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Antiangiogenic Therapy Impedes Infiltration by CD4+ and CD8+ Cells Into an Early Colon Tumor.

Yang YJ, Choi JS, Choi JW - J Cancer Prev (2015)

Bottom Line: Furthermore, the administration of the VEGF antagonist decreased the amounts of anti-tumoral cytokines such as interleukin (IL)-6 and IL-10.We revealed that newly formed vessels during tumorigenesis can be channels for particular anti-tumoral immune cells.Our results may confer insight for the clinical development of an efficient antiangiogenic therapeutic manual and a timely chemoprevention to suppress tumor growth.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology and Dental Research Institute, School of Dentistry, Wonkwang University, Iksan, Korea.

ABSTRACT

Background: While the majority of angiogenesis studies have focused on the late stages of cancer, the emergence of neovascularization in colon tumorigenesis has been observed an earlier stage than expected. Recent reports implied that early angiogenesis might be a defense mechanism to stimulate the natural clearance of microadenomas during colon tumorigenesis. However, little is known about how early angiogenesis affects the natural clearance of tumors.

Methods: Spontaneous colon tumors were developed in adenomatous polyposis coli conditional knockout mice with Cre recombinase adenovirus administration. Vascular endothelial growth factor (VEGF) antagonist, DC101, was administrated to determine the effect of early angiogenesis and then infiltration of immune cells into tumor and concentration of cytokines were evaluated.

Results: The continuous administration of the VEGF receptor 2 antagonist DC101 in the mouse models impeded the infiltration by CD4+ and CD8+ cells into the tumor region. Furthermore, the administration of the VEGF antagonist decreased the amounts of anti-tumoral cytokines such as interleukin (IL)-6 and IL-10.

Conclusions: We revealed that newly formed vessels during tumorigenesis can be channels for particular anti-tumoral immune cells. Our results may confer insight for the clinical development of an efficient antiangiogenic therapeutic manual and a timely chemoprevention to suppress tumor growth.

No MeSH data available.


Related in: MedlinePlus

Normalization of early angiogenesis upon application of anti-vascular endothelial growth factor therapy. (A) Blood vessels in macroadenomas of an adenomatous polyposis coli (Apc) mouse before (week 0) and after (week 10) the DC101 treatment. The white arrows indicate dilated or tortuous vessels, and the yellow arrows indicate apparently normal vessels in the tumor regions. Scale bars: 100 μm. (B) Fluorescent images of the blood vessels in the macroadenomas of an Apc mouse with and without sunitinib treatment. Blue, 4′,6-diamidino-2-phenylindole (DAPI)-stained nucleus; red, CD31-stained blood vessels. Scale bars: 200 μm.
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f2-jcp-20-129: Normalization of early angiogenesis upon application of anti-vascular endothelial growth factor therapy. (A) Blood vessels in macroadenomas of an adenomatous polyposis coli (Apc) mouse before (week 0) and after (week 10) the DC101 treatment. The white arrows indicate dilated or tortuous vessels, and the yellow arrows indicate apparently normal vessels in the tumor regions. Scale bars: 100 μm. (B) Fluorescent images of the blood vessels in the macroadenomas of an Apc mouse with and without sunitinib treatment. Blue, 4′,6-diamidino-2-phenylindole (DAPI)-stained nucleus; red, CD31-stained blood vessels. Scale bars: 200 μm.

Mentions: To investigate the role of early angiogenesis, we tried to suppress the new formation of vessels with antiangiogenenic therapy. First, we tested whether the DC101 VEGFR2 antagonist inhibited early angiogenesis by performing time-lapse confocal endomicroscopy on Apc mice treated with DC101 (30 mg/kg, once every 3 days) for a duration of 10 weeks. In vivo images showed an apparent recover in vascular diameter and tortuosity after the DC101 treatment (Fig. 2A). While the vasculature appeared like hexagonal matrix implying normal condition at week 0, administration of adeno-Cre made them tortured. But, the vasculature in DC101 treated mice showed the normal like shape compared with control mice (Fig. 2A, right panel of each group). The histological analysis of the adenoma tissues that were collected at week 12 showed a significantly smaller CD31-positive area–indicating a lower vascular density–in the sunitinib-treated mice when compared with the corresponding adenoma tissues in the untreated mice (Fig. 2B).


