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Molecular Biology and Genetics |
716 Mouse Intestinal Polyps1
Departments of Pharmacology [H. S., M. O., T. I., H. O., K. T., S. N., M. M. T.] and Gastroenterology and Hepatology [H. S., T. C.], Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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716) mice, a model for human familial adenomatous polyposis. We scored MVD also in several compound mutants carrying Apc716, namely, mice with an additional mutation in Smad4, in which the polyps progress into invasive adenocarcinomas; mice with a cyclooxygenase (COX)-2 gene (Ptgs2) mutation, in which adenoma growth is suppressed; and mice with prostaglandin E2 EP receptor gene mutations. In both simple Apc716 and compound Apc716 Smad4 mutants, MVD increased in a polyp size-dependent manner only in the polyps expanded beyond a threshold of about 1 mm in diameter. These results indicate that tumor angiogenesis is stimulated only after tumors grow to a certain size, and this angiogenic switch is common to both benign adenomas and malignant adenocarcinomas. In Apc716 polyposis attenuated by the COX-2 gene mutation, in contrast, MVD did not increase even in polyps larger than 1 mm. The same phenomenon was observed in the compound mutant mice with Apc716 and the EP2 receptor gene mutations, but not in other EP compound mutants. We also immunohistochemically studied COX-2 and angiogenic factors, vascular endothelial growth factor and basic fibroblast growth factor. Interestingly, expression of these proteins was also increased in polyps larger than 1 mm. These results suggest that, in both benign and malignant mouse intestinal tumors, stromal expression of COX-2 results in elevated prostaglandin E2 levels that stimulate cell surface receptor EP2, followed by induction of vascular endothelial growth factor that causes tumor angiogenesis. |
INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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To determine the role of angiogenesis in colorectal carcinogenesis, we have investigated our mouse models of colon cancer (Fig. 1)
. We earlier constructed Apc3
knockout (Apc716) mice that develop numerous benign polyps in the intestines (12)
and can be used as a model for human FAP. After Apc LOH, a microadenoma is initiated as an outpocketing pouch in a single intestinal crypt and develops into a polyp adenoma (13)
. We also constructed a compound mutant strain that carried Apc716 and Smad4 mutations and demonstrated that the mice develop very invasive adenocarcinomas that are much larger than the Apc716 polyp adenomas (14)
. On the other hand, in another compound mutant strain with Apc716 and the COX-2 gene (Ptgs2) mutations, the polyp number and size are reduced dramatically (15)
, establishing the rationale for treating colonic polyposis in FAP with COX-2 inhibitors (16
, 17) .
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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716, Smad4, and Ptgs2 knockout mice, and Apc716 compound mutants with Smad4 and Ptgs2, respectively, were described previously (12, 13, 14, 15)
. Construction of PGE2 receptor gene knockout mice was also described (19)
. Using five mice for each Ptgs2 genotype, we examined 314, 116, and 51 intestinal polyps from the Apc716 Ptgs2(+/+), Apc716 Ptgs2(+/-), and Apc716 Ptgs2(-/-) mice, respectively. We also examined 33 polyps from eight cis-Apc716 Smad4 mice; 5 polyps larger than 1 mm of 28 polyps from three Apc716 EP2(-/-) mice; 21polyps from five Apc716 EP1(-/-) mice; and 13 polyps from four Apc716 EP3(-/-) mice.
Tissue Preparation and Immunohistochemistry.
Small intestinal sections were prepared as described previously (13, 14, 15)
. They were blocked with 10% normal goat or rabbit serum, and incubated for 2 h at room temperature with polyclonal anti-vWF rabbit serum (1:500; DAKO, Copenhagen, Denmark); polyclonal anti-vascular VEGF goat serum (1:300; R&D Systems, Minneapolis, MN) after a 0.1% trypsin pretreatment; or polyclonal anti-COX-2 goat serum (1:300; Santa Cruz Biotechnology, Santa Cruz, CA). For immunostainings of bFGF, the sections were incubated with anti-bFGF rabbit serum (1:2000; Chemicon International, Temecula, CA) for 12 h at 4°C. The immune complex was visualized using Vectastain Elite kit (Vector Laboratories, Burlingame, CA) according to the manufacturer’s protocol. Sensitivities and specificities of the antibodies had been verified previously (18
, 20, 21, 22)
. Sections incubated with the normal rabbit or goat serum served as negative controls.
