Collagen VII Protein Implicated in Skin Cancer Spread
Mar 18, 2005 - 11:13:38 PM
A protein that normally helps hold the skin intact is also needed by skin cancer cells as they spread to other regions of the body, researchers at the Stanford University School of Medicine have discovered. Identifying this protein's role opens the door for stopping the spread of this deadly cancer-the second most common cancer type in the United States.
The finding came about because roughly two-thirds of children with a blistering skin disorder called recessive dystrophic epidermolysis bullosa, or RDEB - caused by a mutation that leads to an altered or missing collagen VII protein - develop a type of skin cancer called squamous cell carcinoma. This led Paul Khavari, MD, PhD, the Carl J. Herzog Professor in Dermatology, to suspect that the protein had something to do with cancer formation.
What Khavari and postdoctoral scholar Susana Ortiz-Urda, MD, PhD, found is that a fragment of collagen VII is required for the skin cancer cells to break free from the neighboring skin tissue and spread - a step that turns an otherwise benign tumor into a killer. "When we blocked this sequence we also blocked the cancer from spreading," said Khavari, who is also chief of dermatology at the Veterans Affairs Palo Alto Health Care System.
The group found this sequence by studying skin samples from 12 children with RDEB. They used laboratory tools to activate molecular switches that normally turn skin cells cancerous. What they found was surprising. Four of the 12 samples never turned cancerous, no matter what cancer-promoting molecular switches the researchers had flicked. The remaining eight samples became cancerous much like normal skin cells that the researchers had studied previously.
It turns out that the difference in cancer formation had to do with the type of alteration in the children's collagen VII gene. The cancer-resistant skin cells were from children who lacked the collagen VII protein altogether. The remaining cancer-prone samples all contained just a fragment of the protein. Both types of mutations leave the children equally prone to RDEB, but only those cells that contained a portion of the collagen VII protein were susceptible to cancer.
Khavari and his group deduced that this collagen VII protein fragment might be necessary to allow cancer to form. They proved this by adding the fragment to RDEB cells that lacked it-an intervention that restored cancer-forming ability.
Further proof came from work in normal skin cells. The group blocked that protein fragment using an antibody and once again tried to induce the cells to become cancerous. They failed. Without that fragment, the cancer could not spread.
Khavari noted that cells behave differently when they are in a lab dish versus growing as part of an animal. With that in mind, he and his group transplanted some human skin cancer cells onto mice. As expected, those cells formed skin cancers that would kill the mouse if left unchecked.
But when the group treated the mice with the collagen VII-blocking antibody, the skin cancer failed to spread, though the cancer remained. "This cancer isn't deadly unless it spreads," Khavari said.
What's more, it appears that the antibody blocks only the cancer-spreading aspect of collagen VII. The protein is still able to perform its normal job of keeping the skin intact.
Khavari stressed that all this work took place using human cells. "Cancer processes are very different in humans and mice," Khavari said. If they'd found these results in mouse cells, the group would still need to prove that the fragment is relevant for humans. By studying human cells, the group has already shown the fragment's relevance-now it's just a matter of using that knowledge to treat patients.
Khavari said he could imagine a drug that blocks the collagen VII fragment being used pre-emptively to prevent skin cancer from spreading in people who are highly susceptible, such as children with RDEB or people who are chronically immune suppressed due to organ transplantation.
Despite this optimism, Khavari cautions that many further experiments are needed before this work could lead to any cancer treatment.
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