CD34 Expression by Hair Follicle Stem Cells Is Required for Skin Tumor Development in Mice

Abstract

The cell surface marker CD34 marks mouse hair follicle bulge cells, which have attributes of stem cells, including quiescence and multipotency. Using a CD34 knockout (KO) mouse, we tested the hypothesis that CD34 may participate in tumor development in mice because hair follicle stem cells are thought to be a major target of carcinogens in the two-stage model of mouse skin carcinogenesis. Following initiation with 200 nmol 7,12-dimethylbenz(a)anthracene (DMBA), mice were promoted with 12-O-tetradecanoylphorbol-13-acetate (TPA) for 20 weeks. Under these conditions, CD34KO mice failed to develop papillomas. Increasing the initiating dose of DMBA to 400 nmol resulted in tumor development in the CD34KO mice, albeit with an increased latency and lower tumor yield compared with the wild-type (WT) strain. DNA adduct analysis of keratinocytes from DMBA-initiated CD34KO mice revealed that DMBA was metabolically activated into carcinogenic diol epoxides at both 200 and 400 nmol. Chronic exposure to TPA revealed that CD34KO skin developed and sustained epidermal hyperplasia. However, CD34KO hair follicles typically remained in telogen rather than transitioning into anagen growth, confirmed by retention of bromodeoxyuridine-labeled bulge stem cells within the hair follicle. Unique localization of the hair follicle progenitor cell marker MTS24 was found in interfollicular basal cells in TPA-treated WT mice, whereas staining remained restricted to the hair follicles of CD34KO mice, suggesting that progenitor cells migrate into epidermis differently between strains. These data show that CD34 is required for TPA-induced hair follicle stem cell activation and tumor formation in mice. [Cancer Res 2007;67(9):4173-81]

The Tcl1 oncogene defines secondary hair germ cells differentiation at catagen–telogen transition and affects stem-cell marker CD34 expression

“…it is also interesting to observe that HFs derived from CD34 À/À mice and Tcl1 À/À mice are blocked at telogen (Trempus et al, 2007).…”

“…It is known that from the bulge arise, among others, those cells involved in epidermal wound repair (Ito et al, 2005;Trempus et al, 2007). In the absence of secondary HG-cells with proliferative status, bulge cells are progressively lost after some cycles, and this ultimately increases the CD34 þ depletion pool.…”

Development and Homeostasis of the Skin Epidermis

“…KRas G12D expression in the IFE-induced hyperproliferation and hyperplasia, sometimes progressing into papillomas, indicating that cells of the IFE are competent to develop papillomas (Lapouge et al 2011). The cellular origin of DMBA/TPA-induced papilloma and SCC has not been determined yet, but the absence of tumors in DMBA/ TPA-treated CD34-null mice (Trempus et al 2007) and the resistance to DMBA/TPA-induced tumor formation in mice with Stat3 deletion in bulge SCs and their progeny (Chan et al 2004;Kim et al 2009a) indicate that bulge SCs probably participate in papilloma formation.…”

Relationships between stem cell exhaustion, tumour suppression and ageing

“…It is also possible that loss of stem and progenitor cells themselves may decrease the pool of cells available for transformation, according to the hypothesis that some cancers are derived directly from these cell types (Ward and Dirks, 2007). For example, mice disrupted for CD34, a marker of hair follicle bulge stem cells, display a significant delay in follicle cycling and, in contrast to wild-type mice, do not develop skin papillomas in response to 7,12-dimethylbenz(a)anthracene (DMBA) and 12-O-tetradecanoylphorbol-13-acetate (TPA), although DNA adduct formation was similar in both strains (Trempus et al, 2007). While the above studies suggest that decreased regeneration rates affect cancer incidence, a great deal remains to be done to substantiate this hypothesis.…”