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Fish provide window for viewing metastatic cancer

BioPhotonics
Feb 2007
David Shenkenberg

The initial stages of metastasis have been hard to study, but now transgenic zebra fish have enabled visualization of cancer as it begins to spread.

Researchers at the University of California, San Diego, studied breast cancer cells in zebra fish using confocal fluorescence microscopy. The fish were engineered to express GFP in blood vessels, which permitted microscopic observation of breast tumor cells interacting with vasculature, which must occur for cancer to metastasize. The relative transparency of zebra fish allowed easy viewing of tumor cells.

The researchers generated human breast cancer cells that overexpressed RhoC, a protein known to cause metastasis, and labeled them with DsRed, a red fluorescent protein. They also engineered control human breast cancer cells that expressed cyan fluorescent protein and did not overexpress RhoC. They injected both cell lines into the peritoneum of the fish. With a Nikon microscope, they imaged the DsRed-labeled cancer cells interacting with the GFP-labeled blood vessels and compared the cells to control cells labeled with cyan fluorescent protein.

BNFisheye_BPimage.jpg
Tumor cells expressing DsRed (red) are causing new blood vessels expressing GFP (green) to form within a zebra fish, as occurs in the beginning of metastasis. Researchers believe that their transgenic zebra fish can serve as a model for observing cancer progression and for pharmaceutical testing.

he control human breast cancer cells were relatively aggregated, but the RhoC overexpressing human breast cancer cells were comparatively spread throughout the fish tissue. Both control and RhoC-overexpressing cells migrated within the fish tissue. However, RhoC-overexpressing cells moved by faster “amoeboid” cell migration, while control cells used slower “mesenchymal” migration. Blood vessel wall penetration is an initial metastatic step. Significantly, RhoC-overexpressing cells penetrated blood vessel walls, but control cells failed to do so.

Additionally, for RhoC-overexpressing cells, the researchers observed various regions of the cell membrane protruding and fragments completely separating from the rest of the cell. The researchers said that these cellular movements appeared to be novel cell migration mechanisms caused by RhoC. Chemically blocking ROCK, a protein kinase that RhoC acts upon to exert its downstream effects, prevented the cell motility attributed to RhoC. The researchers presented this characterization of RhoC-induced metastasis at the 46th annual meeting of the American Society for Cell Biology in December.

The scientists believe that their zebra fish not only serve as a model for others examining tumor development, but also allow for viewing the action of pharmaceutical agents.

To demonstrate the latter assertion, they used their technique to examine the effects of the VEGF receptor inhibitor SU416 and the Src protein kinase inhibitor PP1. The SU416 shrank tumor cells and tumor-induced vasculature, whereas PP1 simply killed tumor cells.

Study author Konstantin Stoletov said that he envisions two major improvements to the model. He plans to explore ways to affect gene expression in 1-month-old zebra fish, rather than in embryos. Also, because the cells came from humans, the tumor cells had induced immune responses in the fish, so the researchers plan to generate zebra fish tumor cell lines that will cause less of an immune response.

They also plan to test the system with human fibrosarcoma, mouse colon cancer and human melanoma cell lines and will investigate the action of other anticancer compounds, such as specific RhoC inhibitors.


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