Cells in general, and animal cells in particular, are extremely intricate Rube-Goldberg-like mechanisms. Their correct functioning depends on the integrity of 20,000 or so genes (in the case of humans), and at least 5 times as many proteins whose form is specified by the genes. Damage to even one of a few thousand important genes can put a cell on the road to becoming cancerous. So the first fact about cancer isn't really all that hard to understand: cancer (in all of its many forms) is a disease that begins with damage to the DNA of one or more genes.
This damage, which is necessary but not sufficient, can occur in many ways. Sometimes it happens because of the action of external agents, like carcinogenic chemicals or high-energy radiation (including ultraviolet light). Other times it happens simply because of occasional errors made in copying DNA during the process of cell division. These are just a few of many ways in which DNA can suffer damage. It's estimated that from 10,000 to a million DNA mutations can occur in a single human cell per day.
Fortunately, only a few percent of the 3 billion fundamental units (base pairs) of DNA actually occur within genes – everything else is "noncoding DNA". Although much of this noncoding DNA serves some useful purpose, we have little idea at present what that might be. However, it's certainly less critical to cell function than the DNA of actual genes. Even so, 10,000 or so genes in every cell could suffer mutations every day.
Of course, complex multicellular life couldn't exist unless nature had evolved some means for coping with all this random genetic damage. And so, there are a large number of ways that cells have of detecting and repairing the damage that does occur. Then in the relatively small number of cases where damage cannot be repaired, cells have additional fail-safe mechanisms to avoid malfunctions which lead to unlimited proliferation – i. e. cancer. One such mechanism is for a cell to enter a state of "senescence", where it ceases to be able to divide at all. A more drastic, but common, mechanism is for the cell to undergo "apoptosis" – orderly cell death.
A necessary condition, therefore, for a cell to become cancerous, even after DNA damage remains unrepaired (perhaps because of damage to part of the repair mechanism), is that the damage occurs in a gene that codes for proteins needed for one of the various fail-safe mechanisms. Consequently, in almost every case of cancer where a tumor has begun to form, one finds problems in some part of the cell's anti-proliferation machinery.
We'll look at a recent piece of research that identifies one particular way this can happen, and it's interesting for the variety of different cell processes that become involved.
Many of the known "causes" of cancer are fairly easy to understand. Certainly, the cancer risk from DNA-damaging carcinogenic chemicals is obvious enough. And once one understands how important a key protein known as p53 is in crucial cellular processes such as detection of unrepaired DNA damage and invocation of apoptosis if necessary, it's not hard to understand why more than 50% of human tumors have mutated genes for p53.
But there are other factors which have been found, in epidemiological studies, to be statistically associated with cancer development. One of these is inflammation, which is a very normal part of the body's immunological defenses against infection. Inflammation itself is a highly complex process – too complex to outline here. Chronic infections by various agents can cause a state of persistent inflammation. An example is the result of H. pylori bacterial infections. In addition to being responsible for stomach ulcers, such infections are also found in cases of stomach cancer. Obesity is also known as an epidemiological factor in various cancers, and the reason is now thought to be the state of chronic inflammation that obesity often causes.
What is not clear is exactly what mechanism connects inflammation with cancer. There's undoubtedly a variety of mechanisms, given how complicated cellular processes turn out to be when you get down to the finer details. The recent research mentioned above illustrated one such mechanism, in one single type of cancer.
Anti-inflammatory drugs may defeat a treatment-resistant type of cancer (6/24/09)
The research focused on a type of non-Hodgkin lymphoma called diffuse large B-cell lymphoma. In some patients with the disease, chemotherapy works well. In a recent study of 40 patients more than 75 percent of patients with one form of this type of lymphoma survived five years or longer.
But that study also identified a group of patients whose cancer proved difficult to treat. Their tumors failed to respond to chemotherapy, and only 16 percent of patients with this form of lymphoma survived more than five years after they were diagnosed.
Several molecular flags mark this treatment-resistant lymphoma, but the links between them were unknown until now. The new paper reports that tumor cells isolated from these patients have depressed levels of a protein called SHIP1, which was known to suppress tumors. In fact, patients with the lowest levels of SHIP1 are the least likely to survive.
