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[Cancer Research 62, 6846-6849, December 1, 2002]
© 2002 American Association for Cancer Research

Carcinogenesis

Cyclooxygenase-2 Expression in Fibroblasts and Endothelial Cells of Intestinal Polyps1

Masahiro Sonoshita, Kazuaki Takaku, Masanobu Oshima, Ken-ichi Sugihara and Makoto M. Taketo2

Department of Pharmacology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501 [M. S., K. T., M. O., M. M. T.], and Department of Digestive Surgery, Tokyo Medical and Dental University, Tokyo 113-8519 [K-i. S.], Japan


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Cyclooxygenase-2 (COX-2), the inducible COX isozyme, plays a key role in intestinal tumorigenesis. We have demonstrated recently that COX-2 protein is induced in the polyp stroma near the intestinal luminal surface in the Apc{Delta}716 mouse, a model for human familial adenomatous polyposis, and stimulate tumor angiogenesis. However, the precise cell types that express COX-2 are still to be determined. By immunohistochemical analysis, here we show that the majority of COX-2-expressing cells in the intestinal polyps of Apc{Delta}716 mice are fibroblasts and endothelial cells. Furthermore, the COX-2-expressing cells in human familial adenomatous polyposis polyps are also fibroblasts and endothelial cells. In contrast, bone marrow-derived cells such as macrophages and leukocytes express little COX-2 protein in the intestinal polyps. These results clearly indicate that fibroblasts and endothelial cells play important roles in polyp expansion by expressing COX-2, resulting in tumor angiogenesis.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Two isozymes of COX3 have been identified, COX-1 and COX-2 (1) . They metabolize arachidonic acid to PGH2 that is converted further to various prostanoids; PGs, prostacyclin and thromboxane A2. Whereas COX-1 is expressed constitutively and involved in homeostatic functions, COX-2 is induced by various stimuli such as growth factors and cytokines. In human colon cancer, as well as polyps of FAP, COX-2 is significantly induced (2) , and levels of PGE2 are increased (3) . Using Apc{Delta}716 gene-knockout mice as a model for FAP (4) , we have demonstrated recently that COX-2 plays a pivotal role in intestinal tumorigenesis (5 , 6) . Furthermore, we have shown that PGE2 receptor EP2 plays a crucial role for both COX-2 induction by a positive feedback mechanism and polyp formation through angiogenesis (6 , 7) .

Whereas COX-2 is expressed in cancer epithelial cells in human colon and other organs, its expression in benign polyps is found in the stromal cells, in both human FAP and its mouse model Apc mutants (5, 6, 7, 8, 9, 10, 11) . Although myofibroblasts (11) and macrophages (12) have been suggested to express COX-2 in the polyps, quantitative data have been lacking. To determine the cell types that express COX-2 in the polyps, we have quantified immunostained cells with various markers.


   MATERIALS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Apc{Delta}716 Knockout Mouse Construction.
Details of Apc{Delta}716 knockout mouse construction were described previously (4) .

Histological Analysis, Immunohistochemistry, and Immunofluorescence.
To prepare paraffin sections, Apc{Delta}716 intestines were fixed in 4% paraformaldehyde, embedded in paraffin wax, and sectioned at 4-µm thickness. Sections were stained with H&E or incubated with a primary antibody specific for COX-2 (Cayman Chemical Co.) and then with a biotinylated secondary antibody followed by treatment with an avidin-biotin-peroxidase complex (Vector Laboratories). For immunofluorescence staining, Apc{Delta}716 intestines fixed in 4% paraformaldehyde were embedded in OCT compound, frozen, and sectioned at 7-µm thickness. Sections were incubated with the anti-COX-2 antibody simultaneously with a specific antibody for vimentin, {alpha}-SMA (Sigma Chemical Co.) biotinylated with NHS-LC-Biotin (Pierce), CD34 (Santa Cruz Biotechnology), CD31, CD11b (BD PharMingen), or F4/80 (Serotec Ltd.), followed by Alexa Fluor antibodies (Molecular Probes Inc.) or Fluorescein Avidin DCS (Vector Laboratories).

