Last updated: 2009
Cancers: Solid Tumor
- Symptoms and Treatment
- Can stem cells help?
- Cracking the code
- Using stem cells for cancer therapy
- Looking to the Future
When tumors are benign they can be removed, and they usually pose no long term problem. If, however, the tumor is malignant it is considered cancerous because its growth is unregulated and invasive. Malignant tumors expand and impact on the organ that is affected, displacing normal cells and invading normal tissue. Even if a tumor is malignant, if it is confined to one particular organ the cancer can often be cured.
If and when metastasis occurs the prognosis becomes poor. Metastasis means that cancer cells are no longer confined to the tumor but have migrated from the primary site to other organs or tissues, usually through the blood or lymphatic systems. If metastasis occurs in a solid organ then death is the likely outcome.
Solid tumors can develop in virtually any tissue or organ, the most common sites being the lungs, breast, prostate and colon. While there is sometimes a correlation between the type of cancer and exposure to certain toxins (such as lung cancer and smoking), the cause of cancer remain a mystery.
Cancer runs in families but as far as we know, only a small number (5-10 per cent) are due to an inherited gene. However, it is apparent that genetic mutations (changes in DNA over our lifetime) can lead to the development of tumors. How and why these mutations are triggered, and the interaction with environmental factors (a field of inquiry known as "epigenetics") is difficult to say. Why some solid tumors metastasize while others remain contained is also unclear.
There are many theories about what causes cancer and how to prevent it, but none proven thus far by the evidence. The search for a cure is on account of its prevalence, which increases with age. Males in North America have a one in two chance of having cancer at some point in their lives, women one in three.
Symptoms and Treatments
Most cancers appear abruptly, although tumors can grow slowly and present few symptoms, remaining undetectable for some time. An aggressive cancer can appear "from nowhere" and cause death within months. Why patients succumb to cancer is complex, why it metastasizes is not known, and some cancers are more effectively treated than others.
When a diagnosis is made, its stage of development is assessed as a way of making a prognosis and a plan for treatment. In later stages, weakness, weight loss, pain, fatigue and other complications to vital organs can result.
Conventional treatments include surgery to remove the tumor and/or chemotherapy or radiation to kill the cancer cells and thereby eliminate or shrink the tumor. The mix of these approaches varies from cancer to cancer and depends on the presence or degree of metastasis and other factors.
If treatment is successful the cancer is considered in remission and the patient will be routinely monitored for evidence of relapse. Some patients relapse after a successful remission, but as cancer is better understood, more targeted drugs are being developed. These new drugs are not necessarily curing the cancer but are achieving better results -- longer or permanent remissions, with fewer side effects.
It is encouraging that we are now curing some cancer, such as childhood leukemia. Other cancers are easily treatable, especially if detected at an early stage of disease and if it has not invaded other organs. For example, removing "pre-cancerous" moles can prevent skin cancer, or removing "pre-cancerous polyps in the colon can prevent colon cancer. Screening programs have made a difference, especially in breast, colon and prostate cancer for which tests are routinely available in many countries.
After decades of research, scientists are now much closer to piecing together both the causes and triggers of many cancers. This is in part because of the sequencing of the human genome (DNA) and especially the mapping of "gene expression" that indicates which pathways are activated or turned off as cells replicate.
New technology allows scientists to identify genetic markers on the surface of cells and to systematically trace the development of disease. This knowledge is the basis of novel drug therapy to treat cancer, gene therapy to "turn off" the cancer genes, and most recently, stem cell therapy to strengthen the body's natural immune response, deliver therapeutic drugs or replace damaged cells.
While scientists are able to gather this data - which constitutes a person's genomic signature - the challenge is to be able to interpret it so it can lead to an individualized prognosis and meaningful strategies for treatment. This is the next step in an evolutionary process that will lead to treatment that is finely tuned or customized to individual variations.
Cancer stem cells
Stem cell research has become increasingly relevant to cancer research, particularly in regard to how tumors develop. The discovery in 1994, by Canadian scientist Dr John Dick, of a small population of tumor-initiating cells as a distinct type of leukemia cell that drives the cancer led to the discovery of such cells in solid tumors in the breast (2003), brain (2004), prostate (2005), colon (2006) and pancreas (2007).
Increasingly, scientist are recognizing that the ability of a tumor to grow depends on a small group of rogue cells within the tumor - maybe one per cent of the total cell population - that act like stem cells. In fact, tumor-initiating cells have been dubbed cancer stem cells because they are pluripotent - meaning they are able to create all of the other cells in the tumor, much like blood stem cells behave in bone marrow.
Distinct from normal stem cells which are exquisitely regulated, cancer stem cells proliferate uncontrollably. Just like normal stem cells, however, these cancer stem cells are "immortal" - with every cell division they create a duplicate copy of themselves that remains undifferentiated (a process called self-renewal) and a daughter cell (called a multipotent progenitor cell) which subsequently differentiates into the various cells that make up the tumor. These tumor cells then replicate in an erratic and invasive manner.
