Article

Pathobiology of chemotherapy-induced hair loss

Institute of Inflammation and Repair, University of Manchester, Manchester, UK. Electronic address: .
The Lancet Oncology (Impact Factor: 25.12). 02/2013; 14(2):e50-e59. DOI: 10.1016/S1470-2045(12)70553-3
Source: PubMed

ABSTRACT Hair loss can be a psychologically devastating adverse effect of chemotherapy, but satisfactory management strategies for chemotherapy-induced alopecia remain elusive. In this Review we focus on the complex pathobiology of this side-effect. We discuss the clinical features and current management approaches, then draw upon evidence from mouse models and human hair-follicle organ-culture studies to explore the main pathobiology principles and explain why chemotherapy-induced alopecia is so challenging to manage. P53-dependent apoptosis of hair-matrix keratinocytes and chemotherapy-induced hair-cycle abnormalities, driven by the dystrophic anagen or dystrophic catagen pathway, play important parts in the degree of hair-follicle damage, alopecia phenotype, and hair-regrowth pattern. Additionally, the degree of hair-follicle stem-cell damage determines whether chemotherapy-induced alopecia is reversible. We highlight the need for carefully designed preclinical research models to generate novel, clinically relevant pointers to how this condition may be overcome.

0 Bookmarks
 · 
177 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Cisplatin (CisPt) is a commonly used platinum-based chemotherapeutic agent. Its efficacy is limited due to drug resistance and multiple side effects, thereby warranting a new approach to improving the pharmacological effect of CisPt. A newly developed mathematical hypothesis suggested that mechanical loading, when coupled with a chemotherapeutic drug such as CisPt and immune cells, would boost tumor cell death. The current study investigated the aforementioned mathematical hypothesis by exposing human hepatocellular liver carcinoma (HepG2) cells to CisPt, peripheral blood mononuclear cells, and mechanical stress individually and in combination. HepG2 cells were also treated with a mixture of CisPt and carnosine with and without mechanical stress to examine one possible mechanism employed by mechanical stress to enhance CisPt effects. Carnosine is a dipeptide that reportedly sequesters platinum-based drugs away from their pharmacological target-site. Mechanical stress was achieved using an orbital shaker that produced 300 rpm with a horizontal circular motion. Our results demonstrated that mechanical stress promoted CisPt-induced death of HepG2 cells (~35% more cell death). Moreover, results showed that CisPt-induced death was compromised when CisPt was left to mix with carnosine 24 hours preceding treatment. Mechanical stress, however, ameliorated cell death (20% more cell death).
    BioMed Research International 10/2014; 2015. DOI:10.1155/2015/430569 · 2.71 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Adenosine triphosphate binding cassette (ABC) transporters are involved in the active transport of an extremely diverse range of substrates across biological membranes. These transporters are commonly implicated in the development of multidrug resistance and are also involved in numerous physiological and homeostatic processes, including lipid transport, cell migration and differentiation. Since the expression of ABC transporters in the human hair follicle (HF) is as yet unclear, this study aimed to close this knowledge gap. By qPCR analysis, numerous members of the ABC transporter superfamily, such as ABCB1, G2 and A12, were found to be transcribed in full-length human scalp HFs. Immunofluorescence microscopy demonstrated that the intrafollicular protein expression of different xenobiotic ABC transporters (ABCB1, ABCC1, ABCC4, ABCG2) varies greatly, with ABCG2 expression primarily restricted to the epithelial stem cell region of the outer root sheath (bulge), whereas both ABCB1, ABCC1 and ABCC4 expression was more widespread. Lipid transporters ABCA1, ABCA12 and ABCA4 were almost uniformly expressed throughout the HF epithelium. Functional ABCB1/G2 activity was demonstrated by exclusion of the substrate dye, Hoechst 33342. In the bulge, this was reversed by ABCB1 and ABCG2 inhibition. These data encourage one to further investigate ABC transporters as potentially important regulators of HF epithelial biology. Clinically, pharmacological modulation of the activity of selected intrafollicular ABC transporters may permit novel therapeutic interventions, such as protecting HF stem cells from chemotherapy-induced damage, counteracting cholesterol-associated hypertrichosis, and manipulating the intrafollicular prostaglandin balance in androgenetic alopecia.This article is protected by copyright. All rights reserved.
    British Journal of Dermatology 11/2014; DOI:10.1111/bjd.13549 · 4.10 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The hair follicle (HF) represents a prototypic ectodermal–mesodermal interaction system in which central questions of modern biology can be studied. A unique feature of these stem-cell-rich mini-organs is that they undergo life-long, cyclic transformations between stages of active regeneration (anagen), apoptotic involution (catagen), and relative proliferative quiescence (telogen). Due to the low proliferation rate and small size of the HF during telogen, this stage was conventionally thought of as a stage of dormancy. However, multiple lines of newly emerging evidence show that HFs during telogen are anything but dormant. Here, we emphasize that telogen is a highly energy-efficient default state of the mammalian coat, whose function centres around maintenance of the hair fibre and prompt responses to its loss. While actively retaining hair fibres with minimal energy expenditure, telogen HFs can launch a new regeneration cycle in response to a variety of stimuli originating in their autonomous micro-environment (including its stem cell niche) as well as in their external tissue macro-environment. Regenerative responses of telogen HFs change as a function of time and can be divided into two sub-stages: early ‘refractory’ and late ‘competent’ telogen. These changing activities are reflected in hundreds of dynamically regulated genes in telogen skin, possibly aimed at establishing a fast response-signalling environment to trauma and other disturbances of skin homeostasis. Furthermore, telogen is an interpreter of circadian output in the timing of anagen initiation and the key stage during which the subsequent organ regeneration (anagen) is actively prepared by suppressing molecular brakes on hair growth while activating pro-regenerative signals. Thus, telogen may serve as an excellent model system for dissecting signalling and cellular interactions that precede the active ‘regenerative mode’ of tissue remodeling. This revised understanding of telogen biology also points to intriguing new therapeutic avenues in the management of common human hair growth disorders.
    Biological Reviews 11/2014; DOI:10.1111/brv.12151 · 10.26 Impact Factor

Full-text

Download
48 Downloads
Available from
May 21, 2014