Dissecting the Impact of Chemotherapy on the Human Hair Follicle

Abstract

Chemotherapy-induced alopecia represents one of the major unresolved problems of clinical oncology. The underlying molecular pathogenesis in humans is virtually unknown because of the lack of adequate research models. Therefore, we have explored whether microdissected, organ-cultured, human scalp hair follicles (HFs) in anagen VI can be exploited for dissecting and manipulating the impact of chemotherapy on human HFs. Here, we show that these organ-cultured HFs respond to a key cyclophosphamide metabolite, 4-hydroperoxycyclophosphamide (4-HC), in a manner that resembles chemotherapy-induced HF dystrophy as it occurs in vivo: namely, 4-HC induced melanin clumping and melanin incontinence, down-regulated keratinocyte proliferation, massively up-regulated apoptosis of hair matrix keratinocytes, prematurely induced catagen, and up-regulated p53. In addition, 4-HC induced DNA oxidation and the mitochondrial DNA common deletion. The organ culture system facilitated the identification of new molecular targets for chemotherapyinduced HF damage by microarray technology (eg, interleukin-8, fibroblast growth factor-18, and glypican 6). It was also used to explore candidate chemotherapy protectants, for which we used the cytoprotective cytokine keratinocyte growth factor as exemplary pilot agent. Thus, this novel system serves as a powerful yet pragmatic tool for dissecting and manipulating the impact of chemotherapy on the human HF. (Am J Pathol

Testing Chemotherapeutic Agents in the Feather Follicle Identifies a Selective Blockade of Cell Proliferation and a Key Role for Sonic Hedgehog Signaling in Chemotherapy-Induced Tissue Damage

“…Indeed, an increased expression of TNFa and IFNg in the feather follicles was noticed (Supplementary Figure S1 online). This is well in line with previous studies documenting altered cytokine production in human scalp hair follicles treated with a CYP derivative (Bodo et al, 2007) and with the fact that anti-inflammatory hormone treatment significantly modulates the response of human hair follicles to chemotherapy-induced damage in vitro (Bodo et al, 2009).…”

“…Yet, the role of Shh signaling in mediating chemotherapy-induced tissue damage as such had not been investigated or even considered in CIA pathobiology research (Paus et al, 2013). Obviously, before the potential clinical relevance of our findings in feather and murine hair follicles can be judged, the role of Shh signaling should be further investigated in chemotherapy-damaged human scalp hair follicles, using established in vitro (Bodo et al, 2007) and in vivo systems (Paus et al, 2013) Wang et al, 2006;Trueb, 2009), and our preliminary results suggest that reactive oxygen species may downregulate Shh gene expression (not shown). Downregulation of Shh gene expression is a rather quick response by CYP treatment--i.e.…”

“…Transmission electron microscopy (TEM) analysis remains the ''gold standard'' of cytomorphological evidence for cell apoptosis (Magerl et al, 2001;Bodo et al, 2007;Elmore, 2007). Again, this demonstrated normal euchromatin ultrastructure in the nuclei of rachis cells, whereas isolated cells in the branching area showed typical condensed heterochromatin, and/or apoptotic bodies ( Figure 2d).…”

“…Intrafollicular apoptosis is a major event during CIA (Lindner et al, 1997, Botchkarev et al, 2000Sharov et al, 2004;Bodo et al, 2007;Paus et al, 1994;. Therefore, apoptosis in feather follicles was investigated with the DNA binding dye propidium iodide (PI).…”

The Influence of Various Parameters on the Success of Sensor-Controlled Scalp Cooling in Preventing Chemotherapy-Induced Alopecia

“…In the 1970s, first attempts were made to reduce cytostatic exposure of the proliferating matrix ceratinocytes of the hair follicles through various methods. The use of tourniquets or ice caps provided no major success [4][5][6][7]. So far, pharmacological attempts to reduce CIA have also been rather ineffective.…”