Weizmann Institute scientists discover a control mechanism for metastasis

[gpawelski]

A metastasis occurs when cancer cells dissociate from the original tumor and migrate via the blood stream to colonize distant organs. This is the main cause of cancer death. For a cell such as a cancer cell to migrate, it first must detach itself from neighboring cells and the intercellular material to which it is anchored. Before it can do this, it receives a signal from outside the cell. This signal takes the form of a substance called a growth factor, which, in addition to controlling movement, can activate a number of processes in the cell including division and differentiation.

The growth factor attaches to a receptor on the cell wall, initiating a sequence of changes in the cellular structure. The cell's internal skeleton - an assembly of densely-packed protein fibers - comes apart and the protein fibers then form thin threads on the outside of the cell membrane that push the cell away from its neighbors. In addition, a number of protein levels change: some get produced in higher quantities and some in less.

To understand which proteins are modulated by the growth factor and the nature of the genetic mechanisms involved in cancer cell migration, a map is needed all of the genetic changes that take place in the cell after the growth factor signal is received. One family of proteins stands out. Tensins are proteins that stabilize the cell structure. The amounts of one family member rise dramatically while, at the same time, the levels of another drop.

Despite a familial similarity, there is a significant difference between them. The protein that drops off has two arms: One arm attaches to the protein fibers forming the skeleton, and the other anchors itself to the cell membrane. This action is what stabilizes the cell's structure. The protein that increases, on the other hand, is made up of one short arm that only attaches to the anchor point on the cell membrane. Rather than structural support, this protein acts as a kind of plug, blocking the anchor point, and allowing the skeletal protein fibers to unravel into the threads that push the cells apart. The cell is then free to move, and, if it's a cancer cell, to metastasize to a new site in the body.

In experiments with genetically engineered cells, scientists have showed that the growth factor directly influences levels of both proteins, and that these, in turn, control the cells' ability to migrate. Blocking production of the short tensin protein kept cells in their place, while overproduction of this protein plug increased their migration.

Scientists at The Weizmann Institute of Science, Rehovot, Israel, carried out tests on tumor samples taken from around 300 patients with inflammatory breast cancer, a rare but swift and deadly form of the disease, which is associated with elevated growth factor levels. The scientists found a strong correlation between high growth factor activity and levels of the 'plug' protein. High levels of this protein, in turn, were associated with cancer metastasis to the lymph nodes -- the first station of migrating cancer cells as they spread to other parts of the body.

In another experiment, the scientists examined the effects of drugs that block the growth factor receptors on the cell walls. In patients who received these drugs, the harmful 'plug' proteins had disappeared from the cancer cells. The mechanism can predict the development of metastasis and possibly how the cancer will respond to treatment. This discovery may, in the future, aid in the development of drugs to prevent or reduce the production of the unwanted protein, and thus prevent metastasis in breast or other cancers.

Source: Weizmann Institute of Science

[gpawelski]

On most cancer message/discussion boards, one of the most common themes is that of "chasing mets" (metatasis). Cancer patients are chasing mets because of the wrong type of chemotherapeutic regimens for their type of cancer histology. But why do patients with histologically similar tumors respond differently to so-called "standard" drug treatments? That is one of the main problems associated with chemotherapy. Patient tumors with the same histology do not necessarily respond identically to the same agent or dose schedule of multiple agents.

Medical oncologists select a drug and must wait to see whether it is effective on a particular patient. Conventionally, oncologists rely on clinical trials in choosing chemotherapy regimens. But the statistical results of these population-based studies might not apply to an individual. And when patients develop metastatic cancer, it is often difficult to select an effective treatment because the tumor develops resistance to many drugs. For many cancers, especially after a relapse, more than one standard treatment exists.

A chemoresponse assay is a diagnostic test (not a treatment) to help measure the "efficacy" of cancer drugs. They cannot make the cancer drugs do better, it can only measure the "best" probability of successful drugs. This is in stark contrast to "standard" or "empiric" therapy (also called physician's choice therapy), in which chemotherapy for a specific patient is based on results from prior clinical studies.

Laboratory screening of samples from a patient's tumor (if available) can help select the appropriate treatment to administer, avoiding ineffective drugs and sparing patients the side effects normally associated with these agents. It can provide predictive information to help physicians choose between chemotherapy drugs, eliminate potentially ineffective drugs from treatment regimens and assist in the formulation of an optimal therapy choice for each patient. This can spare the patient from unnecessary toxicity associated with ineffective treatment and offers a better chance of tumor response resulting in progression-free and overall survival.

