Sie sind auf Seite 1von 10

Review

Pathobiology of chemotherapy-induced hair loss


Ralf Paus, Iain S Haslam, Andrey A Sharov, Vladimir A Botchkarev

Hair loss can be a psychologically devastating adverse eect of chemotherapy, but satisfactory management strategies for
chemotherapy-induced alopecia remain elusive. In this Review we focus on the complex pathobiology of this side-eect.
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 chemotherapyinduced alopecia is so challenging to manage. P53-dependent apoptosis of hair-matrix keratinocytes and chemotherapyinduced 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.

Introduction
Few adverse eects of chemotherapy generate as much
trepidation as the often substantial and sudden hair loss
that can be induced by selected chemotherapeutic agents.
Although some treatment options, such as scalp cooling,
show a degree of ecacy in specic chemotherapy
regimens (eg, taxane monotherapy), many are unsatisfactory. As such, chemotherapy-induced alopecia
represents one of the major unmet challenges in clinical
oncology. Extreme anxiety related to this cosmetic
disgurement reportedly drives 8% of patients to reject
chemotherapy.1 The development of more satisfactory
management strategies for chemotherapy-induced
alopecia, therefore, remains a major research challenge
in clinical oncology.
Chemotherapy-induced alopecia has been studied in
human beings and animals since chemotherapy was rst
introduced into clinical medicine.25 Reviews on the clinical
presentation and management of chemotherapy-induced
alopecia are available,69 but the underlying pathobiology
remains insuciently understood, which results in a lack
of well dened targets for intervention. Research should be
undertaken collaboratively by oncologists, hair biologists,
dermatologists, and pharmacologists, but such an interdisciplinary approach regrettably remains underdeveloped.
In this Review we explore the therapeutic conundrum
of chemotherapy-induced alopecia, which aects patients
and physicians,10 and emphasise the psychosocial burden
of this complication. We summarise the clinical features
and current management strategies, along with the core
principles of the complex pathobiology, deduced from
analysis of experimental models. We close by discussing
concrete strategies to overcome chemotherapy-induced
alopecia and presenting some of the principal open
questions that will need to be addressed.

Clinical characteristics
Chemotherapy-induced alopecia generally presents
suddenly and initially manifests as patterned hair loss
that is most prominent on the scalp.6,9,11,12 The areas of
greatest hair damage seem to be selective, and in
particular aect scalp regions that show low total hair
densities, such as the frontal or occipital hairlines.12 Girls
www.thelancet.com/oncology Vol 14 February 2013

and women have widespread chemotherapy-induced


alopecia more frequently than any other pattern.12 Hairshaft shedding, which manifests as anagen euvium or
telogen euvium,12,13 begins days to weeks after the
initiation of many, although not all, chemotherapeutic
agents.6,8 The visible hair loss results from dened
disturbances of normal hair-shaft production and of hairfollicle cycling (gure 1). Reversibility of alopecia depends
on the degree of hair-follicle stem-cell damage.14
The risk of chemotherapy-induced alopecia and the
degree of hair loss dier substantially between
chemotherapeutic agents. Alkylating agents (cyclophosphamide, ifosfamide), cytotoxics (doxorubicin,
daunorubicin), antimicrotubule agents (docetaxel,
paclitaxel), and topoisomerase inhibitors (etoposide) are
among the agents with the most frequent and severe
eects. Conversely, uorouracil, hydroxycarbamide,
methotrexate, and thiotepa induce alopecia much less
frequently, and the eects are generally mild.6,15,16
Robust data on phenotype and degree of chemotherapyinduced alopecia in homogeneous cohorts of chemotherapy patients are unavailable. Nevertheless, the degree
of hair loss induced by high-risk chemotherapeutic agents,
such as cyclophosphamide, daunorubicin, etoposide, and
paclitaxel, varies by dose, administration regimen, the
patients age, comorbidities, and nutritional and hormonal
statuses, and multiple other factors within individual
patients. Some concomitant factors that can aect the risk
and the phenotype of chemotherapy-induced alopecia are
the chemotherapy protocol (curative vs a palliative
fractionated regimen) the presence of graft-versus-host
disease in patients who have undergone bone-marrow
transplantation, exposure to X-rays, age, and the presence
and progression of androgenetic alopecia.17 Thus, the
provision of a hair-loss prognosis to chemotherapy
patients remains educated guesswork. Helpful practical
suggestions for management and guidance material for
patients have, however, been published.6
Although rare, cases of permanent chemotherapyinduced alopecia, in which hair regrowth is severely
retarded or does not occur at all, are increasingly
reported.18,19 This outcome is frequently associated with
high-dose chemotherapy, typically before bone-marrow

Lancet Oncol 2013; 14: e5059


Department of Dermatology,
University of Lbeck, Lbeck,
Germany (Prof R Paus MD);
Institute of Inammation and
Repair, University of
Manchester, Manchester, UK
(Prof R Paus, I S Haslam PhD);
Centre for Skin Sciences,
University of Bradford,
Bradford, UK
(Prof V A Botchkarev PhD); and
Department of Dermatology,
Boston University School of
Medicine, Boston, MA, USA
(A A Sharov MD,
Prof V A Botchkarev)
Correspondence to:
Prof Ralf Paus, Department of
Dermatology, University of
Lbeck, Ratzeburger Allee 160,
Lbeck D-23538, Germany
ralf.paus@manchester.ac.uk

e50

Review

""""-... Chemotherapy
Catagen

Anageneffluvium
Anagen

Abnormal sheddinq

Inner-roo
, ,', -..,]ft;Lc
' It" u .

_Arrector
pili muscle

Thebulge

Club hair

:. '

sheath - S t e m cells

'-....'

Hair matrix
I

"

...

sheddmq

_:::-'i ~

c1--- i;
l'
I

~E: :::"'og,",

Figure 1: Eects of chemotherapy on the human hair follicle


Chemotherapy-induced alopecia most prominently aects the highly proliferative matrix keratinocytes of anagen hair
follicles, located in the hair bulb. In certain instances, hair-follicle stem cells are also damaged, which can lead to
permanent hair loss. HFPU=hair-follicle pigmentary unit. Modied from reference 14 by permission of American
Society for Clinical Investigation.

transplantation.19 Although the cause of permanent


chemotherapy-induced alopecia remains to be claried,
epithelial hair-follicle stem cells seem to have a crucial role.
When hair shafts have regrown after chemotherapyinduced alopecia, the colour and structure have frequently
changed markedly, although not always in an undesired
manner, and previously straight hair has reappeared as
curls (textural, pigmentary, or both changes in phenotype
of regrowing hair occur in up to 60% of patients).12 Such
changes pose intriguing mechanistic questions.

Management

See Online for appendix

e51

Management of chemotherapy-induced alopecia primarily


consists of counselling and the provision of written information,6 professional psychological support, and the
recommendation to use a wig (appendix).6,9,11,20
The hypothermic eect of scalp cooling is thought to
reduce scalp perfusion and, therefore, access of the bloodborne chemotherapy to the hair follicles, which aects
metabolism, drug uptake, and drug cytotoxic eects.21,22
Scalp-cooling devices produce only mild discomfort in
most patients assessed and seem to have been associated
with reduced hair loss in a substantial proportion.21 The
eectiveness of scalp-cooling caps cannot be judged until
data from satisfactorily designed, multicentre trials
involving well dened cohorts of patients have become
available, yet some trials and meta-analyses suggest
success rates well above 50%.11,21 However, this approach

has been related to some notable safety concerns.


