The primary goal of this preclinical translational proposal is to determine the role of erythroblast macrophage protein (Emp) in tumor progression and to establish its prognostic and predictive value for colorectal cancers (CRCs). In our published and preliminary studies, we have discovered that Emp is involved in erythroblast enucleation, macrophage development, cell growth and differentiation, and cell adhesion and migration. These pathways are hallmarks of cancer progression. Additionally, our preliminary immunohistochemical (IHC) evaluations of human CRC tissues have demonstrated increasing expression of Emp in progression of adenomas to primary adenocarcinomas to metastatic carcinomas. Therefore, we hypothesize that Emp is involved in CRC progression. To test this hypothesis, we propose to evaluate the role of Emp interactions with adhesion molecules for attachment to extracellular membranes (ECM), for molecular cross-talk, for effects on the tumor microenvironment, and for progression of CRCs. This will be accomplished in three aims.
Aim -1 will determine the interaction of Emp with ?1 integrin within focal adhesion plaques and its involvement in tumor progression;
Aim -2 will verify the interaction of Emp with the actin cytoskeleton in ECM functions and in metastasis;
and Aim -3 will establish the prognostic and predictive value of Emp in CRCs. The proposed studies will characterize the molecular interactions of Emp with ?1 integrin, ascertain the effects of Emp on the actin cytoskeleton and other components of the ECM, identify new molecular determinants that contribute to tumor progression, and assess the predictive and prognostic value of Emp in CRCs.
SUMMARY An increased expression of erythroblast macrophage protein (Emp) was identified in preliminary studies of premalignant and malignant lesions of the colorectum. Moreover, abnormal Emp was significantly associated with cell proliferation, growth, differentiation, invasion, adhesion and migration. Therefore, this study will validate the prognostic (disease recurrence and survival) and predictive (efficacy of therapy) value of Emp in colorectal cancers (CRCs). It will also identify sets of Emp-dependent molecular targets that are associated with aggressive behavior of CRCs. These results will provide information that will guide further studies of biologic mechanisms in understanding the role of Emp in CRC tumor progression and in conducting preclinical and clinical studies to assess its usefulness in determining the clinical outcomes.