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. Author manuscript; available in PMC: 2011 Oct 1.
Published in final edited form as: Cancer Prev Res (Phila). 2010 Sep 21;3(10):1217–1221. doi: 10.1158/1940-6207.CAPR-10-0210

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

Pamela Jo Harris 1, Naoko Takebe 1, S Percy Ivy 1
PMCID: PMC2992967  NIHMSID: NIHMS233639  PMID: 20858758

Abstract

The understanding of the anatomy and development of fetal and adult hair follicles and 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 homolog 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 basal cell carcinoma.

Introduction

Over the last 30 years, numerous publications have described how human hair develops in both fetal and post-natal life. Over the last ten years, lessons learned about hair development have led to investigations into the origin of human basal cell carcinoma (BCC) of the skin. Such investigations are shedding light on the central role of embryonic pathway signaling, particularly Sonic hedgehog (Shh) signaling and interactions with the insulin-like growth factor (IGF) axis, in this cancer.

Anatomy of the Hair Follicle

In the embryo, the dermis provides a primary signal causing epidermal cells to develop an epithelial bud, also called a placode and hair bud, which will develop into the outer root sheath of the hair follicle. The epithelial bud signals back to the dermis, which then causes mesenchymal cells to condense and form the dermal condensate, or mesenchymal dermal papilla(1). The mesenchymal dermal condensate provides a secondary signal to the epithelial bud in the epidermis to form the hair follicle sheath and to descend with the mesenchymal dermal papillae into the dermis.

The fetal hair follicle has a region known as the “bulge,” which contains stem cells with the capacity to differentiate into the various cells of the hair follicle, sebaceous gland and duct, apocrine gland and duct (in some hair follicles), and epidermis (2). It also has a region known as the “hair germ,” or “hair matrix,” which contains rapidly proliferating cells that develop the inner root sheath and hair shaft (1, 3).

Post-natal hair growth recapitulates much of embryonic hair growth (Fig. 1). Lying at the base of the outer root shaft of the follicle, “der Wulst,” or “the bulge,” is analogous to the embryonic bulge. It too is composed of pluripotent stem cells (capable of differentiating into different types of mature cells; ref. 3) why do you want this reference to be in a different format? we have used (#) for other references. Also lying at the base of the outer shaft but in an area distinct from the bulge, the germinative matrix is analogous to the embryonic hair germ (4). The base and lateral walls of the post-natal hair follicle envelop the dermis, and together they descend into the dermis and ultimately to the fat.

Fig. 1.

Fig. 1

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Hair follicle with deletion of patched 1 homolog (PTCH1). The rapidly proliferating keratin 14 (K14)+ cells that surround K15+ cells overexpress insulin-like growth factor binding protein 2 (IGFBP-2). K14+ and IGFBP-2+ cells may represent early-transit–amplifying cells. K15+ cells and P63+ transit-amplifying progenitor cells expand. K15+ cells 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. Basal cell carcinoma likely is the result of an abundance of proliferating, non-differentiating cells.

Conversations between the Mesenchyme and the Developing Hair Follicle

The close physical relationship between the mesenchymal dermal papillae and the developing hair follicle facilitates molecular signaling between these two regions. This “conversation” is critical for regulation of normal hair follicle maturation, both in utero and in post-natal life; it occurs primarily between proteins and genes in well-described embryonic pathways. The best-described pathways are Shh, Wingless–related mouse mammary tumor virus integration site (WNT; ref. 5), bone morphogenic protein (BMP), and Notch.

Shh pathway

Shh signaling from the dermis is required for hair-follicle development in the fetus. The critical role of Shh in this “organ” was first described in the late 1990s (6, 7). In post-natal life, immediately before and during anagen, the first and longest phase of the adult hair cycle, during which there is active growth of the follicle, the hedgehog ligand Sonic is produced by dermal cells around the base and lower lateral walls of the developing hair follicle. The other hedgehog ligands, Indian and Desert, are not produced. Sonic ligand binds to the patched homolog 1 (PTCH1) transmembrane receptor and, to a lesser extent, to the PTCH2 transmembrane receptor. Ligand binding inactivates the Ptch1 receptor, resulting in relocalization of Smoothened (SMO) from the cell surface to the tips of cilia; this leads to downstream signaling events, including the activation of the GLI1 proteins (8). Activated GLI1 transcription factors translocate to the nucleus and promote transcription of several genes including cyclin-dependent kinases D and E (cyclin D and cyclin E), vascular endothelial growth factor (VEGF), MYC (Myc), IGF binding protein 2 (IGFBP-2), and IGF-1 (Fig. 2). The hedgehog-interacting protein (HIP), a membrane glycoprotein, was recently shown to attenuate Shh signaling in a manner analogous to that of ligand-free PTCH1 (9). Shh signaling stimulates bulge stem cells to produce transit-amplifying cells, which undergo a limited number of divisions in the germinative matrix before differentiating (10). Without Shh signaling, the latter stages of hair-follicle development would not occur. Shh signaling does not occur during catagen, the transition and shortest phase of the adult hair cycle, during which the hair club is formed, nor during the subsequent intermediate-length resting telogen phase, which results in the final keratinized, dead hair club.