Specically, if clinically unapparent scalp metastases are
present, tumour cells could be protected from the eects
of chemotherapy by reduced drug uptake.23,24 These
concerns, therefore, also need to be carefully investigated.
In terms of medications to prevent chemotherapyinduced alopecia, little information is available. The
topical application of 2% minoxidil did not prevent the
occurrence of chemotherapy-induced alopecia in ve of
six patients in one study.20 In another study, however, hair
regrowth was accelerated in women treated with 2%
minoxidil compared with that in those who received
placebo.25 Although the ecacy of minoxidil in preventing
chemotherapy-induced hair loss needs to be conrmed in
larger trials, it is viewed as a useful and safe promoter of
hair regrowth after chemotherapy-induced alopecia.11 The
encouraging protective eects against hair loss reported
for intravenous ammonium tricholoro(dioxyethyleneO-O)tellurate (AS101),26 an immunomodulatory tellurium
compound that doubles as a candidate anticancer agent,27
have not been followed up in further studies. Topical
vitamin D3 (calcitriol and calcipotriol), which is
commonly used as a dermatological therapy, has not
suppressed chemotherapy-induced alopecia in small
trials.13,28 This nding is not surprising because topical
calcitriol did not prevent cyclophosphamide-induced
alopecia in a mouse model, even though intrafollicular
apoptosis was reduced. Regrowth of normally pigmented
hair was accelerated in the mice,29,30 but hair regrowth
eects have not been assessed in clinical trials. Thus,
reliable preventive pharmacological therapy for
chemotherapy-induced alopecia is still sought.

Psychosocial burden and eects of stress


The state of a persons scalp and facial hair provides
psychosocial signals that range from general wellbeing to
social status, and groups' associations to features such as
sexual attraction, fashion, religion, philosophy, and
political views.31 Chemotherapy-induced alopecia isolates
patients by sending a strong indication of illness and of
deviation from the accepted visual norms. These eects
aggravate the psychosocial burden of cancer, promote
withdrawal from society, and lead to impaired quality of
life (appendix). It adds substantially to the burden of other
chemotherapy-related toxic eects (eg, nausea, bone pain,
fatigue, and peripheral neuropathy).1,32
A purported, although still theoretical, negative
repercussion of chronic psychoemotional stress related to
chemotherapy-induced alopecia is that antitumour
immune defences might be compromised, as has
been suggested in animal models.33,34 Additionally,
chemotherapy-induced hair loss, and the recovery from it,
might be negatively aected by psychoemotional stress.3537
Stress mediators induce severe neurogenic inammation
in rodent and human skin models, which has been
associated with inhibited hair growth.3741 Classic stress
mediators, such as corticotropin-releasing hormone,
www.thelancet.com/oncology Vol 14 February 2013

Review

substance P, and nerve growth factor, inhibit the growth of


human-scalp hair follicles in vitro, and promote catagen
development, which leads to telogen euvium.38,40 Thus,
hair loss could be aggravated by psychoemotional stress,
beyond the level of euvium and alopecia caused by direct
chemotherapy-related damage to hair follicles.

Chemotherapy

DNA damage

Sensors

Pathobiology
Although distinct hair-loss patterns are seen, the overall
nal clinical presentation of chemotherapy-induced
alopecia is similar across patients. Many chemotherapeutic
agents share proapoptotic pathways that have crucial roles
in chemotherapy-induced alopecia, especially P53mediated signalling (gure 2).42,43 The chemotherapeutic
agents most frequently associated with alopecia, however,
have distinct mechanisms of action and dier substantially
according to an individuals genetically determined susceptibility to chemotherapy-induced cytotoxic eects. To treat
chemotherapy-induced alopecia as one entity is, therefore,
misleading. Nevertheless, since the principal hair-follicle
damage-response pathways are shared (gures 1, 2), even
between chemically distinct chemotherapeutic agents, for
practical purposes we do so in this Review.

HUS1, RAD1, RAD9

RAD17

H2AFX

XRCC6/5

RAD50, MRE11A, NBN

12

Models of chemotherapy-induced alopecia


The preclinical development of eective preventive
treatment strategies for chemotherapy-induced alopecia
requires good research models in which pathobiology
can be explored and novel management strategies can be
tested. The best-characterised in-vivo models are in
neonatal rats7,44 and adult C57BL/6 mice.42,45,46 In these
models topical, oral, intravenous, and intraperitoneal
treatments have been tested before and after systemic
administration of the chemotherapeutic agent (eg,
cyclophosphamide or doxorubicin).
As chemotherapy-induced alopecia in human beings
primarily aects pigmented, mature anagen stage VI hair
follicles that have already undergone full cycling (gure 3),
the clinical relevance of the neonatal rat model is limited
because in this model chemotherapy aects hair follicles
that are still in the nal stages of postnatal morphogenesis.
Another major limitation of rodent models is that the hair
cycling is more or less synchronised across all follicles,
whereas in human beings each hair follicle follows its own
cycling rhythm.10 By contrast with organ-cultured humanscalp hair follicles, however, rodent models permit
investigation of how chemotherapy aects the hair-follicle
cycling, which is a crucial factor in the pathobiology of
chemotherapy-induced alopecia (gures 3, 4).4547 Additionally, as in human chemotherapy-induced alopecia, hair
loss in rodent models generally follows specic patterns.
Animal models of chemotherapy-induced alopecia
should be complemented by organ culture of human-scalp
hair follicles where possible.48 Organ culture of scalp hair
follicles enables direct testing of the damaging eects of
dened cytostatic agents (appendix) and provides the most
clinically relevant in-vitro surrogate model for human
www.thelancet.com/oncology Vol 14 February 2013

ATR

Transducers

ATM

P53/MDM2

Eectors and their targets

CDKN1A

GADD45

PRKDC

CHK1, CHK2

Apoptosis

Senescence
14-3-3

HIPK2

CDKN2A
PRB

CASP3/6/7
BAX

Cell-cycle arrest
PIDD

FAS

WEE-1.3
CDK1

CDK4/6
CDC25A/B/C

Figure 2: Molecular damage-response pathways activated by chemotherapy


CDKN1A and CDKN2A are also known as P21 and P16INK4A. XRCC6 and XRCC5 are also known as KU70 and KU80.

chemotherapy-induced alopecia of all currently available


preclinical models.48,49 Surgical grafting of human scalp
skin on to immunocompromised, chemotherapy-treated
mice might, however, become the research model of
choice for chemotherapy-induced alopecia, as it will combine the benets of human and rodent models (appendix).
Despite their limitations, these preclinical models have
provided invaluable insights into the pathobiology of
chemotherapy-induced alopecia that could not have been
identied even by in-depth analysis of clinical hair-loss
patterns.

