Fundamental Questions About Cancer Being Answered by National Jewish Health
National Jewish Health is World Leader in Medical Research and is Striving to Answer the Following Basic Questions About Cancer:
What are the links between immune deficiencies, viruses and cancer?
John Routes, MD, Associate Professor in the Department of Medicine, recently discovered a possible cause of non-Hodgkin’s lymphoma in patients with common variable immunodeficiency (CVID). In patients with CVID, the immune system is deficient and is not able to fight off infections very effectively. Additionally, CVID patients also seem to be disproportionately diagnosed with non-Hodgkin’s lymphoma. This coincidence struck Dr. Routes as unusual and he set forth on a quest to find the connection. What Dr. Routes has found is quite exciting…tissue samples from several patients with CVID and non-Hodgkin’s lymphoma reveal the presence of human herpes virus 8 (HHV8). This intriguing data suggests that the herpes virus might somehow be involved in the development of lymphoma. Dr. Routes’ ongoing research hopes to understand how a virus like herpes can transform healthy cells into a cancerous tumor.
Dr. Routes and his team also compared and contrasted two other very important human viruses…human papillomaviruses (HPV is the culprit of genital warts) and adenoviruses (primarily responsible for upper respiratory tract infections in humans). While quite similar in structure and actions, Dr. Routes’ research has found a very important difference between the two…only HPV can transform human cells into cancerous cells. In fact, adenoviruses trigger a protective immune system response, while HPV fails to elicit an anti-tumor response. These results were published in a leading biomedical journal, Virology. Although a vaccine has recently been discovered to prevent HPV, Dr. Routes plans to continue studying this virus because the new vaccine does not prevent those who are already infected with HPV (of which there are some 20 million in the U.S.) from developing cancer.
Can the immune system be tricked into thinking a tumor is an infectious disease?
A tumor is made of “self” tissue, which means the body’s immune system recognizes it as a normal part of the body and does not attempt to kill it. However, the immune system recognizes cells infected by infective agents such as viruses as foreign intruders and is designed to attack them. Ross Kedl, PhD Assistant Professor in the Integrated Department of Immunology, is hoping to find a way to trick the immune system into thinking a cancerous tumor is an infectious disease so that it would kill cancer cells in the same way.
Dr. Kedl’s focus is on understanding the nature of immune-system regulation: why the immune system goes to work against some diseases and ignores or gets turned off when cancer is involved. His research is an offshoot of vaccine development studies. When cancer patients are vaccinated, they get an initial burst of immunity, a push of immune cells, such as killer T cells, that begin anti-tumor activity. However, eventually the immune system turns itself off. Dr. Kedl is studying melanomas with the hope of finding out what molecular decisions the body makes about turning the immune system off, and what can be done to sustain the immune response once it begins. Such knowledge would allow researchers to develop a more effective cancer vaccine therapy. He hopes to also study this idea with leukemia cells in the future.
Can killer T cells learn to destroy cancer cells?
Jill Slansky, PhD, Assistant Professor in the Integrated Department of Immunology, is studying the immune response to colon and cervical cancers, as well as melanomas. In healthy people, killer T cells search out and destroy cells infected with a bacteria or virus. They do this with receptors that recognize abnormal peptides (a chain of amino acids) on the surface of diseased cells. However, cancer cells are normal cells that begin to act abnormally, but continue to seem normal on their surfaces. So T-cells do not recognize them as dangerous, and cancer cells are then able to “hide” from T cells and continue to grow and mutate. Dr. Slansky is hoping to develop a vaccine that would help T cells “learn” to recognize cancerous cells, and, therefore, be able to kill them. In previous research, she has found that by substituting different amino acids into the peptide chain, T cells were able to recognize that the peptide was abnormal. After being exposed to this altered peptide chain, T cells were better able to recognize cancerous cells. She currently is involved in a study to see which amino acids (out of 30 million possibilities) are most important in this process. Breaking this code will help make vaccines that are able to stimulate a better anti-tumor response in the immune system.
In addition, she has just launched a new project to learn how T cells respond to tumors deep within a tumor. Tumors generally have low oxygen levels and Dr. Slansky wants to find out if helping T cells function in low oxygen levels could lead to immune therapies to treat advanced tumors.
Do autoimmunity and lymphoma have something in common?
The lab of Yosef Refaeli, PhD, Assistant Professor of Cell Biology in the Department of Pediatrics, focuses on the basic mechanisms of how lymphomas and leukemias (blood cancers) arise. There are 60 different types of lymphomas, and they typically occur in young children and older people. They are the fifth most common cancer - more common than melanomas and cancer of the pancreas - and the incidence rate has increased 85 percent in the last 25 years. Lymphomas are the only major form of cancer that has increased in the last 25 years.
