Biomedical subjects

Nicolas Wernert

Publications and source records attributed to Nicolas Wernert.

At least 19 recordsLinked to original sources

PubMed2006

Loss of imprinting of the insulin-like growth factor 2 and the H19 gene in testicular seminomas detected by real-time PCR approach.

IGF2 and H19 are imprinted genes in normal human tissue, but many studies have observed a loss of imprinting (LOI) of these genes in tumors as an epigenetic alteration of the DNA, that leads to a biallelic expression predisposing cells to carcinogenesis and tumor growth. The aim of this study was to test the reliability of LightCycler-assisted Real-time PCR in detecting LOI of IGF2 and H19 in 39 patients with testicular germ cell tumors by comparing these results with the analysis generated by the golden standard restriction fragment length polymorphism (RFLP). With LightCycler-assisted Real-time PCR for IGF2 44% and for H19 49% of the patients were found to be heterozygous. This was consistent with the results obtained by RFLP, but surprisingly RFLP failed in more than 7% of the patients. In detecting LOI (for IGF2 in 41% and for H19 in 68% of the informative patients) the approach by RFLP was superior, since the results derived from LightCycler-assisted Real-time PCR showed reliable results in 76 and 10% of the samples concerning IGF2 and H19, respectively. Again, no discrepancy between the results obtained by the two methods occurred. In sum, LightCycler-assisted Real-time PCR is a sufficiently working approach for the rapid and reliable detection of heterozygosity of IGF2 or H19 gene and identification of LOI of IGF2 and thus may be helpful in conducting large epidemiological studies. However, for the identification of LOI of the H19 gene in this cohort it possesses only restrictive use.

Cohort Studies↗

PubMed2006

Expression pattern of matrix metalloproteinase and TIMP genes in fibroblasts derived from Ets-1 knock-out mice compared to wild-type mouse fibroblasts.

Matrix-degrading proteases play a key role in normal development, wound healing, many diseases such as rheumatoid arthritis and, in particular, tumour invasion. In invasive tumours, these enzymes are expressed by fibroblasts of the tumour stroma. Their expression and activity are tightly regulated at several levels, an important one being transcription. Previous in vitro and in vivo findings pointed to a major role of the Ets-1 transcription factor for this level of regulation. In the present study, we tried to prove this role in fibroblasts. We stimulated wild-type mouse fibroblasts with physiological doses of basic fibroblast growth factor (bFGF, known to induce different proteases and expressed by tumour cells) and compared the results to those obtained in Ets-1 -/- fibroblasts derived from Ets-1 knock-out mice. We found that basal Ets-1 levels are necessary not only for a fast induction of MMPs 2, 3 and 13 by bFGF but also for maintenance of the bFGF-induced expression of tissue inhibitors of metalloproteinases (TIMPs) 1, 2 and 3, which are known not only to inhibit but also participate as activators of certain pro-MMPs.

Animals↗

PubMed2006

Tumour-stroma interactions between metastatic prostate cancer cells and fibroblasts.

Previous work has shown the importance of tumour-stroma interactions for prostate cancer development at the primary site. The aim of the present study was to find out whether evidence can be found for a tumour-stroma cross- talk also between metastatic prostate cancer cell lines and non-prostatic stromal fibroblasts which are encountered by metastatic cells at most sites. We addressed this issue in cell culture systems using 3 metastatic human prostate cancer cell lines (LnCaP, PC-3 and DU-145) on the one hand, and a human fibroblast line (HFF, human foreskin fibroblasts) on the other. We incubated fibroblasts with tumour cell- and tumour cells with fibroblast-conditioned media and evaluated several parameters important for the establishment of metastases such as cell proliferation, migration and expression of matrix degrading proteases. We also determined in the conditioned media the concentrations of several growth factors and cytokines which might be responsible for the observed effects. We found that media conditioned by all 3 metastatic prostate cancer cell lines stimulated fibroblast proliferation which corresponds to fibrous stroma induction in vivo. DU-145 cell conditioned media induced in fibroblasts expression of mmp-1 mRNA known to be important for tumour invasion. ELISA assays revealed that tumour cells secrete bFGF, PDGF and TNFalpha known to stimulate fibroblast proliferation and/or MMP-1 expression. Cultivation of DU-145 carcinoma cells in fibroblast conditioned medium resulted in an enhanced proliferation and anchorage-independent growth of this cell line in soft agar. Fibroblast conditioned medium also increased migration of PC-3 cells in the wound assay and slightly augmented mmp-1 expression. KGF (able to stimulate proliferation of normal and neoplastic prostate epithelial cells) was secreted by fibroblasts at higher concentrations than by all 3 tumour cell lines. In addition, fibroblasts secreted TNFalpha, bFGF, PDGF, HGF and also VEGF, the most important factor for tumour vascularization. Our results provide evidence that tumour-stroma interactions do not only exist at the primary site but also between metastatic prostate cancer cell lines and their fibroblastic microenvironment. These interactions, which are mediated through secreted factors, affect several steps of the metastatic cascade including proliferation, anchorage-independent growth, migration and the secretion of matrix-degrading proteases.

