Previous studies have shown that high levels of MMP-9 can be detected in the serum of patients with various lymphoid malignancies and in leukemia/lymphoma culture supernatants. Indeed, aggressive forms of lymphoma constitutively produce MMP-9 and its elevated levels in the serum or in tissues correlate with advanced stage and poor patient survival. In vitro, MMP-9, which is also produced by the host peritumoral cells in response to the presence of tumors, plays an important role in migration of tumor cells through artificial basement membranes or endothelial cells. In this study, using MMP-9-deficient mice, we show that absence of MMP-9 does not prevent the development of primary T-cell leukemia. Furthermore, MMP-9-deficient cell lines retained their tumorigenic potential, as shown by their ability to induce thymic lymphoma in young syngeneic wild-type animals. In addition, these MMP-9-deficient tumor cells disseminate in normal mice, or mice that are deficient for MMP-9, indicating that tumor growth and dissemination can occur in total absence of MMP-9. These results show for the first time than lymphoma growth can occur in total absence of MMP-9 and have consequences for therapy of invasive cancers with inhibitors of MMPs.
Matrix metalloproteinases (MMPs) have been recognized as extracellular enzymes that favour the development of cancer by enhancing escape of individual tumor cells from the primary tumor and the growth of metastasis.1, 2, 3 For these reasons, several strategies have been developed to inhibit their expression or enzymatic activity in different types of cancer.4 The failure of these strategies have often been attributed to the complexity of MMP expression pattern since in many types of cancer, MMPs are expressed by both the cancer cells and cells from the host.5, 6, 7 In vitro and in vivo studies have reported that an elevated expression of MMP-9 correlates with clinically aggressive tumors, including high-grade non-Hodgkin's lymphomas (NHL).8, 9 NHL patients with high levels of MMP-9 in their tissues have a significantly worse prognosis than patients who do not express MMP-9.9 MMP-9 expression is also markedly increased in high-grade Burkitt's cell lines and in primary T-leukemic cells derived from adult T-cell leukemia patients,10, 11 suggesting that overexpression of MMP-9 in HTLV-I- infected T-leukemic cells or lymphoma cells is responsible for the invasiveness of these cells in peripheral organs. These observations in the human are correlated with results obtained in experimental mouse models. For instance, abnormally high levels of MMP-9 have been found in radiation-induced thymic lymphomas and in the serum of T lymphoma-bearing mice.12 Moreover, overexpression of MMP-9 in T-lymphoma cells accelerates the growth of thymic lymphoma13 and treatment with gelatinase inhibitors has been found to significantly reduce the number and the growth rate of experimental metastases induced by injection of T-lymphoma cells into normal mice.14 Nevertheless, clinical trials with MMP inhibitors have been frustratingly negative, because of their unselectivity and the ignorance of the complete biology of any MMP member. In addition, whether lymphoma growth or dissemination can occur in total absence of MMP-9 remains untested to date.
Materials and methods
Male and female MMP-9-deficient, in which the exons and corresponding introns 3–7 and about half of exon 8 (2067 bp total) were deleted and replaced by the neomycine resistance gene (neo; 1840 bp),15 were backcrossed for at least eight generations into a C57BL/6 background, and wild-type C57BL/6 were bred in our animal facility and maintained under specific pathogen-free conditions in accordance with institutional guidelines. All animal studies were approved by the Institutional Animal Care and Use Committee.
Radiation-induced T-thymic lymphoma
For thymic lymphoma induction, 4- to 8-week-old normal and MMP-9-deficient C57BL/6 mice received a whole-body leukemogenic X-ray treatment of 4 × 175 rad at a rate of 25 rad min−1 at weekly intervals. When moribund, mice were killed and thymic lymphoma was confirmed at necropsy as previously described.16
Culture of cell lines and reagents
The mouse T-lymphoma cell line 164T2 was established in our laboratory from radiation-induced primary T-cell lymphomas in C57BL/6.17 Flow cytometric analysis of these cells, as well as those of the S11 variant, showed that both cells express LFA-1, CD31, CD62L, CD90, ICAM-1, ICAM-2, but not α4β1. They all express CD3ɛ and the TcRαβ, as well as the gp70 and the TL antigen.18 All cells were maintained in RPMI-1640 complete medium (supplemented with 10% (v/v) fetal calf serum, 2 mM L-glutamine, 10 mM 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid buffer, 0.1 unit per ml penicillin, 50 μg ml−1 streptomycin and 55 μM β-mercaptoethanol). All products were from GIBCO Life Technologies (Burlington, ON, Canada). All other reagents were purchased from Sigma, St Louis, MO, USA, unless otherwise indicated.