Fig. 2.

Fig. 2

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Sonic hedgehog (SHH) pathway. Patched 1 homolog (PTCH1) is activated either by binding of SHH ligand from a signaling cell or by intrinsic mutation, leading to relocalization of Smoothened (SMO) from the cell membrane. This activation results in signaling through Costal, COS, and suppressor of fused homolog (SuFu) and subsequent activation of GLI 1/2 transcription factors. Activated GLI transcription factors, which translocate to the nucleus, upregulate some genes—including cyclin-dependent kinases D and E (cyclin D and E); hedgehog-interacting protein (HIP), insulin-like growth factor binding protein-2 (IGFBP-2) and other IGFBPs, hairy and enhancer of split 1 (Hes1), sclerosin domain-containing 1 (Sostdc), phosphatidic acid phosphatase type 2B (Ppap2b), and bone morphogenic protein (BMP)—and downregulate others, including BMP and activin membrane-bound inhibitor (Bambi) and secreted frizzle-related protein 1–2 (Sfrp1-2). Upregulation of IGFBP-2 presumably results in an increase in IGFBP-2 expression in K14+ cells and in secretion of IGFBP-2 into the extracellular space around K14+ cells.

WNT Pathway

The mesenchymal dermis ligands of the WNT family activate the canonical WNT pathway, causing an increase in nuclear β-catenin, which, along with other proteins, upregulates Shh signaling and Ptch in new follicles (11, 12). Overexpression of nuclear β-catenin appears to help determine the type of mature progeny that develop from progenitor cells, a process known as lineage choice. Generally speaking, signals from the WNT pathway activate the Shh pathway. There is evidence, however, that when the Shh pathway is ectopically activated, the reverse occurs, with Shh signals activating the WNT pathway (13). Non-canonical WNT signaling also occurs. There is a dramatic upregulation of WNT 10b at the earliest stages of embryonic hair-follicle development and at the post-natal onset of anagen. WNT 5a appears to require Shh for its expression in developing hair follicles. WNT 10a and 10b are present in the hair follicle placode. WNT 3 is expressed in differentiating hair shaft precursors (14).

Notch Pathway

The Notch pathway is also important in hair-follicle development in both the fetus and after birth and has been studied in this regard most extensively in inner-ear hair follicles (15). In the inner ear, especially in mesenchymal cells, Jagged 1 and 2 and Delta ligands from supporting cells bind to the Notch receptor, leading to γ-secretase cleavage of the receptor and release of the Notch intracellular domain (NICD) into the cytoplasm. The NICD translocates to the nucleus, converting the centromere binding factor-1 (CBF1)–repressor complex into an activating complex that upregulates the basic helix-loop-helix transcript regulators, Hairy and Enhancer of Split (HES) and HES-related genes. HES and HES-related protein genes antagonize the mouse Atonal homolog 1 gene (Math1, Atoh1; ref. 16).

BMP Pathway

BMPs are secreted molecules belonging to the transforming growth factor-beta (TGF-β) super family. Various genes for BMPs and their receptors are found and appear to play a significant role in developing hair follicles in the mouse. During hair-follicle induction, BMP-2 and BMP receptor-IA (BMPR-IA) are expressed in the hair placode; BMP-4 and noggin (whose gene product is an antagonist of BMP) are expressed in the mensenchymal condensate (17, 18). In post-natal life, BMP-4 is expressed in the dermis and germinative hair matrix; upregulation of noggin in the follicle and mesenchyme and down-regulation of BMPR-IA in proliferating cells of the germinative matrix accompany the transition to anagen (19).

IGF pathways genes versus proteins

IGF-I and IGF-II are expressed by mesenchymal cells of the dermis and dermal papillae and IGF-1 receptor (IGF-IR) gene expression has been identified in proliferating cells of the hair matrix (20, 21). The mRNAs of IGFBPs 3–5 are widely expressed in fetal mesenchymal skin cells; IGFBP-2 mRNA, on the other hand, is highly expressed in fetal epithelial cells (20). Together, these findings raise the possibility that IGF pathways, like embryonic pathways, or IGFBPs themselves may contribute to the regulation of hair-follicle development.

Nevoid BCC and Sporadic BCC

Currently, it is generally believed that BCC develops from Shh-activated hair-follicle progenitor cells that proliferate aggressively but fail to differentiate. It is also possible that Shh-activated epidermal stem cells, rather than hair-follicle progenitor cells, are responsible for BC carcinogenesis (22). Patients with nevoid BCC syndrome (NBCCS) have a defect in the Ptch1 gene located on chromosome 9q (9q22.3). They inherit a single defective copy of Ptch1 and subsequently suffer a second somatic hit, which results in loss of wild-type Ptch1 (23). Patients with sporadic BCC have several mutations in the Shh pathway, the most common being mutations in Ptch1. Deletion or inactivation of Ptch1 occurs in 30%–60% of sporadic BCC (24). Activating mutations in SMO are well-described and, although mutations in Gli1, Gli2 and Gli3 are relatively rare, overexpression of Gli1 is common (25–27).

