COMMENTARY

Rev 4: CD003961, doi:10.1002/14651858. Zhao X, Deak E, Soderberg K, Linehan M, finally resulting in cell demise. In this
CD003961.pub2 Spezzano D, Zhu J et al. (2003) Vaginal issue, Fecker et al. (2006) have tackled
Wenzel J, Uerlich M, Worrenkamper E, Freutel S, submucosal dendritic cells, but not Langerhans
cells, induce protective Th1 responses to herpes
the task of identifying novel prognos-
Bieber T, Tuting T (2005) Scarring skin lesions of
discoid lupus erythematosus are characterized simplex virus-2. J Exp Med 197:153–62 tic markers in primary melanomas by
by high numbers of skin-homing cytotoxic Zuliani E, Zwahlen H, Gilliet F, Marone C (2005) expression analysis of several pro- and
lymphocytes associated with strong expression Vancomycin-induced hypersensitivity reaction antiapoptotic proteins in vivo. The authors
of the type I interferon-induced protein MxA. with acute renal failure: resolution following first carefully explored the specificity of
Br J Dermatol 153:1011–5 cyclosporine treatment. Clin Nephrol 64:155–8
their immunohistochemical analysis by
demonstrating positive as well as nega-
tive staining of different tumor samples.
See related article on page 1366 Upon subdivision of the samples accord-
ing to the presence or absence of clini-
cal progression of these tumors over a
"Bak (and Bax) to the Future" — of follow-up period of 10 years, these
tumors were investigated for the prognos-
Primary Melanoma Prognosis? tic relevance of protein expression. What
type of signals may lead to apoptosis in
Martin Leverkus1 and Harald Gollnick1 melanoma? In general, apoptotic signal-
Bcl-2 proteins either block or activate the “intrinsic” mitochondrial apoptosis path- ing is broadly divided into “intrinsic” and
way. Loss of expression of proapoptotic Bcl-2 proteins, namely Bax and Bak, in pri- “extrinsic” pathways: the extrinsic path-
mary melanomas is associated with a worse long-term prognosis. Consequently, way is triggered from the outside of the
inactivation of mitochondrial signaling pathways of apoptosis may not only be a cell by transmembrane proteins called
prerequisite for melanoma progression but may also hamper therapeutic efforts death receptors (Locksley et al., 2001).
with chemotherapeutic drugs. These trigger apoptosis by ligand binding
Journal of Investigative Dermatology (2006) 126, 1212–1214. doi:10.1038/sj.jid.5700239 via recruitment of the initiator caspases
caspase-8 and/or caspase-10, ultimately
resulting in activation of effector cas-
pases (for example, caspase-3; Figure 1).
Despite major efforts to improve diag- justify prognosis-adapted treatment regi- However, this pathway is tightly regu-
nosis and stage-specific therapy, the mens for the patient. This strategy in turn lated by intracellular initiator caspase
incidence of melanoma and its mortality may rely on information gained from inhibitors such as cFLIP, and this inhibi-
rates have increased continuously over the primary melanoma about signal- tion seems to be operative in melanoma
the past two decades. Unfortunately, ing pathways activated or silenced dur- (Bullani et al., 2001). Fecker et al. (2006)
the prognosis of melanoma patients ing melanomagenesis (for review see investigated the protein expression of
with progressive disease is poor, in par- Chudnovsky et al., 2005). One decisive the death receptors DR4 (tumor necrosis
ticular for patients with thick lesions or factor for successful tumor therapy is factor-related apoptosis-inducing ligand-
regional lymph node metastasis. For the initiation of the cell-intrinsic apop- receptor 1 (TRAIL-R1)) and DR5 (TRAIL-
these patients, there is no general agree- totic program that is largely dependent R2) and important cell cycle regulators
ment among dermato-oncologists about on activation of the central executioners such as p21 and retinoblastoma pro-
evidence-based treatment modalities of apoptosis, the caspases (Lavrik et al., tein, the tumor suppressor p53, and its
(Queirolo et al., 2005). Extensive studies 2005). Their activity is critical not only inhibitor MDM2. These studies, although
during the past years have clarified that for successful tumor-cell death but also performed only in a limited number of
alterations within physiological signaling for the mounting of a tumor-specific superficial spreading melanomas (SSMs),
cascades of melanoma cells may be of immune response (Casares et al., 2005). did not show a significant correlation
utmost importance for the understanding Thus the understanding of apoptosis to the prognosis of primary melanoma.
of drug resistance mechanisms and con- signaling in melanoma may ultimately TRAIL-R1 and TRAIL-R2 were expressed
sequently for clinical outcome following result in better treatment strategies for in over 90% of primary SSMs, demon-
treatment (Soengas and Lowe, 2003). this deadly tumor. strating that these two death receptors do
One major challenge is the definition of Apoptosis is tightly regulated in a not predict clinical outcome. However,
wider arrays of prognostic parameters for cell-specific manner by multiple signal- because the death ligand TRAIL or ago-
melanoma after surgical excision of the ing pathways that interact in successive nistic antibodies to TRAIL-R1 or TRAIL-
primary tumor, which may subsequently and interconnected amplification loops, R2 are currently undergoing extensive
preclinical tests for tumor therapy (Kelley
1
and Ashkenazi, 2004), these results of
Laboratory for Experimental Dermatology, Department of Dermatology and Venereology, Otto-von-
Fecker et al. (2006), if confirmed in larger
Guericke-University Magdeburg, Magdeburg, Germany
Correspondence: Dr. Martin Leverkus, Laboratory for Experimental Dermatology, Department of
series of tumors as well as melanoma
Dermatology and Venereology, Otto-von-Guericke-University Magdeburg, Leipziger Strasse 44, 39120 metastasis in vivo, might open a thera-
Magdeburg, Germany. E-mail: leverkus@medizin.uni-magdeburg.de peutic window for these agents for