Lymphomas apparently are not caused by known environmental factors (like lung cancer, which can be caused by smoking, and skin cancer, which is caused by sun exposure). Scientists believe that autoimmunity predisposes people to lymphomas. Autoimmunity is on the rise in this country. People with an autoimmune disease (such as lupus or MS) are 50-200 times more likely to get a lymphoma. Dr. Refaeli believes the mechanism of autoimmunity and lymphoma could be a shared mechanism: the B-cell receptor signal. He is researching the B-cell receptor signal (the signal that arises when B-cells recognize an antigen) and how it contributes to generating lymphoma. Lymphomas are very difficult to treat; doctors usually recommend heavy doses of chemotherapy. Getting at the root cause of the molecular mechanisms of the disease will allow researchers to develop better treatments.
Oncogenes are normal-functioning genes that become cancer-causing genes. His previous research has suggested that a certain oncogene is a critical regulator of immune responses. In an example of how basic research can lead to treatments for more than one disease, Dr. Refaeli is testing how these genes works in asthma in collaboration with Erwin Gelfand, MD Chairman of the Department of Pediatrics. This study could lead to an important target for therapeutic intervention for asthmatics, as well as those with cancers of the immune system.
He is also collaborating with Philippa Marrack, PhD a Professor in the Integrated Department of Immunology, and John Cambier, PhD, Chairman of the Integrated Department of Immunology, on a study to better understand aging and the immune system. The propensity to get lymphomas increase as people age (two of the most common lymphomas strike people age 40-70). Drs. Marrack, Cambier and Refaeli want to find out if getting such diseases is an inherent affect of the aging process itself. These findings may potentially unveil the reason for increased autoimmunity and decreased immune capability in older individuals.
Can increasing a protein present in the body treat breast cancer?
A protein known as cdk6 inhibits proliferation of some cell types and may play a role in the development of breast cancer, according to a report by National Jewish Health researchers. Joseph Lucas, PhD, Associate Professor of Cell Biology in the Department of Pediatrics, and Dr. Gelfand, reported in the February 2004 issue of Molecular Cancer Research, that breast-cancer cells have low to nonexistent levels of cdk6, while normal cells have relatively high levels. Cell growth in two tumor-cell lines dropped significantly when levels of cdk6 were increased inside the cells. These findings suggest a new and promising avenue of breast-cancer research. If our scientists can learn how to keep cdk6 levels up in breast tumors, they may be able to prevent the malignant cells from dividing. This protein also may be used as a diagnostic tool by determining if cells are normal or malignant depending upon the amount of cdk6 found in them. National Jewish Health has applied for a patent on the use of cdk6 as a marker for cancer and as a target to control cell growth.
Can a different protein inhibit the growth of breast tumors?
Invasion and metastasis are the most lethal characteristics of cancer. Transforming growth factor-beta (TGF-β) is a protein naturally produced by the body to suppress cancer. However, in patients with cancer, TGF-β fails to stop the cancer and instead promotes cancer growth, invasion and ultimately metastasis. The paradoxical activity of TGF-b is thought to be indirectly related to a change in the cell’s protein levels. That is, scientists think that TGF-b influences protein expression on a cellular level. The microenvironment created by the change in these protein levels is thought to play a role in the TGF-b paradox.
In another breast cancer study, William P. Schiemann, PhD, Assistant Professor of Cell Biology in the Department of Pediatrics, is trying to identify proteins whose expression are regulated by TGF-b in order to understand how changes in protein levels may or may not contribute to the cancer process. Dr. Schiemann recently identified a protein named Fibulin-5 (FBLN-5), which, when turned on by TGF-b, serves as a signaling molecule on normal cells and cancer cells. Dr. Schiemann’s current research is investigating FBLN-5’s role in tumor development. Importantly, his research has already revealed that FBLN-5 may act as a novel suppressor of breast cancer. He has found that in 100 percent of human breast cancers, FBLN-5 is absent; whereas, in normal breast tissue there are detectable levels of FBLN-5. FBLN-5 has also been found to weaken DNA production in breast cancer cells, thus slowing their growth and destruction. This indicates that FBLN-5 may play a role in stopping cancerous growth.
Based on these findings, Dr. Schiemann’s newest research will try to confirm that without the correct levels of FBLN-5, breast cancers are able to form and progress. In doing so, his findings may one day improve the prognosis of breast cancer patients by enhancing our understanding of how cancer progresses, and ultimately by developing FBLN-5 as a drug to treat breast cancer.