Shh Pathway, Ptch1, and IGFBP-2 Expression Linked in the Evolution of BCC

New insights into the roles of IGFBP-2 in BCC are reported elsewhere in this issue of the journal (28). Keratin 14 (K14)–Cre: Ptch1lox/lox mice, which have a deletion of Ptch1 in rapidly proliferating K14+ cells, are shown to have the following characteristics: Ectopic activation of hedgehog signaling; early post-natal loss of hair-follicle structure; expansion of the population of K14+ cells in the permanent region of the outer-root sheath around the hair follicle bulge; expansion of the population of K15+ bulge stem cells; increased numbers of P63+ transit-amplifying progenitor cells; expansion of the interfollicular epithelial basal cell layer; and, later in the post-natal period, the development of BCC. K14+ cells in this murine model have increased expression of IGFBP-2.

The expanded populations of K15+ and P63+ cells in the hair follicle, but not P63+ cells in the interfollicular epithelium, remain undifferentiated. Data support the hypothesis that Ptch1 deletion in K14+ cells increases the pluripotent stem-cell niche and inhibits differentiation, whereas IGFBP-2 may increase epidermal progenitor cells and indirectly inhibit hair-follicle proliferation (28). When IGFBP-2 is blocked, the epidermal progenitor-cell population fails to expand. These undifferentiated, proliferating cells are responsible for the formation of BCC, which also expresses IGFBP-2. As in K14–Cre: Ptch1lox/lox mice, this report shows that IGFBP-2 was overexpressed in 20 of 23 human BCC samples. Ptch1 mutations in BCC are suggested by analogy to be associated with IGFBP-2 overexpression and BCC induction in humans (Fig. 2). The occurrence of IGF signaling in mice, however, could not be demonstrated (29, 30).

IGFBP-2 is probably secreted into the extracellular space around K14+ cells, which is not discussed in the new report (28). Other researchers have demonstrated the extensive interactions between Shh activation and downstream target genes in murine mesodermal-cell experiments; these downstream target genes regulate the Shh pathway and provide cross-talk between embryonic signaling pathways (29, 30). In the murine mesodermal cell experiments, Shh-pathway signaling caused upregulation of the following genes: Hes 1, which is critical in Notch signaling; HIP, which is important in the WNT and Shh pathways; sclerosin domain-containing 1 (Sostdc1), which is important in the WNT and BMP pathways; phosphatidic acid phosphatase type 2B (Ppap2b), important in the WNT pathway; and BMP-5 in the BMP pathway. Hedgehog activation causes downregulation of the following genes: BMP and activin membrane–bound inhibitor (Bambi), an inhibitor of the BMP pathway; secreted frizzle-related protein 1 and 2 (Sfrp2) in the WNT pathway; and WNT- 5b. One of the ways in which upregulation of Shh genes influences cross-talk with embryonic pathways is via the proteins they secrete. Therefore, it would be interesting to better understand whether, and how much, IGFBP-2 is secreted into the extracellular space around K14–Cre: Ptch1lox/lox cells. This information could lead to a deeper understanding of how IGFBP-2 regulates embryonic pathways. Furthermore and of importance, demonstration of secreted IGFBP-2 around K14–Cre: Ptch1lox/lox cells would potentially provide another avenue for understanding the relationship between IGFBP-2 and IGF pathway modulation in BCC. This issue deserves future exploration.

Consideration of why IGFBP-2 is localized where it is within the cell could also be informative. Does intercellular IGFBP-2 limit the availability of IGF-1, a putative mitogen (31)? Is there a receptor for IGFBP-2 on the BCC cell membrane or is IGFBP-2 endocytosed? Furthermore, although the authors note IGFBP-2 expression in both mesenchymal and epithelial cells of K14–Cre: Ptch1lox/lox mice, they do not elaborate on this expression, for example, by hypothesizing about the relative significance of IGFBP-2 expression in these two cell types.

It is well accepted that the genes for IGF and IGFBPs are upregulated by GLI transcription factors in the nucleus of Shh pathway–activated cells. The elegant experimental data appearing elsewhere in this issue of the journal (28) support an interesting link between the Shh pathway, Ptch1 expression, and Igfbp-2 expression in the evolution of BCC. We hope that future experiments will help provide answers to the important questions raised here.

Acknowledgments

With grateful appreciation to Ronald Warren, PSI International, for editorial assistance and to Christopher Risch, Technical Resources International, for assistance with the figures.

Footnotes

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

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