1212 Journal of Investigative Dermatology (2006), Volume 126

 COMMENTARY

These antiapoptotic molecules are in

turn inactivated by “BH3-only” proteins
such as Bim, Bid, Bmf, Bik, Noxa, and
Puma (Figure 1). BH3-only proteins bind
to a hydrophobic BH3-binding groove
in antiapoptotic Bcl-2 proteins and are
currently viewed as crucial sensors of
cellular stress that regulate the activa-
tion of the intrinsic cell death pathway
(Strasser, 2005). This pathway is acti-
vated by a plethora of stimuli, including
cytotoxic drugs, genotoxic stress, growth
factor withdrawal, DNA damage,
anchorage loss, and so-called immune
response modifiers such as imidazoqui-
nolines (Leverkus, 2004). Therefore, Bcl-
2 proteins control a critical checkpoint
that has to be overcome for efficient
treatment of cancer cells. Importantly,
multiple prosurvival proteins must be
inactivated to unleash proapoptotic Bax
and Bak, which ultimately drive apop-
tosis via the mitochondria (Cory et al.,

Loss of expression of

|
the proapoptotic Bcl-2
family members Bax and
Bak was significantly
correlated with SSM
Figure 1. Bcl-2-controlled apoptosis signaling pathways. In principle, two distinct pathways mediate prognosis.
apoptosis, and these converge at the level of activation of effector caspases (for example, caspase-3).
Extrinsic pathways initiate effector caspase activation directly via initiator caspase-8, which is activated by
2003). Therefore, strategies to inacti-
ligation of death receptors. This receptor-proximal activation of caspase-8 is inhibited by cellular FLICE-
inhibitory protein (cFLIP). The intrinsic pathway regulates the release of cytochrome c and other factors
vate Bcl-2 family-controlled pathways
from mitochondria that are required for caspase-9 activation and/or inhibitor-of-apoptosis protein (IAP) by genetic or epigenetic mechanisms
inactivation. These signals are tightly controlled by Bcl-2 family members. The antiapoptotic members (for might thus protect melanoma cells
example, Bcl-2, Bcl-xl, Bcl-w, A1, Mcl-1, and Boo) probably act by inactivation of proteins of the Bax/Bak against apoptotic elimination by either
subfamily (containing Bax, Bak, Bok, and Bcl-xs). Bax/Bak proteins act by multimerization and integration the immune system or cytotoxic drugs.
into mitochondrial membranes, thereby exerting their proapoptotic function. The “BH3-only” proteins (for Intriguingly, Fecker et al. (2006) found
example, Bim, Bid, Bmf, Noxa, and Puma) most likely act by interfering with the antiapoptotic function
in their study that loss of expression of
of distinct subsets of the antiapoptotic Bcl-2 family members. Once activated by initiator caspase-8 or
caspase-9, active effector caspases then cleave crucial structural protein, and this ultimately leads to full
the proapoptotic Bcl-2 family members
cell demolition. Bax and Bak was significantly correlated
with SSM prognosis, even though the
patient collectives did not significantly
melanoma treatment. Still, if the reported mitochondrial intrinsic cell death path- differ in age or Breslow tumor thick-
high expression of cFLIP in melanoma way, is currently divided into subgroups ness. In contrast, neither Bcl-2, Mcl-1,
can be confirmed in larger series (Bullani of molecules with antiapoptotic func- nor Bok was informative with regard to
et al., 2001), therapy will require addi- tion (for example, Bcl-2, Bcl-xl, Bcl-w, patient prognosis. Moreover, tumors that
tional interference with intracellular A1, Mcl-1, and Boo) and proapoptotic had lost both Bax and Bak expression
cFLIP-inhibitory pathways by com- function (“BH3-only” proteins such as were found exclusively in the group of
pounds such as small interfering RNAs Bim, Bid, Bmf, Noxa, and Puma; and SSMs with progression, suggesting that,
(C Drewniok et al., 2006). the subgroup of Bax/Bak-like proteins). at least in SSM, a Bax/Bak-controlled
Fecker et al. (2006) then identically Current models suggest that the Bax/Bak pathway needs to be operative to pre-
investigated the expression of a number subgroup of molecules (including Bax, vent tumor progression.
of Bcl-2 family members. The rap- Bak, Bok, and Bcl-x5), central to the Many important questions arise from
idly growing Bcl-2 family of proteins, proapoptotic function, are held in check this study. Why is loss of Bax and Bak
for a long time known to control the by the antiapoptotic Bcl-2 proteins. rather confined to SSM? What could be

