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Japanese Journal of Clinical Oncology Pages 615-620

The Role of Myofibroblasts at the Tumor Border of Invasive Colorectal Adenocarcinomas
Introduction
Materials And Methods
Results
Discussion
Acknowledgments
References
The Role of Myofibroblasts at the Tumor Border of Invasive Colorectal Adenocarcinomas

The Role of Myofibroblasts at the Tumor Border of Invasive Colorectal Adenocarcinomas

Hirofumi Nakayama, Hideaki Enzan, Eriko Miyazaki, Keishi Naruse, Hiroshi Kiyoku and Makoto Hiroi

First Department of Pathology, Kochi Medical School, Kochi, Japan

Background: In order to elucidate the significance of myofibroblasts in invasive growth of colorectal adenocarcinomas, we examined the number of myofibroblasts at the tumor border of colorectal adenocarcinomas.
Method: A total of 91 invasive colorectal adenocarcinomas were examined immunohistochemically using anti-alpha-smooth muscle actin (ASMA) and high-molecular-weight caldesmon (h-CD) antibodies; 25 carcinomas confined to the submucosa (sm carcinomas), 40 carcinomas confined to the muscularis propria (mp carcinomas) and 26 carcinomas invading the subserosa or adventitia (ss carcinomas). We considered ASMA-positive and h-CD-negative stromal cells as myofibroblasts.
Results: Twenty-seven (67%) of the 40 mp carcinomas and 25 (96%) of the 26 ss carcinomas had a small number of myofibroblasts at the tumor border facing the muscularis propria.
Conclusions: Although direct evidence is lacking, there is a possibility that the further immediately vertical and radial invasion of carcinoma cells into the subserosa or adventitia is associated with a smaller number of myofibroblasts at the tumor border facing the muscularis propria in mp carcinomas, resulting in a low incidence of mp and a high incidence of ss carcinomas in the colorectum.

Key words: myofibroblasts - tumor border - colorectal carcinomas

INTRODUCTION

Many invasive and metastatic carcinomas are characterized by hard consistency and retraction and are often fixed to adjacent tissues (1). This hard consistency and the retraction phenomenon are due to the desmoplastic stromal reaction (1). Myofibroblasts are particularly numerous within the stroma of primary invasive and metastatic carcinomas (1). In colorectal carcinomas, it is said that alpha-smooth muscle actin (ASMA)-positive stromal cells between tumor nests are transformed myofibroblasts originating from colonic pericryptal fibroblasts (PCFs) belonging to specialized subsets of mesenchymal cells, displaying morphological smooth muscle differentiation features associated with migrating and proliferative properties (2). However, in the tumor border of the advanced colorectal carcinomas, stromal reactions apart from a lymphocytic infiltrate have not been analyzed intensively (3,4).

According to Report Nos 1-6 of the Japanese Research Society for Cancer of the Colon and Rectum, about 80% of the colorectal carcinomas registered had invaded the subserosa or adventitia at the time of surgery; only 13.5% of the registered tumors were confined to the muscularis propria (5). The prognosis of colorectal tumors confined to the muscularis propria is much better than those invading the subserosa or adventitia (5). Therefore, the mechanism of tumor invasion from the muscularis propria to the subserosa or adventitia must be examined intensively.

In the present study, we examined myofibroblasts at the tumor border of invasive colorectal adenocarcinomas and tried to elucidate the significance of myofibroblasts, especially in invasive growth from the muscularis propria to the subserosa. It has already been elucidated that PCFs gradually decrease in the sequence of adenoma, intramucosal carcinoma and submucosal invasive carcinoma (6); however, the role of myofibroblasts at the tumor border in invasion from the submucosa to further deep layers has not been studied intensively in the colorectum.

MATERIALS AND METHODS

We used 91 human surgically resected primary colorectal adenocarcinomas (well and moderately differentiated types) from the surgical pathology files of the First Department of Pathology, Kochi Medical School, and its affiliated hospitals, from 1993 to 1997; 25 tumors confined to the submucosa and 40 tumors to the propria muscle were obtained from the surgical pathology files of the First Department of Pathology, Kochi Medical School, and its affiliated hospitals, from 1993 to 1997; the remaining 26 tumors invading the subserosa were from the First Department of Pathology, Kochi Medical School, from 1995 to 1996. The definitions used for histological classification and depth of tumor invasion were based on the criteria of the Japanese Research Society for Cancer of the Colon and Rectum (7). Depth of tumor invasion was classified as follows: sm, submucosa; mp, muscularis propria; and ss, subserosa or adventitia (7).

