Melissa Gaskill

Stem cells are cells that seem to have the ability to divide perpetually, live indefinitely and, most important, possess the ability to reconstitute tissue or an entire organ.

The original stem cell is the fertilized egg, explains Aline Betancourt, PhD, research associate professor at the Tulane Center for Stem Cell Research and Regenerative Medicine in New Orleans. As it grows, internal cues cause it to “differentiate,” or to eventually become one thing or another, such as an eye or an ear. All this from one cell.

A current theory holds that cancers can develop from a rare type of cell that has the same infinite growth potential as a stem cell. Some see these not as true stem cells, but as a highly malignant and drug-resistant subpopulation of cancer cells. Others think they are, in fact, cancer stem cells, and that they are involved in metastasis as well.

Betancourt falls into the latter camp. She points to research where tumor cells that grow uncontrollably in a human don’t grow at all in a lab animal, evidence that only certain cells in a tumor can recreate that tumor.

There is a very intricate connection between cancer and our body’s immune response.

As adults, we have small pools of original stem cells remaining in specific organs. These stem cells respond to injury in that tissue. They also respond to injury signals from tumors, Betancourt says, which could make it possible to use stem cells to deliver anti-cancer agents directly to a tumor. This method could not only make treatment more effective, but also it would likely reduce side effects.

In some laboratory studies, normal stem cells have been shown to inhibit tumor growth and spread. In others, however, they seemed to encourage it. Clearly, employing these cells in treatment will require figuring out why that happens. Betancourt suspects the immune response plays a key role.

“There is a very intricate connection between cancer and our body’s immune response,” she says. “Yet the majority of studies we’re doing today are in immune-incompetent models, which miss half the picture, in my opinion. We’re working to model tumors in an immune-competent animal, so we can see if we get the same reaction as in its human counterpart.”

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Stem cells are cells that seem to have the ability to divide perpetually, but what does that mean in cancer?

Stem Cells: Helpful or Hurtful?

In May 1999, Ann Pendley, then a 44-year-old speech and language therapist in Fort Collins, Colo., found a lump in her breast during a self-exam. Even though nothing had shown up on her latest mammogram and her doctor waved it off, Pendley insisted on getting a biopsy, which identified an aggressive cancer. She immediately had a lumpectomy and, when the surgeon couldn’t get clean margins, a mastectomy. After more than six months of chemotherapy, she was declared disease-free.

In 2004, after a routine scan, Pendley was told her cancer had metastasized to her lungs. The multiple spots were kept under control with chemotherapy. Then, in November 2011, tumors were found in her brain and bones. The brain tumors responded well to directed radiation therapy, but Pendley is doing research and talking to her oncologists about next steps.

“Now that it has spread past the blood-brain barrier, it’s a whole new ball game,” she says. She deals with a lot of paperwork, her insurance rates have gone up and she is using specialty pharmacies for drugs she can’t get locally. She hopes to sell her therapy practice to make life a bit easier, but that could leave her without coverage.

Such is life with metastatic disease. But for Pendley, it is life.

“I could be around for a while,” she says. “For years, I kept thinking, I don’t have to worry about that, I’ll be gone by then. But I’m not.”

Metastatic disease is cancer that has spread from the place in the body where it first started to one or more places. The resulting tumors are called metastatic tumors or metastases.

A primary tumor the size of a grape contains a billion cells, and more than a million of them may enter the circulatory system every day, says Isaiah Fidler, PhD, director of the Metastasis Research Laboratory at M.D. Anderson Cancer Center. Only a few of those cells survive and fewer still are believed capable of spreading. But a few may be all it takes.

While each cancer metastasizes in its own unique way, the most common sites for metastases to occur are the lungs, bones and liver. Some types of primary tumors seem more prone to metastasis, and certain cancers tend to spread to specific locations—breast cancer to the lungs and liver, for example, and prostate cancer to the bones and lungs. The majority of metastatic tumors land in the first capillary bed beyond the primary tumor, says Patricia Steeg, PhD, chief of the Women’s Cancers Section at the National Cancer Institute, but 30 percent don’t follow this pattern. Interaction between the tumor cell and potential host organ plays a key role; just as not all tumor cells are capable of metastasizing, not all organs can sustain one.

A cancer that spreads to another part of the body is still considered the original type of cancer—colon cancer that spreads to the liver is still colon cancer, for example, and is usually treated with drugs used for colon cancer.

Many patients have evidence at initial diagnosis that tumor cells have spread beyond the primary site, Steeg says. This may be a reflection of when certain types of cancer are caught. “For example, we’re bad at finding early-stage ovarian or pancreatic cancer, so when we find it, it has had a lot of time to metastasize,” she says. “In theory, though, in the lab there are cancers that seem prone to metastasize and those that don’t.”