Underlying principles of pathobiology


Rapidly proliferating, and therefore maximally vulnerable,
anagen hair follicles and their pigmentary system, which
is very sensitive to toxins, are the main targets of
chemotherapy-induced hair-follicle damage.24,45 In fact,
the proliferation rate of hair-matrix keratinocytes in
healthy anagen hair follicles is extremely high and easily
beats that of most malignant tumours.47,50 Moreover, the
specialised melanocytes of the hair-follicle pigmentary
unit (gure 1) generate huge amounts of melanin
(packaged into melanosomes) during anagen, but also
need to perfectly transfer them into the correct, terminally
dierentiating hair-follicle keratinocyte populations that
form the hair shaft.47 These tissue systems, therefore,
rank among those most sensitive to toxins and drugs in
the mammalian body, and can easily undergo rapid
apoptosis during chemotherapy.45,46,51,52 Telogen hair
follicles are less sensitive than anagen hair follicles to
chemotherapy,46 presumably because of low-level
proliferation and arrested pigmentary activity.50 Similarly,
the slow-cycling epithelial and melanocyte stem cells of
e52

Review

Late anagen
Damage to epithelial stem cells
determines reversibility of alopecia
Damage to melanocyte stem cells?

Telogen
euvium

Chemotherapy

Main damage
target: anagen
hair matrix
Additional damage to
hair-follicle vasculature
and mesenchyme?

Dystrophic anagen
Hair-shaft shedding (euvium/alopecia)
Continued but retarded growth of depigmented
and/or structurally abnormal hair shaft
Anagen abnormally prolonged

Dystrophic catagen
Accelerated hair regrowth of normal hair shafts by
shortened and accelerated re-entry into anagen

Exogen
Telogen
Late catagen

Figure 3: Eects of chemotherapy on the hair cycle


Whether and how chemotherapy increases active hair-shaft shedding (exogen) are unknown.9,38 Additionally, the eects of chemotherapy on the intrafollicular
oscillator system, which drives the hair cycle,47 remains to be determined.

hair follicles, which are located primarily in the bulge,


have low sensitivity (gure 1),53,54 although neither is by
any means invulnerable. Additionally, chemotherapeutic
agents damage the hair-follicle vasculature55 and the
sebaceous gland,56 which negatively aects hair-follicle
health and function. The slow-cycling inductive
broblasts of the dermal papilla (gure 1),47,57 however,
seem to be little damaged by chemotherapy.51 Yet, even
the hair-follicle mesenchyme seems to be aected, at least
in some models of chemotherapy-induced alopecia.48
Since the largest, most prominent, and most densely
seeded population of terminal anagen hair follicles is
found on the scalp, the response to chemotherapy in this
region dominates the clinical phenotype of chemotherapyinduced alopecia. For example, cyclophosphamide drives
human-scalp anagen hair follicles into apoptosis-driven
regression (catagen; gure 1).2,48 This change leads to
telogen euvium,10,13 which is characterised by shedding
of club hairs (loosely anchored hair shafts whose
proximal tip is depigmented; during catagen, the hair
shaft formed in the preceding anagen is transformed
into a club hair and shed during telogen or exogen). Even
a slight increase in the percentage of catagen hair follicles
results in a substantial increase in the number of club
hairs and visible shedding.10
The most characteristic hair-follicle response to
chemotherapy-induced damage is anagen euviumthe
e53

shedding of fully pigmented hair shafts while hair follicles


are still in the growth phase (gure 1). Normal
intrafollicular melanogenesis, melanin transfer, and
melanocyte survival become severely disrupted in the
anagen hair bulb (gures 3, 4, appendix).45,46,52 Nevertheless,
telogen euvium is more frequent during chemotherapyinduced alopecia than is generally assumed.6,13 This pattern
attests to the astounding capacity of human hair follicles to
cope with chemotherapy via several interacting molecular
mechanisms of damage control.58 Subthreshold hairfollicle damage induced, for example, by cyclophosphamide
in human hair-matrix keratinocytes can increase
proliferative activity, albeit briey, presumably as a repair
strategy.48 This damage defence and repair eciency of
anagen hair follicles58 explains why most patients with
chemotherapy-induced alopecia do not experience total
baldness, but more frequently have patchy, unevenly
distributed anagen euvium or diuse telogen euvium6
and rapid hair regrowth after the discontinuation of
chemotherapy. Therefore, the visible degree of hair loss in
chemotherapy-induced alopecia reects the net result of
how most aected anagen hair follicles have responded to
chemotherapy-induced damage.
Another important pathobiological principle is that the
degree of visible hair loss in chemotherapy-induced
alopecia does not always reect the failure of hair-follicle
repair systems. Paradoxically, a large degree of alopecia can
www.thelancet.com/oncology Vol 14 February 2013

Review

Dystrophic anagen pathway


Less alopecia, retarded hair regrowth
Ciclosporin, tacrolimus,
IL-15, PTH/PTHrp 734

Hair-shaft
shedding

Primary
recovery

Poor-quality
hair shaft
Secondary
Normal, fully recovery
pigmented
hair shaft

Lower
toxic eects

Long
recovery

Shortened
dystrophic
telogen

Hair-shaft
shedding

Severe
toxic aects

Chemotherapy
Cyclophosphamide

Short
recovery

Calcitriol,
glucocorticoids,
oestradiol,
PTH 134

Dystrophic catagen pathway


Massive alopecia, accelerated hair regrowth

Figure 4: Damage-response pathways in the human hair follicle after chemotherapy


Chemotherapy-damaged anagen hair follicles engage two major damage-response pathways, dystrophic anagen or dystrophic catagen. Several hormones and drugs
can manipulate which damage-response pathway is chosen by a chemotherapy-treated hair follicle.29,45,46,51,5961 IL-15=interleukin 15. PTHrp=PTH-related-peptide.

indicate that an eective damage-response strategy has


developed in damaged hair follicles (gure 4).45,46 The
sharing of this concept with distressed patients undergoing
chemotherapy might be a useful approach for oncologists.

less damaged dystrophic anagen hair follicles actually


recover much more slowly than dystrophic catagen hair
follicles. This principle of severe damage being associated
with increased speed of recovery is crucial to understanding
the pathobiology of chemotherapy-induced alopecia.

