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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

Peritoneal ovarian cancer growth is reduced in LPP1 KO mice.Following IP injection of ID8ip2Luc cells, mice were imaged weekly to monitor tumor growth kinetically. (A) Representative luminescence images of wild type and LPP1 KO mice with tumor taken at 2-week intervals. (B) Quantification of total flux (photons/second) was determined weekly for wild type (n = 10) and LPP1 KO (n = 12) mice. Data represent mean ± std err; p < 0.001 determined by 2-way ANOVA followed by Tukey’s multiple comparisons test. (C) Data represent the number of macroscopic tumor nodules per mouse determined 8 weeks after tumor initiation. Mice with too many nodules to count were assigned a value of 200. Data represent median with 25th and 75th percentiles; p = 0.02 determined using the Wilcoxan-Mann-Whitney test. (D) Tumor volume was determined by weighing the omentum (primary site of tumor formation) and all associated tumor nodules 8 weeks after tumor initiation; each point indicates an individual mouse. Data represent median with 25th and 75th percentiles; p = 0.0031 determined by Student’s t-test.
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pone.0120071.g002: Peritoneal ovarian cancer growth is reduced in LPP1 KO mice.Following IP injection of ID8ip2Luc cells, mice were imaged weekly to monitor tumor growth kinetically. (A) Representative luminescence images of wild type and LPP1 KO mice with tumor taken at 2-week intervals. (B) Quantification of total flux (photons/second) was determined weekly for wild type (n = 10) and LPP1 KO (n = 12) mice. Data represent mean ± std err; p < 0.001 determined by 2-way ANOVA followed by Tukey’s multiple comparisons test. (C) Data represent the number of macroscopic tumor nodules per mouse determined 8 weeks after tumor initiation. Mice with too many nodules to count were assigned a value of 200. Data represent median with 25th and 75th percentiles; p = 0.02 determined using the Wilcoxan-Mann-Whitney test. (D) Tumor volume was determined by weighing the omentum (primary site of tumor formation) and all associated tumor nodules 8 weeks after tumor initiation; each point indicates an individual mouse. Data represent median with 25th and 75th percentiles; p = 0.0031 determined by Student’s t-test.

Mentions: While the microenvironment of LPP1 KO mice favors tumor implantation in the peritoneal cavity, wild type mice showed equivalent tumor burden indicated by luminesence within 3 weeks of initiation (Fig. 1A). More strikingly, robust tumor growth ensued in wild type mice as shown by increased luminescence over time while tumors plateaued in the LPP1 KO mice at 3 weeks (Fig. 2A and 2B). Additionally, wild type mice had increased numbers of macroscopic tumor nodules studding the peritoneal cavity and increased tumor volume determined by weighing the omentum and associated tumors (Fig. 2C and 2D). To determine whether the lack of tumor growth in the LPP1 KO mice was due to less proliferation or increased apoptosis, tumors were stained for the proliferative marker Ki67 or cleaved caspase 3, as a marker of apoptosis. Tumors derived from wild type and LPP1 KO mice had equivalent levels of proliferation (Fig. 3A). However, tumors from LPP1 KO mice had 3 times more cells staining positively for cleaved caspase 3 compared to wild type (Fig. 3B) indicating a significant increase in apoptosis. Therefore, while loss of LPP1 in the tumor microenvironment facilitates tumor seeding, it is insufficient to sustain tumor growth over time due at least in part to an increase in apoptosis.


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)

Peritoneal ovarian cancer growth is reduced in LPP1 KO mice.Following IP injection of ID8ip2Luc cells, mice were imaged weekly to monitor tumor growth kinetically. (A) Representative luminescence images of wild type and LPP1 KO mice with tumor taken at 2-week intervals. (B) Quantification of total flux (photons/second) was determined weekly for wild type (n = 10) and LPP1 KO (n = 12) mice. Data represent mean ± std err; p < 0.001 determined by 2-way ANOVA followed by Tukey’s multiple comparisons test. (C) Data represent the number of macroscopic tumor nodules per mouse determined 8 weeks after tumor initiation. Mice with too many nodules to count were assigned a value of 200. Data represent median with 25th and 75th percentiles; p = 0.02 determined using the Wilcoxan-Mann-Whitney test. (D) Tumor volume was determined by weighing the omentum (primary site of tumor formation) and all associated tumor nodules 8 weeks after tumor initiation; each point indicates an individual mouse. Data represent median with 25th and 75th percentiles; p = 0.0031 determined by 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.g002: Peritoneal ovarian cancer growth is reduced in LPP1 KO mice.Following IP injection of ID8ip2Luc cells, mice were imaged weekly to monitor tumor growth kinetically. (A) Representative luminescence images of wild type and LPP1 KO mice with tumor taken at 2-week intervals. (B) Quantification of total flux (photons/second) was determined weekly for wild type (n = 10) and LPP1 KO (n = 12) mice. Data represent mean ± std err; p < 0.001 determined by 2-way ANOVA followed by Tukey’s multiple comparisons test. (C) Data represent the number of macroscopic tumor nodules per mouse determined 8 weeks after tumor initiation. Mice with too many nodules to count were assigned a value of 200. Data represent median with 25th and 75th percentiles; p = 0.02 determined using the Wilcoxan-Mann-Whitney test. (D) Tumor volume was determined by weighing the omentum (primary site of tumor formation) and all associated tumor nodules 8 weeks after tumor initiation; each point indicates an individual mouse. Data represent median with 25th and 75th percentiles; p = 0.0031 determined by Student’s t-test.
Mentions: While the microenvironment of LPP1 KO mice favors tumor implantation in the peritoneal cavity, wild type mice showed equivalent tumor burden indicated by luminesence within 3 weeks of initiation (Fig. 1A). More strikingly, robust tumor growth ensued in wild type mice as shown by increased luminescence over time while tumors plateaued in the LPP1 KO mice at 3 weeks (Fig. 2A and 2B). Additionally, wild type mice had increased numbers of macroscopic tumor nodules studding the peritoneal cavity and increased tumor volume determined by weighing the omentum and associated tumors (Fig. 2C and 2D). To determine whether the lack of tumor growth in the LPP1 KO mice was due to less proliferation or increased apoptosis, tumors were stained for the proliferative marker Ki67 or cleaved caspase 3, as a marker of apoptosis. Tumors derived from wild type and LPP1 KO mice had equivalent levels of proliferation (Fig. 3A). However, tumors from LPP1 KO mice had 3 times more cells staining positively for cleaved caspase 3 compared to wild type (Fig. 3B) indicating a significant increase in apoptosis. Therefore, while loss of LPP1 in the tumor microenvironment facilitates tumor seeding, it is insufficient to sustain tumor growth over time due at least in part to an increase in apoptosis.

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