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Newswise — CHICAGO — The incidence of breast cancer-associated metastasis was increased in animal models of the chronic inflammatory condition arthritis, according to results of a preclinical study presented at the AACR Annual Meeting 2012, held here March 31 - April 4. The results indicate that inflammatory cells known as mast cells play a key role in this increase and that interfering with mast cells reduces the occurrence of bone and lung metastases.
“The most devastating aspect of breast cancer is the emergence of tumor cells that grow to distant organs,” said Lopamudra Das Roy, Ph.D., research assistant professor at the University of North Carolina in Charlotte, N.C. “It has been reported that sites of chronic inflammation are associated with the establishment and growth of tumor cells.”
Prior research conducted by Das Roy established that the incidence of breast cancer metastasis to the bone and lungs was increased in arthritic mice. Because both breast cancer and arthritis are prevalent in women, specifically postmenopausal women, the researchers conducted an additional study using two groups of mice to identify what might be causing the association between arthritis and breast cancer metastases.
The first group of mice had spontaneous arthritis and was induced to have breast cancer. The second group of mice had spontaneous breast cancer and was induced to have arthritis. Because mice in both groups had enhanced numbers of mast cells within the bone and lung, Das Roy and colleagues focused on understanding how these cells might influence breast cancer metastasis.
“We found that there were many proinflammatory factors that are upregulated in the arthritic microenvironment and several of these proinflammatory factors known to influence metastases are produced by mast cells, which are activated by tumor-derived stem cell factor (SCF) binding to its receptor c-Kit,” Das Roy said.
A subsequent key finding was that SCF/c-Kit signaling was increased in arthritic mice with breast cancer versus nonarthritic mice with breast cancer. This set the stage for examining the effects of blocking this signaling.
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.
“The clinical implications of this research are huge,” Das Roy said. “We already have data that show that women with breast cancer and arthritis have lower survival as compared with women with breast cancer and no arthritis. This research indicates that we may be able to design a therapy to block SCF/c-Kit signaling, which could help reduce metastases to the bone and lungs.”
This research was funded by a postdoctoral grant on behalf of the Fiscal Year 2008 Department of Defense Breast Cancer Research Program.
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Presenter: Lopamudra Das Roy, Ph.D.
Abstract Number: 1389
Title: Metastasis models: from cell autonomous genes to the niche
Author Block: Lopamudra Das Roy1, Jennifer M. Curry1, Mahnaz Sahraei1, Amritha Kidiyoor1, Dahlia M. Besmer1, Helen E. Gruber2, Pinku Mukherjee1. 1Univ. of North Carolina at Charlotte, Charlotte, NC; 2Carolina Medical Center, Charlotte, NC
Background: Breast Cancer remains the second leading cause of cancer-related deaths in the United States. In 2011, an estimated 458,000 women are expected to die from the disease due to metastasis. Metastasis is regulated not only by intrinsic genetic changes in malignant cells, but also by the microenvironment, especially those associated with chronic inflammation. We have reported that mice that suffer from autoimmune arthritis have significantly increased incidence of bone and lung metastasis and decreased survival associated with breast cancer. In this study, we evaluated the mechanism contributing to the increased metastasis. Our preliminary studies show that the metastatic niches (bone and lung) in the arthritic mice express significantly higher levels of mast cells than their non-arthritic counterparts. It is known the SCF/c-kit signaling within the metastatic niche triggers the activation of mast cells which are known to aid the metastatic process via up-regulation of various pro-inflammatory factors. Thus, we hypothesize that increase in mast cells triggered by SCF/cKit signaling may be the underlying cause for increased metastasis and that targeting the SCF-cKit interaction may prevent metastasis.Methods: We used two mouse models; one that develops spontaneous autoimmune arthritis (SKG mice) injected with metastatic breast cancer cells (4T1), and second, that develops spontaneous breast cancer (MMTV-PyV MT mice) injected with type II collagen to induce autoimmune arthritis. Mice were left untreated or treated with anti cKit receptor antibody ± celecoxib (a known drug used to treat autoimmune arthritis). Mast cell levels and metastasis were monitored along with the pro-inflammatory factors associated with mast cell activation.Results: i) Differentiation of mast cells from bone marrow derived stem cells was significantly higher in the arthritic versus the non-arthritic tumor-bearing mice; ii) Mast cell population within the bone and lung lesions were significantly higher in the arthritic versus non-arthritic tumor-bearing mice; iii) The SCF/cKit signaling was significantly up regulated within the metastatic lesions of the arthritic versus the non-arthritic tumor-bearing mice; and iv) Treatment with the anti-cKit receptor antibody + celecoxib significantly reduced the differentiation of mast cells and consequently reduced breast cancer-associated metastasis.Conclusion: Mast cell levels and SCF/cKit signaling are significantly higher in breast cancer mice that suffer from autoimmune arthritis versus their non-arthritic counterparts. Mice treated with anti-cKit receptor + celecoxib shows decreased metastasis and mast cells. Thus, mast cells play a critical role in not only remodeling the tumor microenvironment but also the metastatic niche to facilitate efficient metastasis.