By Krista Conger
Illustration by Greg Mably
“I’ve got a better wine than that.”
If Irving Weissman was taken aback by the challenge, he didn’t say so. It was 2002, and he’d just finished describing his latest stem cell research to a rapt audience at Arrillaga Alumni Center. During the talk, he’d told how the outcome of a friendly science bet with a colleague had netted him a bottle of Australian Penfolds Grange 1990 — a Wine Spectator wine of the year.
He’d also mentioned an up-and-coming theory: that the growth of many solid cancers is driven by a malign subset of cancer cells, called cancer stem cells.
What came next “was really incredible,” says Weissman, MD, who directs Stanford’s Institute for Stem Cell Biology and Regenerative Medicine. “I had mentioned cancer stem cells almost as an aside, in response to a question from the audience.” But after the talk, Weissman was approached by Napa Valley vintners Jim and Carolyn Pride.
Jim Pride obviously took issue with Weissman’s pleasure in winning the Penfolds, and wasted no time setting him straight about the merits of Australian versus California wines. But he followed that up with a question about cancer stem cells: Had anyone identified one for bladder cancer?
Pride was deeply vested in the question. He had bladder cancer himself and was undergoing treatment at Stanford Hospital & Clinics. But he wasn’t alone in his interest. In the past five years, cancer and stem cell researchers alike have increasingly focused on cancer stem cells as the Achilles’ heel of a disease that has rebuffed nearly 40 years of concerted eradication efforts.
Stanford has become an epicenter of such investigations, hosting not just Weissman, but also recruiting stem cell notables Michael Clarke, MD, and Philip Beachy, PhD. Since 2003, Stanford researchers have identified cancer stem cells in breast, brain, head and neck, colorectal, blood and, most recently, bladder cancer. This last discovery is due in large part to Pride, who, after his discussion with Weissman, agreed to donate $500,000 to fund a postdoctoral scholar in Weissman’s laboratory dedicated to finding the bladder cancer stem cell.
In February, President Barack Obama announced an initiative to seek “a cure for cancer in our time.” If scientists are right about cancer stem cells playing a pivotal role in disease, that effort has a good chance of success. It could be the break they’ve been waiting for.
We can thank former President Richard Nixon for the first war on cancer. In 1971 he declared an all-out attack on what he called “the dread disease” that was then killing hundreds of thousands of people every year. Twenty years later, in 1991, the cancer death rate did begin to fall, but nothing approaching a universal cure has been found. In 2009, over half a million people in the United States will die from the disease.
The crux of the problem lies in the fact that there is no such thing as cancer — instead there are hundreds of different diseases. And while each shares the hallmark of uncontrolled cell growth, the underlying genetic and molecular causes vary tremendously. Not surprisingly, some types of cancer respond well to treatments while others, such as pancreatic and bladder cancer, remain intractable. Finding a weak link common to many types of cancer would be a major coup.
Cancer stem cells might be that link. In the last decade, researchers have discovered that the cellular makeup of many tumors appears to mimic that of normal tissue. Some cells, the stem cells, are able to create the tissue’s more highly differentiated cells as well to generate more of themselves. Like queen bees in a hive, these self-perpetuating, or self-renewing, cells are responsible for generating the bulk of the tumor. They also seem to be more resistant to many common types of cancer therapies — perhaps explaining why cancer patients sometimes relapse after years of remission.
“We’ve made some very significant advances in understanding these cells in the last three years,” says Clarke, Stanford’s Karel H. and Avice N. Beekhuis Professor in Cancer Biology. “But just like with normal stem cells, we’re just scratching the surface of what we need to know.”
The crux of the problem lies in the fact that there is no such thing as cancer.
The first experimental proof of the existence of cancer stem cells came in 1994, from studies of patients with a blood cancer called acute myeloid leukemia. In the study, researchers at the Hospital for Sick Children at the University of Toronto drew the patients’ blood and injected it into mice with compromised immune systems. They found that only about one in every 250,000 blood cells caused tumors, and those tumors that did arise sported a varied portfolio of cells mimicking that of the original tumor. This suggested that the cancer-causing cells were, like the stem cells that give rise to our organs and tissues, able both to self-renew and to divide and become many types of cells. Since then, researchers have identified cancer stem cells in approximately 10 human cancers.
