How Our Own Immune Systems Aid the Spread of Breast Cancer


Our immune systems help us fight off diseases and invasions of our bodies by foreign organisms. How surprising might it be to learn that our immune systems actually help tumors spread through our bodies?

Dr. Karin de Visser and her team at the Netherlands Cancer Institute have discovered that breast tumors cells induce certain immune cells to enable the spread of cancer cells. They published their findings online on March 30 in the journal Nature.

About one in eight women will develop breast cancer in Western countries. Of those women who die of this disease, 90 percent of them die because the cancer has spread to other parts of their body and formed metastases. Given these grim facts, cancer researchers are spending a good deal of time, treasure and energy to understand how metastasis occurs. A few years ago, several cancer biologists reported that breast cancer patients who showed high numbers of immune cells called neutrophils in their blood show an increased risk of developing metastatic breast cancers. Immune cells like neutrophils are supposed to protect our body. Why then are high neutrophil levels linked to worse outcome in women with breast cancer?

Neutrophils
Neutrophils in a blood smear amidst red blood cells.

 

Dr. Karin de Visser, group leader at the Netherlands Cancer Institute, and her team discovered that certain types of breast tumors use a signaling molecule called Interleukin-17 to initiate a domino effect of reactions within the immune system. The tumor cells stimulate the body to produce lots of neutrophils, which typically occurs during an inflammatory reaction. However, these tumor-induced neutrophils behave differently from normal neutrophils. These tumor-induced neutrophils block the actions of other immune cells, known as T cells. T cells are the cells that can (sometimes) recognize and kill cancer cells.

De Visser and her team went on to define the role of the signaling protein called interleukin-17 (or IL-17) in this process. “We saw in our experiments that IL-17 is crucial for the increased production of neutrophils”, says De Visser. “And not only that, it turns out that this is also the molecule that changes the behavior of the neutrophils, causing them to become T cell inhibitory.”

The first author of the Nature paper, postdoctoral researcher Seth Coffelt, showed the importance of the IL-17-neutrophil pathway when he inhibited the IL-17 pathway in a mouse model that mimics human breast cancer metastasis. When these neutrophils were inhibited, the animals developed much less metastases than animals from the control group, in which the IL-17-neutrophil route was not inhibited. “What’s notable is that blocking the IL-17-neutrophil route prevented the development of metastases, but did not affect the primary tumor,” De Visser comments. “So this could be a promising strategy to prevent the tumor from spreading.”

Inhibiting neutrophils would not be a prudent clinical strategy, since drugs that inhibit neutrophils would make patients susceptible to all kinds of infections. However, Inhibition of IL-17 might be a safer strategy. Fortunately, drugs that inhibit IL-17 already exist.  Presently, anti-IL-17 drugs are being tested in clinical trials as a treatment for inflammatory diseases, like psoriasis and rheumatism. Last month, the first anti-IL-17 based therapy for psoriasis patients was approved by the U.S. Federal Drug Administration (FDA). “It would be very interesting to investigate whether these already existing drugs are beneficial for breast cancer patients. It may be possible to turn these traitors of the immune system back towards the good side and prevent their ability to promote breast cancer metastasis,” De Visser says.

A Link Between Stem Cells, Atherosclerosis, and Cholesterol


Researchers at the University of Buffalo have discovered that stem cells are involved in the inflammation that promotes atherosclerosis.

Atherosclerosis or hardening of the arteries occurs when fat, cholesterol, and other substances build up in the walls of arteries and form hard structures called plaques. With the passage of time, these plaques can grow and block the arteries, depriving tissues of oxygen and nutrition.

High serum cholesterol levels have been unequivocally linked to an increased risk of arteriosclerosis. However, the deposition of cholesterol and other molecules underneath the inner layer (intima) of arteries requires a phenomenon known as inflammation. Inflammation occurs in response to tissue damage and it involves the dilation of blood vessels, increased blood flow the damaged area, the recruitment of white blood cells to the area, and increased heart, volume, and pain at the area in question. Increased inflammation within blood vessels damages the intimal layer and allows the deposition of cholesterol and other molecules underneath it to form an atheroma or a plaque.