Dystrophic anagen versus dystrophic catagen damageresponse pathways

Hair regrowth

The C57BL/6 mouse model of cyclophosphamide-induced


alopecia shows that chemotherapy-damaged hair follicles
engage two major damage-response pathways that lead to
very dierent clinical outcomes. If the chemotherapyinduced damage is mild to moderate, the dystrophic
anagen response pathway is initiated, whereas more severe
damage activates the dystrophic catagen response pathway
(gures 3, 4).10,45 These distinct damage-response patterns
also apply to human-scalp hair follicles48,49 and have major
clinical consequences because they dictate the dynamics
and degree of chemotherapy-induced hair loss and the
speed and quality of hair regrowth (gure 4). Paradoxically,

In the C57BL/6 mouse model, changes in hair phenotype


are frequently seen during regrowth. These changes are
associated with the predominant damage-response
pathway involved in hair loss (gure 4). If the dystrophic
anagen pathway is involved, hair-shaft production
resumes during the same anagen phase that was
disrupted by chemotherapy (primary recovery).
Paradoxically, dystrophic anagen is frequently longer than
the duration of normal anagen, and the texture and
structure of the shafts are frequently of decreased quality
and show pigmentary defects. By contrast, if the
dystrophic catagen pathway is involved, hair-shaft

www.thelancet.com/oncology Vol 14 February 2013

e54

Review

production is resumed only in the subsequent anagen


phase, following a greatly shortened telogen phase
(secondary recovery). Therefore, the hair matrix is newly
generated and fully functional (unless the hair-follicle
epithelial and melanocyte stem cells have suered major
damage). Consequently, regrowing hair shafts retain a
normal structure and are fully pigmented (gures 3, 4).45,46
The shape of the hair shafts (curly or straight) seems to
be controlled by asymmetric proliferation in the hair
bulb along with asymmetric dierentiation in the
precortical hair matrix.62 Therefore, chemotherapyinduced modulation of these hair-bulb asymmetries, and
perhaps of hair keratin gene expression,62 during the
anagen phase that follows the hair loss seems feasible.48
These eects might lead to alteration to the structure of
the hair shaft (eg, curly to straight).63

Pharmacological manipulation of hair-follicle response and


recovery
In mice, hair-follicle response to and recovery from
chemotherapy can be pharmacologically manipulated
by steroid hormones and immunophilin ligands
(gure 4).29,30,45,46,59 These ndings in mice might also
apply to human-scalp hair follicles. Glucocorticosteroids
and oestradiol promote the dystrophic catagen pathway
in vitro in organ-cultured, chemotherapy-damaged
human hair follicles,49 just as they do in mice in vivo,46,59
which provides important pharmacological pointers to
therapeutic modulation of chemotherapy-induced
alopecia and hair regrowth.

Eects of chemotherapy on the hair-follicle pigmentary unit


Chemotherapy causes oxidative damage to the hair follicle
pigmentary unit (gure 1), which is very sensitive to
reactive oxygen species64 and dierentially aects distinct
subpopulations of hair-follicle melanocytes: hair-bulb
melanocytes expressing FAS undergo apoptosis, whereas
those expressing the KIT receptor proliferate and migrate
upwards along the outer root sheath towards the epidermis;
the latter eect can be abolished by administration of a
KIT-neutralising antibody.65 Chemotherapy, therefore,
induces a complex melanocyte response. Nevertheless, if
damage to the melanocyte stem cells located in the bulge
(gure 1)54 is reversible, pigmentation abnormalities
should also be reversible, at least in principle. Moreover,
hair colour is determined by the proportion of eumelanin
(black) in relation to that of pheomelanin (red), which are
enzymatically determined.66 Thus, chemotherapy-induced
changes in the colour of regrowing hair shafts must reect
changes in the intrafollicular synthesis of eumelanin and
pheomelanin.

Molecular factors in pathobiology


Central role of P53
Anticancer drugs impair mitotic and metabolic processes
in actively growing hair follicles and induce DNA-damage
responses in rapidly proliferating hair-matrix cells.42,48
e55

DNA-damage responses are regulated by several factors,


including response sensors, transducers, and eectors
(gure 2). Sites of DNA damage are recognised by the
primary damage sensor, the MRN complex (MRE11A,
RAD50, and NBN), which detects the lesion. ATM is
recruited and activated to phosphorylate the histone
H2AFX around the lesion to form -H2AX.67 MDC1
protein binds to -H2AX, additional copies of MRN and
ATM, and 53BP1 and BRAC1, whereas single-stranded
DNA is recognised by replication protein A and ATR
kinase is recruited to the damaged sites.67 ATM and ATR
kinases operate as transducers in DNA-damage response
to trigger eector-induced cell-cycle arrest (CHK1 and
CHK2 kinases), apoptosis (P53, FAS, etc), and senescence
(CDKN1A and CDKN2A [also known as P21 and
P16INK4A]; gure 2).67
Although the importance of many molecular factors in
the DNA-damage response remains to be elucidated in
chemotherapy-induced alopecia, P53 and its target genes
have recognised crucial roles in cyclophosphamideinduced apoptosis, hair loss, and damage to the hair
follicles in vivo in mice42 and in vitro in human hair
follicles.48 In the C57BL/6 mouse model, administration
of cyclophosphamide was associated with rapid increase
of P53 concentrations in hair-matrix keratinocytes,
followed by apoptosis.42,51 By contrast, genetic P53 ablation
renders hair follicles completely resistant to
cyclophosphamide.42 FAS as a P53 target is also involved
in mediation of apoptosis in murine hair-matrix keratinocytes and melanocytes during the exposure of hair
follicles to cyclophosphamide.51,65,68 This relation is
supported by the observation that interleukin 15, a potent
inhibitor of FAS-mediated cell death, also inhibits
cyclophosphamide-induced hair-follicle apoptosis in
vivo.51 Other P53 targets, such as BAX or IGFBP3, are
upregulated in cyclophosphamide-treated hair-matrix
keratinocytes.42,51,68,69 P53 also transactivates EDA2R during
murine chemotherapy-induced alopecia, which might,
therefore, be involved in the execution of P53 functions.70
Although the exact functions of these dierent elements
in the mediation of chemotherapy-induced keratinocyte
apoptosis in human hair follicles remain to be elucidated,
they are rational molecular targets to explore for
therapeutic intervention.

Other molecular factors


Members of the broblast-growth-factor family, including
FGF7, which are prominently produced by hair follicles
and regulate their growth, are protective against
chemotherapy-induced alopecia in rodent models.7,71 FGF7
has also shown a slight inhibitory eect against freeradical-induced dystrophy and apoptosis in in-vitro studies
of human hair follicles.72 Inhibition of the generation of
reactive oxygen species by antioxidants reduces the
proapoptotic eect of cisplatin, which suggests an
essential role for hydroxyl radicals in cisplatin-induced cell
death of hair-follicle cells, perhaps through regulation of
www.thelancet.com/oncology Vol 14 February 2013

Review

BCL2.73 The role of BCL2 in chemotherapy-induced


alopecia, however, remains unclear, as overexpression
driven by the keratin-14 promoter in murine hair-follicle
epithelium unexpectedly augmented cyclophosphamideinduced apoptosis and hair loss in transgenic mice.69
Erythropoietin, which is frequently administered to treat
tumour-induced anaemia, also inhibited keratinocyte
apoptosis in the human hair matrix induced by a
cyclophosphamide metabolite in vitro.74
How hair-follicle responses to chemotherapy-induced
damage in the dystrophic anagen and dystrophic catagen
pathways dier and relate to the DNA-damage response
and repair machinery needs to be better understood
(gures 2, 4). For example, expression of molecules that
induce cell-cycle arrest (eg, CHK1 and CHK2 kinases)
versus proapoptotic molecules (eg, P53, FAS) might be
distinct in the two pathways. In this context, global geneexpression proling of the response of the human hair
follicle to chemotherapy48 is likely to identify useful new
molecular targets for therapeutic intervention in
chemotherapy-induced alopecia.

