Metastasis genes identified

Researchers have identified four breast cancer genes that work in tandem to spread the cancer to the lungs, providing an inside-look at how some tumor cells likely interact with normal cells to produce cancer, according to a report appearing in this week's Nature.

By knocking down these four genes alone or in combination in mice, Joan Massagu￩'s group at Memorial Sloan - Kettering Cancer Center found that the genes were involved in tumor angiogenesis, the spread of tumor cells throughout the circulatory system, and the successful invasion of tumor cells into lung parenchyma.

"What we've discovered is that this set of four genes synergistically enables tumor cells to communicate with endothelial cells during cancer progression," first author Gaorav Gupta, at Memorial Sloan Kettering, told The Scientist.

The four genes tested in this study are EREG, a growth factor gene; MMP1 and MMP2, two matrix remodeling proteinases; and COX2, which produces an inflammatory protein. In 2005, Massagu￩'s group found that these genes were a part of a group of 18 genes associated with breast cancer metastasis to the lungs.

It has long been postulated that tumor cells interact with normal cells in the tumor microenvironment, and this paper suggests a mode of action by which these genes enable that interaction.

The genes are present in lung metastasis, but also produce proteins and molecules important for normal endothelial function, making them of interest to vascular biologists. In the case of metastasis, however, "these gene products have been co-opted by tumor cells for malignant purposes," Gupta added.

In order to uncover exactly how the genes were enabling tumors to spread, the researchers knocked down gene expression using a short hairpin RNA (shRNA) in mice, targeting these specific genes either alone or in combination. The researchers then observed the effects on breast tumors in mice.

The genes had the strongest anti-metastasis effects when silenced in combination, rather than separately. When overexpressed together, they helped the primary tumor cell's already leaky, tortuous blood vessels spread into the circulatory system. Once the cells reach the lungs, the proteins expressed by this set of genes help the cancer elbow its way into the lung capillaries. Silencing these four genes suppressed all of this activity.

"It's path-finding work," Robert Weinberg at the Whitehead Institute, who was not involved in the study, told The Scientist. "But it needs to be generalized to other types of tumors. It's not clear whether it informs on other types of tumors or reflects just on breast cancers."

Indeed, the next step will be to look at the other genes associated with breast cancer and lung metastasis from the 2005 study, and observe their effects on tumor cells, said Gupta.

These four genes are already targets of FDA-approved drugs, said Yibin Kang at Princeton University, who was not involved in the study but worked as a postdoc under Massagu￩. "This shortens the process of going from mouse to patient dramatically," he told The Scientist.

Indeed, the authors tested the effects of a combination of gene inhibitor drugs: cetuximab, GM6001, and celecoxib, which target the EGFR, MMP, and COX2 genes, respectively. In this study the drugs appeared to stall primary tumor growth and the spread of the tumor cells into the circulatory system, as well as reduce tumor growth once cancer had reached the lungs.

Both cetuximab and celecoxib are currently in clinical testing for an array of cancers, including breast, lung, and colon; celecoxib, also known as Celebrex, is currently prescribed as a treatment for arthritis. GM6001 has been tested as a treatment for autoimmune encephalomyelitis.

The list of genes that act as potential therapeutic targets will likely get much longer, predicted Kang. "The number of genes suitable for targeting will keep growing as long as we continue this research."

Andrea Gawrylewski
mail@the-scientist.com

Correction (Posted May 8): The original version of this story misspelled first author Gaorav Gupta's name. The Scientist regrets the error, which has been corrected.

Links within this article:

R. Lewis, "Breast cancer: The big picture emerges," The Scientist, February 10. 2003.
http://www.the-scientist.com/article/display/13530

G. Gupta et al. "Mediators of vascular remodeling co-opted for sequential steps in lung metastasis," Nature, 436: 765-770, April 2007.
http://www.nature.com

Joan Massagu￩
'http://www.mskcc.org/mskcc/html/10614.cfm

A.J. Minn at el. "Genes that mediate breast cancer metastasis to lung," Nature, 436:518-524, 2005.
http://www.the-scientist.com/pubmed/16049480

P. Kenny et al. "The ecology of tumors," The Scientist, April 2006.
http://www.the-scientist.com/article/display/23272/

K. Wary et al. "Analysis of VEGF-responsive genes involved in the activation of endothelial cells," Molecular Cancer, 2:25, July 9, 2003.
http://www.the-scientist.com/pubmed/12904264

Robert Weinberg
http://www.wi.mit.edu/research/faculty/weinberg.html

Yibin Kang
http://www.molbio.princeton.edu/index.php?option=content&task=view&id=216

Cetuximab and trastuzumab in breast cancer
http://www.clinicaltrials.gov/ct/show/NCT00367250?order=109

Cetuximab in non small-cell lung cancer
http://www.clinicaltrials.gov/ct/show/NCT00085501?order=27

Celecoxib in colorectal cancer
http://www.clinicaltrials.gov/ct/show/NCT00258232?order=47

K. Gijbels et al, "Reversal of experimental autoimmune encephalomyelitis with a hydroxamate inhibitor of matrix matelloproteases," Journal of Clinical Investigation, 94: 2177-2182, 1994.
http://www.the-scientist.com/pubmed/7989572