PCR genotype analysis
The genotypes of the MMP-9-deficient mice and wild types were confirmed by PCR from genomic DNA obtained from tail biopsies. The primers used for amplification of the normal allele were 5′-IndexTermACAGGCATACTTGTACCGCTATGG-3′ (sense) which is specific for the exon II of the murine MMP-9 gene and 5′-IndexTermGAAGCAGCGACTAGGGATTGTGGG-3′ (antisense) which is specific for intron III were used to detect the normal (N) allele (a 700 bp amplicon) in both MMP-9-deficient mice and radiation-induced thymic lymphoma cell lines derived from these mice). To detect the mutated allele (M), an antisense primer (5′-IndexTermAACGAGATCAGCAGCCTCTGTTCC-3′) specific for the neo cassette used to disrupt the MMP-9 gene15 was used for PCR analysis. The 5′-IndexTermCGGAGTCAACGGATTTGGTCGTAT-3′ (sense) and 5′-IndexTermAGCCTTCTCCATGGTGGTGAAGAC-3′ (antisense) primers were used for the amplification of the glyceraldehyde-3-phosphate dehydrogenase (GAPDH) gene as a control. Amplification was performed in a PTC-100 thermal cycler (MJ Research, Waltham, MA, USA) using the following protocol: 120 s at 94 °C and then 35 cycles of three steps consisting of 60 s at 94 °C, 60 s at 58 °C and 60 s at 72 °C. The reaction mixture was size separated on an agarose gel, and specifically amplified products were detected by ethidium bromide staining and ultraviolet transillumination.
Zymography was performed in polyacrylamide gels that had been cast in the presence of gelatin as previously described.18 Briefly, samples (100 μl) were resuspended in loading buffer and, without prior denaturation, were run on a 7.5% sodium dodecyl sulfate (SDS)-polyacrylamide gel containing 0.5 mg ml−1 of gelatin. After electrophoresis, gels were washed to remove SDS and incubated for 18 h at 37 °C in a renaturing buffer (50 mM Tris, 5 mM CaCl2, 0.02% NaN3, 1% Triton X-100). Gels were subsequently stained with Coomassie brilliant blue G-250 and destained in 30% methanol/10% acetic acid (v/v) to detect gelatinase secretion.
Tumorigenic and metastasis assays
Male or female C57BL/6 mice (4- to 5-week-olds) were injected intrathymically in each lobe with the indicated number of lymphoma cells. Mice were observed periodically for clinical signs of thymic lymphoma: runting, swelling of the thorax and dyspnea. When moribund, mice were killed and thymic lymphoma was confirmed at necropsy. To induce lymphoma in peripheral organs, mice at least 6- to 8-week-old were injected via the tail vein with the indicated number of lymphoma cells.18 When clinical signs of lymphoma became evident (dyspnea, runting and splenomegaly), the animals were killed and spleen, kidneys and liver harvested, weighed and fixed in 10% formalin for histological examination or frozen for PCR analysis.
RNA isolation and semiquantitative PCR
Total RNA was isolated from tissues or lymphoma cells using Trizol reagent according to the manufacturer's instructions (Invitrogen Canada Inc., Burlington, ON, Canada). Total RNA (2 μg) was reverse transcribed using the Omniscript reverse transcriptase (Qiagen, Mississauga, ON, Canada) and PCR amplified using the following conditions: 94 °C for 0.5 min, 58 °C for 1 min and 72 °C for 1 min This was followed by a final extension step at 72 °C for 10 min. The primers used for PCR amplification were (5′-IndexTermCGAGTGGACGCGACCGTAGTTGG-3′) for sense murine MMP-9 and (5′-IndexTermCAGGCTGAGCACGCCATACAG-3′) for antisense, (5′-IndexTermCGGAGTCAACGGATTTGGTCGTAT-3′) for sense GAPDH and (5′-IndexTermAGCCTTCTCCATGGTGGTGAAGAC-3′) for antisense. Amplifications were performed in a thermal cycler (model PTC-100 TM, MJ Research). PCR assays using equal amounts of RNAs that were reverse transcribed and amplified by PCR for 25–40 cycles with gene-specific primers confirmed that the amplification was in the linear range for each gene. Furthermore, each assay was repeated two to four times to verify the accuracy of the results. As an internal control, amplification of GAPDH mRNA was carried out by reverse-transcription (RT)–PCR using specific primers. Amplified products were analyzed by electrophoresis on agarose gels using ethidium bromide staining and UV illumination. Loading was equalized to the internal control mRNA.
Comparisons between different groups for tumor uptake and survival distribution (mean survival time (MST)) were made using a log-rank test. The level of significance was determined at P<0.05.