Hair-matrix versus hair-follicle stem-cell damage


Hair-follicle epithelial stem cells are a vital progenitor
population for all epithelial lineages within the follicle.52,7577
By virtue of quiescence, these stem cells have evolved
mechanisms that promote survival and resistance to
apoptosis, and they are designed to replenish the whole
hair follicle numerous times throughout life.53,63,75,76 By
contrast, hair-matrix keratinocytes are shortlived, highly
proliferative progenitor cells that terminally dierentiate
into the layered structure of the hair bre.47,50,77 Hair loss is
frequently reversible within 6 weeks of cessation of
chemotherapy,6,9 which indicates that hair-follicle epithelial
stem cells in the bulge (gure 1) must have retained their
capacity to generate new epithelial progeny, as this function
is a prerequisite for hair regrowth.47,78 When permanent
chemotherapy-induced alopecia is seen, for instance after
additional ionising radiation,6,19,79 irreversible damage has
been caused to the epithelial stem cells.
The mechanisms underlying permanent chemotherapy-induced alopecia are unknown, but at present
evidence suggests that resistance of epithelial hair-follicle
stem cells to apoptosis depends on various factors. Most
hair-follicle stem cells are in the G0/G1 phase of the cell
cycle and, therefore, are resistant to cell-cycle-specic
chemotherapy agents.53,75 Enhanced DNA repair via the
non-homologous end-joining pathway, which is mediated
by PRKDC, and asynchronous DNA synthesis protect the
cells from DNA errors induced by replication and repair.80
During asynchronous DNA synthesis, the parental,
immortal, DNA strand always segregates with the stem
cell and not the dierentiating progeny.80 This mechanism
reduces the risk of being aected by DNA-damaging
agents and accumulation of replication-associated
mutations. Rapid inhibition of P53 activity in hair-follicle
stem cells via increased MDM2 expression promotes
www.thelancet.com/oncology Vol 14 February 2013

survival of hair-follicle stem cells after DNA damage.80 A


P53 null mutation in mice was associated with prevention
of cyclophosphamide-induced apoptosis.42 Stem cells
more highly express members of the BCL2 family and
other inhibitors of apoptosis than do their dierentiated
progeny, which also protects the stem-cell compartment.80
Multidrug-resistant proteins employ ATP hydrolysis to
actively eux drugs from cells, which protects them from
cytotoxic eects.81 In mice, epithelial progenitor cells in
skin express high levels of transporter proteins, such as
Abcg2 (also known as Bcrp), and P-glycoprotein.81
Whether homologous eux transport proteins have
similar eects in the human hair-follicle bulge remains to
be investigated. Finally, epithelial stem cells in human
hair follicles actively obstruct gap junctional transport
(eg, downregulation of GJA1 [also known as connexin-43]
expression),14,82 which hampers the entry of xenobiotics
and small-molecule toxins.
These mechanisms might reect chemoresistance of
hair-follicle epithelial stem cells. By contrast, the
molecular mechanisms noted above could explain the
heightened sensitivity of hair-follicle stem cells to selected
cytotoxins, such as taxanes,79 and might contribute to the
degree of damage in an individual patients bulge stem
cells in response to a given chemotherapeutic agent.79

Optimisation of models
The importance of developing the best possible preclinical
research models of chemotherapy-induced alopecia
cannot be overemphasised. Much more thought, funding,
and interdisciplinary eort are required to achieve this
goal. Neither the established C57BL/6 mouse model nor
the human hair-follicle organ-culture model is fully
satisfactory. Notable limitations of the latter model are that
it does not involve a full hair cycle and that the hair follicles
begin to degenerate after 12 weeks in culture. In the
mouse model, cyclophosphamide is given as one very
high dose rather than in multiple, fractionated doses,
which does not imitate the application schedule of
standard chemotherapy regimens. This dierence is
important, since in clinical oncology, human-scalp hair
follicles damaged by cyclophosphamide will still be in the
recovery phase (gure 3) when they are exposed to the
next cycle of chemotherapy. Subsequent response to
chemotherapy is likely to be aected by this timing, and
the repair capacity of hair follicles might decline over time
(gure 3). Moreover, it is unknown to what extent data
from murine models of chemotherapy-induced alopecia
can be translated to the human condition.
One possible approach that will improve alopecia
research models is the transplantation of healthy, adult
human-scalp skin onto mice with severe combined
immunodeciency to enable testing of long-term cycling
and repeated exposure to chemotherapy in schedules
that imitate standard clinical regimens. Preliminary
evidence suggests that this model is feasible (appendix).
In conjunction with the assay for chemotherapy-induced
e56

Review

dystrophy in organ-cultured human-scalp hair follicles,48


such humanised mouse models should enable
systematic dissection and pharmacological manipulation
of molecular triggers of pathobiological events in
chemotherapy-induced alopecia.

Future management strategies


The search for future therapies to overcome chemotherapy-induced alopecia may follow several research
strategies. Many leads to potentially promising novel
agents that might prevent chemotherapy-induced
alopecia have been reported in animal studies68 and need
to be followed up with mechanistic studies and in organcultured human hair follicles. Possible useful agents
include AS101,26 orally administered N-acetylcysteine7
and zinc ions,83 FGF7,7,71,72 and PTH/PTH-related-peptide
receptor ligands.60 The biological-response modier
ImuVert might also be useful but is not yet licensed for
clinical use.44
Some agents can greatly reduce initial hair loss. For
example, murine hair follicles enter only mildly
dystrophic anagen and show minimal hair loss if potent
calcineurin inhibitors (ciclosporin or tacrolimus) are
administered topically or systemically before and after
cyclophosphamide administration.45,46,61 Such anagenprotective agents might reduce visible hair loss in human
beings to a tolerable degree. Nevertheless, although
ciclosporin stimulates hair growth,10,45,61 oncologists would
be ill advised to risk further compromise of a patients
tumour immunosurveillance by use of such a potent
immunosuppressant. Therefore, topically applicable nonimmunosuppressive calcineurin inhibitors that retain
anagen-promoting eects, prevent hair-follicle dystrophy,
or protect against chemotherapy-induced hair loss and
suppress activity of the transcription factor NFAT1c84 need
to be explored as alternative prevention strategies for
chemotherapy-induced alopecia.
The cell cycle of anagen hair-matrix keratinocytes may
be arrested before and during chemotherapy to lessen
vulnerability to apoptosis. Such cell-cycle arrest would,
however, have to be strictly limited to the hair-follicle
epithelium, for example by hair-follicle-targeting

Search strategy and selection criteria


We searched PubMed for articles published from January, 1950, to May, 2012, with the
terms chemotherapy-induced alopecia and chemotherapy combined with
hair loss/mechanisms/anagen euvium/mouse model/human hair follicle/stem cell/
treatment, alone or in combination. Pathobiologically relevant murine in-vivo and
human in-vitro assays with direct relevance to chemotherapy-induced alopecia and
studies on cyclophosphamide-induced alopecia were preferentially selected for
discussion, complemented by selected historical and background papers on hair research.
Alopecia induced by non-classic chemotherapy, such as that with tyrosine-kinase
inhibitors, was not included. Older references cited in retrieved publications were traced
individually through our institutional library search services. Meeting abstracts were not
considered. Only articles published in English or German were selected.

e57

nanoparticles,85 to avoid favouring intracutaneous micrometastases. Unfortunately, though, agents that cause
cell-cycle arrest in the hair matrix also frequently
terminate anagen, which leads to telogen euvium and
would, therefore, not prevent hair loss. The development
of topically applicable agents that induce temporary cellcycle arrest in hair-follicle keratinocytes without
induction of apoptosis and premature catagen would,
therefore, be desirable.
Pharmacological agents are needed that protect
epithelial and melanocyte hair-follicle stem cells from
chemotherapy-induced damage, especially from taxanes
and high-dose polychemotherapy.79 The selective
upregulation of ABC transporter expression in the bulge
by topical agents is one possibility. Another is to bolster
the chemoresistance of hair-follicle stem cells by
upregulation of the intrafollicular expression and activity
of endogenous hair-follicle damage-repair agents and
systems, such as melatonin,86,87 melanin,58 erythropoietin,74
and enzymes that scavenge for reactive oxygen species or
repair DNA damage.58,64,87 Again, the eects of such agents
would have to be limited to the hair-follicle epithelium.