Determination of MVD.
MVD was determined as described previously (18)
. Briefly, the microscopic field that contained the highest number of capillaries was chosen for each sample by an initial scan at a low-magnification (x100). Then, the vessels were counted in high-magnification fields (x400).
Statistical Analysis.
Nonrepeated measures ANOVA, Dunnett’s test, unpaired Student’s t tests, and 
2 test were used for comparison of the data sets, and Ps smaller than 0.01 were considered as statistically significant.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. The Apc716 heterozygous mutant is a mouse model for FAP (12)
, whereas the polyps in the cis-compound Apc716 Smad4 heterozygotes progress to adenocarcinomas with marked submucosal invasion and desmoplasia (14)
. On the other hand, introduction of a COX-2 gene (Ptgs2) mutation into the Apc716 mice dramatically attenuates intestinal polyposis (15)
.
In polyps smaller than 1 mm, small numbers of stained vessels were found in mice of all of the genotypes examined (Fig. 2A
, and data not shown). In contrast, in larger polyps of the Apc716 and cis-Apc716 Smad4 mice, abundant vessels were found in the tumor stroma near the luminal surface (Fig. 2B
, and data not shown). These results indicate that angiogenesis is stimulated only after the polyps expand to about 1 mm in diameter (see next paragraph). Furthermore, some vessels with relatively large lumens (often >50 µm) were found at the base of the polyps larger than 1 mm (Fig. 2C)
, although such large vessels were not prominent in smaller polyps nor in the normal mucosa (Fig. 2D)
. To characterize these vessels, we then immunostained the sections with an antibody for 
SMA, a marker for periendothelial cells. It has been reported that newly formed tumor vessels might not have periendothelial cells (8)
. The small vessels near the polyp luminal surface were not stained for SMA (Fig. 2E)
, although they were strongly positive for vWF (Fig. 2B)
. In contrast, most vessels near the polyp base (Fig. 2C)
were strongly stained for SMA (Fig. 2F)
. These data suggest that the small vessels near the luminal surface are newly formed vessels, whereas the vessels near the polyp base are mature arterioles or venules expanded from preexisting vessels. In other words, two vascular changes take place in polyp formation: genuine angiogenesis at the luminal side, and expansion of preexisting vessels at the polyp base (see below). The increase in MVD was contributed essentially by that of the angiogenic vessels on the luminal side of the polyp, and they reached about 65% of the total vessels in large polyps.
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. The mean MVD was approximately 18 in the polyps smaller than 1 mm, without any significant difference from that in the normal intestinal mucosa. In larger polyps of Apc716 and cis-Apc716 Smad4 mice, on the other hand, MVD was significantly higher than in the normal mucosa, correlating with the polyp size. Interestingly, however, there was no significant difference in MVD between the polyps of the Apc716 polyps and the cis-Apc716 Smad4 compound mutant. In polyps larger than 3 mm, MVD was 
29, i.e., 1.6 times higher than that in the nascent polyps (<0.5 mm). It is worth noting that, in the cis-Apc716 Smad4 compound mutant, most polyps larger than 3 mm were invasive adenocarcinomas (14)
. In contrast, MVD in the Apc716 Ptgs2(+/-) mice was not significantly higher even in the small number of polyps larger than 1 mm. In the Apc716 Ptgs2(-/-) mice, polyps larger than 1 mm were scarcely seen, and we could not determine their MVD in a statistically meaningful manner. These results suggest that polyps in the 12-mm size class could not expand further because of the lack of MVD increase and indicate that COX-2 plays a key role in angiogenesis in these mouse intestinal tumors.
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716 Polyps Are Mediated by PGE2 Receptor EP2.716 knockout mice with the respective EP receptor gene knockout mice (19)
, we recently demonstrated that the compound mutation with the EP2 gene homozygosity caused a significant suppression of intestinal polyposis; a phenotype very similar to that of the Apc and Ptgs2 compound mutation (26)
. To determine whether this suppression of intestinal polyposis was caused by angiogenesis attenuation, we scored MVD in the polyps of the compound mutants between the Apc716 and EP receptor gene knockouts for EP1, EP2, and EP3, respectively. Because most EP4 gene homozygotes are neonatally lethal (19)
, its compound mutants with Apc716 could not be investigated.
