COMMENTARY
compounds that circumvent a block of Bullani RR, Huard B, Viard-Leveugle I, Byers HR,
the mitochondrial apoptotic signaling
pathway? Fecker et al. (2006) examined
a limited panel of metastatic tumors
and, surprisingly, found not only loss
of proapoptotic Bax, Bak, and Bok, but
also loss of antiapoptotic Bcl-2 fam-
ily members such as Bcl-2 and Mcl-1.
Why are antiapoptotic molecules such
as Bcl-2 and Mcl-1 downregulated in
metastatic melanoma? Although at first
glance counterintuitive, these findings
might be in line with a recent report that
antiapoptotic Bcl-2 family members are
immunogenic (Andersen et al., 2005).
Thus downregulation of these molecules
during tumor progression might be
needed to overcome tumor immune sur-
veillance, and these tumor cells might
survive only if they also lose expression
of the proapoptotic Bax and Bak. Of
note, small molecules that inhibit the
BH3-binding groove are highly promis-
ing in preclinical testing for solid-can-
cer therapy (Oltersdorf et al., 2005).
However, the data of Fecker et al. (2006)
hint at the possibility that melanoma
treatment would have to circumvent loss
of Bax and Bak to overcome apoptosis
resistance. Obviously the studies will
have to be extended to larger panels of
tumors and metastases, most interest-
ingly in samples of primary and metas-
tasized tumors in the same individuals.
Because sentinel lymph node biopsy
is now widely performed for primary
melanoma (Ulrich et al., 2004), this infor-
mation may soon be available and might
confirm whether early loss of Bax or Bak
is indeed relevant for prognosis at the
time of primary diagnosis of melanoma.
Intriguingly, it can be envisioned that,
beyond being classified solely by histo-
pathological analysis, melanomas may
be best described on the basis of their
inactivation profile of distinct signaling
pathways, and these molecular patterns
might reflect distinct oncogenic profiles
(Curtin et al., 2005). In this context, Bax
and Bak may help us “back to the future”
of primary melanoma prognosis.
CONFLICT OF INTEREST
The authors state no conflict of interest.
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Andersen MH, Svane IM, Kvistborg P, Nielsen OJ,
Balslev E, Reker S et al. (2005) Immunogenicity
of Bcl-2 in patients with cancer. Blood
105:728–34
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receptors in cancer with Apo2L/TRAIL. Curr
Irmler M, Saurat JH et al. (2001) Selective Opin Pharmacol 4:333–9
expression of FLIP in malignant melanocytic Lavrik IN, Golks A, Krammer PH (2005) Caspases:
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F, Roux S, Chaput N et al. (2005) Caspase- Leverkus M (2004) Imiquimod: unexpected killer.
dependent immunogenicity of doxorubicin- J Invest Dermatol 122:XV–XVI
induced tumor cell death. J Exp Med 202:1691–
701 Locksley RM, Killeen N, Lenardo MJ (2001) The
TNF and TNF receptor superfamilies: integrating
Chudnovsky Y, Khavari PA, Adams AE (2005) mammalian biology. Cell 104:487–501
Melanoma genetics and the development of
rational therapeutics. J Clin Invest 115:813–24
Oltersdorf T, Elmore SW, Shoemaker AR, Armstrong
RC, Augeri DJ, Belli BA et al. (2005) An inhibitor
Cory S, Huang DC, Adams JM (2003) The Bcl-2 of Bcl-2 family proteins induces regression of
family: roles in cell survival and oncogenesis. solid tumours. Nature 435:677–81
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Queirolo P, Acquati M, Kirkwood JM, Eggermont
Curtin JA, Fridlyand J, Kageshita T, Patel HN, Busam AM, Rocca A, Testori A (2005) Update: current
KJ, Kutzner H et al. (2005) Distinct sets of management issues in malignant melanoma.
genetic alterations in melanoma. N Engl J Med Melanoma Res 15:319–24
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Drewniok C, Kavuri S, Sprick MR, Haas T, Gollnick melanoma chemoresistance. Oncogene
H, Walczak H et al. (2006) Downregulation of 22:3138–51
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C, Kurbanov BM (2006) Loss of proapoptotic Schon MP, Steinke R et al. (2004) Prognostic
Bcl-2-related multidomain proteins in primary significance of detecting micrometastases
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Kelley SK, Ashkenazi A (2004) Targeting death melanoma patients. Eur J Cancer 40:2812–9
See related article on page 1372
Genomic Instability and Tumor Stem
Cells
James M. Grichnik1
Wang et al. point to the existance of a common progenitor tumor stem cell that
gives rise to genomically unstable progeny in malignant melanoma. Although it
is not known what creates this genomic instability, given the presence of testis
antigens in melanoma, it is tempting to speculate that it is caused by a collision
of meiotic and mitotic pathways.