Results and discussion
To determine whether leukemogenesis can occur in absence of MMP-9, we have compared the incidence of radiation-induced leukemia in normal and MMP-9-deficient mice. Such a model (4 weekly doses of 175 cGy) results in thymic lymphomas in most of the animals after a latency period varying between 3 and 6 months.17 Our results showed that T-cell leukemogenesis occurred in all mice treated with the radioleukemogenic regimen (Figure 1), whether or not MMP-9 was present. Moreover, the absence of MMP-9 did not significantly accelerate or delay the onsets of thymic leukemia, as the MST in wild-type and MMP-9-deficient mice (150.8±34.6 days versus 149.2±21.7 days, respectively) in both groups of mice was similar (P>0.05).
Since MMP-9-deficient mice did develop thymic lymphoma upon exposure to radiation, we took advantage of this opportunity to generate MMP-9-deficient T-lymphoma cell lines to test whether absence of MMP-9 in lymphoma cells can affect their tumorigenic potential and their ability to disseminate at distant sites after their intravenous injection in normal and MMP-9-deficient animals. Two MMP-9-deficient T-lymphoma cell lines, lines 2325 and 2333, were thus established from two different tumors that were collected from MMP-9-deficient mice. These cell lines were characterized at the genomic level and the presence of the homozygous mutation at the MMP-9 locus was confirmed by PCR on the genomic DNA (Figure 2a). Moreover, their inability to express MMP-9 either constitutively or following stimulation with PMA, a pharmacological agent known to stimulate MMP-9 in most cell types,19 including lymphoma cells, was confirmed at the mRNA and protein level by RT–PCR (Figure 2b) and gelatin zymography (Figure 2c). The MMP-9 deficiency in these leukemic cells did not affect the levels of MMP-2, or other MMP tested, including MMP-3, MMP-10 and MMP-7 as compared to 164T2 lymphoma cells (Figures 2b and c, and data not shown). Most importantly, we found that both MMP-9-deficient cell lines retained their tumorigenic potential, as shown by their ability to induce thymic lymphoma following intrathymic injection in young syngeneic wild-type animals (Figure 2d). Both cell lines were also capable of inducing thymic lymphoma in MMP-9-deficient mice, indicating that total absence of MMP-9 did not affect the tumorigenic potential of T-lymphoma cells. Interestingly, the intrathymic injection of the MMP-9-deficient 2333 lymphoma cells induced the growth of thymic lymphoma within a shorter time interval than that of another MMP-9-deficient cell line (2325) in both wild-type (55.0±9.6 days versus 29.8±0.4 days; P<0.01) and MMP-9-deficient mice (50.25±4.1days versus 35.0±0.1 days; P<0.01), indicating that the tumourigenic potential of T-lymphoma cells can be expressed independently of MMP expression.
To determine whether the incapacity of lymphoma cells to express MMP-9 can impair their ability to disseminate at distant sites, we injected the MMP-9-deficient lymphoma cells intravenously and compared the distribution of lymphoma in MMP-9-deficient mice with that of normal mice. In this model, injection of T-lymphoma cells induces the formation of lymphoid tumors in spleen, kidneys and liver with massive infiltration of tumor cells in the parenchyma.20, 21, 22 Evidence of tumor development was ascertained by macroscopic and histological examinations. Our results showed that MMP-9-deficient lymphoma cells can induce the formation of lymphoid tumors at distant sites without significant differences in the MST in both normal or MMP-9-deficient mice (Figure 3a). The MST for the wild-type mice (36.21 days±0.43) and the MMP-9-deficient mice (37.75 days±2.48) was indeed comparable when mice were injected with 2333 MMP-9-deficient mice (P>0.05). Similar results were obtained in mice injected with the 2325 MMP-9-deficient cell line. The MST for the wild-type mice (53.67 days±9.22) and the MMP-9-deficient mice (58.82 days±7.41) was also comparable when mice were injected with the wild-type 164T2 T-lymphoma cells (P>0.05). The ability of T lymphoma to form secondary tumor in peripheral tissues in complete absence of MMP-9 was confirmed by RT–PCR analysis in from tissues isolated from tumors in the liver and the kidneys (Figure 3b). While we could detect a constitutive expression of MMP-9 gene expression in normal tissues from kidneys and the liver of wild-type mice, no MMP-9 expression was detected in normal or tumor-bearing MMP-9-deficient mice. At necropsy, macroscopic examinations of mice injected with the MMP-9-deficient cells showed that MMP-9-deficient mice had large tumors in liver, spleen and kidneys, comparable to that observed in wild-type hosts. This observation was evident by histological analysis, which showed a severe infiltration of lymphoma cells in tissues of these organs in MMP-9-deficient animals and in normal mice (Figure 3c).