At Stanford, in addition to identifying the bladder cancer stem cell, the researchers investigated what makes the cells special. They found that unlike the other cells in the tumor, the bladder cancer stem cells produced the gene for a protective protein called CD47. The protein, which they also found on normal blood stem cells in certain circumstances, acts as a neutralizing signal, preventing the cells from being engulfed and destroyed by an arm of the body’s roving cellular army called macrophages.
“This is the first time we’ve found this ‘don’t eat me signal’ in a stem cell of a solid tumor,” says Weissman. The finding was particularly exciting because, a few weeks earlier, he, assistant professor of hematology Ravi Majeti, MD, and MD/PhD students Siddhartha Jaiswal and Mark Chao had found that leukemia stem cells also express CD47 on their surface. The fact that stem cells from two very different types of cancers use the same mechanism to stay out of trouble with the immune system suggests that these and other cancers may be vulnerable to anti-CD47 therapies.
“We’re now moving as fast as we can to look at other tumors to see if this is a universal strategy of all or most cancer stem cells,” says Weissman.
Targeting cancer stem cells for destruction is an enticing prospect. So enticing that at least 40 companies around the world (including one, OncoMed Pharmaceuticals, founded by Clarke in 2004) are pursuing the concept. But Weissman’s research underscores a pitfall of this strategy: Because cancer stem cells are very similar to the normal stem cells that carry out the everyday tasks of replacing our body’s lost or dead tissues, it’s no simple matter to kill one type without killing the other. Researchers have begun looking for distinguishing features, starting by figuring out where cancer stem cells come from and how they work.
Where do they come from? One theory postulates that cancer stem cells arise when an ordinary adult stem cell acquires mutations that interfere with its ability to regulate its own growth. This is what the Toronto researchers originally thought was the case for acute myeloid leukemia. The other proposes that a more differentiated, or specialized, cell reverts back to a stem-cell-like state, or at least becomes able to self-renew. In 2000, Weissman’s group showed that this is what happens in AML. Evidence exists to support each, and they’re not necessarily mutually exclusive.
“It certainly could be both,” says Clarke, contrasting the seemingly very early origin of the chronic myelogenous leukemia stem cell, which must accumulate and perpetuate individual mutations before becoming fully malignant, with the seemingly more differentiated origin of other leukemia stem cells.
Both Weissman and Clarke believe that the therapeutic key lies in understanding the molecular minutiae of not just how cancer stem cells arise, but also how they survive and prosper. Clarke’s lab is homing in on the cellular pathways that allow both normal and cancer stem cells to self-renew. As a rule, non-stem cells lack this capability. Exploiting any slight differences between these two pathways could allow physicians to specifically impair diseased cells.
“We need to show that selectively wiping out cancer stem cells, but not the other cancer cells, does stop the disease,” says Weissman. This would work because the remaining cancer cells would not be able to self-renew, and would eventually die off. Targeting CD47, for example, might be an option. “We are testing a variety of approaches right now on leukemia, non-Hodgkin’s lymphoma, ovarian cancer, melanoma, bladder cancer, colon cancer, breast cancer and two brain cancers — medulloblastoma and glioblastoma,” says Weissman, “all here at Stanford. That’s a lot.”
Finally, Clarke and his colleagues are exploring why cancer stem cells seem to be more resistant than other cancer cells to traditional cell-killing therapies. They’ve found, for example, that cancer stem cells also crib from normal stem cells to protect themselves from radiation — in this case by producing elevated levels of protective molecules.
It’s clear that the cancer stem cells’ close relationship with normal stem cells makes them formidable adversaries. “Although your body would normally eliminate cells with chromosomal damage, it also needs to spare those cells responsible for regenerating and maintaining the surrounding tissue — the stem cells,” Clarke explains. “It’s protective.”
