Regulating growth and development
Andrzej “Anj” Dlugosz, M.D., the Poth Professor of Cutaneous Oncology, is hedgehog’s biggest fan. He has spent more than 13 years trying to figure out how the gene controls the behavior of normal skin cells and cancer cells via a pathway of biological signals. In a human embryo, signals from the hedgehog pathway control cell division and differentiation — for example, turning a limb bud into a fully developed arm and hand with five fingers, with the correct size, shape and placement. After birth, the hedgehog pathway continues to regulate brain and bone development in babies and children. In adults, it controls the growth of hair follicles and may be involved in recovery from injury.
“The best example of hedgehog’s role in adult regeneration is the hair follicle,” says Dlugosz, professor of dermatology and of cell and developmental biology. “Hair follicles are miniature organs that cycle through periods of growth, regression, and rest during adult life. When the follicle goes into its resting phase and shuts down, the hedgehog pathway is turned off. When the follicle starts growing again, the pathway is turned on. If you block the hedgehog pathway, hair follicles cannot regenerate and produce hair.”
Because the hedgehog pathway is so powerful, it can be dangerous. So the body has evolved many ways to keep unintended hedgehog signals from reaching a cell’s DNA where they cause changes in gene expression. One of the most important is a hedgehog receptor molecule called PTCH1. When hedgehog is not present and PTCH1 is working as it should, it blocks a protein called SMO and prevents it from turning on other proteins in the pathway.
“PTCH1 works like the brakes and SMO like the accelerator,” says Dlugosz. “In a resting cell, the brakes are on and this prevents activation of the pathway. During development, hedgehog molecules bind and inhibit PTCH1, so the brakes are off and now SMO can activate the pathway. Normally, the hedgehog proteins are made only for a specific period of time, and once they’re gone PTCH1 can again block the pathway and the cell goes into a resting state.
“But in cancer, there are either mutations in the PTCH1 gene that make it non-functional, like brakes that aren’t working, or mutations in the SMO gene that prevent it from being inhibited, like an accelerator that’s stuck, or cells start making abnormally large amounts of hedgehog molecules — and they don’t stop.”
In each case, the result is the same: Uncontrolled hedgehog signaling stimulates abnormal growth of a cell that leads to cancer. If the hedgehog pathway is permanently activated in a developing brain cell, the result is medulloblastoma, a serious pediatric brain cancer, says Dlugosz. When uncontrolled hedgehog signaling occurs in skin cells, it causes basal-cell cancer.
“The critical thing about the hedgehog pathway is that it must be carefully regulated, being turned on and then off at specific times and places throughout the developing embryo and in a few adult organs” says Dlugosz. “In normal cells, hedgehog signaling is tightly controlled. But in basal-cell cancer and some other cancers, it’s turned on and it stays on.”
So what determines whether a skin cell gives rise to a basal-cell cancer? Why does one patient develop a tumor on his nose, while another patient gets one on her cheek?
“Much of it could be pure chance,” Dlugosz says. “Not every cell responds to UV radiation or other DNA-damaging stimuli in the same way, and there are mechanisms in place to repair mutations. Even if cancer-causing hedgehog pathway mutations do occur in many skin cells, it’s possible that only some of those cells, possibly just the stem cells, have the long-term growth capacity they would need to become a cancer. It’s also possible that potential basal-cell cancer cells may require changes in other signaling pathways that interact with the hedgehog pathway, or signals from surrounding cells that may be needed to initiate and maintain tumor growth. At this point we really don’t know all the details, but we do know that uncontrolled hedgehog signaling is a key event in BCC development and is probably required for growth and survival of tumor cells.”
Easy to miss — or dismiss
Unlike melanoma, there’s nothing sinister-looking about the early stages of basal-cell cancer. It begins as a small red spot, a raised pink or pearly bump, or a sore that won’t heal — usually on the head or face. Assuming it will go away, people often ignore the lesion and wait months or years before they see a doctor and get a biopsy.
Basal-cell cancer occurs four times more often than squamous cell — the second-most common form of skin cancer — and it’s most common in people with fair skin, blue or green eyes, and blonde or red hair.
