenes and tumor suppressor genes [1]. In this regard, cytogenetic and molecular studies have demonstrated that somatic mutations that activate oncogenes (e.g., Ras, Myc, ErbB2, EGFR, bcl2, int-2, hst-1, ems-1, cyclinDI), as well as point mutations, deletion, or hypermethylation that lead to tumor suppressor genes inactivation (e.g., pl6, TP53, PTEN, Rb), are involved in and account for the development and progression of HNSCC [2-4].

Int-2 (FGF3) and hst-1 (FGF4) oncogenes are fibroblast growth factor (FGF) family members and have been shown to be involved in the induction of cell proliferation and angio-genesis [5-8]. Int-2 and hst-1 have been found to be amplified and coamplified in 30-52% of HNSCC [9]. However, because they are not expressed in a significant percentage of HNSCC [10], their function in this disease still remains unclear. Analysis conducted on HNSCC specimens reported a consistent loss of hetero-zygosity (LOH) clustered around several chromosomal bands or regions, particularly lpl 1-12, lp22, lq25, 3pl 1-ql 1, 5ql0, 5ql3, 8ql0, llql3, 10q23, and 17p31 [11,12], Moreover, deletions at 3pl3-p24, 5ql2-q23, 8p22-p23, 9p21-p24, and 18q22-q23 [13] and LOH on chromosome arms 5q and 19p [14] frequently occur in HNSCC.

The LOH analysis of 87 head and neck tumors, including benign and premalignant lesions, led Califano et al. [15] to propose a preliminary progression model for tumorigenesis in HNSCC (Fig. 7.1). In accordance with this model, loss of chromosome 9p appears to be the earliest event in benign and preinvasive lesions, whereas 3p and 17p (p53 locus) deletions are observed in the dyplastic phase. Carcinoma in situ is the result of alterations of pl6, p53 genes, and loss of 1 lq, 13q, and 14q and invasive lesions occur on 6p, 8p, and 4p chromosomal region loss. This review focuses on the tumor/stromal interaction evidenced as tumor angiogenesis.

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