We divided the tumor border into two areas, deep border (DB) and lateral border (LB), as shown in Fig. 1. Regarding DB, the DB of sm tumors (smDB) was the area facing the surrounding submucosa (Fig. 1A). The DB of mp tumors and that of ss tumors, i.e. mpDB and ssDB, were the areas in which they faced the muscularis propria and subserosa, respectively (Fig. 1B and C). Concerning LB, the LB of mp tumors was the area which they faced the surrounding submucosa (mpLBsm) (Fig. 1B). In ss cases, the LB consisted of the areas in which they faced the surrounding submucosa (ssLBsm) and muscularis propria (ssLBmp) (Fig. 1C).


Figure 1. Definition of tumor border: deep border (DB) and lateral border (LB). At the left side, we describe the layers of the colorectal wall; m, mucosa propria; mm, muscularis mucosa; sm, submucosa; mp, muscularis propria; ss or a, subserosa or adventitia. (A, left) smDB, the growing edge of the sm carcinoma. (B, center) mpDB, the growing edge of the mp carcinoma facing the surrounding muscularis propria; mpLBsm, the growing edge of the mp carcinoma facing the surrounding submucosa. (C, right) ssDB, the growing edge of the ss carcinoma facing the surrounding subserosa; ssLBsm, the growing edge of the ss carcinoma facing the surrounding submucosa; ssLBmp, the growing edge of the ss carcinoma facing the surrounding muscularis propria. The three black masses are invasive carcinomas.

First, we describe the features of myofibroblasts and smooth muscle cells at the tumor border of colorectal adenocarcinomas. The myofibroblasts have vesicular nuclei, pale eosinophilic elongated cytoplasm and indistinct cell border (Fig. 2a), whereas the smooth muscle cells contain fusiform blunt-ended nuclei, eosinophilic cytoplasm and distinct cell border (Fig. 2b).

   a
   b

Figure 2. Microscopic findings of myofibroblasts and smooth muscle cells at the tumor border. (a) Myofibroblasts showing vesicular nuclei, pale eosinophilic cytoplasm and indistinct cell border; (b) smooth muscle cells showing fusiform blunt-ended nuclei, elongated cytoplasm and distinct cell border.

   A (i)

   A (iii)
   A (ii)
   B (i)

   C (i)
   B (ii)

   C (ii)

Figure 3. Grades of myofibroblasts. (A) grade (+) [Case No. MP004, confined to the muscularis propria, stains for (i) ASMA (low-power view), (ii) ASMA (high-power view) and (iii) h-CD (high-power view)], a small number of myofibroblasts positive for ASMA but negative for h-CD, showing thin bundle formation between the arrows. (B) grade (++) [Case No. MP032, confined to the muscularis propria, stains for (i) ASMA and (ii) h-CD], a moderate number of myofibroblasts positive for ASMA but negative for h-CD, showing relatively thick bundle formation between the arrows. (C) grade (+++) [Case No. MP005, confined to the muscularis propria, stains for (i) ASMA and (ii) h-CD], a large number of myofibroblasts positive for ASMA but negative for h-CD, surrounding the mpDB.

In order to differentiate myofibroblasts from adjacent smooth muscle cells more precisely, we used two monoclonal antibodies to ASMA (clone: 1A4) and high-molecular-weight caldesmon (h-CD) (clone: h-CD) purchased from DAKO (Kyoto, Japan). Recently, h-CD has been used as a marker for smooth muscle cells, which is expressed in smooth muscle cells and part of myoepithelial cells but not in fibroblasts or myofibroblasts (8,9). The antibodies were diluted to 1:50. An immunohistochemical study was performed with streptavidin-biotin methods. Concerning immunostaining for h-CD, deparaffinized tissue sections in 10 mM citrate buffer (pH 6.0) received heat treatment in a microwave oven for 15 min before the primary antibody reaction. In the present study, we considered stromal cells positive for ASMA granularly and negative for h-CD as myofibroblasts (8,9). The immunoreactivity at the tumor border of the tissues was graded as + to +++ according to the number of cells stained. The grades were defined as follows: +, a small number of myofibroblasts surrounding less than half of the border, often showing very thin bundle formation; ++, a moderate number of myofibroblasts surrounding less than half of the border, often showing relatively thick bundle formation; and +++, a large number of myofibroblasts surrounding more than half of the border, often showing thick bundle formation. Tumor borders which contain almost no myofibroblasts were graded as +. According to this grading protocol, two independent attending pathologists (H.N. and H.E.) examined all the immunostained specimens randomly. After grading by the two independent pathologists, all six authors discussed the grading of each case to make the grading as objective as possible. Representative pictures of each grade are shown in Fig. 3.

Statistical comparison for significance was carried out using the chi-squared test. P < 0.05 or Pc < 0.05 was considered to be statistically significant.

