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.

Discarded White Blood Cells Induce Relocation of Blood Stem Cells


Researchers at the Fundación Centro Nacional de Investigaciones Cardiovasculares or CNIC in Madrid, Spain have discovered that the clearance of the white blood cells called neutrophils induces the release of blood cell making stem cells into the bloodstream.

Our blood consists of a liquid component known as plasma and cells collectively known as “formed elements.” Formed elements include red blood cells and a whole encore of white blood cells. Red blood cells contain hemoglobin that ferry oxygen from the lungs to the tissues. White blood cells come in two flavors: granulocytes, which contain granules, and agranulocytes, which are devoid of granules.

Granulocytes are a subgroup of white blood cells characterized by the presence of cytoplasmic granules. Granulocytes are formed in the bone marrow and can be classified as basophils, eosinophils, or neutrophils. These particular cell types are named according to their distinct staining characteristics using hematoxylin and eosin (H&E) histological preparations. Granules in basophils stain dark blue, eosinophilic components stain bright red, and neutrophilic components stain a neutral pink.

Granulocytes

The most abundant white blood cells is known as a neutrophil. Neutrophils comprise 50-70% of all white blood cells and are a critical component of the immune system. When immature, neutrophils have a distinct band-shaped nucleus that changes into a segmented nucleus following maturation. Neutrophils are normally in circulating blood, but they migrate to sites of infection via chemotaxis under the direction of molecules such as Leukotriene B4. The main function of neutrophils is to destroy microorganisms and foreign particles by phagocytosis.

Granulocytes-blood smear

Because neutrophils are packed with granules that are toxic to microorganisms and our own cells, damaged neutrophils can spill a plethora of pernicious chemicals into our bodies. To prevent neutrophils from aging and becoming a problem, they live hard and die young. in the vicinity of 1011 neutrophils are eliminated every day. They are rapidly replaced, however, and the means of replacement includes stem cell mobilization from the bone marrow to the bloodstream.

Workers in the laboratory of Andrés Hidalgo have discovered what happens to the discarded neutrophils. Earlier work in mice showed that injections of dead or dying neutrophils increase the number of circulating blood cell-making stem cells. Therefore, something about dead neutrophils causes the hematopoietic stem cells to move from the bone marrow to the bloodstream. By following marked, dying neutrophils, Hidalgo and his coworkers showed that the neutrophils went to the bone marrow to die. While in the bone marrow, the dying neutrophils were phagocytosed (gobbled up) by special cells called macrophages.

Once these bone marrow-located macrophages phagocytose aged neutrophils, they begin to signal to hematopoietic stem cells in the bone marrow, and these signals drive them to move from the bone marrow to the bloodstream to replenish the neutrophil population.

Hidalgo admits that even though his research has produced some unique answers to age-old questions, it also poses almost as many questions as it answers. For example, Hidalgo and his colleagues showed that neutrophils follow a circadian or day/night rhythm and this has implications for diseases. For instance, the vast majority of heart attacks are in the morning. Does this have something to do with neutrophil aging cycles?

“Our study shows that stem cells are affected by day/night cycles thanks to this cell recycling . It is possible that the malign stem cells that cause cancer use this mechanism to relocate, for example, during metastasis,” said Hidalgo.

Daily changes in neutrophil function could be part of the reason that acute cardiovascular and inflammatory events such as heart attack, sepsis or stroke tend to occur during particular times of the day.

“Given that this new discovery describes fundamental processes in the body that were unknown before, it will now be possible to interpret the alterations to certain physiological patterns that occur in many diseases,” Hidalgo said.

See Cell 2013; 153(5): 1025 DOI:10.1016/j.cell.2013.04.040.