In the polyps smaller than 1 mm, MVD was essentially the same in all three EP compound mutant strains (Fig. 3B
, and data not shown). As in the compound mutants with Ptgs2(+/-) (Fig. 3A)
, however, the polyps between 1 and 2 mm in the EP2(-/-) compound mutant exhibited a significantly lower MVD than in the simple Apc716 polyps (Fig. 3B)
. This MVD was essentially at the same level as that of the normal mucosa and the polyps smaller than 1 mm. Polyps larger than 2 mm were very rare and could not be evaluated in the EP2 (-/-) compound mutant. On the other hand, the polyp MVD in the compound mutants with the EP1(-/-) or EP3 (-/-) did not show any significant difference from that in the simple Apc716 polyps in any size classes (Fig. 3B
, and data not shown). These results strongly indicate that the suppression of polyp angiogenesis in the COX-2 gene mutant polyps is caused by the lack of the PGE2 signaling through the EP2 receptor. In other words, intestinal polyposis in the simple Apc716 heterozygotes is stimulated by the COX-2-induced PGE2 signal that is transduced through the EP2 receptor to cause angiogenesis. It is worth noting, however, that the extent of angiogenesis suppression in the Apc716 EP2(-/-) polyps was similar to that in the Apc716 Ptgs2 (+/-) polyps, and that the Apc716 Ptgs2 (-/-) mice produced few polyps larger than 1 mm. These results collectively suggest that COX-2 plays some additional roles in polyp formation other than the EP2-mediated angiogenesis (see "Discussion").
Induction of COX-2 in Polyps Larger Than 1 mm in Diameter.
To further investigate the role of COX-2 in angiogenesis, we determined COX-2 expression by immunostaining the intestinal polyps in the Apc716 mice. Polyps smaller than 1 mm showed little COX-2 expression (Fig. 4A)
. In contrast, >75% of the polyps larger than 1 mm expressed COX-2 on the luminal side. As we reported previously (15
, 22
, 27
, 28)
, this expression was found exclusively in the polyp stromal cells but not in the adenoma epithelium (Fig. 4, B and C)
. These results are summarized as a histogram in Fig. 4J
. Like the higher MVD, COX-2 expression at significant levels was found only in the polyps larger than 1 mm in diameter (compare Fig. 4J
with Fig. 3A
), and the proportion of COX-2-stained polyps was significantly higher in the polyps that were larger than 1 mm in diameter (P < 0.01).
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716 and Apc716 Ptgs2(+/-) mouse polyps. In the Apc716 mouse, polyps <1 mm in diameter showed little VEGF staining (Fig. 4D)
. However, like COX-2, VEGF was expressed strongly in the stromal cells on the luminal side of the polyps larger than 1 mm (Fig. 4, E and F)
. Although some immunostaining of bFGF was detected in polyps larger than 1 mm, it was found essentially in the stroma at the polyp base (Fig. 4, H and I)
where mature vessels were found (Fig. 2, E and F)
. Weak staining of bFGF was detected also in the stroma of the normal portions of the intestinal mucosa (Fig. 4G
, arrowheads), as reported previously (21)
. These results are consistent with the interpretation that VEGF is responsible for polyp angiogenesis, whereas bFGF plays a role in the expansion and maintenance of the preexisting vessels. As summarized in Fig. 4K
, the proportions of the VEGF- and bFGF-expressing polyps, respectively, increased in a size-dependent manner. To investigate the effects of COX-2 on the expression of VEGF and bFGF, we then analyzed these factors in the Apc716 Ptgs2(+/-) mouse intestinal polyps. Although the polyp number and size decreased in the compound mutant, we chose the size class between 1 and 2 mm, because no difference in MVD was detected in the polyps smaller than 1 mm as described above (Fig. 3)
. As shown in Fig. 4L
, the proportions of stained polyps decreased from 90% to 36% for VEGF, and from 80% to 37% for bFGF, respectively, when the COX-2 heterozygous mutation was introduced. |
DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. As in the earlier transgenic mouse models, the angiogenic switch is turned on at an early stage in our intestinal tumorigenesis models also. Our immunohistochemical analysis showed that VEGF was expressed in the same polyp stromal subregion in which MVD was increased and COX-2 and cytosolic phospholipase A2 were also expressed (26)