Detection of metastasis varies from one type of cancer to another, says George W. Sledge Jr., MD, an oncologist in Indianapolis. A high percentage of metastases are diagnosed because an individual experienced symptoms. In the case of breast cancer, monitoring asymptomatic patients for recurrence with blood tests and scans actually does not appear to improve outcomes and is generally not recommended, but evaluations of symptoms should be pursued by appropriate scanning.

If you're having a symptom and it gradually gets worse, that is absolutely, positively a reason to contact your physician and be evaluated.

“Vigilance on the part of the patient is appropriate, and part of the discussion to have with your physician post-treatment is what you should be looking for,” he says. Two key words for symptoms are persistent and progressive. “When a cancer comes back, you tend to have the same symptoms day after day in the same place, and they tend to get worse over time.”

That was the case for Maria Wetzel, 67, a retired clinical laboratory specialist in Michigan who received a diagnosis of stage 2 invasive ductal carcinoma in 1996 and was treated for recurrence in 2004. About five years later, she noticed shortness of breath, which continued to worsen. Imaging tests confirmed metastatic disease in her lungs and liver.

“If you’re having a symptom and it gradually gets worse, that is absolutely, positively a reason to contact your physician and be evaluated,” Sledge stresses. “As a general rule of thumb, if it is enough to worry the patient, it ought to be enough to worry the doctor.”

For some cancers, the American Society of Clinical Oncology (ASCO) recommends routine follow-up testing to detect metastasis. This testing can include blood tests for high levels of carcinoembryonic antigen (ASCO recommends this for stage 2 and 3 colon cancer, for example), abnormal hormone levels or other markers; periodic imaging scans; and physical exams. Both of Pendley’s recurrences showed up in routine scans.

Although metastatic tumors maintain many of the attributes of the original tumor, there can be key differences, including different mutations and gene expression profiles, and, of course, a different environment from the primary site. While surgery can eliminate many primary tumors, and cancer treatments using medical therapies inhibit tumor growth, additional treatments may be needed to address the metastatic process.

In theory, it would be easier to prevent metastasis than to treat it. “To shrink an already established metastatic tumor, you have to kill billions of tumor cells,” Steeg says, “but to prevent the outgrowth, you only have to get a few cells.” This is the principle underlying the use of adjuvant therapy—that is to treat the individual who has had complete removal of the primary tumor, but in whom there is a high risk of cancer recurrence and spreading. Even with full adjuvant therapy, unfortunately, the risk of metastasis is lowered, but cancer can still spread. Moreover, the effectiveness of adjuvant therapy, as well as the best drugs to use, varies from cancer types and subtypes.

We have to take care of the seed, learn about the soil that it likes and target both. Something that does that will probably be our best therapeutic.

Effectively preventing or treating metastatic cancer requires understanding the relationship between cancer cells and their environment. The seed and soil hypothesis, first proposed in 1889 by Stephen Paget and later verified through modern research, theorizes that metastatic tumor cells (the “seeds”) need to find favorable microenvironments (the “soil”) in order to thrive.

“We have to take care of the seed, learn about the soil that it likes and target both,” says Aline Betancourt, PhD, research associate professor at the Tulane Center for Stem Cell Research and Regenerative Medicine in New Orleans. “Something that does that will probably be our best therapeutic.”

Regardless of the therapy, though, given the variety of types of cells in a tumor, and the vast quantity of them, some of those cells inevitably prove resistant to it, Fidler says. Over time, the cells that are resistant to treatment replace those that aren’t.

This resistance can be very disease-dependent, Sledge says. Cancer of the prostate, and leukemias and lymphomas, for example, have high survival rates, he says. “With most solid cancers, however, we’re not very good at curing metastatic disease. Our goals shift from the primary goal of cure to the goal of prolonging life, managing symptoms and maintaining quality of life.” The approach becomes long-term management and fortunately, for the most part, as one treatment stops working, something different is available.

“As we get better at identifying those mechanisms of resistance, we’ll become better at overcoming them,” Sledge adds. “It’s like a criminal trying to escape town. The cops throw up a roadblock, and if all the criminal has to do is turn around and leave by a different route, it won’t take him long to get out of town. It’s a matter of throwing up a sufficient number of roadblocks in strategic places.”

Creating those roadblocks and identifying strategic places to put them are huge challenges. Meanwhile, those with metastatic disease wonder where the bad guys will show up next.

Living with this uncertainty becomes the new normal. “With metastatic disease, you really don’t know,” Pendley says. “I didn’t think I’d still be here now. But you just keep showing up.”