Carcinoma↗

PubMed2005

Spatial expression of germ cell markers during maturation of human fetal male gonads: an immunohistochemical study.

BACKGROUND: The aim of the present study was to examine fetal male germ cells for expression of proteins associated with differentiation and maturation and to compare them with morphologically defined subpopulations. METHODS: Testes of 61 fetuses from week 12 of gestation to the newborn period were selected. Immunohistochemistry was performed using antibodies to proteins associated with differentiation of germ cells (c-KIT, AP-2gamma) or pluripotency (OCT3/4), oncofetal protein M2A and spermatogonial marker MAGE-A4. RESULTS: Two subtypes of fetal germ cells were detected by quantification and immunohistochemistry. Nearly all germ cells with morphological criteria of gonocytes and intermediate cells co-expressed OCT3/4, c-KIT, M2A and AP-2gamma. Starting from week 12, their number increased up to week 18/19 and then declined continuously during further development. After week 25, pre-spermatogonia were predominant and expressed MAGE-A4 selectively. CONCLUSIONS: Fetal male germ cells are comprised of two major groups with distinct immunohistochemical phenotypes. Germ cells that are predominantly found before week 25 of gestation co-express oncofetal proteins OCT3/4, c-KIT, M2A and AP-2gamma. After week 25, most germ cells have lost their pluripotent potential and acquire a spermatogonial phenotype defined by expression of MAGE-A4.

Antigens, Neoplasm↗

PubMed2005

Cells of primarily extra-valvular origin in degenerative aortic valves and bioprostheses.

AIMS: We assessed aortic valves from patients with non-rheumatic aortic valve stenosis (AS) and with degenerative aortic valve bioprostheses (BP) for the presence of progenitor cell and leukocyte subtype-specific markers. METHODS AND RESULTS: Diseased valve probes from a total of 87 patients (60 AS and 27 BP) were studied. We assessed presence and localization of endothelial progenitor cells (EPCs: CD34, CD133), dendritic cells (DCs: S100), T-lymphocytes (CD3), and macrophages (CD68) by immunohistochemical and morphometric analyses. In the majority of valves, we detected cell-bound signals of CD34 (48% of AS, 74% of BP, respectively), CD133 (58%/81%), S100 (58%/93%), CD3 (62%/81%), and CD68 (78%/93%). Labelled cells were predominantly localized within the valvular fibrosa. As key results, frequency of EPCs, DCs, macrophages, and lymphocytes was found significantly higher in BP when compared with AS (CD34: 19.2+/-23.2 vs. 5.7+/-13.0%; CD133: 13.7+/-12.4 vs. 5.5+/-8.3%; S100: 15.2+/-12.2 vs. 5.7+/-8.9%; CD3: 3.3+/-2.7 vs. 1.1+/-1.4%; CD68: 35.3+/-26.6 vs. 3.4+/-4.1%; each P<or=0.001). CONCLUSION: EPCs and DCs were detected in a large collective of degenerative aortic valves, more frequently in bioprostheses than in native cusps. Aortoluminal presence of these primarily extra-valvular cells co-localized with inflammatory cells is a novel key feature involved in aortic valve degeneration.

Aged↗

PubMed2005

Ets-1 expression promotes epithelial cell transformation by inducing migration, invasion and anchorage-independent growth.

Ets-1 is the prototype of the family of ETS transcription factors. In human tumors, Ets-1 is expressed in endothelial cells and fibroblasts of the tumor stroma and is proposed to play a role in tumor vascularization and invasion by upregulating expression of matrix-degrading proteases. In human carcinomas, Ets-1 is also expressed by neoplastic cells, but little is known about the functional implications of this observation. We have addressed the role of Ets-1 in epithelial HeLa tumor cells by selecting stably Ets-1 over and underexpressing HeLa cells. Ets-1 expression increases the transformed phenotype of HeLa cells, by promoting cell migration, invasion and anchorage-independent growth, while Ets-1 downregulation reduces cell attachment. In correlation with these results, Ets-1 upregulation increases integrinbeta2 expression but not that of other integrins. These results suggest that, in addition to its role in the tumor stroma, Ets-1 may also promote tumor development and progression by increasing neoplastic transformation.

