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Posted on Fri, May 6, 2011 : 8 a.m.

U-M scientists are at the forefront of cancer stem cell research

By Betsy de Parry

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U-M scientists who identified cancer stem cells, from left to right: Dr. Max Wicha, breast, 2003; Dr. Ronald Buckanovich, ovarian, 2011; Dr. Diane Simeone, prostate, 2007; Dr. Mark Prince, head and neck, 2007

Nine years ago, I walked into the University of Michigan Comprehensive Cancer Center for the first time and walked out as a terrified cancer patient. During all the months that I was in treatment, I never saw the labs or gave a thought to the research that was being conducted in them.

And then, when standard treatment failed to stop my cancer, I was rescued by a new therapy that was pioneered at U-M by Dr. Mark Kaminski, and I began to appreciate those labs we patients never see and the discoveries that are made in them. Discoveries, after all, save lives.

Indeed, labs are hotbeds of discovery. And the labs at Michigan are turning out stem cell research that is revolutionizing the way many cancers are treated.

I know — stem cells are two words that stir passion and debate, but there are stem cells... and there are stem cells. What distinguishes them from other cells is their ability to divide and make exact copies of themselves indefinitely, a process called self-renewal, and their ability to change, or differentiate, into other types of cells.

Embryonic stem cells — the controversial ones — have unlimited potential to become any type of cell.

Adult stem cells — with which we're born — are more restricted than embryonic stem cells in terms of what they can become, but they can still differentiate. For example, adult stem cells in our bone marrow, known as hematopoietic cells, constantly differentiate and pump out the various types of blood cells that are vital to life, such as red blood cells, platelets and lymphocytes.

Adult stem cells also reside dormant in organs until they are needed to help repair damage. For example, mesenchymal stem cells, which reside in the bone marrow, rush to the heart and secrete hormones to help heal it after a heart attack.

And then there are the bad guys: cancer stem cells, a small population of particularly diabolical cells that sustain tumors and fuel their growth. What makes them stem cells is their ability to live indefinitely, unlike other cancer cells which have a limited lifespan. And they're telling scientists that — in addition to eradicating the regular cancer cells — they also need to eradicate the cancer stem cells.

While some tumors perish from chemotherapy or radiation and some are easily cut away, others grow back and are much harder to treat, no thanks to a small number of hardy stem cells that behave like dandelions: cut the grass and they appear to be gone, but the roots remain and the weeds grow back.

And so it is with some cancers, says Dr. Max Wicha, Director of the University of Michigan Comprehensive Cancer Center. When the roots — that is, the cancer stem cells — are left behind, they can incite a recurrence in the same location or in a new one, in which case the cancer is said to have metastasized. And most cancer deaths are the result of metastasis.

Cancer stem cells were first identified in a blood cancer — acute myelogenous leukemia — at the University of Toronto in 1994, but few scientists took note and fewer still were persuaded that cancer stem cells existed, much less that they could be found in solid tumors such as the breast, colon, prostate or brain.

Dr. Wicha is one of the scientists who did take note, and he and his colleagues got busy. In 2003, they identified cancer stem cells in breast cancer the first ever to be found in a solid tumor — and their findings rocked the cancer research world. After all, the stakes were huge: if cancer stem cells really existed in solid tumors, the direction of cancer research would have to change if incurable or metastatic cancers were ever to be cured.

Dr. Wicha's findings sparked controversy, but — good news for patients — controversy sparked debate and debate drove progress. Experiments were made. Meetings were held. Papers were written. And in just eight years, researchers identified cancer stem cells in many other types of tumors, including head and neck cancer, pancreatic cancer and, mostly recently, ovarian cancer, all found at Michigan.

Scientists also learned that cancer stem cells don't socialize with their fellow cancer cells, but set up separate residences in places that scientists called niches, which are essentially microenvironments within our bodies that protect them from traditional therapies — much like bunkers protect soldiers from enemy attacks.

Identifying cancer stem cells — and their places of residence — is a tedious, painstaking process that requires sophisticated laboratory equipment, mice, money, and patient, persistent, genius scientists. And once cancer stem cells are identified, then what?

Scientists are developing tests to determine who has them and who doesn't, and they're developing combinations of drugs that knock out the tumor and the cancer stem cells in patients who have them. And of course, we're going to need some new drugs, but they're working on developing those, too.

"It's been known for a long time," says Dr. Wicha, "that the cells in a tumor are not all the same." Some are more or less potent and treatment-resistant. Cancer stem cells form only a small population, he says, but they are the seeds which drive the cancer, and potentially, even a single cancer stem cell that remains after treatment can form another tumor.

