Normal development of myeloid cells and the role of immature myeloid cells in chronic inflammation and carcinogenesis of the colorectal carcinoma

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This proposal addresses the link between inflammation and cancer and seeks to define the role of myeloid progenitors in cancer. The enzyme histidine decarboxylase (HDC), which catalyzes the conversion of L-histidine to histamine, plays a key role in the regulation of numerous physiologic processes. While HDC has now been well studied as a regulator of acid secretion downstream of CKK-¿/gastrin receptor signalling, the group of Timothy Wang, MD has recently identified a critical function of histidine decaboxylase (HDC) in early immature myeloid cells (IMCs) that characterizes both myeloid derived suppressor cells (MDSCs) and tumor associated neutrophils (TANs). Thus, in the described studies, HDC will be used as a marker to investigate the role of these cell types in cancer initiation and progression. They have also identified a key role for histamine in differentiation and maturation of myeloid cells and thus there is a potential target for modulating cancer risk. It is believed that this work has the potential to alter the paradigm for myeloid cells and their role in cancer. Immature myeloid cells, such as MDSCs and TANs, have been shown to accumulate in human cancers and contribute to the development and progression of cancer. The proposed studies will define further the utility of HDC as a novel marker for immature myeloid cells that contribute to cancer and the role of histamine in possibly suppressing MDSCs/TANs. In addition, the work may help elucidate strategies for targeting IMCs in order to prevent or treat gastrointestinal cancers.The following specific aims are proposed, each of which addresses a specific hypothesis:1. Are HDC-expressing CD11b+Gr1+ cells myeloid precursors that give rise to mature monocytes and granulocytes and other cell types?2. What is the effect of HDC-deficiency and carcinogenesis on spleen vs. bone marrow maturation?3. How are HDC-expressing IMCs recruited during carcinogenic stimuli?