The lab under the guidance of Pinku Mukherjee, Irwin Belk Distinguished Scholar of Cancer Research at UNC Charlotte, has conducted experiments that demonstrate the intimate link between mast cells in the immune system and metastatic tumors. This new research displays how patients suffering from both arthritis and breast cancer seem to have more aggressive cancer. In other words, metastasis (which is the transference of disease-producing cells to other parts of the body by blood lymphatic vessels, or membranous surfaces) progresses faster in arthritic patients with breast cancer than those who don't have arthritis.
Mast cells are a special kind of immune cell that are found in tissues throughout the body and that are loaded with histamines, compounds that cause inflammation. When these cells are triggered, they release the histamines and inflammation occurs. My interpretation of this is the mast cells are like little bombs that are hidden in the tissue.
The researchers studied with two strains of mice. The first group had spontaneous arthritis (SKG mice) and the second group of mice had spontaneous breast cancer (MMTV-PyV MT mice). Each of the mouse strains were artificially induced to develop the other disease and then tested for differences.
Most recently, the UNC Charlotte researchers have found the mast cells are present in larger numbers in the bones and lungs of arthritic mice than in non-arthritic mice. Arthritis is an acute or chronic inflammation of a joint accompanied by pain and structural changes. This particular relationship is only with autoimmune arthritis- that is caused by a malfunction of the autoimmune system. Arthritis has many diverse causes ranging from infections to crystal deposition and even injury.
“Epidemiological studies have implied that breast cancer survival is significantly lower in patients who also had autoimmune arthritis,” Mukherjee said. “As there is no obvious reason this should be so, we were interested in exploring possible cancer mechanisms that might explain why,” she added.
Lopamudra Das Roy, under the guidance of Mukherjee, established that metastases associated with breast cancer were significantly higher in arthritic mice, with a threefold increase in lung metastases and a twofold increase in bone metastases. The researchers suspected that the higher number of mast cells present in the tissue might be connected to the greater number of metastases.
The team’s research further indicates a relationship between the transmembrane stem cell factor (SCF) ligand found on metastatic breast cancer cells and the cKit receptor found on mast cells. This interaction (between SCF and cKit) appears to play a critical role in facilitating metastasis. Mast cells provide an anchor for SCF in the membrane of the metastatic breast cancer cell and it also encourages the growth of other breast cancer cells.
“We confirmed the relationship we suspected between autoimmune disease and metastatic breast cancer cells,” Mukherjee said. “This is an exciting result for us because it confirms an interesting interdependence between cancer metastasis and a specific component of the immune system.”
A press release about the finding described how this works: “Mast cells are the only ‘terminally differentiated’ (mature) cells in the body that develop, like blood cells, from stem cells in the bone marrow and that also have a c-Kit receptor. Suspecting a relationship between the c-Kit receptor on the mast cells and the SCF ligand expressed by the metastatic cancer cells, the researchers tested the effect of blocking receptor by treating the mice with an anti-c-Kit receptor antibody and celecoxib, an anti-inflammatory medication."
Among the findings of the analysis was that the population of mast cells within bone and lung tumors was also significantly higher in the mice with arthritis and breast cancer vs. the mice without arthritis and breast cancer. The differentiation of mast cells from bone marrow derived from stem cells was also significantly higher in the arthritic versus the non-arthritic tumor-bearing mice.
|top: the foot of an arthritic mouse.|
The researchers theorized that they might be able to block the formation of metastases by targeting the receptor on the mast cells.
“When the mice were treated with a therapy to target the c-Kit mast cell receptor in combination with celecoxib -- a drug used to treat autoimmune arthritis -- the incidence of breast cancer metastasis to the bone and lung was greatly reduced,” Das Roy noted.
The researchers conclude that in an arthritic condition, SCF expression in metastatic breast cancer cells induces the differentiation of mast cells from bone marrow through SCF/CKit signaling. Mast cells, in turn, facilitate the efficient metastasis of the breast cancer cells in bone and lung tissue. Autoimmune arthritis disease increases the intensity of metastatic breast cancer because bone marrow stem cells in autoimmune arthritis victims have greater potential to develop into mast cells.
In future studies, the researchers plan to examine the presence of mast cells in human tumor samples.
This research was funded by Das Roy’s postdoctoral grant from the 2008 Department of Defense Breast cancer research program.