. Several reports suggest that COX-2 regulates angiogenesis, in part through the induction of VEGF and bFGF (29
, 30)
. In our mouse models, the proportion of VEGF-positive polyps was much smaller in the Apc716 Ptgs2(+/-) mice than in the simple Apc716 heterozygotes. Thus, COX-2 appears to regulate angiogenesis through the VEGF induction in the Apc716 polyps, and this induction is dependent on the PGE2 signal that is transduced through the EP2 receptor. It is established that EP2 receptor is coupled with G protein Gs and elevates the cytoplasmic cAMP level (24
, 25)
. Because no cAMP responsive elements (CRE) have been found in the 1.2-kb region of the mouse VEGF promoter sequence (32)
, it is likely that VEGF expression is induced indirectly by increased cAMP level through protein kinase A (33)
. This is consistent with a report that Ptgs2(-/-) mouse fibroblasts produce decreased levels of VEGF (34)
. In contrast to VEGF, bFGF was expressed in a different stromal subregion from that of the COX-2 expression, namely, at the polyp base where vessels with relatively large lumens express periendothelial marker SMA (Fig. 2, E and F
, and Fig. 4, H and I
). Accordingly, it is conceivable that paracrine factors other than COX-2-induced PGE2 regulate bFGF expression, and that bFGF plays a role in the expansion of preexisting arterioles and venules. This interpretation is consistent with a recent report that VEGF affects the initiation of tumor angiogenesis, whereas bFGF plays a role in both the onset and the maintenance of angiogenesis (35)
. It is worth noting that, in endothelial cells, hypoxia induces VEGF expression through hypoxia-inducible factor-1 (36)
, and COX-2 appears to be involved in the process as well (37)
.
One of the major arachidonic acid metabolites by COX-2 that is elevated in FAP patients is PGE2, implicating its role in polyposis (23)
. We recently demonstrated that the cell surface PGE2 receptor EP2 is strongly induced in the Apc716 polyps. Disruption of the EP2 gene in the Apc716 mice reduces the polyp number and size significantly, indicating that the COX-2 signal for polyposis is transduced through EP2 (26)
. Because signaling through EP2 increases intracellular cAMP level, and because the COX-2 gene is under the control of cAMP (38)
, EP2 is responsible for up-regulation of the COX-2 gene through a positive feedback mechanism by PGE2 (26)
. At the same time, we also demonstrated that a basement membrane protein laminin 2, which is secreted from the stromal cells, is strongly up-regulated in the Apc716 polyps through EP2. These results collectively indicate that COX-2 induction plays a dual role in intestinal polyp development: angiogenesis and basement membrane protein biosynthesis.
The results of our MVD analysis suggest that tumor angiogenesis is stimulated not necessarily by malignant transformation but rather by other factors, such as tissue remodeling or hypoxia during tumor enlargement. Recently, it was reported that reexpression of SMAD4 in a SMAD4-negative pancreatic cancer cell line restores slower tumor transplant growth, and that such a change is caused by suppression of angiogenesis rather than the recovery of transforming growth factor ß-mediated growth inhibition (39)
. Interestingly, this SMAD4-dependent angiogenic change is seen in larger vessels rather than in capillaries, which is inconsistent with our cis-Apc716 Smad4 compound mutant data. It is possible that the pancreatic cancer cell line in the other report contains additional mutations.
In conclusion, MVD increased in a tumor size-dependent manner in both benign and malignant intestinal tumorigenesis models. Tumor angiogenesis is regulated by COX-2 and PGE2 receptor EP2 expressed in the tumor stromal cells rather than by malignant transformation of the adenoma epithelium.
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FOOTNOTES |
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1 Supported by grants from the Ministry of Education, Culture, Sports, Science and Technology and the Organization of Pharmaceutical Safety and Research, Japan. 
