When Good Cells Go Bad
By Kari Bohlke, ScD
Cancer. The word has taken on a meaning that extends beyond the medical definition. Cancer is deadly; it is dangerous; it means bad news. But when we hear the words, “You have cancer,” what do we really need to know about what is happening in the body?
A general definition of cancer is probably familiar to many of us: cancer involves the out-of-control growth of abnormal cells. But how does a cell become cancerous? And what distinguishes cancer from other conditions that involve abnormal cell growth?
The causes and the manifestations of cancer vary, but changes in the function of genes lie at the heart of all types of cancer. A gene that normally protects from abnormal cell growth, for example, may become inactive in one of the body’s cells (or someone may be born with an inactive version of that gene in all cells). As that cell replicates, the change is passed on to subsequent generations of the cell. Additional genetic changes may be acquired along the way, and over time a cell may acquire all the changes necessary to function as a cancer cell. This first cancer cell is the starting point for all the cancer cells that follow.
So what types of changes are characteristic of cancer cells? In a highly cited article titled “Hallmarks of Cancer,” originally published in the journal Cell in 20001 and updated in 2011,2 researchers Douglas Hanahan and Robert A. Weinberg provide several biological characteristics that cells acquire as they progress from normal to cancerous:
- They continue to proliferate even when there are no messages telling them to do so.
- They circumvent the messages that would normally stop cell proliferation.
- They resist the normal process of cell death.
- They proliferate indefinitely (normal cells replicate only a certain number of times).
- They stimulate the growth of new blood vessels to acquire the nutrients and the oxygen that they need to grow.
- They have the potential to invade other tissues and spread to other parts of the body.
- They also tend to be good at avoiding destruction by the immune system and at changing their metabolism in ways that support their growth.2
This is not the only model of how cancer develops, but it does highlight several features that have commonly gone awry in cancer cells. Of these the potential for spread throughout the body is the characteristic that most clearly distinguishes cancer from benign tumors. Benign (non-cancerous) tumors do not spread beyond the organ where they start. They may become quite large and require treatment, but they do not invade nearby tissues or spread to other parts of the body. Uterine fibroids are an example of benign tumors.
So how do factors as diverse as radiation and estrogen affect the risk of cancer? Some factors, such as radiation, act directly on a cell’s genetic material, causing damage that can persist and affect how the cell functions. Other factors (such as estrogen) may not directly affect the cell’s genetic material, but they do increase cell division in certain types of tissue. Frequent cell division increases the likelihood of genetic errors.3
Cancers may be referred to by many different names, depending on where the cancer begins:4
- Carcinoma is a cancer that begins in the skin or in tissues that line or cover internal organs. Many common types of cancer—such as breast, colon, prostate, and lung cancer—are carcinomas.
- Sarcoma is a cancer that begins in bone, cartilage, fat, muscle, blood vessels, or other connective or supportive tissue.
- Leukemia is cancer that starts in blood-forming tissue such as the bone marrow and causes large numbers of abnormal blood cells to be produced and enter the blood.
- Lymphoma and myeloma are cancers that begin in the cells of the immune system.
- Central nervous system cancers are those that begin in the tissues of the brain and the spinal cord.
In 2013 an estimated 1.6 million people were diagnosed with cancer in the United States.5 This number does not include very early-stage (Stage 0) cancers, such as ductal carcinoma in situ of the breast, nor does it include nonmelanoma skin cancers (such as basal cell carcinoma and squamous cell carcinoma). Cancer continues to kill more than a half million people each year, but the good news is that cancer mortality rates have declined by more than 20 percent since their peak in 1991.5 Lung cancer remains the leading cause of cancer death in the United States, accounting for 26 percent of cancer deaths in women and 28 percent of cancer deaths in men.
From “Disorder” to “Cancer”: Myeloproliferative Neoplasms
Cancers known as myeloproliferative neoplasms (MPNs) illustrate how our understanding and classification of diseases can evolve over time. MPNs are blood cancers in which the bone marrow cells that produce blood cells develop and function abnormally. “I would view them most accurately as a type of chronic leukemia,” says Ruben Mesa, MD, chair of the Division of Hematology and Medical Oncology and deputy director of the Mayo Clinic Cancer Center in Arizona. The three main types of MPNs are polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis.
“Initially,” explains Dr. Mesa, “they were called myeloproliferative disorders.” At that time it was unclear whether these conditions should actually be considered cancers. Eventually, however, it was determined that they were clonal (the abnormal cells could all be traced back to the same, initial abnormal cell) and could all progress to a fast-growing type of leukemia known as acute myeloid leukemia. In 2008 the World Health Organization changed the name to myeloproliferative neoplasms (abnormal growths), and MPNs are now considered cancers.