RESULTS

Regarding the DB, as shown in Table 1, 39 (43%) of the 91 cases had a small number of myofibroblasts (graded as +), whereas the remaining 52 cases (57%) had a moderate or large number of myofibroblasts (graded as ++ or +++). A moderate or large number of myofibroblasts graded as ++ or +++ were detected in 18 (72%) of the 25 sm cases and 21 (81%) of the 26 ss tumors, respectively. In contrast, only 13 (33%) of the 40 mp tumors had myofibroblasts graded as ++ or +++; the remaining 27 (67%) mp tumors had myofibroblasts graded as +; 18 (69%) of the 26 ss tumors had myofibroblasts graded as +++ at the ssDB, whereas only one (3%) of the 40 mp tumors was graded as +++ at the mpDB. Compared with the smDB, the mpDB had a tendency to contain smaller numbers of myofibroblasts (statistically significant, P < 0.01), as did the mpDB compared with the ssDB (statistically significant, Pc < 0.01).

Table 1. Relationship between the tumor depth and the number of myofibroblasts at the DB of colorectal adenocarcinomas
Depth of tumor No. of cases Myofibroblasts
+ ++ +++
sm 25 7 (28%) 18 (72%) 01
mp 40 27 (67%) 12 (30%) 1 (3%)1,2
ss 26 5 (19%) 3 (12%) 18 (69%)2
Total 91 39 (43%) 33 (36%) 19 (21%)
Grade of myofibroblasts: +, a small number; ++, a moderate number; +++, a large number. 1P < 0.01. 2Pc < 0.01.

Table 2. Relationship between LB and the number of myofibroblasts in colorectal adenocarcinomas
Depth of tumor No. of cases Lateral border Myofibroblasts
+ ++ +++
mp 40 sm (= mpLBsm) 7 (17%) 30 (75%) 3 (8%)1
ss 26 sm (= ssLBsm) 12 (46%) 12 (46%) 2 (8%)2
    mp (= ssLBmp) 25 (96%) 0 1 (4%)1,2
Grade of myofibroblasts: +, a small number; ++, a moderate number; +++, a large number. 1,2Pc < 0.01.

The results concerning myofibroblasts in the LB of the tumors are summarized in Table 2. Seven (17%) of the 40 mp cases and 12 (46%) of the 26 ss cases had a small number of myofibroblasts (graded as +) in their mpLBsm and ssLBsm, respectively. In contrast, 25 (96%) of the 26 ss cases had myofibroblasts graded as + in the ssLBmp. No PCFs surrounding the carcinomatous glands were seen, as was the case in one previous report (3). Compared with the mpLBsm, the ssLBmp had a tendency to contain smaller numbers of myofibroblasts (statistically significant, Pc < 0.01), as did the ssLBmp compared with the ssLBsm (statistically significant, Pc < 0.01).

DISCUSSION

The host commands several responses to neoplasia (10). As a result of the expression of tumor-associated antigens, the immune system contributes lymphocytes, macrophages and antibodies, a reflection of immunological surveillance against neoplasia (10). Tumor neovascularization induced by a tumor-angiogenesis factor represents a secondary response, possibly deleterious, for it may facilitate tumor dissemination (10). The stromal myofibroblast reaction to many invasive and metastatic carcinomas may constitute a third, albeit more primitive, response (10). The collagen produced by the myofibroblasts may signify an attempt to entrap the neoplasm and impede vascular invasion (10). In one report, some carcinomatous glands were surrounded by myofibroblasts with considerable variations at the periphery of the tumor, whereas the typical desmoplastic reaction displayed rows of stromal cells in the central parts of the tumors (11). In another report, myofibroblasts were of moderate to high abundance in the tumor center of the colorectal tumors; by contrast, myofibroblasts were present in only small numbers at the peripheral tumoral zone of all colorectal carcinomas studied and were even more sparse in the adjacent host tissue, suggesting that desmoplastic response may reduce the invasive activity of neoplastic cells in the tumor center and that desmoplasia deficiency promotes the spread of colorectal cancer at the tumor border (12). However, no study was found in the English literature focused on the relationship among the tumor depths, their tumor borders and myofibroblasts, except one report that colorectal carcinomas only induce a vigorous desmoplastic reaction following invasive growth through the muscularis mucosa (13). Desmoplasia, i.e. the remodeling process of local tissue damage by carcinoma invasion, generally represents a host response analogous to that observed in healing wounds (1,14); recent studies on expression of TGF-[beta]1 and matrix-degrading enzymes such as membrane-type metalloproteinase (MT1-MMP) and geletinase A (MMP-2) in human gastrointestinal carcinomas support this concept (15-17). Myofibroblasts are present in wound repair processes; however, they are thought to arise from resident fibroblasts and are known to be only transiently present (18).

