When the terrible news comes, it’s often presented in singular terms: “You’ve got cancer.” But cancer is not a single disease. Rather, it’s more than 100 distinct afflictions that can involve virtually any type of tissue in the human body.
A diagnosis of breast cancer means something entirely different from one of prostate or skin cancer. The symptoms, treatments, and prognoses are disparate. Our knowledge of what causes cancer and how to effectively treat patients with any of the different types is wildly uneven. Some cancers can now be cured, or at least reduced to a chronic, manageable condition, though often the therapies employ mechanisms not entirely understood. Conversely, other cancers remain incorrigibly aggressive killers, resistant to any current therapy. In 1971, Richard Nixon famously declared a “war on cancer.” He boldly predicted victory within five years.
Today, the American Cancer Society estimates almost 12 million Americans have some form of cancer. More than half a million Americans will die from cancer this year, roughly 1,500 every day. Cancer is the second leading cause of death after heart disease. Clearly, the war rages on.
But there has been progress and there is hope. I believe there is a real possibility that some of the clues to conquering cancer might be found in resolving the mysteries of a single form of cancer called chronic lymphocytic leukemia or CLL. CLL is a cancer of the blood, the most common form of leukemia. Its prevalence in the United States is high: 1 out of every 20 people over the age of 40 may have apparently pre-cancerous CLL-like cells in their blood. Such people may develop actual CLL at a rate of about 1 percent per year. Roughly 15,000 Americans are diagnosed with CLL every year. The cause or causes of CLL are not known, but its nature and tendency for clinical progression have been well documented by an army of scientists and doctors, including myself. (I’ve been studying and treating CLL for 26 years, the last 20 at the UC San Diego Moores Cancer Center, one of just 40 National Cancer Institute-designated Comprehensive Cancer Centers in the United States.)
CLL is a malignancy of B lymphocytes, commonly called B cells. These cells are part of the body’s adaptive immune system. Their principle function is to make antibodies to antigens – molecules and substances perceived as foreign and potentially harmful. For reasons unknown, a clone of B cells in CLL patients goes awry. B cells from a single clone are produced in great numbers, but they never mature into effective immune system cells. Over time, they disrupt the body’s immune system, reduce its ability to quickly react to invaders or infections and crowd out other essential blood cell types in the bone marrow. Eventually, the immune system of a CLL patient may weaken, increasing the chance that the patient might develop severe or life-threatening infections.
Patient diagnosed with CLL may not have any symptoms for years, sometimes decades. Some patients never become symptomatic at all. It is the insidious advancement of CLL that provides the opportunity to perhaps truly and finally figure out the fundamentals of cancer. Acute leukemias and other cancers typically act and kill quickly. There is little time to reflect upon the nature of the disease or study its natural progression. The paramount mission is to save the patient—to keep him or her alive for as long as possible. CLL can be diagnosed easily and early. Many patients are not recommended for treatment for several years after diagnosis, if at all. In fact, existing therapies applied early may cause problems that can be worse than the disease, particularly for patients who are asymptomatic. Often the prescribed treatment is simply to monitor the disease for clear evidence of progression. In that time, doctors and researchers can investigate fundamental questions that remain imperfectly answered: Where did the cancer originate? How does it progress? What changes occur? When? Why does the same cancer behave differently in different patients?
Though CLL is a blood cancer, it shares many qualities with solid tumor cancers like sarcomas, carcinomas, and lymphomas. Indeed, much of what we’ve learned about solid tumors in recent years has been derived from leukemia research. For example, work in my lab, in collaboration with Dr. Carlo Croce of the CLL Research Consortium, revealed that microRNAs (miRs) have a major role in causing this disease. There are hundreds of different miRs, which are short sequences of ribonucleic acid. Each miR can repress or turn off the activities of hundreds of different genes. No one suspected miRs had a role in cancer. Now, it’s been shown they are a major player in many cancers. Last year, for example, Drs. David Cheresh, Sudarshan Anand and colleagues at the Moores Cancer Center identified and described the key role of a particular miR in regulating blood vessel growth (angiogenesis), a key factor in the development and spread of tumors.
In 2000, my colleagues and I discovered “nurse-like cells.” These cells are derived from blood cells that, in the presence of CLL cells, morph into round, fat orbs that attract leukemia cells, which in turn are nurtured and protected from dying. As with miRs, subsequent research by my lab and others has shown that the microenviroment surrounding cancer cells of all types is just as important to disease development and spread as what’s happening with the cancer cells themselves.
Without a doubt, research on solid tumors is absolutely vital and necessary to understanding these cancers. However, this research is often hampered by the inability to access the primary tumor in affected patients. Cancer researchers frequently cannot study their particular disease directly because there is no easy access to the actual tumor. Instead, we often turn to models or cancer cell lines, which may be considered shadows of the actual disease. A great advantage of studying CLL is that we can focus direct attention upon the tumor cells of patients with this disease. These cells are frequently abundant in the blood; obtaining access to them can be as easy as drawing a tube of blood. This confers some distinct benefits: Scientists can evaluate these cancer cells over time in the same patient. They can compare samples from different patients. They can assess the activity of various drugs on cancer cells taken at the same time or from the same patient.
Solid tumor research can be much more daunting and problematic. For one thing, to even determine whether a patient has a malignant solid tumor generally means performing some kind of surgery, which evokes the troubling (if unavoidable) ethical dilemma of doing surgery on the assumption that there might be cancer.
CLL presents none of these problems. It is a complex, still-confounding disease, but it represents the lowhanging fruit on the tree of cancer discovery. By untangling its secrets, we will obtain clues to the secrets of other cancers, including solid tumors. That won’t mean we’ve won the war, but certainly it should put us a major step closer toward ultimate victory.