Abstract 1389: Arthritis augments breast cancer metastasis: Role of mast cells and SCF/c-Kit signaling

Abstract

Abstract 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. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1389. doi:1538-7445.AM2012-1389