Overexpression of MMP-9 has been shown to promote the migration and invasion of cancer cells in several experimental models.23, 24, 25 This activity has been attributed at least in part to the ability of MMP-9 to increase blood vessel formation by proteolytically degrading type IV collagen in the basement membrane.26 Recent studies using in vivo models have shown, however, that inhibition of MMP-9 gene expression does not always results in the inhibition of tumor growth or metastasis, as predicted from many studies conducted using in vitro experiments. For instance, Deryugina et al.27 have observed that a substantial downregulation of MMP-9 expression by siRNA increased intravasation and metastasis in vivo. These results are reminiscent to a certain extent of those observed by Coussens et al.,28 who found that although MMP-9-deficient mice crossed with K14-HPV16 mice developed fewer tumors, higher-grade carcinomas with a less-differentiated phenotype were found in MMP-9-deficient animals as compared to wild types. Few other cases also exist where expression of MMPs negatively correlates with cancer progression. MMP-8-deficient mice have been shown to be more susceptible to 7,12-dimethylbenz[α]anthracene, to 12-O-tetradecanoyl-phorbol-13-acetate and to methylcholantrene chemically induced papillomas than normal mice.29 Like MMP-8, MMP-9 is also highly expressed by granulocytes, supporting the idea that MMP secreted by the host, such as the immune cells, can be protective against different types of cancer.30 More recently, Houghton et al.31 have also shown that MMP-12-deficient mice develop significantly more pulmonary metastases than their wild-type counterparts, suggesting that macrophage-derived MMP-12 may serve the host in some circumstances against tumor growth. The question then remains why the lymphoma cells disseminate with efficiency in the liver, kidneys and spleen in total absence of MMP-9 since this enzyme has been associated with high-grade lymphomas? We propose that while MMP-9 is not essential for the development of primary lymphoid tumors and the dissemination of lymphoma cells in peripheral tissues, elevated levels of MMP-9 may nevertheless increase the tumorigenic potential of lymphoma cells. In the present study, although mice injected with the MMP-9-deficient and wild-type T-lymphoma cells may have had some apparent differences in their tumorigenic potential when injected intrathymically in normal or MMP-9-deficient mice, it has not been possible to directly compare the aggressive behavior of these lymphoma cells since they were derived from different primary tumors, thus expressing a distinct genomic profile, a scenario which is reminiscent of what we find in clinical situation. To determine the importance of MMP-9 alone in conferring an aggressive behavior will necessitate the use of specific clones overexpressing MMP-9 and/or the use of siRNA strategies against aggressive lymphoma cell lines expressing high levels of MMP-9 constitutively, and/or to determine whether MMP-9-deficient T-lymphoma cells can evolve toward an aggressive phenotype as efficiently as do lymphoma cells with an intact MMP-9 gene. These experiments are currently in progress in our laboratory.
In conclusion, although the overall survival of mice was not affected by the absence of MMP-9 by the host, our results clearly show that leukemogenesis can occur in absence of MMP-9 and that lymphoma growth and dissemination can occur in total absence of MMP-9, and this deficiency does not alter the ability of tumor cells to invade peripheral sites, bringing up a cautionary note in the use of selective MMP-9 inhibitors for the treatment of invasive cancer. Thus although treatment with such inhibitors may at least partially overcome the aggressive behavior of lymphoma cells mediated by elevated levels of MMP-9, our results suggest such inhibitors will not be sufficient to completely eradicate the dissemination of lymphoma cells, and that combinatorial therapy to achieve such goal. Finally, our results further provide a new model to study the molecular mechanisms that distinguish the role of MMP-9 in different microenvironments, and most importantly what the importance is of the source of MMP-9 in tumor metastasis.
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We thank Doris Legault and Diane Tremblay for their excellent technical support, and Dr Edouard F Potworowski for critical reading of the manuscript. YSP is a scholar of the Fonds de la Recherche en Santé du Québec (FRSQ). MD and CVT were supported by studentships from the Fonds de la Recherche FRSQ. JSR is supported by a studentship from the Fondation Armand-Frappier. This work was supported by the Canadian Institute for Health Research and the National Cancer Institute of Canada (YSP) and the Belgian Foundation against Cancer, the Fund for Scientific Research of Flanders and the Geconcerteerde OnderzoeksActies (2006-2010) (GO).
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Roy, J., Van Themsche, C., Demers, M. et al. Triggering of T-cell leukemia and dissemination of T-cell lymphoma in MMP-9-deficient mice. Leukemia 21, 2506–2511 (2007). https://doi.org/10.1038/sj.leu.2404936
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