Journal of Investigative Dermatology (2006) 126, 1214–1216. doi:10.1038/sj.jid.5700240
Genomic instability is one of the hall- and subsequent recurrences over a 12-
marks of cancer. Curiously, it is not year period. The findings of their study
clear whether genomic instability is point to the existence of a common
causative or just a ramification of the progenitor tumor cell that gives rise to
malignant process — or both. In this genomically unstable progeny.
issue, Wang et al. (2006) present data Wang et al. (2006) karyotyped cells
from a melanoma patient who experi- from successive melanoma recur-
enced apparent complete remissions rences in their patient. The karyo-
1
Division of Dermatology, Department of Medicine, Duke University Medical Center, Durham, North
Carolina, USA
Correspondence: Dr. James M. Grichnik, Box 3135, Division of Dermatology, Department of Medicine,
Duke University Medical Center, Durham, North Carolina 27710, USA. E-mail: grich001@mc.duke.edu

types revealed some similar patterns
of chromosomal aberrations, but the
aberrations for each recurrence were
sufficiently different that they could not
be accounted for by a sequential pro-
cess. In fact, even the cells karyotyped
from the same culture revealed differ-
ences suggesting ongoing chromosom-
al instability within the cell population
isolated from each metastasis. The fact
that the subsequent recurrences did not
build on the genomic alterations found
in the earlier recurrences suggested
that there must have been progenitor
cells responsible for the metastases that
were more genomically stable than the
cells karyotyped.
A 1-bp mutation, a TCT-to-TTT
mutation resulting in a Ser37-to-Phe37
substitution in the β-catenin gene, was
present in all the metastatic cells tested
(Wang et al., 2006). The presence of
this single-base mutation in all the cells
suggested that the mutation was pres-
ent in the common progenitor tumor
cell giving rise to the recurrences. The
role of β-catenin in self-renewal of stem
cells makes this a particularly interest-
ing finding.
Our understanding of the role of
stem cells in cancer development is
evolving quickly. In metastatic mela-
noma, a sub-population of cells with
stem-cell-like features has been noted
(Grichnik et al., 2006). It is proposed
that these tumor stem cells give rise
to transiently amplifying tumor cells
that make up the majority of the tumor
bulk before terminally differentiat-
ing. Theoretically, as long as a nidus
of tumor stem cells are present, the
tumor can continue to expand, and
if the tumor stem cells circulate, they
can give rise to distant metastases.
Combining the findings of Wang et
al. (2006) with the tumor stem cell
concept, a model can be developed.
The patient’s tumor stem cells would
be expected to carry β-catenin (and
potentially other relevant mutations)
but otherwise would still be relative-
ly genomically intact and retain the
capacity to metastasize. The transient-
ly amplifying cell progeny from the
tumor stem cells would be genomi-
cally unstable, creating the majority of
cells in the tumor bulk, but would be
metastatically incompetent.
Although our understanding of
tumor stem cell biology is still in its
infancy, the tumor stem cell model is
attractive because of its integration of
broken, but natural, stem-cell develop-
mental pathways. With this model, it is
no longer necessary to require mature
cells to “dedifferentiate” into less dif-
ferentiated cancer cells. It is no longer
necessary for cells to acquire meta-
static capabilities, as “metastasis” may
simply be the result of tumor stem cells
attempting to follow normal circulatory
and tissue-regenerative stem-cell pro-
cesses. But what about genomic insta-
bility? Is there a normal developmental
mechanism that might account for this
process? Currently the literature would
point toward ineffective DNA repair
mechanisms (Charames and Bapat,
2003) or telomere dysfunction (Gilley
et al., 2005) coupled with the inability
to stop cells from progressing through
the cell cycle. Certainly these processes
could account for increased genomic
instability downstream from the tumor
Cells karyotyped
from the same culture
|
revealed differences
suggesting ongoing
chromosomal instability
within the cell
population isolated from
each metastasis.
stem cell due to the expected telo-
mere shortening and increased prolif-
erative rates that stress the DNA repair
machinery in the transiently amplifying
cells. However, there is another pos-
sible source of genetic instability, one
designed for the express purpose of
mixing up the genome with each gen-
eration: meiosis.
