editorial

What Is a Good Model for Melanoma?

very cancer requires a model for experimental

investigations of its etiology and progression.
For the past 50 years, the field has relied on
models of human cells in culture for the biological
analyses of cancer. Melanoma investigators have
an abundance of cell lines at their disposal, with
an estimated 5,000 independent strains established by many laboratories. Approximately 200
human melanoma cell lines have been thoroughly
characterized for genetic aberrations, global gene
expression patterns, and biological properties
such as independence from serum as nutrient,
anchorage-independent growth in soft agar, invasion in vitro, and tumor and metastasis formation
in immunodeficient mice. Cells from the different
stages of melanoma progression have helped us
understand the stepwise progression from primary
melanomas to metastases.
Cell lines of human melanoma metastases
are optimal. These cells can metastasize to most
organs of an immunodeficient animalif not
spontaneously, then after a short period of adaptation. Metastatic melanoma cells produce most
known angiogenic growth factors; they secrete
most known proteolytic enzymes, hijack fibroblasts, control the vasculature, are stimulated
by otherwise growth inhibitory factors, and can
mimic the functions of endothelial cells, fibroblasts, and even monocytes. The malignant cells
can also either successfully block the entry of
drugs or use their excellent transporter systems
to pump them out. Thus, melanoma cells from
patients metastases have been more widely used
than cells from any other human tumor. The prostate cancer field, for example, relies primarily on
three cell lines and their derivatives. There are
about 150 human breast cancer cell lines in existence, but the number of workhorses in this field
is barely higher than that for prostate cancer.
The ability of melanoma cells to adapt to challenging growth conditions has made them the preferred model of investigatorsbut with a catch. As
we all painfully learned in the early 1990s when
the first melanoma suppressor gene, p16INK4a, was
described by Kamb and collaborators (1994),
Journal of Investigative Dermatology (2010) 130, 911912.
doi:10.1038/jid.2009.441

2010 The Society for Investigative Dermatology

a melanoma cell in a dish is not the same as a

cell in a patient. The high frequency of deletions
of p16INK4a was a culture artifact. Nonetheless,
this cell cycle inhibitor is silenced in the majority of patients melanomas. Cell lines from human
melanomas continue to be widely used in cancer
research. The best models mimic the tissue environment in patients lesions, such as growth in
three-dimensional matrix substrates or maintenance in immunodeficient mice without any prior
culture. Each melanoma cell can act as a stem cell
because it self-renews and induces tumors. The
data of Morrison and co-workers suggest that one
in four melanoma cells has stem cell characteristics (Quintana et al., 2008). The most recent data
from our laboratory suggest that each melanoma
cell from metastases is tumorigenic in the immunodeficient host.
The second most widely used model is the B16
murine melanoma cell line, which comes in two
varieties: F1 has low and F10 has high metastatic
activities. The B16 cell line was derived more than
60 years ago from a chemically induced tumor
in C57BL/6 mice. The F10 variant was derived by
Fidler in the mid-1970s through serial passages in
mice (Fidler and Nicolson, 1976). This cell line
continues to be widely used by many laboratories.
Its major appeal is its rapid growth in vivo, leading to tumor-induced death within 2 to 4 weeks;
the F10 variant is aggressively metastatic to the
lungs. Because of its strong pigmentation, many
researchers feel comfortable with this line as a
model for melanoma. The major problem is that
most of its adhesion and growth factor profiles are
unlike those of its human melanoma counterparts.
Even the enzymes used for invasion into tissues,
the ability of cells to overpower the immune system, the antiapoptotic mechanisms, and many
other cancer cell hallmarks do not reflect the
human disease.
What are the B16 melanoma cells good for?
Not muchbecause we now have murine melanoma models that better reflect the human disease. B16 melanoma cells should not be used
for biological studies because the interpretation
of data derived from this model may lead to false
conclusions. Instead, investigators should use cells
from genetic models of melanoma, particularly
www.jidonline.org 911

editorial

the highly metastatic BrafV600E/Pten/ melanoma model recently

presented by the McMahon/Bosenberg laboratories (Dankort
et al., 2009). A similar model was described by the Marais/
Larue laboratories (Dhomen et al., 2009). These murine melanomas have been provided to other laboratories, and cell lines
areor will beavailable from all models. Even immunologists will soon be able to work with at least one of the models,
because the animals are currently crossbred to homozygosity
in C57BL/6 mice (M. McMahon, M. Bosenberg, and D. Herlyn,
personal communication).
Which is the best model? There is not one single model but
several, from both humans and mice. Researchers should be
encouraged to use human and mouse melanoma cells in parallel, preferably those that have been least exposed to stress
caused by tissue culture.

CONFLICT OF INTEREST

The authors state no conflict of interest.

References

Dankort D, Curley DP, Cartlidge RA et al. (2009) Braf(V600E) cooperates

with Pten loss to induce metastatic melanoma. Nat Genet 41:54452
Dhomen N, Reis-Filho JS, da Rocha Dias S et al. (2009) Oncogenic Braf
induces melanocyte senescence and melanoma in mice. Cancer Cell
15:294303
Fidler IJ, Nicolson GL (1976) Organ selectivity for implantation survival
and growth of B16 melanoma variant tumor lines. J Natl Cancer Inst
57:1199202
Kamb A, Gruis NA, Weaver-Feldhaus J et al. (1994) A cell cycle regulator
potentially involved in genesis of many tumor types. Science
264:43640
Quintana E, Shackleton M, Sabel MS et al. (2008) Efficient tumour
formation by single human melanoma cells. Nature 456:5938

Meenhard Herlyn1,2 and Mizuho Fukunaga-Kalabis2

Section Editor and 2The Wistar Institute, Philadelphia, Pennsylvania, USA

Correspondence: Meenhard Herlyn, Program of Molecular and Cellular

Oncogenesis, The Wistar Institute, 3601 Spruce Street,
Philadelphia, Pennsylvania 19104, USA. E-mail: herlynm@wistar.org

912 Journal of Investigative Dermatology (2010), Volume 130

2010 The Society for Investigative Dermatology