A recent advance in the understanding of these cancers is the identification of gene mutations that contribute to their growth. “There are some relatively newly described genetic changes, such as changes in a gene known as JAK2, that are very common across these diseases,” says Dr. Mesa. “The mutations in JAK2, which is an on/off switch for cell growth and proliferation, are present in almost everyone who has PV and about half of those with ET and myelofibrosis.”
Asked about the effect of these findings, Dr. Mesa says, “First it truly helps with the diagnosis, particularly of individuals who have more-borderline cases. The second and probably even more important effect is that it has led to a tremendous amount of additional scientific scrutiny into the diseases and has fueled the development of many potential targeted therapies.”
Targeted therapies are drugs that interfere with specific biological pathways that contribute to cancer growth. One targeted therapy has already been approved for the treatment of certain patients with myelofibrosis: the JAK inhibitor Jakafi® (ruxolitinib), which was approved in 2011.
Development of new approaches to treatment will provide important benefits to people with MPNs. “About half of those with ET and PV have symptoms that are inadequately controlled with current therapy options,” says Dr. Mesa. “The disease-related symptoms—such as itching, fatigue, night sweats, difficulties with concentration, and other issues—can significantly affect quality of life. And prior to JAK2 inhibition, the majority of people with myelofibrosis had very poor therapeutic options.”
Asked if people with MPNs should receive care from someone who specializes in these cancers, Dr. Mesa replies, “Well, these are diseases with a lot of subtlety in terms of management. The busy general oncology practitioner sees very few of these patients. So I do think that it is helpful to have someone involved in the broader team who has much more of a focus in this area. There’s a network of folks who focus on MPNs around the country. The NCI [National Cancer Institute] helps fund the MPD Research Consortium, with its base at the Mount Sinai School of Medicine [Icahn School of Medicine at Mount Sinai] in New York. We’re a network of many sites in the US and in Europe for clinical trials and things of that nature.”
Although MPNs are not common cancers, they are cancers for which important progress is being made. “I would say that if I were a patient with MPN, I would be very hopeful,” concludes Dr. Mesa. “There’s never been a period of time where there’s been more scientific energy and focus on these diseases. In addition, the things that we’re learning about the MPNs have implications for many other cancers.”
1. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100(1):57-70.
2. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646-74. doi: 10.1016/j.cell.2011.02.013.
3. Preston-Martin S, Pike MC, Ross RK, Jones PA, Henderson BE. Increased cell division as a cause of human cancer. Cancer Research. 1990;50(23):7415-21.
4. What Is Cancer? National Cancer Institute website.http://www.cancer.gov/cancertopics/cancerlibrary/what-is-cancer. Accessed January 20, 2014.
5. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA: A Cancer Journal for Clinicians. 2013;63(1):11-30.
6. Esserman LJ, Thompson IM Jr., Reid B. Overdiagnosis and overtreatment in cancer. An opportunity for improvement. Journal of the American Medical Association. 2013;310(8):797798.
When is a cancer not a cancer?
The example of myeloproliferative neoplasms illustrates how “disorders” can be reclassified as cancers. But can the reverse also happen? Can conditions that we currently refer to as cancer be redefined as something that sounds (and is) far less scary?
This is an active area of research and discussion. Researchers have begun to recognize that some “cancers” are so slow growing that they will never affect a person’s health. This occurs in several types of cancer, including prostate cancer and breast cancer. Because we do not currently have a good way to distinguish these indolent cancers from more-aggressive cancers, detection of any cancer often leads to treatment (although men with low-risk prostate cancer have the option of surveillance). For people with very indolent cancers, cancer treatment carries the usual risks but provides no benefit. Overdiagnosis refers to detection of cancers (through routine cancer screening, for example) that do not need to be detected. Overdiagnosis is often followed by overtreatment—treatment of a cancer that does not threaten life or health.
Development of tests that reliably distinguish very indolent from more-aggressive cancers may allow some cancers to be redefined as something other than cancer. A 2013 article in the Journal of the American
Medical Association argues, “Use of the term ‘cancer’ should be reserved for describing lesions with a reasonable likelihood of lethal progression if left untreated.”6 The idea that some cancers do not require detection or treatment is a difficult one, but by using science to refine our definition of cancer we may be able to limit the rigors of cancer treatment to those who truly need it.
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