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Inhibitory effects of anti-VEGF antibody on the growth and angiogenesis of estrogen-induced pituitary prolactinoma in Fischer 344 Rats: animal model of VEGF-targeted therapy for human endocrine tumors.

Miyajima K, Takekoshi S, Itoh J, Kakimoto K, Miyakoshi T, Osamura RY - Acta Histochem Cytochem (2010)

Bottom Line: With simultaneous treatment with G6-31 for the latter three weeks of the 13-week period of E2 stimulation (E2+G6-31 group), the following inhibitory effects on the PRLoma were observed in the E2+G6-31 group as compared with the E2-only group.In the E2+G6-31 group, a tendency to reduction in pituitary weight was observed and significant differences were observed as (1) reductions in the Ki-67-positive anterior cells, (2) increases in TUNEL-positive anterior cells, and (3) repair of the microvessel count by CD34-immunohistochemistry.Thus, our results demonstrate that anti-VEGF antibody exerted inhibitory effects on pituitary tumorigenesis in well-established E2 induced PRLomas.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa 259-1193, Japan.

ABSTRACT
Estrogen-induced pituitary prolactin-producing tumors (PRLoma) in F344 rats express a high level of vascular endothelial growth factor (VEGF) associated with marked angiogenesis and angiectasis. To investigate whether tumor development in E2-induced PRLoma is inhibited by anti-VEGF monoclonal antibody (G6-31), we evaluated tumor growth and observed the vascular structures. With simultaneous treatment with G6-31 for the latter three weeks of the 13-week period of E2 stimulation (E2+G6-31 group), the following inhibitory effects on the PRLoma were observed in the E2+G6-31 group as compared with the E2-only group. In the E2+G6-31 group, a tendency to reduction in pituitary weight was observed and significant differences were observed as (1) reductions in the Ki-67-positive anterior cells, (2) increases in TUNEL-positive anterior cells, and (3) repair of the microvessel count by CD34-immunohistochemistry. The characteristic "blood lakes" in PRLomas were improved and replaced by repaired microvascular structures on 3D observation using confocal laser scanning microscope. These inhibitory effects due to anti-VEGF antibody might be related to the autocrine/paracrine action of VEGF on the tumor cells, because VEGF and its receptor are co-expressed on the tumor cells. Thus, our results demonstrate that anti-VEGF antibody exerted inhibitory effects on pituitary tumorigenesis in well-established E2 induced PRLomas.

No MeSH data available.


Related in: MedlinePlus

Immunohistochemistry of pituitary PRLoma in F344 rats. Staining of PTTG (A to C) and HIF-1α (D to F). Counterstaining was done with hematoxylin. Bar=20 µm. G and H: Gene expression of PTTG (G) and HIF-1α (H) in pituitary PRLoma in F344 rats. The columns show the mean value of the relative expression of PTTG and HIF-1α compared with GAPDH as an endogenous control. *: P<0.05, E2 versus E2+G6-31 group.
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Figure 6: Immunohistochemistry of pituitary PRLoma in F344 rats. Staining of PTTG (A to C) and HIF-1α (D to F). Counterstaining was done with hematoxylin. Bar=20 µm. G and H: Gene expression of PTTG (G) and HIF-1α (H) in pituitary PRLoma in F344 rats. The columns show the mean value of the relative expression of PTTG and HIF-1α compared with GAPDH as an endogenous control. *: P<0.05, E2 versus E2+G6-31 group.

Mentions: PTTG localized in the cytoplasm of the anterior pituitary cells and PTTG-positive cells were increased after treatment with E2 (Fig. 6A and 6B). Similarly with real time qRT-PCR, PTTG1 mRNA levels were also significantly increased in the E2 group (Fig. 6G). On the other hand, in the E2+G6-31 group a decrease in the number of positive cells and weakened staining intensity were observed in the pituitary cells (Fig. 6C). Significant decrease was also observed in the expression levels of PTTG mRNA in the E2+G6-31 group compare to the E2 group (Fig. 6G).


