SHIP prevents metastasis

Src-homology-2-containing inositol-5´-phosphatase, SHIP (also known as SHIP1), is a tumor suppressor that negatively regulates the phosphatidylinositol 3-kinase (PI3K) pathway by hydrolyzing the PI3K-generated second messenger phosphatidylinositol-3,4,5-triphosphate (PIP 3) to PI-3,4-P 2. SHIP expression is restricted primarily to hematopoietic cells, but has also been reported in mesenchymal stem cells (MSCs) and osteoblasts [1]. SHIP levels can be reduced by inactivating mutations, single nucleotide polymorphisms, or miR-155 activity [2], and SHIP expression decreases in the aging MSC compartment of murine bone marrow, skewing hematopoiesis toward production of myeloid cells [1] and potentially leading to the development of myeloproliferative syndromes or myeloid neoplasms with age. It is unknown whether SHIP levels change during the aging process in hematopoietic cells, although aberrant PI3K activity in human neutrophils increases with age, potentially via reduction in SHIP, and negatively impacts neutrophil migration and function [3]. While reduction of SHIP has been associated with the development of leukemias and lymphomas[4], the potential role of SHIP in solid tumor growth has received very little attention to date, likely because most researchers believe neoplasms derived from non-hematopoietic tissues should not be affected by SHIP status. However, there is a great deal of evidence that normal cells in the stroma (e.g., fibroblasts, endothelial cells, inflammatory cells) have a profound influence on the development and growth of solid primary tumors and tumor metastases. Stephen Paget's seed-and-soil hypothesis identified the soil in distant tissues as a key limitation of metastatic tumor growth, and recent evidence suggests that inflammatory cells may act as fertilizer for the metastatic soil, with aggregates of normal cells (often derived from the bone marrow) creating permissive niches that support future metastatic tumor growth in tissues [5]. Cells that suppress the immune response against tumor cells may be particularly important, with myeloid-derived suppressor cells (MDSCs), alternatively-activated M2 macrophages (Mφs), and regulatory T cells (Tregs) often being elevated in tissues that support metastatic tumor growth. Expansion and activity of each of these immune suppres-Editorial sive cell types are known to be restricted by SHIP [4] and it stands to reason that loss of SHIP may lead to increased immune suppressive cell accumulation and activity in tissues, suppressed T-cell mediated anti-tumor immunity, and therefore increased metastatic tumor growth. Support for this concept comes from studies in which SHIP has been deleted in various mouse strains. Specifically, deleting SHIP from C57BL/6 mice leads to runted mice that overproduce myeloid cells and die …