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Molecular Conversations and the Development of the Hair Follicle and Basal Cell Carcinoma

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Molecular Conversations and the Development of the Hair Follicle and Basal Cell Carcinoma Published OnlineFirst September 21, 2010; DOI: 10.1158/1940-6207.CAPR-10-0210 Published OnlineFirst on September 21, 2010 as 10.1158/1940-6207.CAPR-10-0210 Review Cancer Prevention Research Molecular Conversations and the Development of the Hair Follicle and Basal Cell Carcinoma Pamela Jo Harris, Naoko Takebe, and S. Percy Ivy Abstract The understanding of the anatomy and development of fetal and adult hair follicles and the molecular study of the major embryonic pathways that regulate the hair follicle have led to exciting discoveries concerning the development of basal cell carcinoma (BCC). These studies have shed light on the major roles of Sonic hedgehog (Shh) signaling and its interactions with the insulin-like growth factor (IGF) axis in BCC development. New work, for example, explores a link between Shh signaling and IGF binding protein-2 (IGFBP-2) in the hair follicle as it transforms into BCC. IGFBP-2 was overexpressed in specific hair follicle cells of mice with ectopically activated Shh signaling [keratin 14 (K14)-Cre: patched homo- logue 1 (Cre: Ptch1)lox/lox mice]. Ptch1 deletion resulted in both an expansion of the stem cell niche and inhibition of cell differentiation. In transformed hair follicles, IGFBP-2 mediates epidermal progenitor cell expansion. Evidence also indicated that IGFBP-2 is expressed in human BCC. Cancer Prev Res; 3(10); 1217–21. ©2010 AACR. Introduction The fetal hair follicle has a region known as the “bulge,” which contains stem cells with the capacity to differentiate Over the last 30 years, numerous publications have into various cells of the hair follicle, sebaceous gland and described how human hair develops in both fetal and duct, apocrine gland and duct (in some hair follicles), and postnatal life. Over the last 10 years, lessons learned about epidermis (2). It also has a region known as the “hair hair development have led to investigations into the origin germ,” or “hair matrix,” which contains rapidly prolife- of human basal cell carcinoma (BCC) of the skin. Such rating cells that develop the inner root sheath and hair investigations are shedding light on the central role of shaft (1, 3). embryonic pathway signaling, particularly Sonic hedgehog Postnatal hair growth recapitulates much of embryon- (Shh) signaling and interactions with the insulin-like ic hair growth (Fig. 1). Lying at the base of the outer growth factor (IGF) axis, in this cancer. root shaft of the follicle, “der Wulst,” or “the bulge,” is analogous to the embryonic bulge. It is also com- Anatomy of the Hair Follicle posed of pluripotent stem cells (capable of differentiat- ing into different types of mature cells; ref. 3). Also In the embryo, the dermis provides a primary signal, lying at the base of the outer shaft but in an area dis- causing epidermal cells to develop an epithelial bud, also tinct from the bulge, the germinative matrix is analo- called a placode and hair bud, which will develop into the gous to the embryonic hair germ (4). The base and outer root sheath of the hair follicle. The epithelial bud lateral walls of the postnatal hair follicle envelop the signals back to the dermis, which then causes mesench- dermis, and together they descend into the dermis and ymal cells to condense and form the dermal condensate ultimately to the fat. or mesenchymal dermal papilla (1). The mesenchymal dermal condensate provides a secondary signal to the Conversations between the Mesenchyme and epithelial bud in the epidermis to form the hair follicle the Developing Hair Follicle sheath and to descend with the mesenchymal dermal papillae into the dermis. The close physical relationship between the mesenchy- mal dermal papillae and the developing hair follicle fa- cilitates molecular signaling between these two regions. Authors' Affiliation: Cancer Therapy Evaluation Program, National This “conversation” is critical for regulation of normal Cancer Institute, NIH, Bethesda, Maryland hair follicle maturation, both in utero and in postnatal Corresponding Author: S. Percy Ivy, Cancer Therapy Evaluation Program, National Cancer Institute, 6130 Executive Plaza North, Suite life; it occurs primarily between proteins and genes in 7131, Bethesda, MD 20892-7426. Phone: 301-496-1196; Fax: 301-402- well-described embryonic pathways. The best-described 0428; E-mail: [email protected]. pathways are Shh, Wingless-related mouse mammary tu- doi: 10.1158/1940-6207.CAPR-10-0210 mor virus integration site (WNT; ref. 5), bone morpho- ©2010 American Association for Cancer Research. genic protein (BMP), and Notch. www.aacrjournals.org 1217 Downloaded from cancerpreventionresearch.aacrjournals.org on October 2, 