Conclusions
Even though chemotherapy-induced alopecia is a
daunting therapeutic challenge, feasible strategies to
meet it are available for exploration. Success will only be
achieved, however, if adequate funding and
interdisciplinary research eorts are invested into
development of the best possible preclinical models of
chemotherapy-induced alopecia and of topically
applicable agents that target the hair follicle.
Despite substantial progress in research, many
important questions remain in relation chemotherapyinduced alopecia. A particularly dicult one is whether
attempts to counteract chemotherapy-induced alopecia is
well advised at all. The dystrophic catagen pathway is
associated with the fastest and most complete recovery of
damaged hair follicles (gure 4). Development of
eective antagonists of this inbuilt, highly eective
organ-repair programme could reduce chemotherapyinduced alopecia. This approach, however, also increases
the risk that the lifespan of dangerously damaged hairfollicle cells that would otherwise undergo P53-mediated
apoptosis would be prolonged. Such an eect might have
harmful long-term eects, such as formation of hairfollicle-derived tumours. Long-term observations in
appropriate animal models (appendix) must be made to
shed light on this vexing question.
In view of the increasing incidence of permanent
chemotherapy-induced alopecia, mostly after therapy
with taxanes and in combination with bone-marrow
transplantation,79 another important question is how to
develop agents that will protect hair-follicle stem cells but
not increase survival of cancer stem cells that have
seeded the heavily vascularised scalp. What the best
vehicles will be for the topical application of such agents
www.thelancet.com/oncology Vol 14 February 2013

Review

to reliably target hair-follicle progenitor cells but not


tumour stem cells will also need to be investigated.85
Additional important questions to consider are the
most basic enquiries made by patients about whether
they will experience hair loss and its degree, duration,
and regrowth, to which there are often no easy answers.
To be able to provide at least reasonably reliable answers
in the future, we need to clarify which individual factors
are most important when assessing the risk of
chemotherapy-induced alopecia. In turn, this approach
requires the development of a uniform, internationally
standardised method for the classication of chemotherapy-induced alopecia, and of a much improved,
objective, individualised prognosis system that factors in
individual parameters and characteristics of the patient.
With these tasks laid out clearly before us, and with a
deeper understanding of its pathobiology, more
satisfactory management of chemotherapy-induced
alopecia in the future should be possible.
Contributors
RP wrote the overall drafts of the Review. ISH, AAS, and VAB provided
additional text and helped to extensively revise the paper.
Conicts of interest
We declare that we have no conicts of interest.
References
1
McGarvey EL, Baum LD, Pinkerton RC, Rogers LM. Psychological
sequelae and alopecia among women with cancer. Cancer Pract 2001;
9: 28389.
2
Braun-Falco O. Klinik und Pathomechanismus der Endoxan-Alopecie
als Beitrag zum Wesen cytostatischer Alopecien.
Arch Klin Exp Dermatol 1961; 212: 194216.
3
Homan ER, Zendzian RP, Busey WM, Rall DP. Loss of hair in
experimental animals induced by cyclophosphamide. Nature 1969;
221: 105859.
4
Van Scott EJ, Reinertson RP, Steinmuller R. The growing hair roots
of the human scalp and morphologic changes therein following
amethopterin therapy. J Invest Dermatol 1957; 29: 197204.
5
Van Scott EJ, Reinertson RP. Detection of radiation eects on hair
roots of the human scalp. J Invest Dermatol 1957; 29: 20512.
6
Chon SY, Champion RW, Geddes ER, Rashid RM. Chemotherapyinduced alopecia. J Am Acad Dermatol 2011; 67: e3747.
7
Jimenez JJ, Roberts SM, Mejia J, et al. Prevention of chemotherapyinduced alopecia in rodent models. Cell Stress Chaperones 2008;
13: 3138.
8
Wang J, Lu Z, Au JL. Protection against chemotherapy-induced
alopecia. Pharm Res 2006; 23: 250514.
9
Trueb RM. Chemotherapy-induced hair loss.
Skin Therapy Lett (Canada) 2010; 15: 57.
10 Paus R. Therapeutic strategies for treating hair loss.
Drug Discovery Today Ther Strateg 2006; 3: 10110.
11 Yeager CE, Olsen EA. Treatment of chemotherapy-induced alopecia.
Dermatol Ther 2011; 24: 43242.
12 Yun SJ, Kim SJ. Hair loss pattern due to chemotherapy-induced
anagen euvium: a cross-sectional observation. Dermatology 2007;
215: 3640.
13 Bleiker TO, Nicolaou N, Traulsen J, Hutchinson PE. Atrophic telogen
euvium from cytotoxic drugs and a randomized controlled trial to
investigate the possible protective eect of pretreatment with a topical
vitamin D analogue in humans. Br J Dermatol 2005; 153: 10312.
14 Cotsarelis G. Gene expression proling gets to the root of human hair
follicle stem cells. J Clin Invest 2006; 116: 1922.
15 Alley E, Green R, Schuchter L. Cutaneous toxicities of cancer therapy.
Curr Opin Oncol 2002; 14: 21216.
16 Batchelor D. Hair and cancer chemotherapy: consequences and
nursing carea literature study. Eur J Cancer Care (Engl) 2001;
10: 14763.

www.thelancet.com/oncology Vol 14 February 2013

17

18

19

20

21
22

23

24

25

26

27
28

29

30

31

32

33

34

35
36

37

38

39

Arrieta O, Michel Ortega RM, Villanueva-Rodriguez G, et al.