Fortunately, this type of skin cancer grows slowly and rarely spreads to other organs in the body. Low-risk basal-cell cancers, such as superficial tumors on the trunk or extremities, can usually be scraped off and cauterized. High-risk tumors, based on their size, location on the head and neck, or infiltrative growth pattern, are usually removed surgically, often using a specialized procedure called Mohs micrographic surgery that has a five-year cure rate of 99 percent, and is performed at many health centers, including the U-M Comprehensive Cancer Center.
Because it’s less aggressive and more easily treated than other skin cancers — such as squamous-cell, melanoma or Merkel cell — it’s easy to dismiss BCC as no big deal. But there’s nothing trivial about basal-cell carcinoma. Without treatment, the tumor can spread and be quite destructive, particularly on the face where it can grow into the nose, eye or ear. Although Mohs surgery minimizes the amount of surrounding tissue that needs to be removed, excising the tumor leaves permanent scars, and since BCC is most common on the head or face, the after-effects of treatment are visible and can be disfiguring in advanced cases. Unless every malignant cell is cut out or destroyed, the tumor can grow back and is more difficult to remove the second time.
The risk of developing another basal-cell cancer is 10 times higher for people with a history of BCC than it is for the general population. Even more alarming, a recent study found that the risk for other types of cancer — especially lung, colorectal, breast, prostate and pancreatic cancer — was twice as high in people previously diagnosed with any type of non-melanoma skin cancer than it was for those who never had skin cancer. The association was strongest for adults ages 25-44.
Blocking the pathway
In addition to basal cell cancer, several internal malignancies have abnormally activated hedgehog signaling, so pharmaceutical companies have been aggressively searching for drugs to block the activity of molecules in the hedgehog pathway. The goal is to develop targeted drugs to treat hedgehog-activated tumors, with a response in BCC serving as proof of concept, and with the hope that an oral or topical inhibitor could eliminate BCCs or at least shrink them, making them easier to remove with surgery.
One of the first experimental drugs in clinical trials, a compound called GDC-0449, was developed by scientists at Genentech in collaboration with Curis. The drug inhibits SMO to effectively shut down hedgehog signaling, and the results of a phase I clinical trial in basal-cell cancer published in the September 2009 issue of the New England Journal of Medicine were very encouraging. The drug is now being tested as an oral agent in additional clinical trials, at the U-M and elsewhere, in patients with locally advanced or metastatic basal-cell cancer, as well as in patients with breast, colorectal and pancreatic cancer. Later this year, Dlugosz and his colleagues will be participating in a phase II/III study of a topical SMO inhibitor from Novartis.
“If you could use a cream to block the hedgehog pathway and treat basal cell cancer, that could be a great alternative to surgery in selected cases,” says Dlugosz. “But there are still many questions to answer. At this point, we don’t know if tumors will develop resistance to these drugs or if they leave some residual tumor cells behind, so the cancer could return once the treatment is stopped. This is a real concern because that’s what we saw in a mouse model of BCC, where we genetically turned off the hedgehog pathway and tumors regressed, but they quickly grew back when we reactivated the pathway.
“So one possibility for the future would be to first treat with a hedgehog pathway inhibitor to reduce tumor burden, and then go ahead with surgery. We also don’t know if shutting down the hedgehog pathway has toxic side-effects, but that should be less of a concern for a topical treatment. So far, some patients have taken the drug orally for over a year without serious side-effects, but it’s really too early to know for certain until many more patients are treated.”
There is one side-effect to turning off the hedgehog pathway, which Dlugosz and other researchers predicted based on experiments done several years ago with mice. Since hair follicles need hedgehog signaling to grow new hair shafts, mice taking hedgehog inhibitors lose their hair — something which also has been reported by some patients on the drug in clinical trials.
If clinical trials of hedgehog inhibitors are successful, physicians could have a less-expensive, non-invasive treatment option for some patients with basal-cell skin cancer.
For younger Americans, protecting your skin from UV radiation is still the best way to prevent basal-cell cancer. Use sunscreen. Stay out of tanning beds. Wear a hat. The DNA you save will be your own.
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