title: SHIP represses lung inflammation and inhibits mammary tumor metastasis in BALB/c mice.
abstract: SH2-containing-inositol-5'-phosphatase (SHIP) is a negative regulator of the phosphatidylinositol-3-kinase pathway in hematopoietic cells and limits the development of leukemias and lymphomas. The potential role of SHIP in solid tumor development and metastasis remains unknown. While SHIP restricts the aberrant development of myeloid cells in C57BL/6 mice, there are conflicting reports regarding the effect of SHIP deletion in BALB/c mice with important consequences for determining the influence of SHIP in different model tumor systems. We generated SHIP-/- BALB/c mice and challenged them with syngeneic non-metastatic 67NR or metastatic 4T1 mammary tumors. We demonstrate that SHIP restricts the development, alternative-activation, and immunosuppressive function of myeloid cells in tumor-free and tumor-bearing BALB/c mice. Tumor-free SHIP-/- BALB/c mice exhibited pulmonary inflammation, myeloid hyperplasia, and M2-polarized macrophages and this phenotype was greatly exacerbated by 4T1, but not 67NR, tumors. 4T1-bearing SHIP-/- mice rapidly lost weight and died from necrohemorrhagic inflammatory pulmonary disease, characterized by massive infiltration of pulmonary macrophages and myeloid-derived suppressor cells that were more M2-polarized and immunosuppressive than wild-type cells. Importantly, while SHIP loss did not affect primary tumor growth, 4T1-bearing SHIP-/- mice had 7.5-fold more metastatic tumor cells in their lungs than wild-type mice, consistent with the influence of immunosuppressive myeloid cells on metastatic growth. Our findings identify the hematopoietic cell-restricted protein SHIP as an intriguing target to influence the development of solid tumor metastases, and support development of SHIP agonists to prevent the accumulation of immunosuppressive myeloid cells and tumor metastases in the lungs to improve treatment of metastatic breast cancer.
authors.affiliation: Department of Integrative Oncology, British Columbia Cancer Agency Research Centre, Vancouver, BC, Canada.
authors.forename: Melisa J
authors.initials: MJ
authors.lastname: Hamilton
authors.affiliation: Department of Integrative Oncology, British Columbia Cancer Agency Research Centre, Vancouver, BC, Canada.
authors.forename: Elizabeth C
authors.initials: EC
authors.lastname: Halvorsen
authors.affiliation: Department of Integrative Oncology, British Columbia Cancer Agency Research Centre, Vancouver, BC, Canada.
authors.forename: Nancy E
authors.initials: NE
authors.lastname: LePard
authors.affiliation: Department of Integrative Oncology, British Columbia Cancer Agency Research Centre, Vancouver, BC, Canada.
authors.forename: Momir
authors.initials: M
authors.lastname: Bosiljcic
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency Research Centre, Vancouver, BC, Canada.
authors.forename: Victor W
authors.initials: VW
authors.lastname: Ho
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency Research Centre, Vancouver, BC, Canada.
authors.forename: Vivian
authors.initials: V
authors.lastname: Lam
authors.affiliation: Department of Integrative Oncology, British Columbia Cancer Agency Research Centre, Vancouver, BC, Canada.
authors.forename: Judit
authors.initials: J
authors.lastname: Banáth
authors.affiliation: Department of Integrative Oncology, British Columbia Cancer Agency Research Centre, Vancouver, BC, Canada.
authors.forename: Kevin L
authors.initials: KL
authors.lastname: Bennewith
authors.affiliation: Terry Fox Laboratory, British Columbia Cancer Agency Research Centre, Vancouver, BC, Canada.
authors.forename: Gerald
authors.initials: G
authors.lastname: Krystal
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D049109:Cell Proliferation; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D000072181:Inositol Polyphosphate 5-Phosphatases; D008175:Lung Neoplasms / Q000235:genetics / Q000517:prevention & control* / Q000556:secondary; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000378:metabolism / Q000473:pathology; D010744:Phosphoric Monoester Hydrolases / Q000502:physiology*; D011014:Pneumonia / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D010744:Phosphoric Monoester Hydrolases; D000072181:Inositol Polyphosphate 5-Phosphatases
keywords: 4T1; BALB/c; SHIP; metastasis; myeloid cells