Association of nutritional status and serum albumin levels with
development of toxicity in patients with advanced non-small cell lung
cancer treated with paclitaxel-cisplatin chemotherapy:
a prospective study. BMC Cancer 2010; 10: 50.
Prevezas C, Matard B, Pinquier L, Reygagne P. Irreversible and severe
alopecia following docetaxel or paclitaxel cytotoxic therapy for breast
cancer. Br J Dermatol 2009; 160: 88385.
Machado M, Moreb JS, Khan SA. Six cases of permanent alopecia
after various conditioning regimens commonly used in
hematopoietic stem cell transplantation. Bone Marrow Transplant
2007: 40: 97982.
Hesketh PJ, Batchelor D, Golant M, Lyman GH, Rhodes N, Yardley D.
Chemotherapy-induced alopecia: psychosocial impact and therapeutic
approaches. Support Care Cancer 2004; 12: 54349.
Grevelman EG, Breed WP. Prevention of chemotherapy-induced hair
loss by scalp cooling. Ann Oncol 2005; 16: 35258.
van den Hurk CJ, Peerbooms M, van de Poll-Franse LV, Nortier JW,
Coebergh JW, Breed WP. Scalp cooling for hair preservation and
associated characteristics in 1411 chemotherapy patientsresults of
the Dutch Scalp Cooling Registry. Acta Oncol 2012; 51: 497504.
Lemieux J, Amireault C, Provencher L, Maunsell E. Incidence of scalp
metastases in breast cancer: a retrospective cohort study in women
who were oered scalp cooling. Breast Cancer Res Treat 2009;
118: 54752.
Lemieux J, Desbiens C, Hogue JC. Breast cancer scalp metastasis as
rst metastatic site after scalp cooling: two cases of occurrence after 7and 9-year follow-up. Breast Cancer Res Treat 2011; 128: 56366.
Duvic M, Lemak NA, Valero V, et al. A randomized trial of minoxidil
in chemotherapy-induced alopecia. J Am Acad Dermatol 1996;
35: 7478.
Sredni B, Xu RH, Albeck M, et al. The protective role of the
immunomodulator AS101 against chemotherapy-induced alopecia
studies on human and animal models. Int J Cancer 1996; 65: 97103.
Sredni B. Immunomodulating tellurium compounds as anti-cancer
agents. Semin Cancer Biol 2012; 22: 6069.
Hidalgo M, Rinaldi D, Medina G, Grin T, Turner J, Von Ho DD. A
phase I trial of topical topitriol (calcitriol, 1,25-dihydroxyvitamin D3)
to prevent chemotherapy-induced alopecia. Anticancer Drugs 1999;
10: 39395.
Paus R, Schilli MB, Handjiski B, Menrad A, Henz BM, Plonka P.
Topical calcitriol enhances normal hair regrowth but does not prevent
chemotherapy-induced alopecia in mice. Cancer Res 1996; 56: 443843.
Schilli MB, Paus R, Menrad A. Reduction of intrafollicular apoptosis
in chemotherapy-induced alopecia by topical calcitriol-analogs.
J Invest Dermatol 1998; 111: 598604.
Hadshiew IM, Foitzik K, Arck PC, Paus R. Burden of hair loss: stress
and the underestimated psychosocial impact of telogen euvium and
androgenetic alopecia. J Invest Dermatol 2004; 123: 45557.
Boehmke MM, Dickerson SS. Symptom, symptom experiences, and
symptom distress encountered by women with breast cancer
undergoing current treatment modalities. Cancer Nursing 2005;
28: 38289.
Frick LR, Arcos ML, Rapanelli M, et al. Chronic restraint stress
impairs T-cell immunity and promotes tumour progression in mice.
Stress 2009; 12: 13443.
Li T, Harada M, Tamada K, Abe K, Nomoto K. Repeated restraint
stress impairs the antitumor T cell response through its suppressive
eect on Th1-type CD4+ T cells. Anticancer Res 1997; 17: 425968.
Johnson KL, Renn C. The hypothalamic-pituitary-adrenal axis in
critical illness. AACN Clin Issues 2006; 17: 3949.
Kim IR, Cho J, Choi EK, et al. Perception, attitudes, preparedness and
experience of chemotherapy-induced alopecia among breast cancer
patients: a qualitative study. Asian Pac J Cancer Prev 2012; 13: 138388.
Arck PC, Slominski A, Theoharides TC, Peters EM, Paus R.
Neuroimmunology of stress: skin takes center stage. J Invest Dermatol
2006; 126: 169704.
Peters EM, Liotiri S, Bodo E, et al. Probing the eects of stress
mediators on the human hair follicle: substance P holds central
position. Am J Pathol 2007; 171: 187286.
Peters EM, Arck PC, Paus R. Hair growth inhibition by
psychoemotional stress: a mouse model for neural mechanisms in
hair growth control. Exp Dermatol 2006; 15: 113.

e58

Review

40

41

42
43
44

45

46

47
48

49

50
51

52

53
54

55

56

57

58
59

60

61

62
63

e59

Ito N, Ito T, Kromminga A, et al. Human hair follicles display a


functional equivalent of the hypothalamic-pituitary-adrenal axis and
synthesize cortisol. FASEB J 2005; 19: 133234.
Arck PC, Handjiski B, Kuhlmei A, et al. Mast cell decient and
neurokinin-1 receptor knockout mice are protected from stressinduced hair growth inhibition. J Mol Med (Berl) 2005; 83: 38696.
Botchkarev VA, Komarova EA, Siebenhaar F, et al. p53 is essential for
chemotherapy-induced hair loss. Cancer Res 2000; 60: 500206.
Jackson SP, Bartek J. The DNA-damage response in human biology
and disease. Nature 2009; 461: 107178.
Hussein AM, Jimenez JJ, McCall CA, Yunis AA. Protection from
chemotherapy-induced alopecia in a rat model. Science 1990;
249: 156466.
Paus R, Handjiski B, Eichmuller S, Czarnetzki BM.
Chemotherapy-induced alopecia in mice. Induction by
cyclophosphamide, inhibition by cyclosporine A, and modulation by
dexamethasone. Am J Pathol 1994; 144: 71934.
Hendrix S, Handjiski B, Peters EM, Paus R. A guide to assessing
damage response pathways of the hair follicle: lessons from
cyclophosphamide-induced alopecia in mice. J Invest Dermatol 2005;
125: 4251.
Paus R, Foitzik K. In search of the hair cycle clock: a guided tour.
Dierentiation 2004; 72: 489511.
Bodo E, Tobin DJ, Kamenisch Y, et al. Dissecting the impact of
chemotherapy on the human hair follicle: a pragmatic in vitro assay
for studying the pathogenesis and potential management of hair
follicle dystrophy. Am J Pathol 2007; 171: 115367.
Bodo E, van Beek N, Naumann V, et al. Modulation of
chemotherapy-induced human hair follicle damage by 17-beta
estradiol and prednisolone: potential stimulators of normal hair
regrowth by dystrophic catagen promotion? J Invest Dermatol 2009;
129: 50609.
Stenn KS, Paus R. Controls of hair follicle cycling. Physiol Rev 2001;
81: 44994.
Lindner G, Rckert R, Bulfone-Paus S, Paus R. Inhibition of
chemotherapy-induced keratinocyte apoptosis in vivo by an
interleukin-15-IgG fusion protein. J Invest Dermatol 1998;
110: 45758.
Tobin DJ, Hagen E, Botchkarev VA, Paus R. Do hair bulb melanocytes
undergo apoptosis during hair follicle regression (catagen)?
J Invest Dermatol 1998; 111: 94147.
Cotsarelis G. Epithelial stem cells: a folliculocentric view.
J Invest Dermatol 2006; 126: 145968.
Nishimura EK, Granter SR, Fisher DE. Mechanisms of hair graying:
incomplete melanocyte stem cell maintenance in the niche. Science
2005; 307: 72024.
Amoh Y, Li L, Katsuoka K, Homan RM. Chemotherapy targets the
hair-follicle vascular network but not the stem cells. J Invest Dermatol
2007; 127: 1115.
Selleri S, Seltmann H, Gariboldi S, et al. Doxorubicin-induced
alopecia is associated with sebaceous gland degeneration.
J Invest Dermatol 2006; 126: 71120.
Ohyama M, Zheng Y, Paus R, Stenn KS. The mesenchymal
component of hair follicle neogenesis: background, methods and
molecular characterization. Exp Dermatol 2010; 19: 8999.
Paus R. A neuroendocrinological perspective on human hair follicle
pigmentation. Pigment Cell Melanoma Res 2011; 24: 89106.
Ohnemus U, Unalan M, Handjiski B, Paus R. Topical estrogen
accelerates hair regrowth in mice after chemotherapy-induced
alopecia by favoring the dystrophic catagen response pathway to
damage. J Invest Dermatol 2004; 122: 713.
Peters EM, Foitzik K, Paus R, Ray S, Holick MF. A new strategy for
modulating chemotherapy-induced alopecia, using PTH/PTHrP
receptor agonist and antagonist. J Invest Dermatol 2001; 117: 17378.
Maurer M, Handjiski B, Paus R. Hair growth modulation by topical
immunophilin ligands: induction of anagen, inhibition of massive
catagen development, and relative protection from chemotherapyinduced alopecia. Am J Pathol 1997; 150: 143341.
Thibaut S, Barbarat P, Leroy F, Bernard BA. Human hair keratin
network and curvature. Int J Dermatol 2007; 46 (suppl 1): 710.
Lindner J, Hillmann K, Blume-Peytavi U, et al. Hair shaft
abnormalities after chemotherapy and tamoxifen therapy in patients
with breast cancer evaluated by optical coherence tomography.
Br J Dermatol 2012; 167: 127278.