2 To whom requests for reprints should be addressed, at Department of Pharmacology, Kyoto University Graduate School of Medicine, Yoshida-Konoé-cho, Sakyo-ku, Kyoto 606-8501, Japan. Phone: 81-75-753-4391; Fax: 81-75-753-4402; E-mail: taketo{at}mfour.med.kyoto-u.ac.jp
3 The abbreviations used are: Apc, adenomatous polyposis coli (gene); SMA, -smooth muscle actin; bFGF, basic fibroblast growth factor; cAMP, cyclic AMP; COX-2, cyclooxygenase 2; FAP, familial adenomatous polyposis; LOH, loss of heterozygosity; PGE2, prostaglandin E2; VEGF, vascular endothelial growth factor; vWF, von Willebrand factor; MVD, microvessel density.
Received 7/16/01. Accepted 11/12/01.
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 T. Okazaki, S. Ebihara, H. Takahashi, M. Asada, A. Kanda, and H. Sasaki Macrophage Colony-Stimulating Factor Induces Vascular Endothelial Growth Factor Production in Skeletal Muscle and Promotes Tumor Angiogenesis J. Immunol., June 15, 2005; 174(12): 7531 - 7538. [Abstract] [Full Text] [PDF]
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S.-H. Chang, Y. Ai, R. M. Breyer, T. F. Lane, and T. Hla The Prostaglandin E2 Receptor EP2 Is Required for Cyclooxygenase 2-Mediated Mammary Hyperplasia Cancer Res., June 1, 2005; 65(11): 4496 - 4499. [Abstract] [Full Text] [PDF]
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 J. R. Brown and R. N. DuBois COX-2: A Molecular Target for Colorectal Cancer Prevention J. Clin. Oncol., April 20, 2005; 23(12): 2840 - 2855. [Abstract] [Full Text] [PDF]
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 N. Smakman, O. Kranenburg, J. M. Vogten, A. L.A. Bloemendaal, P. van Diest, and I. H.M. Borel Rinkes Cyclooxygenase-2 Is a Target of KRASD12, Which Facilitates the Outgrowth of Murine C26 Colorectal Liver Metastases Clin. Cancer Res., January 1, 2005; 11(1): 41 - 48. [Abstract] [Full Text] [PDF]
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L. T. Soumaoro, H. Uetake, T. Higuchi, Y. Takagi, M. Enomoto, and K. Sugihara Cyclooxygenase-2 Expression: A Significant Prognostic Indicator for Patients With Colorectal Cancer Clin. Cancer Res., December 15, 2004; 10(24): 8465 - 8471. [Abstract] [Full Text] [PDF]
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 K. J. Sales, S. Battersby, A. R. W. Williams, R. A. Anderson, and H. N. Jabbour Prostaglandin E2 Mediates Phosphorylation and Down-Regulation of the Tuberous Sclerosis-2 Tumor Suppressor (Tuberin) in Human Endometrial Adenocarcinoma Cells via the Akt Signaling Pathway J. Clin. Endocrinol. Metab., December 1, 2004; 89(12): 6112 - 6118. [Abstract] [Full Text] [PDF]
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F. Spinella, L. Rosano, V. Di Castro, P. G. Natali, and A. Bagnato Endothelin-1-induced Prostaglandin E2-EP2, EP4 Signaling Regulates Vascular Endothelial Growth Factor Production and Ovarian Carcinoma Cell Invasion J. Biol. Chem., November 5, 2004; 279(45): 46700 - 46705. [Abstract] [Full Text] [PDF]
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 G. D. Basu, L. B. Pathangey, T. L. Tinder, M. LaGioia, S. J. Gendler, and P. Mukherjee Cyclooxygenase-2 Inhibitor Induces Apoptosis in Breast Cancer Cells in an In vivo Model of Spontaneous Metastatic Breast Cancer Mol. Cancer Res., November 1, 2004; 2(11): 632 - 642. [Abstract] [Full Text] [PDF]
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P. A. Adegboyega, O. Ololade, J. Saada, R. Mifflin, J. F. Di Mari, and D. W. Powell Subepithelial Myofibroblasts Express Cyclooxygenase-2 in Colorectal Tubular Adenomas Clin. Cancer Res., September 1, 2004; 10(17): 5870 - 5879. [Abstract] [Full Text] [PDF]
