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Protein Found to Cause Low- Oxygen Induced Metastasis by Jennifer Huang Controlling Metastatic Cancer T

Protein Found to Cause Low- Oxygen Induced Metastasis

by Jennifer Huang

Controlling

Metastatic

Cancer

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 wasdevelopedtofurther examine its impact on tumor metastasis. Researchersengineered human breast and

cervical cancer cells that expressed lower levels of Lox. These cells were injected into

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

its movement. A normal, non-motile cell typically maintains Dr. Janine Erler is studying through metastasis. how

Dr.

Janine

Erler

is

studying

through metastasis.

how

cells

die

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

of the most aggressive and dangerous metastatic cancers. S J ENNIFER H UANG is a freshman

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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