64

65

66
67
68

69

70

71

72

73

74

75
76

77
78
79

80

81
82

83

84

85

86

87

Wood JM, Decker H, Hartmann H, et al. Senile hair graying: H2O2mediated oxidative stress aects human hair color by blunting
methionine sulfoxide repair. FASEB J 2009; 23: 206575.
Sharov AA, Li GZ, Palkina TN, Sharova TY, Gilchrest BA,
Botchkarev VA. Fas and c-kit are involved in the control of hair follicle
melanocyte apoptosis and migration in chemotherapy-induced hair
loss. J Invest Dermatol 2003; 120: 2735.
Tobin DJ. The cell biology of human hair follicle pigmentation.
Pigment Cell Melanoma Res 2011; 24: 7588.
Ciccia A, Elledge SJ. The DNA damage response: making it safe to
play with knives. Mol Cell 2010; 40: 179204.
Sharov AA, Siebenhaar F, Sharova TY, Botchkareva NV, Gilchrest BA,
Botchkarev VA. Fas signaling is involved in the control of hair follicle
response to chemotherapy. Cancer Res 2004; 64: 626670.
Muller-Rover S, Rossiter H, Paus R, et al. Overexpression of Bcl-2
protects from ultraviolet B-induced apoptosis but promotes hair
follicle regression and chemotherapy-induced alopecia. Am J Pathol
2000; 156: 1395405.
Brosh R, Sarig R, Natan EB, et al. p53-dependent transcriptional
regulation of EDA2R and its involvement in chemotherapy-induced
hair loss. FEBS Lett 2010; 584: 247377.
Danilenko DM, Ring BD, Yanagihara D, et al. Keratinocyte growth
factor is an important endogenous mediator of hair follicle growth,
development, and dierentiation. Normalization of the nu/nu
follicular dierentiation defect and amelioration of
chemotherapy-induced alopecia. Am J Pathol 1995; 147: 14554.
Braun S, Krampert M, Bodo E, et al. Keratinocyte growth factor
protects epidermis and hair follicles from cell death induced by
UV irradiation, chemotherapeutic or cytotoxic agents. J Cell Sci 2006;
119: 484149.
Luanpitpong S, Nimmannit U, Chanvorachote P, et al. Hydroxyl
radical mediates cisplatin-induced apoptosis in human hair follicle
dermal papilla cells and keratinocytes through Bcl-2-dependent
mechanism. Apoptosis 2011; 16: 76982.
Bodo E, Kromminga A, Funk W, et al. Human hair follicles are an
extrarenal source and a nonhematopoietic target of erythropoietin.
FASEB J 2007; 21: 334654.
Goldstein J, Horsley V. Home sweet home: skin stem cell niches.
Cell Mol Life Sci 2012; 69: 257382.
Rompolas P, Deschene ER, Zito G, et al. Live imaging of stem cell
and progeny behaviour in physiological hair-follicle regeneration.
Nature 2012; 487: 49699.
Schneider MR, Schmidt-Ullrich R, Paus R. The hair follicle as a
dynamic miniorgan. Curr Biol 2009; 19: R13242.
Harries MJ, Paus R. The pathogenesis of primary cicatricial alopecias.
Am J Pathol 2010; 177: 215262.
Palamaras I, Misciali C, Vincenzi C, Robles WS, Tosti A. Permanent
chemotherapy-induced alopecia: a review. J Am Acad Dermatol 2011;
64: 60406.
Blanpain C, Mohrin M, Sotiropoulou PA, Passegu E. DNA-damage
response in tissue-specic and cancer stem cells. Cell Stem Cell 2011;
8: 1629.
DeGorter MK, Xia CQ, Yang JJ, Kim RB. Drug transporters in drug
ecacy and toxicity. Annu Rev Pharmacol Toxicol 2012; 52: 24973.
Kloepper JE, Tiede S, Brinckmann J, et al. Immunophenotyping of
the human bulge region: the quest to dene useful in situ markers for
human epithelial hair follicle stem cells and their niche. Exp Dermatol
2008; 17: 592609.
Plonka PM, Handjiski B, Popik M, Michalczyk D, Paus R. Zinc as an
ambivalent but potent modulator of murine hair growth in
vivo- preliminary observations. Exp Dermatol 2005; 14: 84453.
Horsley V, Aliprantis AO, Polak L, Glimcher LH, Fuchs E. NFATc1
balances quiescence and proliferation of skin stem cells. Cell 2008;
132: 299310.
Lademann J, Richter H, Teichmann A, et al. Nanoparticlesan
ecient carrier for drug delivery into the hair follicles.
Eur J Pharm Biopharm 2007; 66: 15964.
Kobayashi H, Kromminga A, Dunlop TW, et al. A role of melatonin in
neuroectodermal-mesodermal interactions: the hair follicle
synthesizes melatonin and expresses functional melatonin receptors.
FASEB J 2005; 19: 171012.
Slominski A, Tobin DJ, Zmijewski MA, Wortsman J, Paus R.
Melatonin in the skin: synthesis, metabolism and functions.
Trends Endocrinol Metab 2008; 19: 1724.

www.thelancet.com/oncology Vol 14 February 2013