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 N. Ferrara Vascular Endothelial Growth Factor: Basic Science and Clinical Progress Endocr. Rev., August 1, 2004; 25(4): 581 - 611. [Abstract] [Full Text] [PDF]
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M. A. Hull, S. C.W. Ko, and G. Hawcroft Prostaglandin EP receptors: Targets for treatment and prevention of colorectal cancer? Mol. Cancer Ther., August 1, 2004; 3(8): 1031 - 1039. [Abstract] [Full Text] [PDF]
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J. C. H. Hardwick, M. van Santen, G. R. van den Brink, S. J. H. van Deventer, and M. P. Peppelenbosch DNA array analysis of the effects of aspirin on colon cancer cells: involvement of Rac1 Carcinogenesis, July 1, 2004; 25(7): 1293 - 1298. [Abstract] [Full Text] [PDF]
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 K. J. Sales, S. Maudsley, and H. N. Jabbour Elevated Prostaglandin EP2 Receptor in Endometrial Adenocarcinoma Cells Promotes Vascular Endothelial Growth Factor Expression via Cyclic 3',5'-Adenosine Monophosphate-Mediated Transactivation of the Epidermal Growth Factor Receptor and Extracellular Signal-Regulated Kinase 1/2 Signaling Pathways Mol. Endocrinol., June 1, 2004; 18(6): 1533 - 1545. [Abstract] [Full Text] [PDF]
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D. Golijanin, J.-Y. Tan, A. Kazior, E. G. Cohen, P. Russo, G. Dalbagni, K. J. Auborn, K. Subbaramaiah, and A. J. Dannenberg Cyclooxygenase-2 and Microsomal Prostaglandin E Synthase-1 Are Overexpressed in Squamous Cell Carcinoma of the Penis Clin. Cancer Res., February 1, 2004; 10(3): 1024 - 1031. [Abstract] [Full Text] [PDF]
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J.-L. Su, J.-Y. Shih, M.-L. Yen, Y.-M. Jeng, C.-C. Chang, C.-Y. Hsieh, L.-H. Wei, P.-C. Yang, and M.-L. Kuo Cyclooxygenase-2 Induces EP1- and HER-2/Neu-Dependent Vascular Endothelial Growth Factor-C Up-Regulation: A Novel Mechanism of Lymphangiogenesis in Lung Adenocarcinoma Cancer Res., January 15, 2004; 64(2): 554 - 564. [Abstract] [Full Text] [PDF]
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S.-H. Chang, C. H. Liu, R. Conway, D. K. Han, K. Nithipatikom, O. C. Trifan, T. F. Lane, and T. Hla From the Cover: Role of prostaglandin E2-dependent angiogenic switch in cyclooxygenase 2-induced breast cancer progression PNAS, January 13, 2004; 101(2): 591 - 596. [Abstract] [Full Text] [PDF]
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 J. M. Ward and D. E. Devor-Henneman Mouse Models of Human Familial Cancer Syndromes Toxicol Pathol, January 1, 2004; 32(1_suppl): 90 - 98. [Abstract] [PDF]
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G. B. Perchick and H. N. Jabbour Cyclooxygenase-2 Overexpression Inhibits Cathepsin D-Mediated Cleavage of Plasminogen to the Potent Antiangiogenic Factor Angiostatin Endocrinology, December 1, 2003; 144(12): 5322 - 5328. [Abstract] [Full Text] [PDF]
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H. N. Jabbour and S. C. Boddy Prostaglandin E2 Induces Proliferation of Glandular Epithelial Cells of the Human Endometrium via Extracellular Regulated Kinase 1/2-Mediated Pathway J. Clin. Endocrinol. Metab., September 1, 2003; 88(9): 4481 - 4487. [Abstract] [Full Text] [PDF]
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H. Takeda, M. Sonoshita, H. Oshima, K.-i. Sugihara, P. C. Chulada, R. Langenbach, M. Oshima, and M. M. Taketo Cooperation of Cyclooxygenase 1 and Cyclooxygenase 2 in Intestinal Polyposis Cancer Res., August 15, 2003; 63(16): 4872 - 4877. [Abstract] [Full Text] [PDF]