Despite the fact that are relatively rare, cancer stem cells appear to be driving the disease. Conventional chemotherapy is directed against the bulk population of tumor cells, attempting to kill as many cancer cells as possible. Unfortunately, not only do these drugs often damage healthy tissue in the process, but they may be missing the cancer stem cells. Even if the tumor is eliminated, a few cancer stem cells that survive can regroup and recreate the original tumor over time - the best explanation we have for why relapse can occur after years of remission.
While not all scientists agree that this hypothesis explains all of cancer, it is an extremely promising and intriguing line of research that makes headlines almost daily.
Cracking the code
Stem cell research is increasingly focused on the signaling mechanisms and pathways that are responsible for the self-renewal of stem cells as a clue to what goes wrong with cancer cells, why they proliferate and cause tumors to form. This is related to understanding the hierarchy of cells within the tumor, and the special role of cancer stem cells.
The environment around the stem cells is called the niche and appears to have a central role as a feedback loop in the process of self-renewal. Scientists hope to interfere with the cues being given to prompt them to proliferate - akin to "pulling out the rug" from under the cancer stem cell by attacking its supportive niche.
In general, this refined and targeted approach is possible because of new technology that allows scientists to isolate the culprit cells, identify markers on the surface of cells which indicate which genes are being expressed to what effect, track the messages that appear to drive tumor expansion, and, most intriguing, alter the pathways that maintain the immortality or "stemness" of the cancer stem cell.
For example, researchers recently were able to identify human pancreatic cancer stem cells for the first time and use them to create tumors in mice which in turn revealed the protein markers that drive this deadly cancer. It turns out that some of the same protein markers are found in other tumors as well, so the rate of discovery is quickening as evidence converges from across the cancer spectrum on the role of these rogue stem cells.
Some scientists hope to alter these pathways when they understand what's driving the cancer ; others hope to train immune cells to recognize cancer cells and destroy them; others are exploring ways to intercept the messages coming from the cellular environment that appear to direct the tumor development; yet others are looking for ways to force cancer stem cells to differentiate, which would take away their ability to replicate indefinitely.
Using stem cells for cancer therapy
One of the setbacks suffered by researchers in designing therapeutic uses for stem cells is that in laboratory animals sometimes tumors can arise. This has injected a degree of caution in moving stem cell therapy into clinical trials until these results are better understood.
On the one hand, they need to make sure that turning on a normal stem cell won't develop a cancer. On the other hand, drugs that would neutralize the self-renewing capacity of cancer stem cells might also harm normal stem cells which are required for the regeneration of blood, skin, muscle tissue, the lining of the intestines, and neurons which, among other things, help us to create new memories.
The knowledge created by stem cell research, especially as it relates to cancer, may be more useful to curing disease in the long run than using stem cells themselves therapeutically. For example, we know that only one colon cancer cell in 60,000 has the ability to keep the tumor going and that ordinary tumor cells stop growing without direction from cancer stem cells. Interrupting these signals may be the best therapy one could hope for.
That being said, there are a few developments that exploit the properties of stem cells to deliver therapeutic benefit to those suffering with cancer. One of these is for patients with advanced cancer where they are unable to tolerate the large doses of chemotherapy needed to kill their tumor, or for patients whose cancer has metastasized.
Some childhood cancer involving solid tumors can be treated with large doses of chemotherapy that obliterate the child's immune system in the interest of killing tumor cells, followed by blood stem cell transplantation to reconstitute the immune system. These are regimens that have been used for the treatment of leukemia and other childhood diseases for some time and are being refined for other types of cancer.
Looking to the future
While the cancer stem cell hypothesis is rejected by some and continues to be rigorously tested and refined by new research, stem cell biology - particularly the regulation of the property of self-renewal - has become critical to understanding cancer. In fact, some would define cancer simply as unregulated self-renewal of cells.
Studies being conducted in the US, Canada, the United Kingdom, Italy, Israel Germany and several other countries - identifying cancer stem cells in the brain, pancreas, breast, colon, skin, and prostrate and other organs - increasingly support the theory that tumors originate from the transformation of normal stem cells into cancerous stem cells which continue to proliferate as the "engine" of the tumor.
How will this research help patients? Already scientists are beginning to design therapeutic interventions that are no longer "hit or miss" but quite specific to the signaling pathways used in tumor development in various organs. For example, researchers at Johns Hopkins University recently showed that a drug known to inhibit the cell signaling system "Hedgehog" - which is a critical pathway in the development of brain tumors in children - successfully killed the cancer stem cells that otherwise survive radiation therapy.
With a technology known as high-throughput screening, the drug discovery process is not only being shortened but compounds can be tailored to the profile of specific tumors. This is done by culturing a patient's cancer stem cells in the laboratory and then using them to test various drug compounds. In this regard, trials are likely to be undertaken in the clinic as a matter of course. This kind of protocol is the beginning of personalized medicine made possible by stem cell genomics, what Genome Canada calls a "smart bomb" approach to treating cancer.