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Tumor Biology |
Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique/Institut National de la Santé et de la Recherche Médicale U184/ULP BP 163, 67404 Illkirch Cedex, Communauté Urbaine de Strasbourg [A. B., R. M., M. E. F., P. B., M-C. R.]; Service d’Anatomie Pathologique Générale, Centre Hospitalier Universitaire de Hautepierre, 67098 Strasbourg Cedex [M-P. C., J-P. B.]; and Institut Curie, Institut National de la Santé et de la Recherche Médicale U255, 75248 Paris Cedex 05 [L. C., C. S-F.], France
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Among the 20 or so MMPs currently known, ST3 (MMP11; Refs. 7
, 8 ) exhibits particular features. Although it cleaves MMP substrates such as 
1-antitrypsin (9)
or IGF-BP1 (10)
, ST3 is unable to degrade any major ECM component (11)
. Furthermore, in contrast to most of the other MMPs that are activated extracellularly, ST3 is predominantly secreted in a potentially active form; pro-ST3 is intracellularly processed by furin-dependent proteolytic cleavage (12)
. Thus, ST3 clearly differs from other MMPs suggesting that it may have a unique role among the MMPs.
Normal ST3 expression is associated with the intense tissue remodeling occurring during embryogenesis (13) , tissue involution (14) , wound healing (15) , and metamorphosis (16) . ST3 is mainly detected in cells of mesenchymal origin, predominantly in fibroblasts located in the vicinity of stressed epithelial cells. These observations suggest that ST3 is a connective tissue-derived factor that may play a role in the homeostasis of epithelial cell compartments (17) .
Malignant epithelial cells depend on environmental stromal cells including fibroblastic, endothelial, and inflammatory cells to develop primary and secondary tumors (18 , 19) . ST3 expression is observed in stromal fibroblastic cells of most types of human carcinomas, including preinvasive lesions of high grades. Furthermore, strong ST3 gene expression is correlated with both increased aggressiveness of tumors and a poor clinical outcome (7) . Therefore, ST3 represents an appropriate target for specific MMP inhibitor(s) in future cytostatic therapeutical approaches (8 , 20) .
Evidence of the participation of ST3 in tumorigenesis has been obtained in vivo. The level of ST3 expression is a critical factor in the ability of MCF7 human breast cancer cells to generate tumors in nude mice (21) . Furthermore, ST3 null (ST3-/-) mice exhibit a lower propensity to develop 7,12-dimethylbenzanthracene-induced carcinomas than the wild-type (ST3+/+) animals (22) . Stromal ST3 deficiency is associated with a delayed period of latency before tumor appearance and a lower tumor incidence. In addition, ST3+/+ but not ST3-/- embryonic fibroblasts increase the tumorigenicity of coinjected MCF7 cells in nude mice, and this effect is mediated through ECM-associated factors (22) . Together, these findings indicate that fibroblastic ST3 promotes tumorigenicity in a paracrine manner, presumably by favoring cancer cell survival and/or implantation in connective host tissues.
In the present study, because no in vitro models were available, we designed a syngeneic tumor model developed in either ST3+/+ or ST3-/- mice to investigate the nature of the cellular process in which ST3 may participate in promoting tumorigenesis. We show that ST3 acts during early steps of tumor development after s.c. injection of cancer cells and that it does not increase tumor neoangiogenesis or malignant cell proliferation but, in contrast, lowers malignant epithelial cell death. Thus, among the MMPs, ST3 exhibits an original cellular function because other members of the MMP family are mainly proangiogenic and/or proapoptotic factors.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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C26 cells were derived from colon carcinomas induced in BALB/c mice by repeated intrarectal instillations of N-nitroso-N-methylurethan and exhibited an in vivo doubling time of 1.7 days (23) .
Tumorigenicity Assays.
