Transparent zebrafish provides new insight into breast cancer.

November 14th, 2007 - 2:42 am ICT by admin  
“By watching human breast cancer cells in real time in the live transgenic zebrafish, we were able to determine that two proteins are required in order for breast tumor cells to complete the most critical step of metastasis - entering the blood vessels,” said Dr. Konstantin Stoletov of the department of pathology at the UC-San Diego School of Medicine, who is the first author of the paper published in the online edition of the Proceedings of the National Academy of Science.

The two proteins identified by the researchers are vascular endothelial growth factor (VEGF) and Rhoc. While the former is made by cancerous cells and stimulates new blood vessel formation, the latter is involved in cell movement or migration and is overexpressed in highly metastatic forms of breast cancer.

Dr. Stoletoy has revealed that the two proteins promote metastasis by allowing cancerous breast tumours to enter the blood vessels. He says that neither VEGF nor RhoC alone interact with blood vessels to allow the cancerous tumour to enter the blood vessels (also known as intravasate), “but together, they promote rapid intravasation.”

For their study, the researchers developed an immuno-suppressed zebrafish that expresses green fluorescent protein (commonly known as GFP) only in its blood vessels, so that it would enable them to view the tumour-induced blood vessel formation.

The fish was injected with IBC cells tagged in different colours to study the very rapid tumour progression. While the parental cancer cells were tagged in blue, and the migrating cells that over-expressed RhoC were tagged in red.

The researchers watched the cancer’s progression over several weeks by using high resolution, multi-colour confocal microscopy.

They discovered that RhoC induces an amoeboid-like mode of invasion, in which the cancerous cells move by means of temporary projections or ‘false feet’. They also found that secretion of VEGF was required in order for the cancer cells to penetrate and enter the blood vessel.

“In later stages of the cancerous tumour, the VEGF induces rapid formation of irregular, leaky blood vessels. We discovered that intravasation requires the secretion of VEGF, which disrupts the blood vessel wall, creating small openings that allow the tumour cells to penetrate and enter,” said Dr. Stoletov.

Dr. Richard Klemke, professor of pathology at UCSD School of Medicine and the UCSD Moores Cancer Center who led this study, believes that finding a way to suppress VEGF, and thus inhibiting the growth of “leaky” blood vessels, may stop the movement of cancer cells into the blood vessels and the tumour’s subsequent metastasis.

The transparency of the fish model in the study also enabled researchers to image and analyse, in three dimensions, images of a potential anti-cancer compound that inhibits the VEGF compound.

They say that the inhibitor prevents the formation of the vascular openings, and thereby inhibits intravasation. (ANI)

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