Cancers: Blood Cancers
- Symptoms and treatment
- How can stem cells help?
- Understanding cancer stem cells
- Bone marrow and stem cell transplantation
- Looking to the future
Usually when a cell is damaged it is eliminated by a process called apoptosis, or programmed cell death. Cancer cells avoid apoptosis and multiply in an unregulated manner, spreading to adjacent tissue or traveling through the bloodstream or lymphatic system, a process called metastasis. In these cases, the primary cancer is a solid malignant tumor in the lungs, breast, colon, pancreas, stomach, skin, liver or other organ.
Blood cancers, on the other hand, are cancers found in the blood, bone marrow, lymph nodes or lymphatic tissue, primarily in the various types of white blood cells, or leukocytes, that circulate. The regeneration of blood cells to transport oxygen to cells, remove waste from tissues, and protect your body from infection is the primary task of the bone marrow. White blood cells develop from stem cells in the bone marrow and are dispersed into the circulatory and lymphatic systems to support the body's immune system.
Leukemia and lymphoma, found in the blood and lymphatic systems respectively, are the two major types of cancer that develop when immature leukocytes multiply abnormally because of mutations in the cells' DNA. This uncontrolled proliferation of rogue white blood cells disrupts the normal cycles of cell production and cell death and compromises the body's immune response.
In leukemia, the cancerous white blood cells replace normal cells in the bone marrow or lymph tissue and sometimes invade other organs. Leukemia can be chronic or acute, the latter being found usually in children and progressing rapidly.
Lymphomas are malignant tumors that originate in the lymph glands and tissue, specified as either Hodgkin's disease or non-Hodgkin's lymphoma, depending upon which cells are present in the tumors. As these cancers progress they sometimes also affect the blood, bone marrow and other organs.
Symptoms and treatment
Leukemia
The American Cancer Society estimates that in 2007, almost 45,000 people in the United States will be newly diagnosed with leukemia resulting in over 20,000 deaths. It is one of the most common cancers found in children, but it represents only about ten percent of all cases. Treatment of childhood leukemia is now effective in the majority of cases, whereas other types of leukemia are less responsive to treatment.
As leukemia cells grow and eventually outnumber normal cells circulating in the blood, the normal blood cells are disabled. This results in frequent infections, bleeding problems, poor wound healing and anemia. Leukemia cells may collect in certain parts of the body causing pain, swelling and other problems. The different types of leukemia are associated with differing prognosis, the acute types having a higher mortality rate and requiring more aggressive treatment.
Lymphoma
Lymphoma is cancer of the lymphatic system, a system involving the lymph glands, spleen, thymus and other tissue that purifies the blood and lymphatic fluids that support the immune system. Symptoms may include swollen lymph nodes, itching, fatigue, night sweats and susceptibility to infections. There are more than 29 different types of lymphoma. It is estimated that this year in the United States over 70,000 people will be newly diagnosed, with almost 20,000 deaths.
Hodgkin's disease - found mostly in young adults and far less prevalent than non-Hodgkin's lymphoma - is being successfully treated in the majority of cases. Conversely, since the early 1970's the incidence of non-Hodgkin's lymphoma has nearly doubled with a higher prevalence in women. This is partly because it is one complication of HIV-AIDS, but otherwise the trend is unexplained.
Though a variety of risk factors have been associated with lymphomas, including celiac disease or gluten intolerance, most are associated with a severely depressed immune system or an environmental trigger. The cause of the majority of lymphomas is unknown, but a family history is linked to increased risk.
Treatments of both leukemias and lymphomas rely on a combination of chemotherapy and radiation therapy, with a percentage of patients undergoing bone marrow transplantation or blood transfusions. While radiation, chemotherapy and transplant regimens continue to be refined to be safer and more effective, new drugs are being designed such as Gleevec which targets an enzyme that turns off cancerous overproduction of white blood cells.
How can stem cells help?
It was in researching leukemia nearly 50 years ago in Canada that Dr James Till and Dr Ernest McCulloch discovered blood forming stem cells in the bone marrow and blood cancers continue to be at the forefront of stem cell research today. In 1994, University of Toronto scientists continued the tradition of discovery by identifying cancer stem cells, first in leukemia. By 1997, they were able to isolate and inject them into healthy mice that then went on to develop leukemia.
In 2007, the same team, led by Dr John Dick, was able to insert just one cancerous gene into a human stem cell and seed the human form of leukemia in laboratory mice. This animal model is significant because scientists can now "watch" the human form of leukemia develop from the beginning and track the proliferation of the original cancer stem cell into many different types of cells, connecting this process to the progression of disease symptoms in patients.