C26 cells (n = 5 x 104; 0.2 ml PBS) were s.c. injected on both shaved flanks of 9-week-old mice. Ten ST3+/+ and 10 ST3-/- mice were checked every 2 days for palpable tumor appearance. For the study of microcarcinoma, large areas containing the injection sites were excised from six ST3+/+ and six ST3-/- mice at 6, 8, 10, and 12 days after injection. BrdUrd (2 mg) were injected i.p. into mice 3 h before they were sacrificed. All of the experiments were performed in triplicate.
Specimens collected were either frozen in liquid nitrogen or fixed in phosphate-buffered formalin (4%) and embedded in paraffin. Histological examination was performed on H&E-stained paraffin sections.
Immunohistochemistry Analyses.
Immunohistochemistry analyses were performed using standard techniques and reagents (24)
. Hematopoietic cells were characterized using biotinylated anti-CD45R/B220, anti-CD3
, and anti-CD11b(M1/70) or nonbiotinylated anti-Ly-6G(Gr1) and mac3 (M3/84) antibodies (PharMingen, San Diego, CA). Endothelial cells were stained using a peroxidase-conjugated mAb directed against CD31 (PharMingen), a cell adhesion molecule constitutively expressed on the surface of endothelial cells. Similar results were obtained using a polyclonal antibody directed against the von Willebrand factor (DAKO Corp., Carpinteria, CA). Proliferating cells were detected with anti-BrdUrd antibody (Sigma Chemical Co., Saint Louis, MO). Apoptotic cells were identified using the TUNEL technique using the Apoptag Peroxidase kit (Oncor, Gaithersburg, MD). TUNEL positive cells, in general, had round nuclei typical of cancer cells and were distinguishable from PMN nuclei, which were smaller and granular.
Counterstaining was either Meyer’s hematoxylin or Harris blue.
Quantitative and Statistical Analyses.
The larger (a) and smaller (b) diameters of the palpable tumors were measured using a caliper and served for tumor volume calculation according to a x b2 x 0.4 (25)
. Tumor incidence was defined as the percentage of tumors of at least 40 mm3. The data were statistically analyzed with the log-rank test (26)
.
Volumes of nonpalpable microcarcinomas (mm3) and necrotic (percentage of tumor area) and PMN (percentage of total cells) indexes were determined by light microscopic analysis of H&E-stained sections. The number of vessels and the proliferation and apoptosis indexes (percentage of stained cells in the cancer cell population) were established using immunostained sections. A total of five randomly chosen fields of view at a magnification of x400 were counted/slide assayed, and the counts were averaged to guarantee representativeness.
Statistical differences between the experimental conditions were evaluated using Student’s t test, and Ps lower than 0.01 were considered as significant.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. Indeed, 2 weeks after injection, tumors were observed solely in ST3+/+ mice. After 3 weeks, the tumor incidence was 2-fold higher (60% versus 30%) in favor of ST3+/+ mice. The number and sizes of palpable C26 tumors developed in ST3+/+ mice were significantly higher than in ST3-/- animals, showing that host ST3 is required for optimal efficiency of C26 tumorigenesis. These results corroborated our previous observations showing lower tumorigenesis in the absence of fibroblastic ST3 (21
, 22) and validated the use of the C26 syngeneic model to investigate the cellular function of ST3 during tumorigenesis.
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. At 6 days, tumors were already seen to be smaller in ST3-/- than in ST3+/+ mice (0.06 mm3 versus 0.45 mm3). Similar significant size differences were observed later on, at days 8, 10, and 12 (Fig. 3A)
.
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Host ST3 Deficiency Alters Histological Features of C26 Microcarcinomas.
Histological examination uncovered no obvious differences between palpable C26 tumors developed in ST3+/+ and ST3-/- mice (data not shown), as already observed in previous models (21
, 22)
. However, at day 6 after injection, a prominent intratumoral inflammatory infiltrate, mainly constituted by PMN cells, was observed in microcarcinomas found in ST3-/- mice (Fig. 2C)
. It remained elevated until day 12, whereas it was absent (day 6; Fig. 2D
) or low (days 8 to 12) in microcarcinomas found in ST3+/+ mice. These differences were significant from days 6 to 12 (Fig. 3B)
. In addition, an increased rate of necrosis was observed in ST3-/- mice (Fig. 2, A and B)
. Thus, a large central necrotic area was present at day 8 in ST3-/- but not in ST3+/+ mice. At day 10, comparison of the largest surfaces of the central necrotic core measured on microcarcinoma sections showed that necrosis was 2-fold more intense in ST3-/- than in ST3+/+ mice. At day 12, differences in necrosis were no longer observed (Fig. 3C)
.
