title: Decreased peritoneal ovarian cancer growth in mice lacking expression of lipid phosphate phosphohydrolase 1.
abstract: Lysophosphatidic acid (LPA) is a bioactive lipid that enhances ovarian cancer cell proliferation, migration and invasion in vitro and stimulates peritoneal metastasis in vivo. LPA is generated through the action of autotaxin or phospholipases, and degradation begins with lipid phosphate phosphohydrolase (LPP)-dependent removal of the phosphate. While the effects of LPA on ovarian cancer progression are clear, the effects of LPA metabolism within the tumor microenvironment on peritoneal metastasis have not been reported. We examined the contribution of lipid phosphatase activity to ovarian cancer peritoneal metastasis using mice deficient in LPP1 expression. Homozygous deletion of LPP1 (LPP1 KO) results in elevated levels and decreased turnover of LPA in vivo. Within 2 weeks of intraperitoneal injection of syngeneic mouse ovarian cancer cells, we observed enhanced tumor seeding in the LPP1 KO mice compared to wild type. However, tumor growth plateaued in the LPP1 KO mice by 3 weeks while tumors continued to grow in wild type mice. The decreased tumor burden was accompanied by increased apoptosis and no change in proliferation or angiogenesis. Tumor growth was restored and apoptosis reversed with exogenous administration of LPA. Together, these observations demonstrate that the elevated levels of LPA per se in LPP1 KO mice do not inhibit tumor growth. Rather, the data support the notion that either elevated LPA concentration or altered LPA metabolism affects other growth-promoting contributions of the tumor microenvironment.
authors.affiliation: Department of Obstetrics and Gynecology, The Cancer Center, University of Virginia, Charlottesville, Virginia, United States of America.
authors.forename: John
authors.initials: J
authors.lastname: Nakayama
authors.affiliation: Department of Microbiology, Immunology and Cancer Biology, The Cancer Center, University of Virginia, Charlottesville, Virginia, United States of America.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Raines
authors.affiliation: Department of Pharmacology, The Cancer Center, University of Virginia, Charlottesville, Virginia, United States of America; The Cancer Center, University of Virginia, Charlottesville, Virginia, United States of America.
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Lynch
authors.affiliation: Department of Microbiology, Immunology and Cancer Biology, The Cancer Center, University of Virginia, Charlottesville, Virginia, United States of America; The Cancer Center, University of Virginia, Charlottesville, Virginia, United States of America.
authors.forename: Jill K
authors.initials: JK
authors.lastname: Slack-Davis
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D049109:Cell Proliferation / Q000502:physiology*; D005260:Female; D017353:Gene Deletion; D007150:Immunohistochemistry; D008246:Lysophospholipids / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000503:physiopathology*; D010534:Peritoneal Neoplasms / Q000201:enzymology* / Q000556:secondary*; D059016:Tumor Microenvironment / Q000502:physiology*
chemical_list: C431577:Ltap protein, mouse; D008246:Lysophospholipids; D009419:Nerve Tissue Proteins; C032881:lysophosphatidic acid