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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

Increased peritoneal tumor seeding in LPP1 KO mice.ID8ip2Luc ovarian cancer cells were injected IP into C57BL/6 (WT) or LPP1 KO mice. (A) Mice (WT n = 10; LPP1 KO n = 12) were imaged weekly following tumor initiation to monitor tumor growth. Data represent mean total flux (photons/second) ± std err and were analyzed by 2-way ANOVA followed by Tukey’s multiple comparisons test. (B) The total number of microscopic tumor nodules was counted in an individual, randomly selected, H&E stained section of omentum per mouse obtained 2 weeks after tumor initiation (WT n = 7; LPP1 KO n = 8). Data represent mean ± std err; p = 0.0069 determined by Student’s t-test. (C) The percentage of wild type or LPP1 KO (from (B)) mice with invasive (solid bars) or non-invasive (includes no tumor; stippled bars) tumors 2 weeks after tumor initiation. Number of mice per outcome is indicated. Significance determined by Fisher’s Exact Test. (D) The percentage wild type or LPP1 KO (from (B)) mice with (positive, solid bars) or without (negative, stippled bars) mesothelial VCAM-1 staining by IHC 2 weeks after tumor initiation. Number of mice per outcome is indicated. Significance determined by Fisher’s Exact Test.
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pone.0120071.g001: Increased peritoneal tumor seeding in LPP1 KO mice.ID8ip2Luc ovarian cancer cells were injected IP into C57BL/6 (WT) or LPP1 KO mice. (A) Mice (WT n = 10; LPP1 KO n = 12) were imaged weekly following tumor initiation to monitor tumor growth. Data represent mean total flux (photons/second) ± std err and were analyzed by 2-way ANOVA followed by Tukey’s multiple comparisons test. (B) The total number of microscopic tumor nodules was counted in an individual, randomly selected, H&E stained section of omentum per mouse obtained 2 weeks after tumor initiation (WT n = 7; LPP1 KO n = 8). Data represent mean ± std err; p = 0.0069 determined by Student’s t-test. (C) The percentage of wild type or LPP1 KO (from (B)) mice with invasive (solid bars) or non-invasive (includes no tumor; stippled bars) tumors 2 weeks after tumor initiation. Number of mice per outcome is indicated. Significance determined by Fisher’s Exact Test. (D) The percentage wild type or LPP1 KO (from (B)) mice with (positive, solid bars) or without (negative, stippled bars) mesothelial VCAM-1 staining by IHC 2 weeks after tumor initiation. Number of mice per outcome is indicated. Significance determined by Fisher’s Exact Test.

Mentions: While the contribution of LPA to ovarian cancer growth and progression has been studied extensively [1,2,4,7–11], the effects of LPA metabolism on cancer progression are poorly understood. We investigated the effect of reduced LPA turnover on metastatic peritoneal ovarian cancer growth and progression using mice lacking the lipid phosphatase, LPP1 (LPP1 KO) and a syngeneic mouse ovarian cancer cell line, ID8ip2Luc. In vivo imaging of mice following intraperitoneal (IP) injection of ID8ip2Luc cells revealed increased luminescence in LPP1 KO mice compared to wild type within 2 weeks (Fig. 1A). Physical examination of the peritoneal cavity upon necropsy 2 weeks after tumor initiation showed no indication of tumor nodules (data not shown) and no difference in weights of the omentum (primary site of tumor metastasis) between genotypes (S1 Fig.) or from non-tumor bearing mice (data not shown). However, evaluation of H&E stained sections of the omentum revealed the presence of microscopic tumor nodules (S1 Fig.), consistent with previous observations [26]. Importantly, significantly more microscopic nodules were observed in omentums from LPP1 KO mice compared to wild type (Fig. 1B). Furthermore, LPP1 KO mice were more likely to harbor invasive lesions (Fig. 1C, S1 Fig.) that coincided with mesothelial VCAM-1 expression (Fig. 1D, S1 Fig.), which promotes tumor invasion of the mesothelium [26]. Together, these observations indicate that loss of LPP1 in the tumor microenvironment facilitates tumor seeding and mesothelial invasion of the peritoneal cavity.