Cell Adhesion↗

PubMed2005

Diagnostic and prognostic information in prostate cancer with the help of a small set of hypermethylated gene loci.

PURPOSE: Our study was designed to evaluate promoter CpG island hypermethylation in the diagnosis and prognosis of prostate cancer. EXPERIMENTAL DESIGN: Primary prostate cancers from 53 patients, pelvic lymph nodes, noncancerous prostate tissues, and prostate cell lines were analyzed. Real-time methylation-specific PCR was used to identify CpG island hypermethylation at five promising gene loci (i.e., GSTP1, APC, PTGS2, MDR1, and RASSF1a). RESULTS: At three gene loci (GSTP1, APC, and PTGS1) and CpG island, hypermethylation was highly prevalent in prostate cancers (71-91%), and analysis of receiver operator curves showed that hypermethylation at these three gene loci can distinguish between prostate cancer and noncancerous prostatic tissue (i.e., benign hyperplasia) with a sensitivity of 71.1% to 96.2% and a specificity of 92.9% to 100%. Using sensitive SYBR green methylation-specific PCR technology, we observed a respective 28% and 71% hypermethylation rate at the RASSF1a and MDR1 loci in benign prostate hyperplasia, which may represent early nonaggressive carcinogenesis. Methylation characteristics in prostate cancer metastases (i.e., pelvic lymph nodes) were comparable to the respective primary cancer. Statistical analysis showed no correlation between the methylation status of a single gene locus and clinicopathologic variables (e.g., preoperative prostate specific antigen levels, Gleason score, capsular penetration, involvement of seminal vesicle, and age). In contrast, the methylation of two (GSTP1/APC; GSTP1/PTGS2) or three (GSTP1/APC/PTGS2) gene loci correlated with prognostic indicators (i.e., pathologic stage, extraprostatic extension, and Gleason score, but not with prostate specific antigen levels). CONCLUSIONS: Our data suggest that the evaluation of DNA hypermethylation at three gene loci (i.e., GSTP1, APC, and PTGS2) is of diagnostic and prognostic value in prostate cancer.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2005

Effective antitumour mono- and combination therapy by gene delivery of angiostatin-like molecule and interleukin-12 in a murine hepatoma model.

METHODS: We applied an experimental approach employing two recombinant adenoviral vectors (Ad) that express interleukin-12 (IL-12) and angiostatin-like molecule (K1-3) respectively to a subcutaneous hepatoma model in mice. RESULTS: Injection of AdK1-3 into tumour nodules established by subcutaneous (s.c.) implantation of Hepa129 hepatoma cells in C3H mice resulted in a significant dose-dependent reduction in tumour growth by 57% in the high dosage group (5x10(9) plaque-forming units [pfu], n=8) 10 days after treatment initiation. Similar antitumoural effects were found for the intratumoural mono-therapy with IL-12 (2.5x10(9) pfu, n=8) resulting in 60% tumour inhibition at the same time point. The survival rate was significantly (p=0.009) improved in the IL-12 but not in the K1-3 treatment group. A combination therapy of AdK1-3 and AdIL-12 was also effective, but did not further improve antitumour efficacy compared with the monotherapy. CONCLUSION: In conclusion, both mono- and combination therapy of K1-3 and IL-12 significantly inhibited tumour progression in this experimental tumour model. The co-administration of both compounds did not result in additive antitumour effects. We hypothesise that the lack of additive antitumour effects of the combination treatment might be attributed to partially counteracting antitumour effects and further studies are needed to illustrate the interference of tumour angiogenesis and tumour inflammation in this tumour model.

Adenoviridae↗

PubMed2005

Effective angiostatic treatment in a murine metastatic and orthotopic hepatoma model.