The stem cell link to atherosclerosis is that the bone marrow-based stem cells that make our blood cells (hematopoietic stem/progenitor cells or HSPCs) ramp up their production of white blood cells in response to increased serum cholesterol levels.

Thomas Cimato, assistant professor in the Department of Medicine in the UB School of Medicine and Biomedical Sciences, said of his publication, “Our research opens up a potential new approach to preventing heart attack and stroke, by focusing on interactions between cholesterol and the HSPCs. Cimto also suggested that these findings could lead to the development of a useful therapy in combination with statins, or a treatment in place of statins for those who cannot tolerate statins.

In Cimato’s study, high cholesterol levels were shown to cause increases in the levels of interleukin -17 (IL-17). IL-17 is a cytokine that recruits monocytes and neutrophils to the site of inflammation. IL-17 boosts levels of granulocyte colony stimulating factor (GCSF), which is a factor that induces the release of HSPCs from the bone marrow to the peripheral circulation.

Cimato also found that statin drugs reduce the number of HSPCs in circulation, but not all patients responded similarly to statins. “We’ve extrapolated to humans what other scientists previously found in mice about the interactions between LDL, cholesterol, and these HSPCs,” said Cimato.

In order to transport cholesterol through the bloodstream, cells must construct a vehicle into which the cholesterol is packaged. Cholesterol does not readily dissolve in water. Therefore, packaging cholesterol into lipoprotein particles allows for its transport around the cell. Cell use cholesterol to vary the fluidity of their membranes, and to synthesize steroid hormones. Once cholesterol is absorbed from the diet, the cells of the small intestine package cholesterol and fat into a particle known as a chylomicron.

chylomicron

Chylomicrons are released by the small intestinal cells and they travel to the liver. In the liver, chylomicrons are disassembled and the cholesterol is packaged into a particle known as a very-low density lipoprotein particle (VLDL). After its release and sojourning through the bloodstream, the VLDL looses some surface proteins and is depleted of its fat and becomes known as a low-density lipoprotein or LDL particle.  While these particles sojourn through the bloodstream, they release fat for tissues to use as an energy source.

LDL

LDL particles are gradually removed from circulation. If they build up to high concentrations, they can be taken up by a wandering white blood cell known as a macrophage. If these macrophages take up too much LDL, they can become a foam cell.  Foams cells can become lodged underneath the intimal layer of blood vessels when inflammation occurs inside blood vessels, and this is the cause of atherosclerosis.

Increased LDL levels in mice have been shown to stimulate the release of HSPCs from bone marrow and accelerate the differentiation of these cells into white blood cells (neutrophils and monocytes) that participate in inflammation.

Mice do not regulate their cholesterol levels in the same way humans do.  Cimato commented, “mice used for atherosclerosis studies have very low total cholesterol levels at baseline.  We feed then very high fat diets in order to study high cholesterol but it isn’t easy to interpret what the levels in mice will mean in humans and you don’t know if extrapolating to humans will be valid.”

Therefore, in order to properly model cholesterol regulation in their human subjects, Cimato had them take statins for a two-week period followed by one-month intervals when they were off the drugs.  “We modeled the mechanism of how LDL cholesterol affects stem cell mobilization in humans,” said Cimato.

The experiments showed that increased LDL levels tightly correlated with IL-17 levels.

IL-17 and cholesterol levels

Secondly, blood LDL levels also correlated with GCSF levels.

LDL levels and GCSF levels

Finally, increasing GCSF levels led to higher levels of circulating HSPCs.

CD34 cells and G-CSF levels

These circulating HSPCs increase the numbers of neutrophils, monocytes, and macrophages that are involved in the formation of plaque and atherosclerosis.

The next step is to determine if HSPCs, like LDL cholesterol levels are connected to stroke, cardiovascular disease and heart attacks.