www.jidonline.org 1213
 COMMENTARY

compounds that circumvent a block of
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.
Bullani RR, Huard B, Viard-Leveugle I, Byers HR,
Irmler M, Saurat JH et al. (2001) Selective
expression of FLIP in malignant melanocytic
skin lesions. J Invest Dermatol 117:360–4
Casares N, Pequignot MO, Tesniere A, Ghiringhelli
F, Roux S, Chaput N et al. (2005) Caspase-
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Chudnovsky Y, Khavari PA, Adams AE (2005)
Melanoma genetics and the development of
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Cory S, Huang DC, Adams JM (2003) The Bcl-2
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Curtin JA, Fridlyand J, Kageshita T, Patel HN, Busam
KJ, Kutzner H et al. (2005) Distinct sets of
genetic alterations in melanoma. N Engl J Med
353:2135–47
Drewniok C, Kavuri S, Sprick MR, Haas T, Gollnick
H, Walczak H et al. (2006) Downregulation of
cFLIP sensitizes melanoma cells to TRAIL- or
CD95L-mediated apoptosis. Exp Dermatol
15:237–8
Fecker LF, Geilen CC, Tchernev G, Trefzer U, Assaf
C, Kurbanov BM (2006) Loss of proapoptotic
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melanomas is associated with poor prognosis.
J Invest Dermatol 126:1366–1371
Kelley SK, Ashkenazi A (2004) Targeting death
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-
marks of cancer. Curiously, it is not
clear whether genomic instability is
causative or just a ramification of the
malignant process — or both. In this
issue, Wang et al. (2006) present data
from a melanoma patient who experi-
enced apparent complete remissions
receptors in cancer with Apo2L/TRAIL. Curr
Opin Pharmacol 4:333–9
Lavrik IN, Golks A, Krammer PH (2005) Caspases:
pharmacological manipulation of cell death.
J Clin Invest 115:2665–72
Leverkus M (2004) Imiquimod: unexpected killer.
J Invest Dermatol 122:XV–XVI
Locksley RM, Killeen N, Lenardo MJ (2001) The
TNF and TNF receptor superfamilies: integrating
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Oltersdorf T, Elmore SW, Shoemaker AR, Armstrong
RC, Augeri DJ, Belli BA et al. (2005) An inhibitor
of Bcl-2 family proteins induces regression of
solid tumours. Nature 435:677–81
Queirolo P, Acquati M, Kirkwood JM, Eggermont
AM, Rocca A, Testori A (2005) Update: current
management issues in malignant melanoma.
Melanoma Res 15:319–24
Soengas MS, Lowe SW (2003) Apoptosis and
melanoma chemoresistance. Oncogene
22:3138–51
Strasser A (2005) The role of BH3-only proteins in
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200
Ulrich J, Bonnekoh B, Bockelmann R, Schon M,
Schon MP, Steinke R et al. (2004) Prognostic
significance of detecting micrometastases
by tyrosinase RT/PCR in sentinel lymph
node biopsies: lessons from 322 consecutive
melanoma patients. Eur J Cancer 40:2812–9
and subsequent recurrences over a 12-
year period. The findings of their study
point to the existence of a common
progenitor tumor cell that gives rise to
genomically unstable progeny.
Wang et al. (2006) karyotyped cells
from successive melanoma recur-
rences in their patient. The karyo-

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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

1214 Journal of Investigative Dermatology (2006), Volume 126