Inhibitory effects of anti-VEGF antibody on the growth and angiogenesis of estrogen-induced pituitary prolactinoma in Fischer 344 Rats: animal model of VEGF-targeted therapy for human endocrine tumors.

Miyajima K, Takekoshi S, Itoh J, Kakimoto K, Miyakoshi T, Osamura RY - Acta Histochem Cytochem (2010)

Immunohistochemistry of pituitary PRLoma in F344 rats. Staining of PTTG (A to C) and HIF-1α (D to F). Counterstaining was done with hematoxylin. Bar=20 µm. G and H: Gene expression of PTTG (G) and HIF-1α (H) in pituitary PRLoma in F344 rats. The columns show the mean value of the relative expression of PTTG and HIF-1α compared with GAPDH as an endogenous control. *: P<0.05, E2 versus E2+G6-31 group.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2875861&req=5

Figure 6: Immunohistochemistry of pituitary PRLoma in F344 rats. Staining of PTTG (A to C) and HIF-1α (D to F). Counterstaining was done with hematoxylin. Bar=20 µm. G and H: Gene expression of PTTG (G) and HIF-1α (H) in pituitary PRLoma in F344 rats. The columns show the mean value of the relative expression of PTTG and HIF-1α compared with GAPDH as an endogenous control. *: P<0.05, E2 versus E2+G6-31 group.
Mentions: PTTG localized in the cytoplasm of the anterior pituitary cells and PTTG-positive cells were increased after treatment with E2 (Fig. 6A and 6B). Similarly with real time qRT-PCR, PTTG1 mRNA levels were also significantly increased in the E2 group (Fig. 6G). On the other hand, in the E2+G6-31 group a decrease in the number of positive cells and weakened staining intensity were observed in the pituitary cells (Fig. 6C). Significant decrease was also observed in the expression levels of PTTG mRNA in the E2+G6-31 group compare to the E2 group (Fig. 6G).

Bottom Line: With simultaneous treatment with G6-31 for the latter three weeks of the 13-week period of E2 stimulation (E2+G6-31 group), the following inhibitory effects on the PRLoma were observed in the E2+G6-31 group as compared with the E2-only group.In the E2+G6-31 group, a tendency to reduction in pituitary weight was observed and significant differences were observed as (1) reductions in the Ki-67-positive anterior cells, (2) increases in TUNEL-positive anterior cells, and (3) repair of the microvessel count by CD34-immunohistochemistry.Thus, our results demonstrate that anti-VEGF antibody exerted inhibitory effects on pituitary tumorigenesis in well-established E2 induced PRLomas.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa 259-1193, Japan.

ABSTRACT
Estrogen-induced pituitary prolactin-producing tumors (PRLoma) in F344 rats express a high level of vascular endothelial growth factor (VEGF) associated with marked angiogenesis and angiectasis. To investigate whether tumor development in E2-induced PRLoma is inhibited by anti-VEGF monoclonal antibody (G6-31), we evaluated tumor growth and observed the vascular structures. With simultaneous treatment with G6-31 for the latter three weeks of the 13-week period of E2 stimulation (E2+G6-31 group), the following inhibitory effects on the PRLoma were observed in the E2+G6-31 group as compared with the E2-only group. In the E2+G6-31 group, a tendency to reduction in pituitary weight was observed and significant differences were observed as (1) reductions in the Ki-67-positive anterior cells, (2) increases in TUNEL-positive anterior cells, and (3) repair of the microvessel count by CD34-immunohistochemistry. The characteristic "blood lakes" in PRLomas were improved and replaced by repaired microvascular structures on 3D observation using confocal laser scanning microscope. These inhibitory effects due to anti-VEGF antibody might be related to the autocrine/paracrine action of VEGF on the tumor cells, because VEGF and its receptor are co-expressed on the tumor cells. Thus, our results demonstrate that anti-VEGF antibody exerted inhibitory effects on pituitary tumorigenesis in well-established E2 induced PRLomas.

No MeSH data available.


Related in: MedlinePlus