A long-standing hypothesis is that tumors developing from stem cells will display the maximal range of histopathologies and malignant potential compared with those derived from transient amplifying cells or differentiating compartments. The persistence of the initiated cell (Yuspa, 1994) points to the stem cell as the target cell type for carcinogenesis; however, cells in the differentiating compartment are capable of neoplastic transformation (Bailleul et al., 1990; Greenhalgh et al., 1993). Careful histological dissection of progressing lesions and direct oncogene targeting have been used to evaluate systematically the contribution of specific cell populations to skin carcinogenesis (Bailleul et al., 1990; Greenhalgh et al., 1993; Hansen and Tennant 1994; Binder et al., 1997; Brown et al., 1998; Frame and Balmain 1999).
Focal hyperplastic (papilloma precursor) lesions arising during two-stage carcinogenesis were traced to the infundibular region of a single hair follicle that clonally expanded (Binder et al., 1997). Likewise, papillomas arising in TG-AC mice in which oncogenic ras is the under control of the Z-globin promoter can be traced histologically to the permanent portion of the follicle where the mRNA for the ras transgene was initially localized. This indicates that the potential to form squamous tumors persists throughout the hair cycle. However, the transient proliferation of bulge cells during early anagen imparts enhanced responsiveness of the anagen follicle to two-stage carcinogenesis compared to the telogen follicle (Miller et al., 1993). When hair follicle cells and basal interfollicular keratinocytes are isolated in vitro and subjected to transformation by a ras oncogene, they produce squamous tumors in vivo that are indistinguishable, regarding both histopathology and malignant conversion frequency (Weinberg et al., 1991). The contribution of these cell populations to two-stage car-cinogenesis was also evaluated by selective removal of the interfollicular epidermis in vivo following 7,12 dimethyl-benz[a]anthracene (DMBA) initiation (Morris et al., 2000). Mice were promoted with 12-0-tetradecanoylphorbol-13-acetate (TPA) after the remaining hair follicles were allowed to reconstitute the epidermis. Those with intact initiated epidermis developed twice as many papillomas as mice with abraded skin, demonstrating that both cell populations are targets in these carcinogenesis protocols. Incidence of carcinoma, however, was similar between the groups, suggesting that hair follicles harbor initiated cells with increased malignant potential (Morris et al., 2000).
In vivo targeting of oncogenic ras to different epithelial compartments in transgenic skin also influences the tumorigenic outcome. For example, targeting the Ha-ras oncogene primarily to cells of the outer root sheath of mouse hair follicles using a truncated K5 promoter yielded spontaneous papillomas and keratoa-canthomas that were refractory to the tumor promoter TPA (Brown et al., 1998). These tumors expressed keratin 13 and had a high probability of progressing to invasive carcinoma. However, targeting oncogenic ras to the suprabasal cell compartment by K1 or K10 promoters results in hyperkeratosis, and papillo-mas develop only at sites of wounding or following TPA treatment after a long latency (Bailleul et al., 1990; Greenhalgh et al., 1993). These lesions are self-limited with low malignant potential, possibly reflecting their derivation from more differentiated cells. Definitive evidence that stem cells impart the difference in autonomy and malignant potential among these cell types awaits elucidation of stem cell-specific proteins and more selective promoter targeting.
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