FAP Polyp Samples.
Polyp histological specimens were sectioned from colon paraffin blocks of four FAP patients who underwent operation in 1999 at Department of Digestive Surgery, Tokyo Medical and Dental University.


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Fibroblast Appearance of COX-2-expressing Cells in Mouse Intestinal Polyps.
We have demonstrated recently that induction of COX-2 plays a critical role in the expansion of Apc{Delta}716 intestinal and colonic polyps (5, 6, 7) . To determine the cell types that express COX-2 in the polyp stroma, we first analyzed small intestinal samples from Apc{Delta}716 mice by immunohistochemistry (Fig. 1)Citation . Although little COX-2 protein was found in the normal mucosa, abundant COX-2 was expressed in the polyp stroma near the luminal surface (Fig. 1, A and BCitation , arrowheads), consistent with our earlier results (5, 6, 7) . Histological examinations of these COX-2-expressing cells in more detail revealed that the majority of such cells contained relatively large and ovoid nuclei, prominent nucleoli, and extensive cytoplasm (Fig. 1CCitation , arrowheads). These morphological features for the major COX-2-expressing cell population matched those of active fibroblasts (13) .



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  		Fig. 1. COX-2 expression in the Apc{Delta}716 small intestinal polyp stroma. A, COX-2 immunostaining in a section containing a polyp and the normal mucosa (hematoxylin counterstaining). B, higher magnification of the boxed area in (A), showing COX-2-expressing stromal cells with relatively large and ovoid nuclei (arrowheads). C, a serial section of B, showing polyp stromal cells with prominent nucleoli and extensive cytoplasm (arrowheads; H&E). D–F, a cryosection stained for COX-2 (D), vimentin (E), and the merged image (F) showing fibroblasts as the major population of the COX-2-expressing cells. G–I, a cryosection stained for COX-2 (G), {alpha}-SMA (H), and the merged image (I), showing little COX-2 expression in myofibroblasts. Bars, 100 µm in (A) and 10 µm in (B) to (I).

 
Coexpression of COX-2 and Vimentin in Polyp Stromal Cells.
To investigate whether most COX-2-expressing cells were fibroblasts, we next investigated the expression of intermediate filament protein vimentin, a fibroblast marker (14) . As expected, vimentin was also expressed in the polyp stroma near the luminal surface (Fig. 1E)Citation where COX-2 was expressed (Fig. 1D)Citation . In fact, 85% of COX-2-expressing cells were also expressing vimentin as shown in the merged photograph (Fig. 1FCitation ; Table 1Citation ). It should be noted that the fluorescence signals for COX-2 and vimentin were not precisely superimposed inside a single expressing cell, because subcellular localizations of these two markers were different. Whereas COX-2 was expressed in the endoplasmic reticulum and nuclear membrane, intermediate filament vimentin was in the cytoplasm.


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  		Table 1 Colocalization of COX-2 and cell-type markers in the stroma of Apc{Delta}716 polypsa

 
Little Coexpression of COX-2 and {alpha}-Smooth Muscle Actin.
It has been reported that submucosal myofibroblasts, another fibroblast subclass, also express vimentin (14, 15, 16) , and that myofibroblasts express COX-2 in the polyp stroma of ApcMin mice (11) . Accordingly, we double stained the polyp sections for COX-2 and {alpha}-SMA, a marker for myofibroblasts (14, 15, 16) . As we reported previously (6) , {alpha}-SMA immunostaining was rarely found in the polyp stroma near the intestinal lumen where COX-2-expressing cells were found (Fig. 1, G–I)Citation . In fact, only 0.6% of the COX-2-expressing cells were concomitantly stained for {alpha}-SMA (Table 1)Citation .