2021. © 2010 American Association for Cancer Research. Published OnlineFirst September 21, 2010; DOI: 10.1158/1940-6207.CAPR-10-0210 Harris et al. Fig. 1. Hair follicle with deletion of PTCH1. The rapidly proliferating K14+ cells that surround K15+ cells overexpress IGFBP-2 (28). K14+ and IGFBP-2+ cells may represent early-transit–amplifying cells. K15+ cells and P63+ transit– amplifying progenitor cells expand. K15+ and P63+ cells in the hair follicle, but not P63+ cells in the interfollicular epithelium, remain undifferentiated. Deletion of PTCH1 increases the pluripotent stem cell niche and inhibits differentiation. IGFBP-2 may mediate the increase in epidermal P63+ transit-amplifying progenitor cells. BCC likely is the result of an abundance of proliferating, nondifferentiating cells. Shh pathway teins (8). Activated GLI1 transcription factors translocate Shh signaling from the dermis is required for hair fol- to the nucleus and promote transcription of several licle development in the fetus. The critical role of Shh genes, including cyclin-dependent kinases D and E in this “organ” was first described in the late 1990s (cyclin D and cyclin E), vascular endothelial growth (6, 7). In postnatal life, immediately before and during factor (VEGF), MYC (Myc), IGF binding protein 2 anagen, the first and longest phase of the adult hair (IGFBP-2), and IGF-1 (Fig. 2). The hedgehog-interacting cycle, during which there is active growth of the follicle, protein (HIP), a membrane glycoprotein, was recently the hedgehog ligand Sonic is produced by dermal cells shown to attenuate Shh signaling in a manner analogous around the base and lower lateral walls of the develop- to that of ligand-free PTCH1 (9). Shh signaling stimulates ing hair follicle. The other hedgehog ligands, Indian and bulge stem cells to produce transit-amplifying cells, which Desert, are not produced. Sonic ligand binds to the undergo a limited number of divisions in the germinative patched homologue 1 (PTCH1) transmembrane receptor matrix before differentiating (10). Without Shh signaling, and, to a lesser extent, to the PTCH2 transmembrane the latter stages of hair follicle development would not receptor. Ligand binding inactivates the Ptch1 receptor, occur. Shh signaling does not occur during catagen, the resulting in relocalization of Smoothened (SMO) from transition and shortest phase of the adult hair cycle, during the cell surface to the tips of cilia; this leads to down- which the hair club is formed, nor during the subsequent stream signaling events, including the activation of the intermediate-length resting telogen phase, which results in glioma-associated oncogene homologue 1 (GLI1) pro- the final keratinized, dead hair club. 1218 Cancer Prev Res; 3(10) October 2010 Cancer Prevention Research Downloaded from cancerpreventionresearch.aacrjournals.org on October 2, 2021. © 2010 American Association for Cancer Research. Published OnlineFirst September 21, 2010; DOI: 10.1158/1940-6207.CAPR-10-0210 Molecular Conversations, Hair Follicle, Basal Cell Carcinoma WNT pathway Notch pathway The mesenchymal dermis ligands of the WNT family The Notch pathway is also important in hair follicle de- activate the canonical WNT pathway, causing an increase velopment in both the fetus and after birth and has been in nuclear β-catenin, which, along with other proteins, studied in this regard most extensively in inner-ear hair upregulates Shh signaling and Ptch in new follicles follicles (15). In the inner ear, especially in mesenchymal (11, 12). Overexpression of nuclear β-catenin seems to cells, Jagged 1 and 2 and Delta ligands from supporting help determine the type of mature progeny that develop cellsbindtotheNotchreceptor,leadingtoγ-secretase from progenitor cells, a process known as lineage choice. cleavage of the receptor and release of the Notch intracel- Generally speaking, signals from the WNT pathway acti- lular domain into the cytoplasm. The Notch intracellular vate the Shh pathway. There is evidence, however, that domain translocates to the nucleus, converting the centro- when the Shh pathway is ectopically activated, the re- mere binding factor-1 repressor complex into an activating verse occurs, with Shh signals activating the WNT path- complex that upregulates the basic helix-loop-helix tran- way (13). Noncanonical WNT signaling also occurs. script regulators, hairy and enhancer of split (HES), and There is a dramatic upregulation of WNT 10b at the ear- HES-related genes. HES and HES-related protein genes liest stages of embryonic hair follicle development and antagonize the mouse atonal homologue 1 gene (Math1, at the postnatal onset of anagen. WNT 5a seems to re- Atoh1; ref. 16). quire Shh for its expression in developing hair follicles. WNT 10a and 10b are present in the hair follicle pla- BMP pathway code. WNT 3 is expressed in differentiating hair shaft BMPs
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