this is great information. Cancer is such a terrible disease to deal with. this is explained very well.
Posted by on 05/23 at 02:30 PM
The very roots of cancer
The steadfast gardener tackles his weed-covered lawn with a vengeance, yanking and slashing crabgrass and clover until the grass is pristine and perfect. But within weeks, the weeds sprout back, spawned by once-dormant bulbs and seeds that remained hidden under the soil. A similar scene might be playing out every day on a far more life-and-death stage: the human body.
Researchers at City of Hope and beyond increasingly believe that cancer is not a single, united enemy to fight. Instead, the tumor cells that are felled and killed by chemotherapy and radiation are just the easier targets — the more vulnerable components of cancer. Behind them, quiet and ready to grow back after treatment, remain the hardy survivors.
Many scientists call them cancer stem cells.
FOREVER YOUNG
Normal, healthy stem cells are key to the cellular renewal humans need to stay alive and thrive.
After blood donation or blood loss from an accident, the body must replenish its blood cells. After a sunburn, damaged skin cells must be replaced. Even daily living eventually wears out most cells, which are swept away and swapped for more vigorous ones. Stem cells spur this rejuvenation.
Two types of stem cells have received considerable attention: embryonic stem cells and adult stem cells.
Embryonic stem cells are like blank slates: They can divide and produce any and all of the more than 200 different cell types in the human body. The inner mass of a five-day-old human embryo contains about 30 to 40 of these cells, which are the ancestors of all the human body’s cells in the years to come.
But stem cells are not just for embryos. Adults and children have stem cells, too. These are called adult stem cells, and they are more specialized than embryonic stem cells. Most of these cells can differentiate into a variety of cells within a certain family. For example, certain stem cells can give rise only to the types of cells that make up blood; others can only create nerve cells.
Because of the way stem cells divide, they not only create specialized cells, but they also create exact copies of themselves. That means they can truly renew themselves and create cells that are forever young.
This constant self-renewal is great for healthy cells and a healthy body, but self-renewal strays into dangerous territory if the seemingly immortal cell is cancerous. And that possibility is exactly what scientists grapple with today.
LURKING BEHIND LEUKEMIA
Ravi Bhatia, M.D., chief of the Division of Hematopoietic Stem Cell and Leukemia Research, has seen leukemia strike many patients. Although modern treatments beat back the disease, it frequently returns. He believes leukemia stem cells are to blame.
“Within leukemia, there is a certain population of cells that give rise to other leukemia cells,” Bhatia said. These are defective, abnormal stem cells that not only appear to produce cancerous cells, but also duplicate themselves, becoming cancer factories.
Scientists raised the possibility of a leukemia stem cell about 20 years ago, and despite doubts, research by Canadian scientist John Dick, Ph.D., in the 1990s finally verified it, Bhatia said. First came Dick’s discovery of a cancerous stem cell in a patient with acute myeloid leukemia; then came discoveries of stem cells in other leukemias, as well as breast, pancreatic, head and neck, and other cancers.
As Bhatia explained, leukemia happens when the blood cell creation process breaks down. Production of abnormal “leukemic” blood cells outpaces the creation of healthy blood cells. The overabundance of leukemia cells can crowd the bone marrow, allowing no space for healthy blood cells to grow or pump out defective white blood cells, which can render the immune system ineffective against infection.
Leukemia, Bhatia said, may very well depend on leukemia stem cells to keep itself going, even though only one in every 10,000 leukemia cells is believed to be a leukemia stem cell.
“There is the possibility that if there were no leukemia stem cells, then any spontaneous production of leukemic cells could not be sustained or grow and develop into full-blown leukemia,” said Bhatia, because cancer stem cells fuel the process.
Cancer stem cells also explain the incomplete success of chemotherapy. Chemotherapy battles cancer because it seizes on a central characteristic of the disease: Cancer cells divide, grow and proliferate — quickly.
Traditional chemotherapies specifically target and kill fast-growing cells, which is why chemotherapies can shrink tumors and kill spreading cells. It is also why chemotherapy kills other healthy cells that happen to grow quickly such as those in hair follicles and the intestinal lining, causing the familiar side effects of cancer treatment.
But many cancers return after chemotherapy, and they may return more aggressively.
“It’s the average cancer cell that divides very fast. Leukemia stem cells are usually quiescent, which means that they are not very active,” said Takahiro Maeda, M.D., Ph.D., assistant professor in the Division of Hematopoietic Stem Cell and Leukemia Research. “They can sit around not doing anything until they get a signal that they need to produce more cells.”
That means leukemia stem cells may survive chemotherapy unscathed and remain ready to produce more leukemia cells. The ability to evade chemotherapy by lying dormant makes leukemia stem cells an important area for research.
“Current standard treatment for hematological malignancies like leukemia and lymphoma can eradicate most cancer cells, but they do not target the cancer stem cells that can give rise to new cancer cells and eventual recurrence of the malignancy,” Maeda said.
STEMMING THE TIDE
Researchers at City of Hope are taking many different approaches to understanding cancer stem cells. Bhatia’s investigations focus on specific receptors in cancer cells that help them divide and grow.