Thus, histological differences were observed in nonpalpable microcarcinomas, and all of the further investigations were performed from day 6 to 12 after C26 cell injection.
Host ST3 Deficiency Leads to Intense PMN Tumor Infiltrate.
Inflammatory cells reacted with anti-Gr1 mAb, which recognizes an antigen expressed by neutrophils (Fig. 2E)
, and with anti-mac3 mAb, which is detectable on macrophages (Fig. 2G)
. Positive staining was also observed with anti-Mac1 mAb, which reacts with an antigen shared by neutrophils and macrophages. No significant labeling was observed with antibodies directed against T (CD3) or B (B220) lymphocytes (data not shown). Alteration of immune cell-mediated rejection of cancer cell graft by host tissues is improbable because ST3-/- and ST3+/+ mice were littermates of pure genetic background, and their tumors are devoid of the modification of lymphocytes T and B and natural-killer cells. Moreover, in contrast to ST3+/+ microcarcinomas where the few PMN were observed at the periphery of the tumors, in ST3-/- mice, inflammatory cells were present surrounding and throughout the C26 microcarcinomas. Thus, the increased cancer cell death might be mediated via a decrease of the tumor-induced nonspecific inflammatory response from the host tissues.
Host ST3 Deficiency Does Not Lead to Decreased Tumor Neoangiogenesis.
One possible underlying cellular process of ST3-induced C26 tumor promotion may be the improvement of tumor neoangiogenesis. It is currently accepted that, below 2 mm3, factors required for cell growth can diffuse through the tumors, whereas at sizes larger than 2 mm3, tumors are dependent on neoangiogenesis and subsequent correct factor supply for their growth (27)
. In our model, such tumor sizes were reached at days 8 and 10 in ST3+/+ and ST3-/- mice, respectively. Surprisingly, a high number of microvessels were already observed at days 6 and 8 after cell injection in very small tumors (0.06 and 0.40 mm3) that had developed in ST3-/- but not in ST3+/+ mice (Fig. 2, I and J)
. The microvessels were homogeneously distributed within the microcarcinomas. This early vascularization favors the supply of the tumor with inflammatory cells because these vessels contained numerous PMN (Fig. 2I)
. We note that a similar observation of numerous vessels in very small tumors was recently reported (28)
. It was proposed that these vessels do not correspond to neovessels but to co-opted host vessels. The role of ST3 in this process remains to be determined. The presence of numerous vessels also excludes that necrosis observed in ST3-/- mice could result from tumor hypoxia. In tumors larger than 2 mm3 (10–12 days after injection), the number of microvessels was not significantly different between ST3+/+ and ST3-/- mice (Fig. 3D)
. They were, in both conditions, preferentially located at the periphery of tumors (data not shown), originating from host tissues to colonize the tumoral sites as described previously (27)
.
Thus, in contrast to many other MMPs that are proangiogenic factors (Ref. 29 and references therein), ST3 does not favor tumor development through an increase in tumor neoangiogenesis.
Host ST3 Deficiency Does Not Lead to Decreased C26 Cell Proliferation.
Another possibility may be that ST3 promotes tumorigenesis by favoring cancer cell proliferation. Proliferating C26 cells were observed in all of the cases (Fig. 2, K and L)
. From days 6 to 10 after cell injection, C26 proliferation indexes were slightly lower in ST3-/- mice than in ST3+/+ mice (Fig. 3E)
, but these differences were not significant. At day 12, proliferation indexes were identical in both sets of tumors. In all of the cases, the highest numbers of proliferating cells were observed at the periphery of tumors, at the border between the cancer mass and host tissues (Fig. 2, K and L)
. The slight differences of the rate of C26 cell proliferation in favor of microcarcinomas found in ST3+/+ mice cannot account for the size differences observed between the ST3-/- and ST3+/+ microcarcinomas.
