Abstract SY08-02: Normal and neoplastic stem cells

Abstract

Abstract The transition from single cell species to multicellular organisms led to organ and tissue development. The development and maintenance of organs/tissues in multicellular organisms has resulted in the emergence of specialized cells that self-renew as well as differentiate; these rare cells are stem cells. Following embryonic development, most of our tissues and organs are continuously regenerated from tissue/organ specific stem cells. The principal property that distinguishes such stem cells from their daughter cells is self-renewal; when stem cells divide they give rise to stem cells (by self-renewal) and progenitors (by differentiation). In most tissues only the primitive stem cells self-renew. Even within a particular tissue, stem cells may be diverse, and subject to stem cell competition for their niche. We have documented both germline stem cell and somatic stem cell competition in species as diverse as colonial protochordates and humans. Stem cell isolation and transplantation is the basis for regenerative medicine. Self-renewal is dangerous, and therefore strictly regulated. Poorly regulated self-renewal can lead to the genesis of cancer stem cells, the only self-renewing cells in the cancerous tumor. The Weissman lab has followed the progression from hematopoietic stem cells (HSCs) to myelogenous leukemias. They have found that the developing cancer clones progress at the stage of HSCs, until they become fully malignant. At this point, the “leukemia” stem cell is at a stage of a downstream oligolineage or multilineage progenitor that has evaded programmed cell death and programmed cell removal, while acquiring or keeping self-renewal. In the case of chronic myeloid leukemia, bcr-abl+ HSC clones outcompete normal HSCs in the chronic phase. The transition from the chronic phase to myeloid blast crisis results in the leukemia stem cells appearing in the granulocyte-macrophage progenitor (GMP) stage. While there are many ways to defeat programmed cell death and senescence, there appears to be one dominant method to avoid programmed cell removal—the expression of the cell surface “don't eat me” protein CD47, the ligand for macrophage SIRPα. All cancers tested express CD47 to overcome expression of “eat me” signals such as calreticulin. Antibodies that block the CD47-SIRPα interaction enable phagocytosis and killing of the tumor cells in vitro and in vivo. All tested human solid tumors and lymphomas/leukemias/myelomas express CD47 and are susceptible to phagocytosis in the presence of anti-CD47 blocking antibodies. Citation Format: Irving L. Weissman. Normal and neoplastic stem cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr SY08-02.