His studies show that the cancer drug Gleevec works against chronic myelogenous leukemia, or CML, by blocking a specific protein receptor that many of those cancer cells use to function. Although Gleevec kills mature CML cells, leukemia stem cells survive. Often, when they develop into mature leukemia cells, they become resistant to Gleevec.
Bhatia found, though, that adding another new type of drug to the mix seems to cause the leukemia stem cells to self-destruct.
“Our studies so far are encouraging, and we have identified multiple targets that play a role in leukemia stem cell survival and replication,” said Bhatia. “The challenge is to find out which targets are more relevant to controlling or eliminating those stem cells.”
Bhatia and colleagues opened a phase I clinical trial in June to study their new strategy.
Even with more than 20 years of research data that support the existence of leukemia stem cells, scientific debate still continues about the role cancer stem cells actually play in cancer development — and even whether stem cells exist in all types of cancer.
And some scientists ask: What makes a cancer stem cell a cancer stem cell, rather than just a cancer cell that is resistant to chemotherapy? Researcher Margarita Gutova, M.D., Ph.D., has some answers.
“Cancer stem cells in different tumors will have similar qualities.
They will be resistant to chemotherapy, they will demonstrate stem cell-like properties of replication and they will be only a very small population of cells within the tumor,” said Gutova, senior research fellow in the Department of Hematology & Hematopoietic Cell Transplantation. “But they will have differences as well: different genes that are crucial to their functioning, different methods of operation and different behaviors.”
Gutova is researching possible lung cancer stem cells and breast cancer stem cells. She found that the most aggressive form of lung cancer, which is resistant to most chemotherapies, shows high activity of a gene named uPAR. She found a similar set of cells in breast cancer.
“This high level of uPAR activity is similar across many types of tumors,” said Gutova.
“Finding a way to target uPAR may help in multiple cancers, but each type of tumor may have a more effective target that is specific to that tumor.”
Similarities to healthy stem cells also raise more basic questions about the origin of cancer stem cells.
Are they healthy stem cells that somehow get their genetic wires crossed and begin generating cancer cells instead of healthy cells? Or do they start out as normal cancer cells, but then are somehow transformed into immortal cells that produce other cancer cells and refuse to die off? Which comes first, the cancer or the cancer stem cell?
Researchers are still looking for answers.
FROM ALL DIRECTIONS
In the meantime, Maeda knows patients with blood cancers cannot wait, so he is pushing to unlock some of the secrets of these stem cells in his lab.
Maeda’s research focuses on lymphoma and acute leukemia, both of which affect white blood cells. He is investigating a gene that helps in the production of a specific white blood cell important to a healthy immune system. Called leukemia/lymphoma-related factor, or LRF, the same gene is also highly active in lymphoma, which makes it an oncogene, a gene that can be tied directly to the development of cancer.
“We are currently looking to understand how LRF works in a normal, healthy hematopoietic [blood] stem cell,” said Maeda. “If we can understand the difference between healthy expression and oncogene expression, perhaps we can find a target to help us either turn off the cancer stem cell or even turn it back into a healthy, functioning stem cell.”
Yanhong Shi, Ph.D., assistant professor of neurosciences, is conducting similar research into neural stem cells and a protein called TLX that blocks these cells from differentiating into specialized neuron cells. Neurons are cells of the brain and nervous system.
That same TLX protein is found in a small population of brain tumor (glioma) cells that, not surprisingly, demonstrate stem cell-like qualities and are presumably resistant to chemotherapy, as well.
“We are trying to characterize the impact of TLX in glioma cells,” said Shi. “We would like to determine whether TLX is an important target that we can develop new brain tumor therapies around.”
Shi is not alone at City of Hope in investigating stem cells’ role in brain and nervous system cancers. Qiang Lu, Ph.D., assistant professor of neurosciences, studies ephrin, a receptor molecule found in brain tumors, as well as pancreatic, colon and breast cancer, among others. Ephrin helps signal cells to move to specific locations and grow blood vessels; scientists suspect it also helps tumor cells to break off and spread to other areas in the body.
“We study how neural stem cells maintain themselves as stem cells. We found that ephrin is required, and its absence makes those stem cells differentiate into neurons,” said Lu. “Since it is also expressed in gliomas, targeting ephrin may help in treating the cancer. We are currently actively exploring this possibility.”
In another laboratory, Ya-Huei Kuo, Ph.D., assistant professor in the Division of Hematopoietic Stem Cell and Leukemia Research, studies how functions of leukemia stem cells are regulated and sees potential in research into RNA interference. In that strategy, scientists engineer short fragments of genetic code to switch specific genes on or off to treat cancer. Whatever the strategy, Kuo and her colleagues all share a single desire: weeding out the seeds of cancer and finding better treatments for the disease.
“My ultimate goal is to find a cure, and the best way to do that is to understand how cancer develops, understand the role of cancer stem cells, and use that knowledge to design a better treatment,” said Kuo. “Much of my work so far has been about seeing how we get cancer. I would also like to see if we can go back and maybe change the cancer stem cell. Hopefully, we can.”
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