TitleTumor burden induces a self-amplifying loop of myelopoiesis that Is mediated by NFκB-kit ligand signaling
NameZhao, Xin (author), Rabson, Arnold B (chair), Tischfield, Jay A (co-chair), Shao, Changshun (internal member), Shi, Yufang (outside member), Rutgers University, Graduate School - New Brunswick,
SubjectMicrobiology and Molecular Genetics,
DescriptionCancer cells induce an inflammatory microenvironment which consists of inflammatory cells, cytokines and chemokines. In the meanwhile, malignant tumors are associated with hematological abnormalities that disrupt homeostasis of hematopoiesis. Therefore how tumor burden influence hematopoiesis through inflammatory cytokines is studied in this thesis. Firstly, IFNγ was found to play a major role in lineagelowSca-1+C-kit+ (LSK) cell expansion by activating the expression of Sca-1 in lineagelowSca-1-C-kit+ cells in vivo and in vitro. This process was dependent on IFNγR1 signaling and the STAT1 pathway. The IFNγ-induced LSK cells had a higher proliferation potential than control LSK cells. Moreover, the IFNγ-induced hematopoiesis was more biased toward the differentiation of myeloid lineages. Therefore, our findings demonstrated a novel role of IFNγ in activating hematopoietic progenitor cells and provide a new insight into the clinical application of interferon. Secondly, in tumor-bearing mice, with the decline of hematopoiesis in bone marrow, spleens are greatly enlarged and harbor a greatly expanded population of hematopoietic progenitor cells (HPCs). While such HPCs can differentiate into both myeloid and lymphoid lineages when transplanted into tumor-free hosts, they preferentially give rise to myeloid lineages including macrophages/monocytes in tumor-bearing hosts. We further showed that macrophages/monocytes, derivatives of HPCs, are essential for the expansion of HPCs in spleen. Thus, HPCs and myeloid cells form a positive feedback loop in sustaining splenic myelopoiesis during tumorigenesis. This self-amplifying loop of HPCs and myeloid cells depends on an NFkB-Kit signaling cascade. Tumor-stimulated inflammatory factors are essential for the increased production of Kit ligands by macrophages/monocytes that drives splenic myelopoiesis. Targeting this HPC-myeloid loop may have potential in impeding tumor progression in cancer therapy. In conclusion, we found that the inflammatory cytokine IFNγ was demonstrated to enhance the expansion of hematopoietic stem cells (LSK cells) in vitro and in vivo, which provides important insights into studying the interaction between inflammation and hematopoiesis. Moreover, via mouse tumor models, we revealed the cellular and molecular basis for tumor-induced hematopoiesis and how such abnormal hematopoiesis influenced tumor progression. The information is important to understand the relationship between cancer and hematopoiesis, lending novel hope for cancer therapy.
NoteIncludes bibliographical references
Noteby Xin Zhao
CollectionGraduate School - New Brunswick Electronic Theses and Dissertations
Organization NameRutgers, The State University of New Jersey
RightsThe author owns the copyright to this work.