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Longitudinal Tracing of Spontaneous Regression and Anti-angiogenic Response of Individual Microadenomas during Colon Tumorigenesis.

Choi JW, Kim P, Kim JK, Kim YR, Fukumura D, Yun SH - Theranostics (2015)

Bottom Line: Anti-angiogenic treatments with vascular endothelial growth factor receptor (VEGFR) antagonists reduced the size of the early lesions and the number of polyps.We found surprisingly that anti-angiogenic treatments delayed the natural clearance of transient lesions by up to several weeks in both genetic models.The results represent the previously unexpected role of early angiogenesis on the spontaneous regression of early-stage colon tumors.

View Article: PubMed Central - PubMed

Affiliation: 1. Harvard Medical School and Wellman Center for Photomedicine, Massachusetts General Hospital, 40 Blossom St., Boston, MA 02114, USA ; 2. Department of Pharmacology and Dental Research Institute, School of Dentistry / Department of Smart Life-Care Convergence Graduate School, Wonkwang University, Iksan, Chonbuk 570-749, Korea ; 3. Advanced Institute of Convergence Technology, Seoul National University, Suwon Gyeonggi-do 443-270, Korea.

ABSTRACT
Angiogenesis is essential for the progression of cancer, but its involvement in the initial phase of colon tumorigenesis is not well understood. Using intravital endomicroscopy, we visualized the natural history of early pre-tumorous lesions and adenomas in the colon of conditional Apc-knockout and Apc/Kras double mutant mouse models. Early lesions emerged about 4 weeks after the onset of somatic mutations, accompanying vascular dilation when the size of lesions reached about 200 μm, but most lesions regressed spontaneously and cleared within 10 weeks after their emergence. Anti-angiogenic treatments with vascular endothelial growth factor receptor (VEGFR) antagonists reduced the size of the early lesions and the number of polyps. We found surprisingly that anti-angiogenic treatments delayed the natural clearance of transient lesions by up to several weeks in both genetic models. The results represent the previously unexpected role of early angiogenesis on the spontaneous regression of early-stage colon tumors.

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Reduction of apoptosis and proliferation rates in tumors by DC101 treatment. A, Ki-67 antibody-stained immunohistology images of microadenoma and polyps of control and DC101-treated animals. B, The number of Ki-67 positive cells per field of view (FOV, 20X) (n=4). C, TUNEL-stained images of microadenoma and polyps of control and DC101-treated animals. D, The number of TUNEL-positive spots per FOV. Scale bars, 100 µm in A and C. *, P < 0.05; **, P < 0.01 in B and D.
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Figure 5: Reduction of apoptosis and proliferation rates in tumors by DC101 treatment. A, Ki-67 antibody-stained immunohistology images of microadenoma and polyps of control and DC101-treated animals. B, The number of Ki-67 positive cells per field of view (FOV, 20X) (n=4). C, TUNEL-stained images of microadenoma and polyps of control and DC101-treated animals. D, The number of TUNEL-positive spots per FOV. Scale bars, 100 µm in A and C. *, P < 0.05; **, P < 0.01 in B and D.

Mentions: We evaluated the rate of proliferation and apoptosis to gain mechanistic insights into how the anti-angiogenic treatment affected tumor growth in micro and macro adenomas. The number of Ki-67+ proliferative cells was found to be reduced in DC101 treated groups significantly both in microadenoma and polyps (Fig. 5A-B). TUNEL assay showed that apoptosis signal was significantly stronger in polyps than microadenomas in both untreated and treated animals (Fig. 5C-D). However, the apoptosis signal strength is significantly reduced in DC101-treated animals than untreated animals (Fig. 5C-D).


Longitudinal Tracing of Spontaneous Regression and Anti-angiogenic Response of Individual Microadenomas during Colon Tumorigenesis.

Choi JW, Kim P, Kim JK, Kim YR, Fukumura D, Yun SH - Theranostics (2015)

Reduction of apoptosis and proliferation rates in tumors by DC101 treatment. A, Ki-67 antibody-stained immunohistology images of microadenoma and polyps of control and DC101-treated animals. B, The number of Ki-67 positive cells per field of view (FOV, 20X) (n=4). C, TUNEL-stained images of microadenoma and polyps of control and DC101-treated animals. D, The number of TUNEL-positive spots per FOV. Scale bars, 100 µm in A and C. *, P < 0.05; **, P < 0.01 in B and D.
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4402496&req=5

Figure 5: Reduction of apoptosis and proliferation rates in tumors by DC101 treatment. A, Ki-67 antibody-stained immunohistology images of microadenoma and polyps of control and DC101-treated animals. B, The number of Ki-67 positive cells per field of view (FOV, 20X) (n=4). C, TUNEL-stained images of microadenoma and polyps of control and DC101-treated animals. D, The number of TUNEL-positive spots per FOV. Scale bars, 100 µm in A and C. *, P < 0.05; **, P < 0.01 in B and D.
Mentions: We evaluated the rate of proliferation and apoptosis to gain mechanistic insights into how the anti-angiogenic treatment affected tumor growth in micro and macro adenomas. The number of Ki-67+ proliferative cells was found to be reduced in DC101 treated groups significantly both in microadenoma and polyps (Fig. 5A-B). TUNEL assay showed that apoptosis signal was significantly stronger in polyps than microadenomas in both untreated and treated animals (Fig. 5C-D). However, the apoptosis signal strength is significantly reduced in DC101-treated animals than untreated animals (Fig. 5C-D).

Bottom Line: Anti-angiogenic treatments with vascular endothelial growth factor receptor (VEGFR) antagonists reduced the size of the early lesions and the number of polyps.We found surprisingly that anti-angiogenic treatments delayed the natural clearance of transient lesions by up to several weeks in both genetic models.The results represent the previously unexpected role of early angiogenesis on the spontaneous regression of early-stage colon tumors.

View Article: PubMed Central - PubMed

Affiliation: 1. Harvard Medical School and Wellman Center for Photomedicine, Massachusetts General Hospital, 40 Blossom St., Boston, MA 02114, USA ; 2. Department of Pharmacology and Dental Research Institute, School of Dentistry / Department of Smart Life-Care Convergence Graduate School, Wonkwang University, Iksan, Chonbuk 570-749, Korea ; 3. Advanced Institute of Convergence Technology, Seoul National University, Suwon Gyeonggi-do 443-270, Korea.

ABSTRACT
Angiogenesis is essential for the progression of cancer, but its involvement in the initial phase of colon tumorigenesis is not well understood. Using intravital endomicroscopy, we visualized the natural history of early pre-tumorous lesions and adenomas in the colon of conditional Apc-knockout and Apc/Kras double mutant mouse models. Early lesions emerged about 4 weeks after the onset of somatic mutations, accompanying vascular dilation when the size of lesions reached about 200 μm, but most lesions regressed spontaneously and cleared within 10 weeks after their emergence. Anti-angiogenic treatments with vascular endothelial growth factor receptor (VEGFR) antagonists reduced the size of the early lesions and the number of polyps. We found surprisingly that anti-angiogenic treatments delayed the natural clearance of transient lesions by up to several weeks in both genetic models. The results represent the previously unexpected role of early angiogenesis on the spontaneous regression of early-stage colon tumors.

Show MeSH
Related in: MedlinePlus