In August, Pendley joined a phase 2 trial for GRN1005, a chemotherapy drug that uses the LRP-1 pathway to cross the blood-brain barrier and target tumors in the brain. So far, it seems to be working.

“I may not die of cancer,” she says. “I may die of running off the road on my mountain bike.”

Guessing Game: Patients with metastatic cancer live with uncertainty.

What is Metastatic Cancer?

Everyone can do some kind of activity, says the American Cancer Society’s Colleen Doyle, a registered dietitian. But it’s important to keep in mind a few general precautions before exercising during cancer treatment.

Someone who was already active may have to slow down a bit during treatment and perhaps not exercise as intensely as they had before. Doyle recommends that patients assess how they feel and avoid pushing themselves.

People who were sedentary before should start slowly, adding more intensity and frequency as they are able. The overall message, she says, is for patients to consider how active they were before treatment and adjust accordingly. “It’s about managing expectations while encouraging people to be as active as they are able to be.”

Side effects of treatment can determine the most appropriate type of exercise. For example, someone with neuropathy may have numb toes, which would make riding a stationary bike a better choice than walking on a treadmill. Patients experiencing lymphedema have long been discouraged from upper body strength training or vigorous activity, Doyle says. But a number of clinical trials have shown that not only is physical activity safe for these individuals but also may actually reduce the incidence and severity of lymphedema.

It’s about managing expectations while encouraging people to be as active as they are able to be.

Patients undergoing frequent chemotherapy treatments may have lower immune function and should avoid working out in public places, such as gyms. People who are having skin reactions from radiation treatments and those with open wounds or catheters should avoid swimming in chlorinated pools or use a petrolatum-based ointment, such as Aquaphor, on the treatment site as a barrier. An upper-body catheter may necessitate temporarily avoiding upper-body strength training. Patients with advanced disease who experience limitations due to bone metastases should discuss exercise with their healthcare provider and generally use pain or discomfort as a guide for what type of activity to avoid.

It’s important for patients to communicate with their healthcare providers about their activities. “Let them know what you’re doing,” Doyle says. “Exercise should be a very individualized approach, based on age and previous level of activity, type and stage of cancer, and type of treatment. With so many things going into the picture, it’s a good idea to talk to your healthcare team about your plans and what you’re currently doing.” Part of that communication is to discuss any nutritional supplement use.

Exercise, she says, can give patients a better shot at getting through treatment successfully, avoid recurrence and reduce the chance of developing another cancer. “It makes a huge difference.”

What to know as a cancer patient before beginning an exercise program.

Preparing to Exercise

Sara L. B. Brown, an artist and mother of two in Colorado, didn’t exercise regularly before she received a diagnosis of metastatic breast cancer. But then her oncologist told her that patients who ran seemed to survive the longest.  

“I started running while recovering from chemo, first just short distances, then gradually going farther until I could make a mile without stopping,” Brown says. Exercising gave her more energy, and she found that the mental toughness gained from running—that effort required to keep going&mdash;helped her deal with long, sometimes unpleasant procedures as well. 

“When I get the shoes back on and exercise, it makes me stronger mentally and helps me recover faster physically,” Brown says. “Pushing myself helped me heal and get back to where I needed to be.”

Pushing myself just a little farther and a little faster, I learned to say ‘no’ to my body when it wanted to give up on me, and push on to where I had no idea I could be.

Gary T. Kimmel, MD, founder of Cancer Foundation for Life in Tyler, Texas, says there is compelling data on the benefits of exercise during cancer treatment. Some of the most important benefits may be psychological. 

“A major factor during and following chemo, demonstrated repeatedly, is the influence the cancer experience has on your mood and perspective,” Kimmel says. Exercise can be “just as effective as drug therapy in elevating mood and managing that aspect of the experience.”

“When someone gets a diagnosis of cancer and begins that journey, it’s all about what they are going to do to you,” he explains. “You depend on others to treat you and get you well.” But when patients hear that they can participate in their care, they begin to perceive themselves as survivors. 

[Find exercise program for cancer patients and survivors]

“Being active gives you a sense of self-control,” Doyle says. “It is great to have control over something during a trying, difficult time when there is such a sense of loss of control over so many things.”

Brown says exercise helped her develop perseverance. “Pushing myself just a little farther and a little faster, I learned to say ‘no’ to my body when it wanted to give up on me,” she says, “and push on to where I had no idea I could be.”

