Controlling

Protein Found to Cause Low-

Oxygen Induced Metastasis Metastatic
Cancer
by Jennifer Huang

T
he majority of cancer deaths occur when cancer cells
spread from a localized tumor to other parts of the
body during a process called metastasis. Investigations
into the mechanisms of metastasis have revealed that a
low-oxygen micro-environment - hypoxia - within the tumor can
contribute to this lethal process. Dr. Janine Erler and Dr. Amato
Giaccia at the Stanford University School of Medicine found that
a protein called lysyl oxidase (Lox) is related to high metastasis
rates and low-oxygen micro-environments in breast, head and
neck cancers.
Lox is a protein that regulates the development of
connective tissue in the extracellular matrix. A previous
study demonstrated that the expression of Lox protein is
significantly higher in hypoxic environments. By analyzing
tumors in patients with breast, head or neck cancers, Erler
confirmed this relationship, showing that Lox is regulated
by a hypoxia-inducible
factor. Her results
also provided evidence
that high expression
of the Lox protein
significantly lowers a
patient’s survival.
An experimental
model of Lox expression
was developed to further
examine its impact
on tumor metastasis.
Researchers engineered
human breast and
cervical cancer cells
that expressed lower
levels of Lox. These
Dr. Janine Erler is studying how cells die cells were injected into
through metastasis.
mice, and the lower
levels of Lox expression were verified experimentally. When
comparing these tumors with those in mice with an elevated
Lox expression profile, it was found that mice injected with
cells of lower Lox expression had at least five- to ten-fold
fewer metastatic tumors.
Erler also used the Lox expression model to study cell
motility. The cells engineered to express low levels of Lox
displayed a reduction in cell movement, migration, and
cell invasion--the first step in tumor metastasis. This can
be explained because the structure of a cell is critical to its
movement. A normal, non-motile cell typically maintains
a circular or regular structure. However, hypoxic cells
with high Lox expression display extensive branching. The
formation of these cellular projections may facilitate the
migration and metastasis of cancerous tumors.
Metastatic Model
The Lox-expressing cancer cells and the Lox-inhibited
cancer cells grew at similar rates when injected into orthotopic
tissues in mice (tissues that are of the same type and location
as that of the origin of the cancer cells). However, only the
Lox-expressing cancer cells were able to grow when injected
into mice tissue of different origin than the tissue from
which the cancer cells originated. This implies that elevated
Lox levels are implicated in tumor metastasis, since the Lox-
inhibited cells were unable to proliferate when the metastatic
pathway was artificially bypassed.
Erler predicted that Lox inhibition could work effectively
against a wide range of cancers, including difficult to treat
and aggressively lethal metastatic cancers. For patients
with such cancers, Lox inhibition could become a treatment
option.
Challenges facing Lox inhibition treatments
Despite the promise of Lox inhibition treatments, there
are several obstacles to overcome. First, Lox expression is
present both intracellularly and extracellularly, and only the
extracellular expression should be reduced. The tampering
of intracellular Lox expression may increase the risk of cancer
development. More research is thus required to determine
how to specifically target extracellular Lox. Second, further
pre-clinical testing must be performed to confirm the results
before human trials can begin. The first clinical studies
will likely be expensive, costing around $10 million. Erler
hopes to see human trials take place within five years, as this
method may be a promising way to treat many of the most
aggressive and dangerous metastatic cancers. S
JENNIFER HUANG is a freshman majoring in the biological sciences
and hopes to pursue a career in medicine and/or research. She
enjoys rock climbing, hiking, and fencing and loves jigsaw puzzles
and word games.
To Learn More:
Read Erler, J. T. et al. Lysyl oxidase is essential for hypoxia-
induced metastasis. Nature 440. 27. 1222-1226 (2006)

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