Coexpression of COX-2 and CD34 in Some Polyp Endothelial Cells.
Because endothelial cells can also express COX-2 (17) , we then investigated the spatial relationship between the COX-2-expressing cells and vascular endothelial cells by a double staining for COX-2 and CD34, a marker for endothelial cells (Fig. 2, A and B)Citation . As shown in the merged photograph (Fig. 2C)Citation , endothelial cells accounted for 4.7% of all of the COX-2-positive cells (Table 1)Citation . However, it is worth noting that the COX-2 staining in the endothelial cells showed a punctate pattern (Fig. 2C)Citation different from that in the fibroblasts where endoplasmic reticulum and nuclear membranes were stained (Fig. 1F)Citation . Essentially the same results were obtained using antibody for CD31, another representative endothelial cell marker (data not shown).



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  		Fig. 2. COX-2 expression also in some endothelial cells, but not in any bone marrow-derived cells in the Apc{Delta}716 polyps. A–C, a cryosection stained for COX-2 (A), CD34 (B), and the merged image (C), showing expression of COX-2 in a punctate pattern in a small population of the endothelial cells. D–F, a cryosection stained for COX-2 (D), F4/80 (E), and the merged image (F), showing little COX-2 staining in macrophages. Bars, 10 µm.

 
Little Coexpression of COX-2 and F4/80 in Polyp Macrophages.
Because macrophages have been reported to express COX-2 protein in the polyp stroma of the ApcMin mouse intestines (12) , we next stained the Apc{Delta}716 polyp sections for F4/80, one of the representative macrophage markers (18) . As reported (12) , F4/80 immunostainings were found in the stroma near the polyp base (data not shown). Although some macrophages were found also in the polyp stroma where COX-2-positive cells were found (Fig. 2, D and E)Citation , they expressed little COX-2 (Fig. 2F)Citation . In fact, they constituted only 1% of the total COX-2-expressing cells (Table 1)Citation . Likewise, immunostaining for bone marrow-derived cell marker CD11b was also found in the polyp stromal cells different from those expressing COX-2 (data not shown). These results clearly demonstrate that few COX-2-expressing cells in the Apc{Delta}716 polyp stroma are bone marrow-derived cells as macrophages. Essentially the same results were obtained with the Apc{Delta}716 colonic polyps (data not shown).

Analysis of COX-2-expressing Cells in Human FAP Polyps.
To determine whether fibroblasts and endothelial cells express COX-2 in human FAP polyps as in the mouse model, we additionally performed immunostainings on FAP polyp sections. Like in the Apc{Delta}716 polyps, COX-2 immunostaining was found in the stromal cells near the luminal surface (Fig. 3A)Citation . Interestingly, the majority of these cells again showed morphological characteristics of active fibroblasts. Consistent with the mouse polyp results, the human COX-2-expressing cells were also stained for vimentin (Fig. 3B)Citation but not for {alpha}-SMA (Fig. 3C)Citation , indicating that the majority of these cells were fibroblasts. Furthermore, immunostaining of vWF, another representative endothelial cell marker, was also found in some of the COX-2-expressing cells (Fig. 3D)Citation . These results indicate that fibroblasts and endothelial cells express COX-2 in FAP polyps as in the mouse model.



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  		Fig. 3. COX-2 expression in fibroblasts and endothelial cells, but not in myofibroblasts in human FAP polyps. A–D, serial sections immunostained for COX-2 (A), vimentin (B), {alpha}-SMA (C), and vWF (D), respectively, in a polyp of an FAP patient (hematoxylin counterstaining). Bars, 50 µm.

 

   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Accumulating evidence indicates that COX-2 and one of its downstream products, PGE2, play key roles in intestinal tumorigenesis. When the COX-2 gene (Ptgs2) is knocked out in Apc{Delta}716 mice, formation of the intestinal polyp is markedly suppressed (5) . Furthermore, disruption of the gene for EP2, one of four PGE2 receptors, in Apc{Delta}716 mice causes similar suppression to the COX-2 gene disruption, whereas mutation in either EP1 or EP3 gene shows little effect (7) . This effect is largely because of the blockade of the positive feedback mechanism for COX-2 expression by PGE2 in the polyp stromal cells.