And sometimes cancer stem cells lie dormant for years. Dr. Wicha empathetically speaks of the devastation that's felt when cancers recur 15, even 20, years after treatment. It happens, he says, not only in breast cancer but also in others, and cancer stem cells are telling scientists why.

He tells me that breast cancer patients "have been telling us for years that they're convinced that bad stress is related to the cancer coming back. "And for years, he didn't think there was a connection, "but time after time, many of the women had a story to tell around the recurrence. Often, something traumatic happened to them within a year or so before the cancer came back — an automobile accident or the death of their spouse."

Dr. Wicha then says that a link between cancer recurrence and traumatic events has been found.

"If an organ is damaged in an automobile accident," he says, "normal cells of the organ send out distress signals to the stem cells in that organ to start reproducing themselves so they can heal the organ." Scientists now know that cancer stem cells respond to the same signals.

Additionally, he says, hormones known as cytokines are elevated by emotional stress, and cytokines also activate cancer stem cells.

This doesn't mean that all people who experience traumatic events will automatically have a recurrence. If that were the case, we'd all have recurrences because life is full of ups and downs.

What it does mean, says Dr. Wicha, is that "we now understand this, and it's giving us clues how we might prevent the stem cells from reproducing." In other words, by understanding yet another mechanism that triggers cancer, scientists are figuring out how to combat it. Next year, he and his colleagues expect to open a clinical trial that aims to block the cytokines in women with advanced breast cancer.

Stem cells behave differently in different types of cancer, but they have much in common, such as how they travel to various destinations. All cells — normal and malignant — function as a result of signals sent by or to them. Scientists know that the signals travel along signaling pathways, which are essentially highways that even have "street names" such as Notch or Hedgehog.

The key to preventing cancer stem cells from forming tumors is to stop them from reaching their destinations, and in order to do that, all the highways and exits must be blocked so that stem cells can't find alternate routes to their destinations.

And they're doing it. In collaboration with Dana Farber and Baylor College of Medicine, Michigan was the first to open a clinical trial with the goal of inhibiting stem cells. Collectively, they treated 30 women with advanced breast cancer with chemotherapy combined with a drug that blocks the Notch pathway. Although this was a Phase 1 study, which tests for safety rather than effectiveness, the results, Dr. Wicha tells me, are so far encouraging.

And there's more. Several multi-center Phase 1 trials — open for patients with several tumor types — are attempting to inhibit cancer stem cells by blocking the Notch and Hedgehog pathways. If the results are as promising as scientists believe they will be, successful cancer therapy — meaning more lives saved — will advance by a giant leap in some cancers and by many giant leaps in others, such as pancreatic cancer, an especially difficult cancer to treat and from which only about 3 percent of patients survive beyond five years.

That could soon improve dramatically. U-M's Dr. Diane Simeone, who first identified pancreatic stem cells in 2007, says "We've now been able to identify drugs that target cancer stem cells within pancreatic cancer, so we may have an avenue to really make a breakthrough in therapy for this awful disease."

So blocking stem cells is not merely a wish and a prayer or some distant hope. It has already begun. Clinical trials have opened. Most pharmaceutical companies are beginning to develop cancer stem cell inhibitors.

And scientists here at Michigan and around the world are working at breakneck speed to identify cancer stem cells in the cancers in which they haven't been found and how to stop the stem cells from seeding a recurrence in the tumors in which they have been found.

And it all began eight years ago here in Ann Arbor when Dr. Wicha and his team found the first cancer stem cell in a solid tumor. In scientific time, the progress that's been made since is like going from zero to sixty in under a second.

Within five more years, Dr. Wicha believes that tests will be available that tell doctors which therapies will knock out the tumor and the cancer stem cells. And that will save more lives, which is, he says, "the holy grail of this whole field."

And what drives these scientists? Dr. Wicha expresses what many doctors have told me: that nothing motivates them to forge ahead more than seeing what cancer patients go through every day.

And forge ahead they are. Michigan scientists are unraveling many mysteries of cancer, and they stand at the forefront of cancer stem cell research, ushering in a whole new era in cancer treatment.

Questions remain, of course, but they are working tirelessly to find answers so that we and our families, our friends and our colleagues here and around the world can live and love and laugh after cancer. And for that, I am grateful beyond words.

Studies targeting pancreatic stem cells and breast cancer stem cells are currently recruiting patients.

See U-M's website for more information on cancer stem cells, including a video with Dr. Wicha or find U-M clinical trials in cancer.

Next Friday, May 13: Book Helps Children Cope With A Parent's Cancer

Previous installments of Candid Cancer are archived here.

Betsy de Parry is the author of The Roller Coaster Chronicles, a book about her experience with cancer and the shorter, serialized version she wrote for Find her on Facebook or email her.