Spreading cancer survives via signals from nearby blood vessels long before new vessels are grown

December 19, 2003

DURHAM, N.C. -- In one of the clearest models of cancer metastasis, scientists have shown that spreading cancer cells receive growth-sustaining signals from nearby blood vessels telling them where to go for permanent nourishment and oxygen.

These signals actually protect the fledgling cancer cells long before new blood vessels have grown around the cancer to supply it with a more permanent source of nutrients and oxygen, said the researchers from the Duke Comprehensive Cancer Center.

Their results will be published in the Dec. 19, 2003, issue of the Federation of American Societies for Experimental Biology Journal.

"We've demonstrated a give and take relationship in which cancer cells release signals to nearby blood vessels to stimulate new vessel growth, and in turn, blood vessels release signals that sustain the migrating cancer cells as they try to establish themselves in new tissue," said Duke cancer biologist Mark Dewhirst, Ph.D.

Dewhirst said his findings present a model of the earliest stages of cancer metastasis, and they bolster medicine's latest strategy of blocking blood vessel growth as a means of inhibiting cancer's spread.

Scientists have long known that tumors secrete proteins which promote the growth of new blood vessels to sustain the tumor's continued growth. What they didn't realize is that endothelial cells that line the blood vessels are also releasing signals back to the cancer cells that protect the cancer cells from dying and direct them to grow toward the blood vessel.

In fact, the cancer cells respond to the endothelial cells' messages by elongating and stretching toward the blood vessel in a column formation, their study showed. This change occurs within days after the cancer cells are implanted in the tissue, and long before new blood vessels have begun to form.

"Our data show that blood vessel endothelial cells are involved in cancer survival and growth at a far earlier stage than we had originally believed," said Dewhirst. "This discovery energizes our efforts to block these signals from being released and to inhibit new blood vessels from forming." Such a strategy is called anti-angiogenesis.

The two-way dialogue begins when cancer cells secrete proteins -- such as vascular endothelial growth factor (VEGF) and angiopoietin 2 -- that alert blood vessels to their presence. These proteins prime the blood vessels to initiate new blood vessel growth.

In response, blood vessel endothelial cells release numerous growth and survival factors that sustain the tumor's survival and invasion of the tissue, the study indicated.

Dewhirst's team demonstrated this two-way dialogue between cancer cells and blood vessels by testing how certain signals affected cancer cells in the test tube and in animals. They found that:

• a signal called bFGF (also known as a cytokine) known to promote cancer cell survival in the body had no effect on cancer cells in a test tube. This finding shows that bFGF is not directly acting on cancer cells, but instead it is signaling another player -- probably endothelial cells in blood vessels -- to induce cancer cell growth.
• the cancer cell models in the current study do not even have bFGF receptors -- docking sites for proteins to bind to and activate a reaction inside the cell. Without a bFGF receptor, the bFGF protein cannot directly communicate the cancer cell.
• when scientists prevented cancer cells from utilizing VEGF -- a protein that prompts blood vessel growth -- they inhibited cancer cell survival and growth long before new blood vessels had begun to grow.
• by blocking a vessel-growth protein receptor called Tie2, the scientists inhibited cancer cell survival long before new blood vessels had begun to grow. This suggests that Tie2 is also involved in promoting cancer survival, not just blood vessel growth.

Dewhirst said these findings will help them block the earliest stages of cancer metastasis -- or spreading from the primary tumor site -- because they demonstrate how the fledgling metastatic cancer cell adapt and survive in their new environment.

Duke University Medical Center

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