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W. W. J. de Leng, A. M. Westerman, M. A. J. Weterman, F. W. M. de Rooij, H. v. Dekken, A. F. P. M. de Goeij, S. B. Gruber, J. H. P. Wilson, G. J. A. Offerhaus, F. M. Giardiello, et al. Cyclooxygenase 2 Expression and Molecular Alterations in Peutz-Jeghers Hamartomas and Carcinomas Clin. Cancer Res., August 1, 2003; 9(8): 3065 - 3072. [Abstract] [Full Text] [PDF]
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E. G. Cohen, T. Almahmeed, B. Du, D. Golijanin, J. O. Boyle, R. A. Soslow, K. Subbaramaiah, and A. J. Dannenberg Microsomal Prostaglandin E Synthase-1 Is Overexpressed in Head and Neck Squamous Cell Carcinoma Clin. Cancer Res., August 1, 2003; 9(9): 3425 - 3430. [Abstract] [Full Text] [PDF]
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 F. Sennlaub, F. Valamanesh, A. Vazquez-Tello, A.M. El-Asrar, D. Checchin, S. Brault, F. Gobeil, M.H. Beauchamp, B. Mwaikambo, Y. Courtois, et al. Cyclooxygenase-2 in Human and Experimental Ischemic Proliferative Retinopathy Circulation, July 15, 2003; 108(2): 198 - 204. [Abstract] [Full Text] [PDF]
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 H. Chung, D. Wu, S. N. Han, R. Gay, B. Goldin, R. E. Bronson, J. B. Mason, D. E. Smith, and S. N. Meydani Vitamin E Supplementation Does Not Alter Azoxymethane-Induced Colonic Aberrant Crypt Foci Formation in Young or Old Mice J. Nutr., February 1, 2003; 133(2): 528 - 532. [Abstract] [Full Text] [PDF]
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 H. Amano, I. Hayashi, H. Endo, H. Kitasato, S. Yamashina, T. Maruyama, M. Kobayashi, K. Satoh, M. Narita, Y. Sugimoto, et al. Host Prostaglandin E2-EP3 Signaling Regulates Tumor-Associated Angiogenesis and Tumor Growth J. Exp. Med., January 20, 2003; 197(2): 221 - 232. [Abstract] [Full Text] [PDF]
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M. Sonoshita, K. Takaku, M. Oshima, K.-i. Sugihara, and M. M. Taketo Cyclooxygenase-2 Expression in Fibroblasts and Endothelial Cells of Intestinal Polyps Cancer Res., December 1, 2002; 62(23): 6846 - 6849. [Abstract] [Full Text] [PDF]
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R. L. Konger, G. A. Scott, Y. Landt, J. H. Ladenson, and A. P. Pentland Loss of the EP2 Prostaglandin E2 Receptor in Immortalized Human Keratinocytes Results in Increased Invasiveness and Decreased Paxillin Expression Am. J. Pathol., December 1, 2002; 161(6): 2065 - 2078. [Abstract] [Full Text] [PDF]
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C. N. Johnstone, L. M. Chang, and M. Ernst AACR Special Meeting in Cancer Research: Colon Cancer--Genetics to Prevention Cancer Res., November 15, 2002; 62(22): 6779 - 6783. [Full Text] [PDF]
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H. Matsumoto, W.-g. Ma, T. Daikoku, X. Zhao, B. C. Paria, S. K. Das, J. M. Trzaskos, and S. K. Dey Cyclooxygenase-2 Differentially Directs Uterine Angiogenesis during Implantation in Mice J. Biol. Chem., August 2, 2002; 277(32): 29260 - 29267. [Abstract] [Full Text] [PDF]
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K.-i. Sunayama, H. Konno, T. Nakamura, H. Kashiwabara, T. Shoji, T. Tsuneyoshi, and S. Nakamura The role of cyclooxygenase-2 (COX-2) in two different morphological stages of intestinal polyps in APC{Delta}474 knockout mice Carcinogenesis, August 1, 2002; 23(8): 1351 - 1359. [Abstract] [Full Text] [PDF]
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) were scarce, whereas in the Apc
) were rare, and MVD could not be evaluated, accordingly.