From the beginning, however, there have been rumblings of discord over the very notion of cancer stem cells. The idea that merely a subset of cancer cells drives tumor growth ran counter to the prevailing wisdom that cancers are a mish-mash of mutated cells, each dividing uncontrollably and each equally able to seed a new tumor elsewhere in the body. Though it’s widely accepted now that the bad guys in blood cancers are the cancer stem cells, some researchers find it hard to swallow the suggestion that most of the cells in a solid tumor are relatively innocuous.
Mainstream media, including the New York Times and the Globe and Mail, have picked up on the controversy, which gained steam at the end of 2008 with the publication of a paper in the journal Nature by researchers at the University of Michigan in Ann Arbor suggesting that — for one type of solid tumor — cancer stem cells are not rare at all. In fact, they found that about 25 percent of melanoma cells can cause tumors when transplanted into mice with compromised immune systems.
And it would seem to follow that cancer stem cells in melanoma aren’t as invincible as the Stanford researchers believed. Since 25 percent of the melanoma cells caused tumors in the Michigan experiment, yet standard therapies kill more than 75 percent of the tumor cells, those wiped out by treatment must include some cancer stem cells. Which means cancer stem cells are neither rare nor especially dangerous. Right?
Rubbish, says Clarke. He compares the debate to a battle between firmly entrenched philosophies. “You might as well ask me to argue about how many angels can dance on the head of a pin,” he says. “Tell me an experiment to do that will prove or disprove it and I’ll do it.”
Weissman agrees. He’s currently conducting his own experiments on melanomas. “We are looking as exhaustively as we can at both the primary site of cancer and the metastatic form,” he says. “We know from leukemias that the more advanced the cancer is, the more prevalent the cancer stem cells are.” This may be because these cells are more resistant than normal tumor cells to conventional therapies, or because they are better equipped to evade the body’s defensive mechanisms. The melanoma samples studied by the Michigan researchers may have been more advanced than cancers identified in their infancies, says Weissman.
A tentative, temporary peace has been established, however, with both sides agreeing that perhaps not every cancer is identical. “Does every solid cancer have a cancer stem cell?” asks Clarke. “It’s certainly possible. I wouldn’t be surprised. But I also wouldn’t be surprised if there are some exceptions.”
So, what does it all mean, an observer might ask. The Obama administration has vowed to double funding for cancer research over the next eight years. Are these cells the key to winning our new war on cancer? Or just an important, but incremental advance in an ongoing fight? Yes, says Weissman, enigmatically.
“As always, you want to do a healthy and diverse set of studies,” he says. “Oncogeneticists should continue to study oncogenes; immunologists should still pursue cancer immunotherapies. We’re trying to identify what we feel are the most relevant cell populations for study — to help them focus their research. It’s going to be necessary to integrate funding for cancer stem cells with many other types of funding to develop a robust set of therapies for patients.”
It’s too late for Jim Pride, though, who, like hundreds of thousands of other Americans, died of cancer in 2004.
“Jim was a real mover,” remembers Weissman, who had become good friends with Pride, sharing his wine and visiting him in the hospital before he died. “Regardless of the problem, he would always tap the leaders in the field to help him accomplish what he wanted. That’s why his top-level wines are equal to the best in the world. He knew our research would be too late to help him, but he hoped it would help others.” And it may.
“I think we’re really starting to get some traction and make some headway against this disease,” says Clarke. “We’re seeing an increasing number of new drugs and clinical studies targeting cancer stem cells.” At least one, lapatinib, marketed by GlaxoSmithKline, has been approved by the Food and Drug Administration for use in patients with advanced breast cancer, and the company recently applied for permission to use it as a first-line therapy for newly diagnosed women. Many others, including an antibody developed by OncoMed called OMP-21M18, are being tested in clinical trials.
Separating cancer stem cells from the herd of normal stem cells needed to keep our bodies functioning normally is critical, however.
“I want to see drugs that truly and effectively target these cells while sparing normal stem cells,” says Clarke. “If I saw that, I would be doing back-flips.”
Krista Conger is at