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Decreased peritoneal ovarian cancer growth in mice lacking expression of lipid phosphate phosphohydrolase 1.

Nakayama J, Raines TA, Lynch KR, Slack-Davis JK - PLoS ONE (2015)

Bottom Line: Homozygous deletion of LPP1 (LPP1 KO) results in elevated levels and decreased turnover of LPA in vivo.The decreased tumor burden was accompanied by increased apoptosis and no change in proliferation or angiogenesis.Rather, the data support the notion that either elevated LPA concentration or altered LPA metabolism affects other growth-promoting contributions of the tumor microenvironment.

View Article: PubMed Central - PubMed

Affiliation: Department of Obstetrics and Gynecology, The Cancer Center, University of Virginia, Charlottesville, Virginia, United States of America.

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.

No MeSH data available.


Related in: MedlinePlus

Angiogenesis is not defective in LPP1 KO mice.(A) Tumors from mice 8 weeks after initiation were sectioned and stained for CD31, and the total number of CD31 positive vessels per tumor area from 5 high powered fields (hpf; 200X magnification) per mouse for wild type (WT, n = 5) and LPP1 KO (n = 5) mice is plotted. The total number of CD31 positive vessels observed in 5 hpf of matrigel plugs containing conditioned media from ID8ip2Luc cells (B) or FGF/VEGF (C) is plotted (see Materials and Methods). Data are presented with Box and Whiskers plots as described for Fig. 3. *p = 0.0083, Student’s t-test.
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pone.0120071.g004: Angiogenesis is not defective in LPP1 KO mice.(A) Tumors from mice 8 weeks after initiation were sectioned and stained for CD31, and the total number of CD31 positive vessels per tumor area from 5 high powered fields (hpf; 200X magnification) per mouse for wild type (WT, n = 5) and LPP1 KO (n = 5) mice is plotted. The total number of CD31 positive vessels observed in 5 hpf of matrigel plugs containing conditioned media from ID8ip2Luc cells (B) or FGF/VEGF (C) is plotted (see Materials and Methods). Data are presented with Box and Whiskers plots as described for Fig. 3. *p = 0.0083, Student’s t-test.

Mentions: Increased apoptosis in LPP1 KO mice could occur as a result of a lack of nutrients supplied to the tumor due to defective angiogenesis, the absence of a pro-survival factor or the presence of an inducer of cell death. Indeed, mice lacking LPP3 expression are embryonic lethal due to a defect in angiogenesis [27]. To determine whether angiogenesis was defective in LPP1 KO mice, tumors were stained for the endothelial marker CD31. As shown in Fig. 4A, tumors from wild type and LPP1 KO mice had similar levels of CD31 staining. To more objectively evaluate whether there was an intrinsic alteration in angiogenesis, we performed a matrigel plug assay. Briefly, matrigel embedded with tumor cell conditioned media or FGF and VEGF was implanted into the flanks of wild type or LPP1 KO mice to stimulate angiogenesis (S2 Fig.). Tumor cell conditioned media stimulated an equivalent number of vessels in wild type and LPP1 KO mice (Fig. 3B). FGF/VEGF stimulated vessel formation to a greater extent in LPP1 KO mice compared to wild type (Fig. 3C). Together, these observations indicate that the increased apoptosis and accompanying decrease in tumor burden in the LPP1 KO mice was not due to a defect in angiogenesis.


Decreased peritoneal ovarian cancer growth in mice lacking expression of lipid phosphate phosphohydrolase 1.

Nakayama J, Raines TA, Lynch KR, Slack-Davis JK - PLoS ONE (2015)

Angiogenesis is not defective in LPP1 KO mice.(A) Tumors from mice 8 weeks after initiation were sectioned and stained for CD31, and the total number of CD31 positive vessels per tumor area from 5 high powered fields (hpf; 200X magnification) per mouse for wild type (WT, n = 5) and LPP1 KO (n = 5) mice is plotted. The total number of CD31 positive vessels observed in 5 hpf of matrigel plugs containing conditioned media from ID8ip2Luc cells (B) or FGF/VEGF (C) is plotted (see Materials and Methods). Data are presented with Box and Whiskers plots as described for Fig. 3. *p = 0.0083, Student’s t-test.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4359083&req=5

pone.0120071.g004: Angiogenesis is not defective in LPP1 KO mice.(A) Tumors from mice 8 weeks after initiation were sectioned and stained for CD31, and the total number of CD31 positive vessels per tumor area from 5 high powered fields (hpf; 200X magnification) per mouse for wild type (WT, n = 5) and LPP1 KO (n = 5) mice is plotted. The total number of CD31 positive vessels observed in 5 hpf of matrigel plugs containing conditioned media from ID8ip2Luc cells (B) or FGF/VEGF (C) is plotted (see Materials and Methods). Data are presented with Box and Whiskers plots as described for Fig. 3. *p = 0.0083, Student’s t-test.
Mentions: Increased apoptosis in LPP1 KO mice could occur as a result of a lack of nutrients supplied to the tumor due to defective angiogenesis, the absence of a pro-survival factor or the presence of an inducer of cell death. Indeed, mice lacking LPP3 expression are embryonic lethal due to a defect in angiogenesis [27]. To determine whether angiogenesis was defective in LPP1 KO mice, tumors were stained for the endothelial marker CD31. As shown in Fig. 4A, tumors from wild type and LPP1 KO mice had similar levels of CD31 staining. To more objectively evaluate whether there was an intrinsic alteration in angiogenesis, we performed a matrigel plug assay. Briefly, matrigel embedded with tumor cell conditioned media or FGF and VEGF was implanted into the flanks of wild type or LPP1 KO mice to stimulate angiogenesis (S2 Fig.). Tumor cell conditioned media stimulated an equivalent number of vessels in wild type and LPP1 KO mice (Fig. 3B). FGF/VEGF stimulated vessel formation to a greater extent in LPP1 KO mice compared to wild type (Fig. 3C). Together, these observations indicate that the increased apoptosis and accompanying decrease in tumor burden in the LPP1 KO mice was not due to a defect in angiogenesis.

Bottom Line: Homozygous deletion of LPP1 (LPP1 KO) results in elevated levels and decreased turnover of LPA in vivo.The decreased tumor burden was accompanied by increased apoptosis and no change in proliferation or angiogenesis.Rather, the data support the notion that either elevated LPA concentration or altered LPA metabolism affects other growth-promoting contributions of the tumor microenvironment.

View Article: PubMed Central - PubMed

Affiliation: Department of Obstetrics and Gynecology, The Cancer Center, University of Virginia, Charlottesville, Virginia, United States of America.

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.

No MeSH data available.


Related in: MedlinePlus