SCIENTIFIC REPORT 2004 - Sylvester Comprehensive Cancer Center

T U M O R C E L L B I O L O G Y P R O G R A M
HIGHLIGHTS/DISCOVERIES
• In osteosarcoma wild type (wt) cells treated
with agents that inhibit mitochondrial oxidative
phosphorylation (OXPHOS) by interacting
with complexes I, III, and V of the electron
transport chain in different ways—rhodamine
123 (Rho-123), rotenone, oligomycin, and antimycin
A—all of the agents were found to hypersensitize
wt cells to the glycolytic inhibitors
2-deoxyglucose (2-DG) and oxamate.
• In ρ 0 cells that have lost their mitochondrial
DNA and therefore cannot undergo OXPHOS,
cells were found to be ten and 4.9 times more
sensitive to 2-DG and oxamate, respectively,
than wt cells.
• Lactic acid levels, which are a measure of
anaerobic metabolism, were found to be greater
than 3 times higher in ρ 0 than in wt cells.
Moreover, when wt cells were treated with Rho-
123, lactic acid amounts increased as a function
of increasing Rho-123 doses. Under similar
Rho-123 treatment, ρ 0 cells did not increase
their lactic aid levels. These data confirm these
different cell models are similarly sensitive to
glycolytic inhibitors due to their dependence on
anaerobic metabolism.
• These results suggest that inner core tumor cells
are more dependent on glycolysis than outer
growing aerobic cells, which provides a window
of selectivity that can be exploited for therapeutic
gain. Thus, glycolytic inhibitors could be
used to specifically target the hypoxic slowgrowing
cells of solid tumors and thereby increase
the efficacy of current chemotherapeutic
and irradiation protocols designed to kill rapidly
dividing cells. Moreover, glycolytic inhibitors
could be particularly useful in combination
with anti-angiogenic and anti-hypoxic inducible
factor (HIF) agents, which a priori, should
make tumors more anaerobic.
• Recently, Dr. Lampidis has provided proof of
principle in two animal models of human cancer
(non-small cell lung and osteosarcoma ) that
the addition of the glycolytic inhibitor 2-DG
(which targets the slowly growing hypoxic cells
of a tumor), increases the efficacy of standard
chemotherapeutic agents (which target the rapidly
growing aerobic cells) in reducing tumor
size and prolonging survival. In collaboration
with Threshold Pharmaceuticals, the NCI, and
UM/Sylvester, they have received FDA approval
and are now nearing the first human trials testing
his strategy.
JIE LI, M.D., PH.D.
Assistant Professor of Dermatology
and Cutaneous Surgery
DESCRIPTION OF RESEARCH
Among the unanswered critical questions in
cancer research is the mechanism for new
blood vessel formation during tumor development,
a process called tumor angiogenesis, which
is important for both tumor growth and metastasis.
Angiogenesis is dependent on the production
and organization of the basement membrane
zone, a structure underlying endothelial cells in
blood vessels. Dr. Li’s current research focuses on
the role of extracellular matrix laminins of major
basement membrane components in tumor angiogenesis,
invasion, and metastasis. The longterm
goal of the study is to determine their
potential in tumor diagnosis/prognosis and
therapy.
Dr. Li’s laboratory uses cellular and molecular
biological approaches to study the function of
laminins in the two most common and malignant
human skin cancers: melanomas and squamous
cell carcinomas (SCC). She and her
colleagues have found that microvascular endothelial
cells produce two laminins, laminin-8 and
laminin-10. The laboratory has shown that
laminin-8 has strong effects on human endothelial
cell attachment, migration, and capillary tubule
formation. Importantly, they have identified
a high expression of laminin-10 in human melanomas
while there is no expression of laminin-10
in benign nevi. Significantly higher expression of
laminin-10 also was detected in the basement
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UM/Sylvester Comprehensive Cancer Center Scientific Report 2004