Update on the Molecular Biology of Malignant
Amie Y. Lee
Dan J. Raz, MD
Biao He, PhD
David M. Jablons, MD
Department of Surgery, Division of Cardiothoracic
Surgery, University of California, San Francisco,
Malignant mesothelioma (MM) is a highly aggressive tumor with a very poor
prognosis. The disease is largely unresponsive to conventional chemotherapy or
radiotherapy, and most patients die within 10–17 months of the first symptoms.
Novel, more effective therapeutic strategies are needed for this inexorably fatal
disease. Improvement in our understanding of the molecular biology of MM has
identified promising new candidates for targeted treatments. In this review the
key molecular signaling pathways, including vascular endothelial growth factor
(VEGF), epidermal growth factor (EGF), Wnt, and the cell cycle control genes
p53, pRb, and bcl-2 that appear to play an important role in the pathogenesis of
MM are explored. Cancer 2007;109:1454–61. ? 2007 American Cancer Society.
KEYWORDS: mesothelioma, VEGF, EGFR, p16(INK4A), p14(ARF), Wnt, bcl-2 genes.
arises from the surface serosal cells of the pleura and, less fre-
quently, the peritoneum. The incidence of the disease in the major-
ity of Western nations is expected to steadily rise and peak over the
next 2 decades.1There is no known curative modality for MM and
long-term survival is rare even with aggressive multimodal therapy.
A strong link has been established between exposure to asbestos
and increased risk for MM.2Subsequent laboratory research has
confirmed the carcinogenicity of asbestos in mesothelial cell lines
and in animal models. Despite recent restrictions on the use of
asbestos, the incidence of MM is continuing to rise due to the long
latency period for the development of MM after asbestos exposure.
Simian virus 40 (SV40) has also been implicated in the pathogenesis
of MM. SV40 may have synergistic oncogenic effects when com-
bined with asbestos, although the exact role and importance of this
virus in the development of MM is controversial.3One recent study
demonstrated that significantly lower amounts of asbestos were suf-
ficient to cause MM in animals infected with SV40 compared with
uninfected animals, supporting the possible role of SV40 as a co-
carcinogen in this disease.4Using a novel SV40 large T antigen (Tag)
transgenic model of mesothelioma, Robinson et al.5also demon-
strated that asbestos-induced malignant transformation is SV40
dose-dependent, with higher copy numbers of the transgene
increasing the rate of tumor formation.
Treatment of MM with surgery, chemotherapy, or radiation ther-
apy is rarely curative. Clinical trials of single modality treatment
with extrapleural pneumonectomy or pleurectomy, chemotherapy,
or radiation therapy have not shown significant improvement in
survival compared with supportive treatment. Median survival has
ranged from 10–17 months. A multimodal approach, including
alignant mesothelioma (MM) is a highly aggressive tumor that
Supported by a grant from Supported by the
Larry Hall Memorial Trust and National Institutes
of Health Grant (RO1 CA 093708-01A3) (both to
D.M.J.). A.Y.L. is supported by the UCSF Medical
Student Research Committee.
Address for reprints: David M. Jablons, MD, Depart-
ment of Surgery, Cancer Center, 1600 Divisadero
St., Box 1724, San Francisco, CA 94143-1724; Fax:
(415) 353-9530; E-mail: firstname.lastname@example.org. edu
Received August 10, 2006; revision received
December 31, 2006; accepted January 2, 2007.
ª2007 American Cancer Society
Published online 8 March 2007 in Wiley InterScience (www.interscience.wiley.com).
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