The present results concerning myofibroblasts at the DB suggest that about one third of mp colorectal carcinomas have a moderate to large number of myofibroblasts at the mpDB which entrap tumor cells; in contrast, the remaining two thirds may have invaded the subserosa unless these patients had a surgical resection. Actually, in human liver, it has already been elucidated that ASMA-positive hepatic stromal cells (HSCs), resembling myofibroblasts in colorectal adenocarcinomas, are detected not only within but also around hepatocellular carcinomas (19), and it is suggested that ASMA-positive HSCs are responsible for tumor capsule formation in hepatocellular carcinomas (HCCs) (20). The present results with colorectal adenocarcinomas are therefore compatible with the previous report of HCCs (20).

The results of the present study are also compatible with a previous study concerning superficial colorectal tumors (6). Actually, no PCFs surrounding the carcinoma glands in the DB and LB were seen in our present series.

We have to take into consideration that the environment of muscularis propria is different from that of submucosa and subserosa. Muscularis propria is composed exclusively of smooth muscle bundles and contains a small amount of loose connective tissue; in contrast, submucosa and subserosa are composed mainly of loose connective tissue. Hence muscularis propria may play an important role in the direct mechanical protection of invasive growth of mp carcinomas from muscularis propria to subserosa and that of sm carcinomas from submucosa into muscularis propria. However, partially or extensively destroyed by carcinoma cells, the muscularis propria with mp carcinomas is physically weaker than that with superficial colorectal tumors such as sm carcinomas. These structural differences among muscularis propria, submucosa and subserosa therefore suggested that it is much easier for mp carcinomas to invade further deep layers (subserosa) than for sm carcinomas to invade further deep layers (muscularis propria).

To our knowledge, there has been one English publication concerning immunohistochemical analysis for caldesmon expression in stromal cells of human colon carcinomas (21). In that study, myofibroblastic stromal cells were also positive for caldesmon, because the antibody to caldesmon used in that work recognized not only h-CD but also low-molecular-weight caldesmon (l-CD), and the latter molecule is expressed in both non-muscle cells and smooth muscle cells (22).

On the other hand, myofibroblasts may produce paracrine growth factors, which stimulate tumor cell growth and invasion in some circumstances; insulin-like growth factor-I (IGF-I) and IGF-II are important paracrine growth factors secreted from stromal cells (including myofibroblasts) in gastric carcinomas and breast carcinomas, respectively (23,24). Furthermore, it has been already elucidated that myofibroblasts at the tumor border secrete several matrix-degrading enzymes in various human carcinomas (17,25-27). The role of myofibroblasts in tumor growth and invasion appears to include not only inhibitory but also promoting functions associated with adjacent neoplastic cells.

In conclusion, the myofibroblasts at the tumor border in muscularis propria (mpDB and ssLBmp) were generally few in number. Although direct evidence is lacking, judging from our present results, a small number of myofibroblasts at the mpDB and the ssLBmp are associated with insufficient protection against further invasive growth of colorectal adenocarcinomas into the adjacent muscularis propria and the subserosa, resulting in a high incidence of ss carcinomas; a moderate or large number of myofibroblasts at the smDB, mpLBsm, ssLBsm and ssDB may play an important role in protection against tumor spread. On the other hand, myofibroblasts at the tumor border also may promote invasive growth of carcinoma by secreting paracrine growth factors against carcinoma cells and several matrix-degrading enzymes. Further comprehensive studies are needed to clarify the balance of inhibitory and promoting effects on tumor invasion by myofibroblasts at the tumor border.

Acknowledgments

The authors are grateful to Mr Ralph Schultejohann, Assistant Professor, Section of Liberal Arts, for reading the manuscript, Mr Tadatoshi Tokaji, Mr Yoshihiro Hayashi, Ms Hisayo Yamazaki, Ms Miko Mitani, First Department of Pathology, and Mr Masatoshi Shirota, Medical Research Center, Kochi Medical School, for their excellent technical assistance. This work was supported by the Foundation for Promotion of Cancer Research in Japan.

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Received March 19, 1998; accepted July 15, 1998
For reprints and all correspondence : Hirofumi Nakayama, First Department of Pathology, Kochi Medical School, Kohasu, Okoh-cho, Nankoku, Kochi 783-8505, Japan. E-mail: nakayamh{at}kochi-ms.ac.jp
Abbreviations: ASMA, alpha-smooth muscle actin; h-CD, high-molecular-weight caldesmon; l-CD; low-molecular-weight caldesmon; DB, deep border; LB, lateral border; sm, submucosa; mp, muscularis propria; ss, subserosa; PCFs, pericryptal fibroblasts; HSCs, hepatic stromal cells; HCCs, hepatocellular carcinomas; TGF-[beta]1, transforming growth factor-[beta]1; IGF, insulin-like growth factor

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