Understanding cancer stem cells
The discovery of cancer stem cells is revolutionizing the study of cancer, although it is still considered a working hypothesis. It was once thought that every cancer cell was equally responsible for driving the disease, and the fastest growing cells were particularly targeted for therapy because they were thought to be most virulent. It now appears that stem cells, which divide slowly, are the main culprits, even though they are quite rare. Once these cells become cancerous they spawn progenitor cells that do not maturely properly but instead proliferate quickly.
In solid organs, cancer stem cells create all the cells in the tumors. But in blood cancers they create havoc in the circulatory and immune systems by spawning large numbers of immature or abnormal cells (usually white blood cells).
For example, in leukemia, these abnormal cells pool in the bone marrow and displace healthy cells, attack or overwhelm the immune system, or cause a platelet or red blood cell deficiency leading to poor wound healing or anemia. Because a stem cell always retains a "copy" of itself in the process of cell division, the leukemia stem cell has a limitless capacity to sustain the disease process.
Not only do these cells appear to orchestrate the cancer, they often survive chemotherapy and radiation treatment. This helps to explain why leukemia sometimes returns after a remission - the seeds of the disease are in these special cancer stem cells that are by nature self-replicating. Even if only a handful of cancer stem cells survive, they can lie dormant in bone marrow and eventually trigger a new generation of leukemic cells.
Scientists are now concentrating their efforts on mapping the protein markers that are on the surface of stem cells and regulate the behavior of the cells. This gene activity pattern (or gene expression) is being called the "signature" of self-renewal - and scientists expect that knowing this will allow them to identify leukemia stem cells more easily for the purpose of diagnosis and prognosis. Following the trail of the protein that triggers this gene expression, they have already demonstrated that they can disable the mechanism that keeps the cell dividing and replicating. With such detailed analysis of the genetic codes and pathways, scientists will better understand how to change the genetic instructions that mobilize the cancer stem cells. This targeted approach aims to shut down their ability to replicate without harming the normal stem cells that reside in bone marrow and are vital to replenishing the blood supply.
Bone marrow and stem cell transplantation
Bone marrow transplantation or stem cell transplantation from a matched or related donor is advised if other strategies have not been successful in treating leukemia or lymphoma. This treatment requires a source of healthy bone marrow stem cells, or hematopoietic stem cells to replace the abnormal leukocytes that will be killed by chemotherapy and radiation. It is often very difficult to find a matching donor if a close relative is not available.
There are many clinical trials underway to refine the protocol for stem cell transplantation for various types of leukemia and lymphoma. "Autologous" stem cell transplantation, which circumvents the problem of a donor match by purifying the patient's own stem cells of disease, is proving a viable alternative to "allogenic" transplantation, which requires a donor. Injected into the bloodstream, stem cells migrate to the bone marrow and begin to replicate and produce all the blood cells required.
Recently, umbilical cord blood has been effectively used as a source of stem cells for transplantation and is less prone to rejection, a common problem called "graft-versus-host disease." The relative immaturity of cord blood cells appears to be beneficial in the uptake of this therapy, and a precise donor match is not required but the numbers of stem cells in a cord blood donation limits its utility.
Looking to the future
Stem cells are the source from which the entire blood system is derived and regenerated continuously throughout life. Scientists are increasingly able to identify stem cells by examining the protein receptors on the surface of the cell and tracing how they behave, or "express" their genetic instructions, including their ability to self-renew, the hallmark of stem cells.
With 50 years of research and clinical experience using hematopoietic stem cells to treat leukemia, the advanced understanding of blood stem cell pathways is paving the way for understanding how cancer develops in many organs. This involves questions about genes that appear programmed to activate cancer under certain conditions ("oncogenes"), as well as genes that are designed to suppress cancer ("tumor-suppressor genes").
As research in both stem cell therapy and genomics continue to dovetail through the examination of the complex pathways involved in cancer's development, drugs will undoubtedly be developed to target these mechanisms. With the possibility of decoding a unique "signature" that drives the leukemia or lymphoma in a particular person, the treatment will likely become much more targeted and specific, even customized, with far fewer side effects on normal cells.
With umbilical cord blood now being banked in many countries of the world and early studies producing very good results, it may not be long before cord blood transplantation replaces bone marrow transplantation as the primary form of therapy for blood cancers. Canada, the US and the United Kingdom are leading the research in this field, with important contributions from Israel, Germany, Australia and other countries.