Meiosis is an evolved form of mito-
sis that drives genetic diversity by (1)
producing chiasma (chromosomal
crossing-over points) between heter-
ologous chromosomes and (2) seg-
regating homologous chromosomes
“glued” together in meiosis I. What if
a tumor cell were unsure whether it
was to undergo mitosis or meiosis and
COMMENTARY
therefore did a little of each? Crossing
over might not be resolved by the
time chromosomes were pulled apart,
resulting in chromosomal breakage.
Some chromosomes might be held
together as if in meiosis I, resulting in
duplication in some cells and chro-
mosomal loss in others. In support of
this hypothesis, it is important to note
that testis antigens are often expressed
in melanoma (Simpson et al., 2005).
Further, some of these antigens have
now been shown to be specific for
meiosis (Chen et al., 2005; Tureci et
al., 1998). It is possible that the tumor
stem cells produce transiently ampli-
fying cells that are not entirely sure
whether they are somatic cells or germ
cells. A little bit of meiosis mixed in
with mitosis would certainly be suffi-
cient to drive genomic instability.
Whether it is meiosis, defective DNA
repair, and/or telomere dysfunction, it
is of interest that the genomic instability
in successive recurrences in the study
of Wang et al. (2006) shared several
similarities in chromosomal losses and
gains. This suggests that there is some-
thing about the organization of the
genome that reproducibly makes cer-
tain regions more unstable. Bastian et
al. (2000) have noted that certain mela-
nomas tend to have specific genomic
instability patterns. Thus it is reason-
able to assume that this is a consistent
phenomenon in melanoma cells. It is
not clear what makes one part of the
genome more stable than another, but
future efforts may find that genomic
stability configurations are dependent
on nuclear organization patterns that
may be driven inherently by the type of
mutation(s) present in the tumor stem
cell, the type of stem cell involved, or
local environmental influences.
In summary, the findings of Wang
et al. (2006) support an emerging new
cancer model — one based not on
the aggressive acquisition of malig-
nant abilities of mature tissue cells,
but on inherently normal stem-cell
developmental pathways with broken
regulatory mechanisms. It is still too
early to know whether the tumor stem
cell model will hold up, but its future
looks promising and it is likely to have
major ramifications for the understand-
ing of this disease process as well as to
www.jidonline.org 1215
 COMMENTARY

enhance our ability to diagnose and Iseli C, Gure AO et al. (2005) Identification of These exhibit elliptical nodes of nor-
treat malignant tumors. CT46/HORMAD1, an immunogenic cancer/ mal thickness that are regularly sepa-
testis antigen encoding a putative meiosis-
CONFLICT OF INTEREST related protein. Cancer Immun [online] 5:9 rated by dystrophic constrictions. The
James M. Grichnik is major shareholder and Gilley D, Tanaka H, Herbert BS (2005) Telomere
internodes possess a high propensity
founder of DigitalDerm Inc. (MoleMapCD) and dysfunction in aging and cancer. Int J Biochem to break, leading to alopecia; that is,
Malachite Corporation (medical databases). Cell Biol 37:1000–13 short stubble hair associated with fol-
Grichnik JM, Burch JA, Schulteis RD, Shan S, Liu licular keratosis and perifollicular ery-
ACKNOWLEDGMENTS
J, Darrow TL et al. (2006) Melanoma, a tumor thema. In the mildest form, the disease
I thank the Division of Dermatology, Fred and
based on a mutant stem cell? J Invest Dermatol
Sharon Matt, and the other Duke Comprehensive
126:142–53
involves only the occiput and the nape
Cancer Center benefactors for their generous of the neck, but in its severe form, the
financial support. Simpson AJ, Caballero OL, Jungbluth A, Chen
YT, Old LJ (2005) Cancer/testis antigens, entire scalp, secondary hairs, eyebrows,
gametogenesis and cancer. Nat Rev Cancer and eyelashes may also be involved.