SHIP1 is a phosphatase enzyme. That means it removes phosphate groups from proteins. So a phosphatase has the opposite effect of enzymes known as kinases, which attach phosphate groups to proteins. Having a phosphate group attached at the right place on a protein is what enables the protein to take part in a signaling pathway, which is the basic communication mechanism in a cell responsible for making things happen. Therefore, phosphatases disrupt pathways, and stop things from happening. This can be beneficial, for example, if what's happening is the excessive cell division that occurs in cancer. Accordingly, SHIP1 has been found to be a tumor suppressing protein.
In the case of diffuse large B-cell lymphoma (DLBCL), it is found that SHIP1 levels are abnormally low. It's not that the SHIP1 is defective; there's just not enough of it. So the question is why. Is there some other defective gene that's responsible?
Apparently, there is not. Instead, it's the presence of inflammation that's responsible, and in an interesting way. Inflammation is a perfectly normal product of the body's immune system, and it exists to counteract harmful agents such as bacteria. The immune system initiates and regulates the process of inflammation by means of signaling molecules called cytokines. One of the more common and important of these cytokines is TNFα.
Now, TNFα normally goes about its business without causing cancer or other lasting ill effects. In fact, under the right conditions it can induce apoptosis or inhibit tumor formation in other ways. But for some reason, in DLBCL, TNFα suppresses SHIP1, and thus promotes cancer. The research in question also discovered the mechanism of SHIP1 suppression. It turns out that the real culprit here is a small piece of microRNA called miR-155. This little bugger was already known to be involved with leukemia in mice, and with other cancers. (See references in here.)
The resistant type of lymphoma cells also have elevated levels of miR-155, a specific example of a type of genetic material called microRNA, the team found. They demonstrated that miR-155 suppresses SHIP1 by sticking to the template for the protein, preventing its manufacture. ...
The final clue came from earlier reports that an inflammatory molecule called TNFα could boost levels of miR-155. Additional laboratory work confirmed the observation for this type of lymphoma cell.
Some anti-inflammatory drugs, used for diseases such as arthritis and inflammatory bowel disease, where inflammation gets out of hand, work by suppressing TNFα. So it was hypothesized that such a drug might be beneficial in treating DLBCL. And voilà:
The anti-inflammatory drugs etanercept and infliximab, which are currently used to treat arthritis and inflammatory bowel disease, work by suppressing TNFα, suggesting a new way to curb the malignancy of this type of lymphoma.
The team tested the idea in mice that had been injected with aggressive lymphoma cells and found that nascent tumors shrank in six days.
However, mice are not humans, so the drugs need to be tested in human DLBCL patients. Patients are already being recruited for clinical studies.
Now, there are plenty of questions remaining. More needs to be understood about just what pathways SHIP1 disrupts in order to suppress tumors. This should also help in understanding why inflammation and the resulting TNFα do not, fortunately, cause cancer more often. Baby steps. But perhaps significant ones.
Here's the research abstract:
Onco-miR-155 targets SHIP1 to promote TNFα-dependent growth of B cell lymphomas
Non-coding microRNAs (miRs) are a vital component of post-transcriptional modulation of protein expression and, like coding mRNAs harbour oncogenic properties. However, the mechanisms governing miR expression and the identity of the affected transcripts remain poorly understood. Here we identify the inositol phosphatase SHIP1 as a bonafide target of the oncogenic miR-155. We demonstrate that in diffuse large B cell lymphoma (DLBCL) elevated levels of miR-155, and consequent diminished SHIP1 expression are the result of autocrine stimulation by the pro-inflammatory cytokine tumour necrosis factor alpha (TNFα). Anti-TNFα regimen such as eternacept or infliximab were sufficient to reduce miR-155 levels and restored SHIP1 expression in DLBCL cells with an accompanying reduction in cell proliferation. Furthermore, we observed a substantial decrease in tumour burden in DLBCL xenografts in response to eternacept. These findings strongly support the concept that cytokine-regulated miRs can function as a crucial link between inflammation and cancer, and illustrate the feasibility of anti-TNFα therapy as a novel and immediately accessible (co)treatment for DLBCL.
|Pedersen, I., Otero, D., Kao, E., Miletic, A., Hother, C., Ralfkiaer, E., Rickert, R., Gronbaek, K., & David, M. (2009). Onco-miR-155 targets SHIP1 to promote TNFα-dependent growth of B cell lymphomas EMBO Molecular Medicine, 1 (5), 288-295 DOI: 10.1002/emmm.200900028|
Tags: cancer, inflammation
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