This result corroborates previous data (21) showing that fibroblastic ST3, although promoting tumor development, does not favor cancer cell growth.
Host ST3 Deficiency Leads to Increased C26 Cell Apoptosis.
Although essential for optimal tumor development, ST3 does not share any functions with the other MMPs involved in malignant processes. In fact, it has been demonstrated previously (11)
that ST3 is not able to digest any ECM components, and it has been excluded that ST3 may increase cancer cell invasive properties (21)
. We have now shown that ST3 is not a proangiogenic factor and that it does not favor cancer cell proliferation. However, an intense necrosis was observed in C26 tumors developing in ST3-/- mice, suggesting that ST3 might have a function related to cancer cell death processes. These data prompted us to investigate the possible involvement of ST3 in cancer cell apoptosis. C26 apoptotic cells, distributed throughout the tumors, were observed at days 6 to 12 in both ST3-/- and ST3+/+ microcarcinomas (Fig. 2, M and N)
. For a long time, apoptosis and necrosis have been considered as independent processes. However, they have been shown recently to be mechanistically related and areas of necrosis surrounded by a zone of apoptotic cells have been observed in a number of malignant tumors (30)
. Consistently, apoptotic cells were particularly abundant at the periphery of necrotic areas of C26 microcarcinomas (data not shown). The number of apoptotic cells was significantly higher in tumors developed in ST3-/- than in ST3+/+ mice (Fig. 3F)
. From day 6 to 10 after injection, apoptotic indexes were 3-fold higher in microcarcinomas found in ST3-/- mice and 2-fold at 12 days.
Thus, in ST3-/- mice, the rate of cancer cell death by either apoptosis or necrosis is higher than in ST3+/+ animals, indicating that ST3 is directly or indirectly involved in these processes.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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We observed that optimal C26 tumor development requires ST3+/+ host mice and that ST3 does not promote C26 tumorigenesis through increasing neoangiogenesis or cancer cell proliferation but through lowering cancer cell death. These results show that ST3 favors survival of C26 cancer cells injected in s.c. areas. This aberrant tissue localization of the C26 cancer cells can be assimilated to that occurring in human carcinomas, when malignant cells reach proximal or distal connective tissues and organs. In normal conditions, detached and misplaced epithelial cells that are deprived of the specific signals required for their survival die, leading to a correct tissue homeostasis (19) . This apoptotic phenomenon referred to as "anoikis" occurs at the time of alteration of the interaction between epithelial cells and their connective environment (32 , 33) . However, in carcinomas, epithelial malignant cells survive in aberrant cell compartments, suggesting the existence of signals that inhibit cell death. In this context, ST3 may help epithelial cells to circumvent homeostatic mechanisms and survive in an unusual and hostile environment.
The high number of dying cancer cells might explain the consecutive presence in ST3-/- injection sites of neutrophils and macrophages, the primordial function of which is to engulf and destroy cell debris by phagocytosis. However, another possibility is that PMN might be the cause and not the consequence of cancer cell death. In fact, a critical role for activated PMN in the development of tumor cell apoptosis and severe necrosis has also been reported (34) . In this context, because at day 6 both PMN infiltration and apoptosis of C26 cells were already observed, whereas necrotic areas were not clearly constituted, it can be proposed that the accumulation of PMN may induce apoptosis and, subsequently, massive necrosis. A similar scenario was reported in neutrophil-dependent hepatocellular necrosis (35) . This phenomenon could be ascribed to an increased availability of one of the numerous neutrophil-triggered factors such as the interleukin-8 chemokine, which is also a mediator of angiogenesis (36) , or G-CSF, which has already been shown to be ectopically expressed in some malignant tumors (37) . It has been reported that C26 cells stably transfected to express G-CSF lost their tumorigenic potential in nude mice and that the G-CSF antitumoral effect was mediated by recruitment and targeting of PMN to G-CSF-releasing tumor cells (38) . In this context, one of the functions of ST3 may be to inhibit the expression and/or activation of molecule(s) with chemoattractant properties for inflammatory cells.
