Limits...
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

Daily injection of LPA rescues tumor suppression and stimulates ovarian cancer growth.ID8ip2Luc ovarian cancer cells were injected IP into wild type (WT, n = 19) or LPP1 KO (n = 20) mice. Mice received daily injections of LPA (n = 6 WT, n = 7 LPP1 KO) or vehicle (n = 13 for both genotypes) beginning the day after tumor injection. (A) Mice were imaged weekly following tumor initiation to monitor tumor growth. Data represent mean total flux (photons/second) ± std err; *p < 0.001, 2-way ANOVA followed by Tukey’s multiple comparisons test. Tumors were collected 6 weeks after initiation, sectioned and stained for Ki67 (B) or cleaved caspase 3 (C). Quantification of Ki67 and cleaved caspase 3 was achieved by determining the percentage of positively stained cells in 5 high-powered fields (400x magnification) per mouse, 5 mice per group. Data are presented with Box and Whiskers plots as described for Fig. 3. **p < 0.0001, 2-way ANOVA followed by Tukey’s multiple comparisons test.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4359083&req=5

pone.0120071.g005: Daily injection of LPA rescues tumor suppression and stimulates ovarian cancer growth.ID8ip2Luc ovarian cancer cells were injected IP into wild type (WT, n = 19) or LPP1 KO (n = 20) mice. Mice received daily injections of LPA (n = 6 WT, n = 7 LPP1 KO) or vehicle (n = 13 for both genotypes) beginning the day after tumor injection. (A) Mice were imaged weekly following tumor initiation to monitor tumor growth. Data represent mean total flux (photons/second) ± std err; *p < 0.001, 2-way ANOVA followed by Tukey’s multiple comparisons test. Tumors were collected 6 weeks after initiation, sectioned and stained for Ki67 (B) or cleaved caspase 3 (C). Quantification of Ki67 and cleaved caspase 3 was achieved by determining the percentage of positively stained cells in 5 high-powered fields (400x magnification) per mouse, 5 mice per group. Data are presented with Box and Whiskers plots as described for Fig. 3. **p < 0.0001, 2-way ANOVA followed by Tukey’s multiple comparisons test.

Mentions: Reduced tumor growth in the absence of defects in angiogenesis is indicative of the lack of a growth-promoting environment in the LPP1 KO mice. Such an environment could involve a multitude of components including the lack of a growth-promoting (pro-survival) factor, the presence of an inhibitor of growth (inducer of cell death), the inability to recruit auxiliary cells necessary to promote growth, inappropriate cell-cell interactions within the tumor or any combination of these or additional effects. We hypothesized that exogenous administration of high concentrations of a growth factor would override the negative consequences of the growth inhibitory environment. LPA is a well-established stimulator of ovarian cancer cell growth [2,4]. Daily administration of LPA has been reported to stimulate growth of human ovarian cancer cells in immune compromised mice [21] and tumors in the ID8 mouse ovarian cancer model [22]. Therefore, we tested the ability of LPA to stimulate ID8ip2Luc tumor growth in LPP1 KO compared to wild type mice. Daily administration of LPA significantly increased tumor growth in wild type mice starting 4 weeks after initiation and culminated in 3 times more luminescence compared to wild type mice without exogenous LPA (Fig. 5A), consistent with previous observations [22]. LPA also stimulated tumor growth in LPP1 KO mice to the same extent observed in wild type mice treated with LPA (Fig. 5A). In both cases, LPA increased tumor cell proliferation (Fig. 5B). Strikingly, LPA decreased the number of cells that stained positive for cleaved caspase 3 to the level found in tumors from wild type mice with or without LPA (Fig. 5C). The data indicate that delivery of increased concentrations of LPA reverses the negative growth environment found in LPP1 KO mice.


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)

Daily injection of LPA rescues tumor suppression and stimulates ovarian cancer growth.ID8ip2Luc ovarian cancer cells were injected IP into wild type (WT, n = 19) or LPP1 KO (n = 20) mice. Mice received daily injections of LPA (n = 6 WT, n = 7 LPP1 KO) or vehicle (n = 13 for both genotypes) beginning the day after tumor injection. (A) Mice were imaged weekly following tumor initiation to monitor tumor growth. Data represent mean total flux (photons/second) ± std err; *p < 0.001, 2-way ANOVA followed by Tukey’s multiple comparisons test. Tumors were collected 6 weeks after initiation, sectioned and stained for Ki67 (B) or cleaved caspase 3 (C). Quantification of Ki67 and cleaved caspase 3 was achieved by determining the percentage of positively stained cells in 5 high-powered fields (400x magnification) per mouse, 5 mice per group. Data are presented with Box and Whiskers plots as described for Fig. 3. **p < 0.0001, 2-way ANOVA followed by Tukey’s multiple comparisons test.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0120071.g005: Daily injection of LPA rescues tumor suppression and stimulates ovarian cancer growth.ID8ip2Luc ovarian cancer cells were injected IP into wild type (WT, n = 19) or LPP1 KO (n = 20) mice. Mice received daily injections of LPA (n = 6 WT, n = 7 LPP1 KO) or vehicle (n = 13 for both genotypes) beginning the day after tumor injection. (A) Mice were imaged weekly following tumor initiation to monitor tumor growth. Data represent mean total flux (photons/second) ± std err; *p < 0.001, 2-way ANOVA followed by Tukey’s multiple comparisons test. Tumors were collected 6 weeks after initiation, sectioned and stained for Ki67 (B) or cleaved caspase 3 (C). Quantification of Ki67 and cleaved caspase 3 was achieved by determining the percentage of positively stained cells in 5 high-powered fields (400x magnification) per mouse, 5 mice per group. Data are presented with Box and Whiskers plots as described for Fig. 3. **p < 0.0001, 2-way ANOVA followed by Tukey’s multiple comparisons test.
Mentions: Reduced tumor growth in the absence of defects in angiogenesis is indicative of the lack of a growth-promoting environment in the LPP1 KO mice. Such an environment could involve a multitude of components including the lack of a growth-promoting (pro-survival) factor, the presence of an inhibitor of growth (inducer of cell death), the inability to recruit auxiliary cells necessary to promote growth, inappropriate cell-cell interactions within the tumor or any combination of these or additional effects. We hypothesized that exogenous administration of high concentrations of a growth factor would override the negative consequences of the growth inhibitory environment. LPA is a well-established stimulator of ovarian cancer cell growth [2,4]. Daily administration of LPA has been reported to stimulate growth of human ovarian cancer cells in immune compromised mice [21] and tumors in the ID8 mouse ovarian cancer model [22]. Therefore, we tested the ability of LPA to stimulate ID8ip2Luc tumor growth in LPP1 KO compared to wild type mice. Daily administration of LPA significantly increased tumor growth in wild type mice starting 4 weeks after initiation and culminated in 3 times more luminescence compared to wild type mice without exogenous LPA (Fig. 5A), consistent with previous observations [22]. LPA also stimulated tumor growth in LPP1 KO mice to the same extent observed in wild type mice treated with LPA (Fig. 5A). In both cases, LPA increased tumor cell proliferation (Fig. 5B). Strikingly, LPA decreased the number of cells that stained positive for cleaved caspase 3 to the level found in tumors from wild type mice with or without LPA (Fig. 5C). The data indicate that delivery of increased concentrations of LPA reverses the negative growth environment found in LPP1 KO mice.

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