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)

Increased peritoneal tumor seeding in LPP1 KO mice.ID8ip2Luc ovarian cancer cells were injected IP into C57BL/6 (WT) or LPP1 KO mice. (A) Mice (WT n = 10; LPP1 KO n = 12) were imaged weekly following tumor initiation to monitor tumor growth. Data represent mean total flux (photons/second) ± std err and were analyzed by 2-way ANOVA followed by Tukey’s multiple comparisons test. (B) The total number of microscopic tumor nodules was counted in an individual, randomly selected, H&E stained section of omentum per mouse obtained 2 weeks after tumor initiation (WT n = 7; LPP1 KO n = 8). Data represent mean ± std err; p = 0.0069 determined by Student’s t-test. (C) The percentage of wild type or LPP1 KO (from (B)) mice with invasive (solid bars) or non-invasive (includes no tumor; stippled bars) tumors 2 weeks after tumor initiation. Number of mice per outcome is indicated. Significance determined by Fisher’s Exact Test. (D) The percentage wild type or LPP1 KO (from (B)) mice with (positive, solid bars) or without (negative, stippled bars) mesothelial VCAM-1 staining by IHC 2 weeks after tumor initiation. Number of mice per outcome is indicated. Significance determined by Fisher’s Exact Test.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4359083&req=5

pone.0120071.g001: Increased peritoneal tumor seeding in LPP1 KO mice.ID8ip2Luc ovarian cancer cells were injected IP into C57BL/6 (WT) or LPP1 KO mice. (A) Mice (WT n = 10; LPP1 KO n = 12) were imaged weekly following tumor initiation to monitor tumor growth. Data represent mean total flux (photons/second) ± std err and were analyzed by 2-way ANOVA followed by Tukey’s multiple comparisons test. (B) The total number of microscopic tumor nodules was counted in an individual, randomly selected, H&E stained section of omentum per mouse obtained 2 weeks after tumor initiation (WT n = 7; LPP1 KO n = 8). Data represent mean ± std err; p = 0.0069 determined by Student’s t-test. (C) The percentage of wild type or LPP1 KO (from (B)) mice with invasive (solid bars) or non-invasive (includes no tumor; stippled bars) tumors 2 weeks after tumor initiation. Number of mice per outcome is indicated. Significance determined by Fisher’s Exact Test. (D) The percentage wild type or LPP1 KO (from (B)) mice with (positive, solid bars) or without (negative, stippled bars) mesothelial VCAM-1 staining by IHC 2 weeks after tumor initiation. Number of mice per outcome is indicated. Significance determined by Fisher’s Exact Test.
Mentions: While the contribution of LPA to ovarian cancer growth and progression has been studied extensively [1,2,4,7–11], the effects of LPA metabolism on cancer progression are poorly understood. We investigated the effect of reduced LPA turnover on metastatic peritoneal ovarian cancer growth and progression using mice lacking the lipid phosphatase, LPP1 (LPP1 KO) and a syngeneic mouse ovarian cancer cell line, ID8ip2Luc. In vivo imaging of mice following intraperitoneal (IP) injection of ID8ip2Luc cells revealed increased luminescence in LPP1 KO mice compared to wild type within 2 weeks (Fig. 1A). Physical examination of the peritoneal cavity upon necropsy 2 weeks after tumor initiation showed no indication of tumor nodules (data not shown) and no difference in weights of the omentum (primary site of tumor metastasis) between genotypes (S1 Fig.) or from non-tumor bearing mice (data not shown). However, evaluation of H&E stained sections of the omentum revealed the presence of microscopic tumor nodules (S1 Fig.), consistent with previous observations [26]. Importantly, significantly more microscopic nodules were observed in omentums from LPP1 KO mice compared to wild type (Fig. 1B). Furthermore, LPP1 KO mice were more likely to harbor invasive lesions (Fig. 1C, S1 Fig.) that coincided with mesothelial VCAM-1 expression (Fig. 1D, S1 Fig.), which promotes tumor invasion of the mesothelium [26]. Together, these observations indicate that loss of LPP1 in the tumor microenvironment facilitates tumor seeding and mesothelial invasion of the peritoneal cavity.

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