It has recently been shown in vivo that the promoting effect of ST3 on tumorigenesis in mice is dependent on its catalytic function (39) . This result implies that ST3 is involved at a molecular level in posttranslational process(es) leading to protein activation or inhibition. However, unlike other MMPs, ST3 is not capable of cleaving any classical ECM components, and despite numerous studies, its substrate(s) remains unknown (7 , 9 , 11 , 17) . The present results highlight the wideness of the panel of the possible ST3 targets. IGF-I (40) , which has been shown to inhibit malignant cell apoptosis in a paracrine manner (41) , would be a possible mediator. Its pattern of expression is very similar to that of ST3, and it is present throughout the ECM, almost entirely bound to IGF-BPs, which are substrates for ST3 (10) . Thus, ST3 may inhibit epithelial cell apoptosis through regulating IGF-I activity by proteolysis of IGF-BPs. Interestingly, it has been reported recently (42) in an in vitro model that IGF-I prevents ECM-induced apoptosis of mammary epithelial cells.
However, whatever the molecular mechanism involved, ST3 shows an original function for a MMP, because most other members of the MMP family are known to exert proapoptotic function (2, 3, 4, 5, 6) . Interestingly, it was already proposed that, even acting at the time of intense apoptosis, ST3 might favor epithelial cell survival in both physiological (13 , 14) and pathological (21 , 22) conditions. Thus, during organogenesis, metamorphosis, organ involution, and wound-healing processes, ST3 may preserve the viability of regenerating cells during intense tissue remodeling and participate in the regulation of the homeostasis of the epithelial cell compartment (17) . In fact, in these processes, besides intense cell death, some epithelial cells should survive, presumably through an antiapoptotic signal permitting them to escape to cell death (19) . It is tempting to speculate that this is the physiological ST3 function and that it has been subverted by malignant tumors to permit colonization of adjacent connective tissues by malignant epithelial cells during local or distant spreading.
In conclusion, our results support the concept that during tumorigenesis, MMPs may exert a dual effect. In this context, we note that mouse TIMP3, in contrast to TIMP1 and TIMP2, which exhibit antiapoptotic features, promotes smooth muscle cell apoptosis (43) . Inhibition of apoptosis is an important feature of neoplasia, potentially contributing to tumor progression and resistance to therapy (44 , 45) . In this context, anti-ST3 treatments that may restore the ability to properly regulate apoptosis could be of considerable benefit in the treatment of malignancies.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported by funds from the Institut National de la Santé et de la Recherche Médicale, the Center National de la Recherche Scientifique, the Hôpital Universitaire de Strasbourg, the Bristol-Myers Squibb Pharmaceutical Research Institute, the Association pour la Recherche sur le Cancer, and the Fondation de France. 
2 R. M. and A. B. should be considered equally as first authors.
4 To whom requests for reprints should be addressed, at Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM U184/ULP BP 163, 67404 Illkirch Cedex, C.U. de Strasbourg, France. Phone: 03 88 65 34 24; Fax: 03 88 65 32 01; E-mail: rio{at}igbmc.u-strasbg.fr
5 The abbreviations used are: MMP, matrix metalloproteinase; ECM, extracellular matrix; TIMP, tissue inhibitors of matrix metalloproteinase; ST3, stromelysin-3; BrdUrd, bromodeoxyuridine; TUNEL, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling; PMN, polymorphonuclear; mAb, monoclonal antibody; G-CSF, granulocyte colony-stimulating factor; IGF, insulin-like growth factor; IGF-BP, insulin-like growth factor binding protein.
Received 7/ 7/00. Accepted 1/11/01.
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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) and 10 ST3-/- (
) mice. ----, the delay required for tumor development at 50% injection sites. P is indicated. Three independent experiments have been performed that all gave similar significant results.