REFERENCES 5:615–25 In addition, subtle nail defects have
Bastian BC, Kashani-Sabet M, Hamm H, Godfrey Tureci O, Sahin U, Zwick C, Koslowski M, Seitz
T, Moore DH 2nd, Brocker EB et al. (2000)
been reported. Occasionally, regrowth
G, Pfreundschuh M (1998) Identification of a
Gene amplifications characterize acral meiosis-specific protein as a member of the
of apparently normal hair may occur
melanoma and permit the detection of occult class of cancer/testis antigens. Proc Natl Acad at the time of puberty or during preg-
tumor cells in the surrounding skin. Cancer Sci USA 95:5211–6 nancy. Ultrastructurally, vacuolation
Res 60:1968–73
Wang E, Voiculescu S, Le Poole IC, El-Gamil M, Li and alterations in the fibrillar struc-
Charames GS, Bapat B (2003) Genomic instability X, Sabatino M et al. (2006) Clonal persistence
and cancer. Curr Mol Med 3:589–96
tures of lower cortex cells have been
and evolution during a decade of recurrent
Chen YT, Venditti CA, Theiler G, Stevenson BJ, melanoma. J Invest Dermatol 126:1372–7
described (for a review, see Langbein
and Schweizer, 2005).
The three hair keratin genes that
proved to be causal for monilethrix
See related article on page 1281, 1286, and 1292 encode the type II hair keratins Hb1,
Hb3, and Hb6, which share a com-
pletely identical α-helical rod domain
More than One Gene Involved in and, in line with the ultrastructurally
observed disease symptoms, are all
Monilethrix: Intracellular but also expressed in the hair cortex. Besides
sporadic mutations in the 1A helix
Extracellular Players initiation motif, two non-conservative
mutational hot spots in the 2B helix
Jürgen Schweizer1 termination motif, Glu413Lys and
Glu402Lys, were observed, Glu413Lys
Monilethrix, an autosomal dominant human hair disorder, is caused by muta- being most frequent in Hb6 and
tions in three type II hair cortex keratins. Rare cases of the disease with non- Glu402Lys being more abundant in
vertical transmission have now been found to overlap with localized autosomal Hb1 (Langbein and Schweizer, 2005).
recessive hypotrichosis. The underlying gene, desmoglein 4 (DSG4), belongs to Curiously enough, up to now, only
the desmosomal cadherin superfamily and is also expressed in the cortex of the one monilethrix family exhibiting the
hair follicle. equivalent of the Glu402Lys mutation
Journal of Investigative Dermatology (2006) 126, 1216–1220. doi:10.1038/sj.jid.5700266 in Hb3 (Glu407Lys) has been reported
(van Steensel et al., 2005). The numer-
ous monilethrix families that have been
investigated since 1997 indicate that
In 1997 it was demonstrated that the OMIM #158000 and #252200), is con- there is no genotype–phenotype cor-
principle of a causal relationship sidered an autosomal dominant condi- relation for the disease. One impressive
between mutated epithelial keratins tion with high penetrance but variable example of the variability of the pheno-
and human genodermatoses holds expression and belongs to a variety of type was noted in a pedigree in which,
true also for mutated hair keratins and congenital hair diseases whose hall- of three carriers of the Hb1 Glu402Lys
hereditary hair disorders. The respec- mark is an unusually deformed hair mutation, two children exhibited bead-
tive disease, monilethrix (from the Latin shaft. Monilethrix was so named for the ed hairs that were visible either to the
for “necklace” and the Greek for “hair”; beaded appearance of affected hairs. naked eye or upon electron microscop-
ic inspection. In contrast, their moth-
1
ers’ hairs appeared completely healthy,
Section of Normal and Neoplastic Epidermal Differentiation, German Cancer Research Center, Heidel-
berg, Germany
but the moniliform phenotype could
Correspondence: Dr. Jürgen Schweizer, German Cancer Research Center, Section of Normal and Neo-
easily be demonstrated in archival
plastic Epidermal Differentiation, A145; Im Neuenheimerfeld 280, 69120 Heidelberg, Germany. hairs removed from the mother during
E-mail: j.schweizer@dkfz.de early childhood. On the other hand, a

1216 Journal of Investigative Dermatology (2006), Volume 126