To determine what type of cells express COX-2, we performed histological and marker-immunostaining studies. In a histological analysis, the COX-2-expressing cells had a characteristic morphology of active fibroblasts; i.e., relatively large and ovoid nuclei, prominent nucleoli, and extensive cytoplasm (13) . Confirmed by their vimentin expression, these cells have been identified as fibroblasts. This is consistent with our earlier results of immuno-electron-microscopic study showing the COX-2 gene promoter activity in fibroblasts of the Apc{Delta}716 polyp stroma (19) . Interestingly, vimentin-positive stromal cells were found recently to express COX-2 also in human gastric cancer (20) , suggesting that fibroblasts play a key role in not only intestinal but also gastric tumorigenesis by expressing COX-2.

As a subclass of fibroblasts in the intestines, submucosal myofibroblasts should be discriminated from the active or mature fibroblasts for their distinct features; namely, expression of {alpha}-SMA simultaneously with vimentin and the contractile characteristic (15 , 16) . It has been reported that myofibroblasts express COX-2 in the ApcMin polyps, or interleukin 10 knockout mice, a model for inflammatory bowel disease and colitis-associated carcinoma (11) . However, in the present study, we detected little simultaneous immunostainings of COX-2 and {alpha}-SMA in the polyp stroma of Apc{Delta}716 mice or human FAP. Because the anti-{alpha}-SMA antibody 1A4 that we and Shattuck-Brandt et al. (11) used was generated by a mouse hybridoma, endogenous mouse immunoglobulin may be stained as background signals by the secondary antimouse antibody. To avoid this problem, we first biotinylated the 1A4 antibody and detected it with fluorochrome-conjugated avidin. With this improved sensitivity for {alpha}-SMA, myofibroblasts were unambiguously identified for their elongated morphology (Fig. 1H)Citation and epithelium-associated location (data not shown). Although myofibroblasts expressed little COX-2 in this study, they might contribute to tumorigenesis in other ways, such as cytokine production and immune system modulation (15 , 16) . In addition to myofibroblasts, macrophages are suggested to express COX-2 in ApcMin mice (12) . Although we found some macrophages in the stroma near the polyp base, we detected little COX-2 expression in this subregion of the polyp stroma. The results are consistent with our earlier immunostaining study of LacZ reporter protein of which expression is driven by endogenous COX-2 promoter (5) . Although we found little COX-2 expression in polyp macrophages, some of them may play tumorigenic roles by receiving paracrine PGs, because they are found in the vicinity to the COX-2-expressing fibroblasts (Fig. 2F)Citation .

In conclusion, these results clearly show significant roles of fibroblasts and endothelial cells in the intestinal polyp development through COX-2 expression.


   ACKNOWLEDGMENTS
 
We thank Hiroshi Seno for FAP polyp sample preparation.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 Supported in part by grants from the Ministry of Education, Culture, Sports, Science and Technology, Japan, and the Organization for Pharmaceutical Safety and Research, Japan. Back

2 To whom requests for reprints should be addressed, at Department of Pharmacology, Graduate School of Medicine, Kyoto University, Yoshida-Konoé-cho, Sakyo-ku, Kyoto 606-8501, Japan. E-mail: taketo{at}mfour.med.kyoto-u.ac.jp Back

3 The abbreviations used are: COX, cyclooxygenase; Apc, adenomatous polyposis coli; {alpha}-SMA, {alpha}-smooth muscle actin; FAP, familial adenomatous polyposis; PG, prostaglandin; vWF, von Willebrand factor; PGE2, prostaglandin E2. Back

Received 7/11/02. Accepted 10/10/02.


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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