Anna L. Schwartz, PhD, a researcher at Idaho State University and a family nurse practitioner who specializes in oncology and pain management, says exercise also helps with body image, self-esteem and anxiety, as well as depression during treatment. “Exercise boosts endorphins. It’s recommended for healthy people who have mild to moderate depression and is known to decrease mild depression. It has the same effect in cancer patients.”

Exercise conveys a range of physical benefits, too. As Brown learned, it helps combat fatigue, which Kimmel says affects 70 to 80 percent of patients receiving cancer treatment. It also helps control weight gain, which he says sometimes happens during treatment, and may increase the chance of recurrence of certain cancers. Other side effects of treatment that may be favorably influenced by exercise, he adds, include nausea, deconditioning of heart and lungs, and loss of muscle mass and bone strength. 

“When you start exercising, you eat better and you feel better,” Kimmel says. “You may be able to tolerate chemo better. Your bones fare better. Your immune system is stimulated. Exercise treats everything, including the acute and chronic adverse effects of other comorbid diseases. To me, it is a panacea.”

Exercise maintains or improves aerobic function, even during treatment, Schwartz says. “Those who exercise can get stronger muscle-wise, which has benefits. They don’t gain the body fat that most survivors do. We also think it helps maintain bone density.”

According to Schwartz, a growing number of studies show that exercise may help reduce the overall risk for breast, colon and some other types of cancer, and may reduce recurrence as well. “Exercise is one of the most important things healthy people can do to prevent cancer,” she says, “and that patients can do to tolerate treatment well and increase chances for long-term survival.”

While there are plenty of reasons to exercise, some patients may need guidance and motivation, Schwartz says. One challenge is learning how to deal with treatment-related physical limitations (see sidebar). Ironically, another is healthcare providers who may be hesitant to prescribe exercise since it wasn’t encouraged in the past.

“All of our patients are physician-referred,” says Kimmel, “for the simple reason that, if you want someone to make a behavior change, one of the strongest motivators is their doctor. We just want doctors to recommend exercise in general [to their patients].” 

[What to know before you start an exercise program]

Expense can be a major hurdle for those who aren’t ready or able to exercise independently, says Kimmel, which is why his program doesn’t charge and doesn’t set a time limit—nor should others, he believes. “The American Society of Clinical Oncology has recommended exercise during and following treatment. It’s like someone said, we have a new drug available that works in many ways to improve the outcome of cancer patients, but it’s not being manufactured and we’re not going to pay for it.” 

People who didn’t exercise before they had cancer may especially need a structured, individualized program, Kimmel says. Having cancer and being told of the benefits of exercise often will be motivation enough to start, and once patients start an exercise program and see the benefits, they are empowered to continue.

“So many cancer patients don’t even know the importance of exercise,” Kimmel says. “The first few visits, we just want them to leave saying, ‘I can do this.’ Any exercise is awesome, whatever someone will do—swimming, biking, walking, golfing, gardening.” 

A friend who had gone through breast cancer treatment told me that one of the best things I could do to keep up my energy would be to try to stay active. Exercise had a huge impact on my ability to remain active, feel good and not miss work.

Kim Utech, a Milwaukee veterinarian, learned that was true when she received a diagnosis of stage 3C breast cancer in December 2010 at the age of 41. In 2011, she had 16 chemotherapy treatments, two surgeries and 31 radiation treatments.

“A friend who had gone through breast cancer treatment told me that one of the best things I could do to keep up my energy would be to try to stay active,” Utech says. “Exercise had a huge impact on my ability to remain active, feel good and not miss work.”

A little more than six months after whole-brain radiation, Brown is back to running. “Cancer tried to take away my physical body three times, but I kicked it in the behind and kept moving,” she says. ?

In a report released in April by the American Cancer Society (ACS), a group of experts in nutrition, physical activity and cancer survivorship evaluated the scientific evidence and concluded that exercise is not only safe and achievable during cancer treatment, but also can improve quality of life in many ways.

An American College of Sports Medicine roundtable on exercise guidelines for cancer survivors, published in 2010, also concluded that exercise during cancer treatment is safe and can improve physical functioning, quality of life and cancer-related fatigue.

[New guidelines state nutrition and exercise can reduce cancer recurrence]

“The bottom-line message is avoid inactivity,” says Colleen Doyle, a registered dietitian and director of nutrition and physical activity for the ACS. Any kind of activity helps, she adds, referring to a study that showed a significant benefit from simply walking three to five hours a week at an average pace. Walking is simple, cost-free and can be done just about anytime, anywhere. 

Cancer patients can stay strong by remaining active during cancer.

Melissa Gaskill

Stem Cells: Helpful or Hurtful?

What is Metastatic Cancer?

Preparing to Exercise

Exercise During Cancer Treatment Gives Some Patients a Boost

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