Clinical and epidemiological studies suggest an association between inflammation and cancer, but the molecular basis of this association is not well understood. This project will study how sugars expressed in cell surface receptors and ligands that bind to them mediate intracellular activation, gene expression and inflammation-induced colon cancers. NF-?B signaling in tumor cells and macrophages has recently been shown to provide a critical link between colonic inflammation and cancer. Calcium-binding heterodimeric proteins S100A8 and S100A9 are pro-inflammatory mediators that are also highly expressed in many tumors. We have shown earlier that S100A8/A9 bind to carboxylated N-glycans. These glycans are found on macrophages and tumor cells, but not on normal epithelial cells. S100A8/A9 binds to a subpopulation of RAGE enriched for carboxylate glycans. They also bind to tumor cells and macrophages and activate NF-?B signaling. mAbGB3.1, an antibody against the carboxylated glycans blocks S100A8/A9 binding and NF-?B signaling in colon tumor cells most likely through RAGE. Since promoter regions of S100A8 and S100A9 and RAGE have binding sites for NF-?B, ligation of RAGE by S100A8/A9 in inflammation could lead to uncontrolled feed-forward signaling leading to sustained cellular activation that promotes tumor development. In support of this, we found that mAbGB3.1 reduces the incidence of colitis-associated cancer (CAC) in mice and that RAGE-/- mice are resistant to the onset of CAC. In this model we also found infiltrating S100A8/A9 positive myeloid progenitor cells in all regions of dysplasia and adenoma in colon. We therefore propose that RAGE, S100A8/A9 and carboxylated glycans promote carcinogenesis in a pro-inflammatory microenvironment. The overall aim of this proposal is to define the molecular basis of carboxylated glycan and RAGE dependent interactions of S100A8/A9 in tumor cells, and to elucidate the causal relationship between S100A8/A9 and inflammation-related colon cancer.
Our specific aims are as follows:
Aim 1 : To delineate molecular mechanisms and functional consequences of carboxylated glycan dependent S100A8/A9 and RAGE interactions and signaling in colon tumor cells.
This aim i s driven by the hypothesis that S100A8/A9 secreted from myeloid cells in tumor microenvironment promotes signaling and cellular activation in tumor cells in a RAGE and carboxylated glycan dependent manner. We will study colon tumor cells to determine: If RAGE is the key glycan-carrying receptor for S100A8/A9 in tumor cells;What specific NF-?B signaling pathway components are involved;and Whether S100A8/A9 mediated cellular activation increases proliferation and migration of tumor cells and/or secretion of key chemokines and cytokines.
Aim 2 : To define the requirement of S100A8/A9 in inflammation-related colon cancer.
Our second aim i s guided by the hypothesis that S100A8/A9 proteins play a critical role in promoting tumorigenesis in a setting of inflammation. To address this we will: Induce inflammation and tumor formation in S100 deficient mice;Analyze NF-?B signaling pathway in colonic tissues;and Generate bone marrow chimeras to study if S100 deficient mice are more prone to tumors when S100 proteins are restored. These studies would help us understand the impact of carboxylated glycans, RAGE and S100 proteins in the cross-talk between tumor cells and stromal cells leading to CAC.
Colorectal cancer is one of the leading causes of cancer-related deaths in the United States. The American Cancer Society estimates that in 2008 about 150,000 new cases of CRC would be diagnosed and about 50,000 people would die from the disease. Patients with inflammatory bowel diseases are at increased risk for developing colorectal cancer. A functional link between colonic inflammation and cancer has long been suspected, but not proven. This project aims to study how sugar chains expressed on proteins and ligands that bind to them mediate colon inflammation and its progression to cancer. The study hopes to find targets for novel therapies to treat inflammation-based colon cancers.
| Srikrishna, Geetha (2012) S100A8 and S100A9: new insights into their roles in malignancy. J Innate Immun 4:31-40 |
| Ichikawa, Mie; Williams, Roy; Wang, Ling et al. (2011) S100A8/A9 activate key genes and pathways in colon tumor progression. Mol Cancer Res 9:133-48 |
| Srikrishna, Geetha; Nayak, Jonamani; Weigle, Bernd et al. (2010) Carboxylated N-glycans on RAGE promote S100A12 binding and signaling. J Cell Biochem 110:645-59 |
| Srikrishna, Geetha; Freeze, Hudson H (2009) Endogenous damage-associated molecular pattern molecules at the crossroads of inflammation and cancer. Neoplasia 11:615-28 |