Antiangiogenic Therapy Impedes Infiltration by CD4+ and CD8+ Cells Into an Early Colon Tumor.

Yang YJ, Choi JS, Choi JW - J Cancer Prev (2015)

Normalization of early angiogenesis upon application of anti-vascular endothelial growth factor therapy. (A) Blood vessels in macroadenomas of an adenomatous polyposis coli (Apc) mouse before (week 0) and after (week 10) the DC101 treatment. The white arrows indicate dilated or tortuous vessels, and the yellow arrows indicate apparently normal vessels in the tumor regions. Scale bars: 100 μm. (B) Fluorescent images of the blood vessels in the macroadenomas of an Apc mouse with and without sunitinib treatment. Blue, 4′,6-diamidino-2-phenylindole (DAPI)-stained nucleus; red, CD31-stained blood vessels. Scale bars: 200 μm.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4492357&req=5

f2-jcp-20-129: Normalization of early angiogenesis upon application of anti-vascular endothelial growth factor therapy. (A) Blood vessels in macroadenomas of an adenomatous polyposis coli (Apc) mouse before (week 0) and after (week 10) the DC101 treatment. The white arrows indicate dilated or tortuous vessels, and the yellow arrows indicate apparently normal vessels in the tumor regions. Scale bars: 100 μm. (B) Fluorescent images of the blood vessels in the macroadenomas of an Apc mouse with and without sunitinib treatment. Blue, 4′,6-diamidino-2-phenylindole (DAPI)-stained nucleus; red, CD31-stained blood vessels. Scale bars: 200 μm.
Mentions: To investigate the role of early angiogenesis, we tried to suppress the new formation of vessels with antiangiogenenic therapy. First, we tested whether the DC101 VEGFR2 antagonist inhibited early angiogenesis by performing time-lapse confocal endomicroscopy on Apc mice treated with DC101 (30 mg/kg, once every 3 days) for a duration of 10 weeks. In vivo images showed an apparent recover in vascular diameter and tortuosity after the DC101 treatment (Fig. 2A). While the vasculature appeared like hexagonal matrix implying normal condition at week 0, administration of adeno-Cre made them tortured. But, the vasculature in DC101 treated mice showed the normal like shape compared with control mice (Fig. 2A, right panel of each group). The histological analysis of the adenoma tissues that were collected at week 12 showed a significantly smaller CD31-positive area–indicating a lower vascular density–in the sunitinib-treated mice when compared with the corresponding adenoma tissues in the untreated mice (Fig. 2B).

Bottom Line: Furthermore, the administration of the VEGF antagonist decreased the amounts of anti-tumoral cytokines such as interleukin (IL)-6 and IL-10.We revealed that newly formed vessels during tumorigenesis can be channels for particular anti-tumoral immune cells.Our results may confer insight for the clinical development of an efficient antiangiogenic therapeutic manual and a timely chemoprevention to suppress tumor growth.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology and Dental Research Institute, School of Dentistry, Wonkwang University, Iksan, Korea.

ABSTRACT

Background: While the majority of angiogenesis studies have focused on the late stages of cancer, the emergence of neovascularization in colon tumorigenesis has been observed an earlier stage than expected. Recent reports implied that early angiogenesis might be a defense mechanism to stimulate the natural clearance of microadenomas during colon tumorigenesis. However, little is known about how early angiogenesis affects the natural clearance of tumors.

Methods: Spontaneous colon tumors were developed in adenomatous polyposis coli conditional knockout mice with Cre recombinase adenovirus administration. Vascular endothelial growth factor (VEGF) antagonist, DC101, was administrated to determine the effect of early angiogenesis and then infiltration of immune cells into tumor and concentration of cytokines were evaluated.

Results: The continuous administration of the VEGF receptor 2 antagonist DC101 in the mouse models impeded the infiltration by CD4+ and CD8+ cells into the tumor region. Furthermore, the administration of the VEGF antagonist decreased the amounts of anti-tumoral cytokines such as interleukin (IL)-6 and IL-10.

Conclusions: We revealed that newly formed vessels during tumorigenesis can be channels for particular anti-tumoral immune cells. Our results may confer insight for the clinical development of an efficient antiangiogenic therapeutic manual and a timely chemoprevention to suppress tumor growth.

No MeSH data available.


Related in: MedlinePlus