It would be highly desirable to know what drugs are effective against particular cancer cells before cytotoxic agents are systemcially administered into the body. Chemresponse assays are clinically validated drug tests on living (fresh) specimens of cancer cells to determine the optimal combination of chemotherapy drugs. These assays are specifically tailored for each individual patient based on tumor tissue profiling, with no economic ties to outside healthcare organizations, and recommendations are made without financial or scientific prejudice.

Recommendations are designed scientifically for each individual patient. Various assays are performed on a tumor sample to measure drug activity (sensitivity and resistance). This will determine not only what drug or combinations of drugs will not effectively work, but which will be most effective for an "individual's" cancer. Then a treatment recommendation is developed through what is known as "assay-directed" therapy.

[gpawelski]

With respect to the metastasis, it is literally a cancer that has moved. It may have mutated further (cancer is itself a mutation that occurs within a cell that was intended to look and function as a normal cell but somewhere along the line the genetic "wiring" got crossed and instead of simply dying as it should have done, it divided and produced offspring cells that shared the same mutation as the original parent cell) in some respects - often it becomes more resistant to therapy than the primary (original) tumor - but fundamentally, it remains the same tumor-type.

In other words, a rectal cancer in the lung remains rectal cancer. The cell has identifiable characteristics which usually allow the pathologist to determine its point of origin. In fact, sometimes in cancer, a primary tumor never is located but the metastatic cells can be identified as having come from a specific organ system because of the way they look and because they express certain molecules which can be identified chemically.

Therefore, the treatment for a breast cancer, for example, that has metastasized to a different part of the body generally is treated in a similar manner as if the tumor cells all were contained within the region of the breast.

However, from the viewpoint of assay-directed therapy, none of that matters because it doesn't necessarily treat all breast cancers with "the" breast cancer protocol or all rectal cancers with "the" rectal cancer protocol (even if there were only one - in fact, there are several protocols to choose from).

Instead, the whole point of functional tumor cell profiling is to determine, individually - that is, for each patient - precisely which drug or drugs is best able to kill that patient's own cancer cells - no matter which drug that happens to be and no matter what type of cancer it is.

If you visit the National Cancer Institute website, you'll see that for virtually all cancers, there is no single "best" regimen listed. Instead, you'll find that, for each cancer type, many drugs and drug combinations have been proven in clinical trails to produce about the same result among large groups of unselected patients.

However, looking at the individual patients within a clinical trial, all of whom have the same type and stage of cancer, some patients do not respond at all to a specific treatment while others respond very well and, even in some of the very difficult cancer types, some patients achieve long-term remissions and even cures.

What this suggests is, considering that there are many drug regimens which are equally-accepted by the NCI and by oncologists, these drugs regimens should not be administered blindly but rather each patient's cancer cells should be tested to determine which of the otherwise equally-acceptable drug regimen has the very best chance of benefiting that particular patient.

[Ted Hutchinson]

Growth of human gastric cancer cells in nude mice is delayed by a ketogenic diet supplemented with omega-3 fatty acids and medium-chain triglycerides
Among the most prominent metabolic alterations in cancer cells are the increase in glucose consumption and the conversion of glucose to lactic acid via the reduction of pyruvate even in the presence of oxygen. This phenomenon, known as aerobic glycolysis or the Warburg effect, may provide a rationale for therapeutic strategies that inhibit tumour growth by administration of a ketogenic diet with average protein but low in carbohydrates and high in fat enriched with omega-3 fatty acids and medium-chain triglycerides (MCT).

Here we see how those with higher 25(OH)D status reduces the incidence of mesatasis. Higher vitamin d lower rate of mesatasis.

here we see how a vitamin d analogue reduces breast cancer mesatasis and prolongs survival.

Omega-3 polyunsaturated fatty acids down-modulate CXCR4 expression and function in MDA-MB-231 breast cancer cells.our data suggest that n-3 PUFAs may have a preventative effect on breast cancer metastasis in vitro. This suggests a previously unreported potential benefit of n-3 PUFAs to patients with metastatic breast cancer.

Dietary omega-3-polyunsaturated fatty acids prevent the development of metastases of colon carcinoma in rat liver.We could show that omega-3-fatty acids may decrease malignant metastatic tumor growth

There are simple cheap effective strategies you can deploy now such as not feeding cancer cells their preferred fuel, correcting current omega 3 & vitamin d deficiency states that may reduce the risk of further mesatasis.