Vascular endothelial growth factor (VEGF) activity is correlated with a progressive tumor disease in patients with hepatocellular carcinoma (HCC). In spite of the well-recognized role of VEGF in HCC, there are few data available regarding therapeutic strategies to block VEGF activity. Therefore, we employed a recombinant adenoviral vector encoding a soluble dominant negative fragment of VEGF receptor 2 (Flk-1), AdsFlk-1, to control pre-established murine orthotopic and metastatic hepatomas. Vector function was confirmed via reverse-transcriptase polymerase chain reaction and ELISA, and angiostatic effects were analyzed in vitro and in vivo. Antitumoral effects of systemic AdsFlk-1 application were studied in a subcutaneous and orthotopic Hepa129 HCC model. Cell supernatant containing the truncated form of Flk-1 had no direct effect on cell proliferation of Hepa129 cells in vitro but reduced endothelial tube formation on matrigel matrix by approximately 80% in vitro. Endothelial-like cell infiltration into matrigel plugs in vivo was also decreased by 80%. Systemic treatment of tumor-bearing mice inhibited tumor growth by 84% compared with the corresponding control group within 16 days after vector application. Likewise, the survival rate was significantly improved in the AdsFlk-1 group compared with control. Orthotopic tumor growth was reduced by 82%, and development of malignant ascites was also retarded. In conclusion, systemic adenoviral-mediated gene transfer of an Flk-1 fragment significantly inhibited tumor growth in orthotopic and metastatic murine HCC. The data support the value of VEGF blockade as an effective target for HCC treatment.

Adenoviridae↗

PubMed2005

Novel tempeh (fermented soyabean) isoflavones inhibit in vivo angiogenesis in the chicken chorioallantoic membrane assay.

Anti-angiogenic strategies are emerging as an important tool for the treatment of cancer and inflammatory diseases. In the present investigation we isolated several isoflavones from a tempeh (fermented soyabean) extract. The isolated isoflavones were identified as 5,7,4'-trihydroxyisoflavone (genistein), 7,4'-dihydroxyisoflavone (daidzein), 6,7,4'-trihydroxyisoflavone (factor 2), 7,8,4'-trihydroxyisoflavone (7,8,4'-TriOH) and 5,7,3',4'-tetrahydroxyisoflavone (orobol). The effects on angiogenesis of these isoflavones were evaluated in the chicken chorioallantoic membrane assay; their capacity to inhibit vascular endothelial growth factor-induced endothelial cell proliferation and expression of the Ets 1 transcription factor, known to be implicated in the regulation of new blood vessel formation, were also investigated. We found that all isoflavones inhibited angiogenesis, albeit with different potencies. Compared with negative controls, which slightly inhibited in vivo angiogenesis by 6.30 %, genistein reduced angiogenesis by 75.09 %, followed by orobol (67.96 %), factor 2 (56.77 %), daidzein (48.98 %) and 7,8,4'-TriOH (24.42 %). These compounds also inhibited endothelial cell proliferation, with orobol causing the greatest inhibition at lower concentrations. The isoflavones also inhibited Ets 1 expression, providing some insight into the molecular mechanisms of their action. Furthermore, the chemical structure of the different isoflavones suggests a structure-activity relationship. Our present findings suggest that the new isoflavones might be added to the list of low molecular mass therapeutic agents for the inhibition of angiogenesis.

Angiogenesis Inhibitors↗

PubMed2005

A novel component of the ubiquitin pathway, ubiquitin carboxyl extension protein 1 is overexpressed in prostate cancer.

Prostate cancer is among the most common tumors in industrialized nations. However, little is known about the molecular events underlying its development. In the present study we used suppressive subtraction hybridization (SSH) in combination with laser-assisted microdissection in order to compare gene expression between prostate carcinoma and the normal prostate proper. Both are mixed tissues which consist of an epithelial and a stromal compartment. We first compared mRNA (cDNA) expression by SSH and then used real-time quantitative RT-PCR analysis of microdissected tissue probes in order to verify differential expression of subtracted cDNA clones. We also used differentially expressed cDNAs for the synthesis of radiolabelled riboprobes in order to attribute differential expression to specific cell types in tissue sections by in situ hybridization. Using this approach we found an up-regulation of ubiquitin carboxyl extension protein 1 (UBCEP-1) mRNA in prostate carcinoma cells compared to the normal glandular epithelium of the prostate proper. UBCEP-1 mediated ubiquitin chain elongation may promote prostate carcinoma development by increasing via the proteasome pathway the degradation of proteins which are involved in growth inhibition or apoptosis.

Aged↗

PubMed2005

Laser-assisted microdissection, techniques and applications in pathology (review).

Innovations in molecular medicine provided sophisticated tools for analysis of the pathogenesis of diseases. Much emphasis is put on examination of alterations in affected organ systems. However, since in vivo tissues are inherently complex mixtures of different cell types, specific molecular data on individual cell populations are difficult to obtain. The advent of laser assisted microdissection (LAM) now allows efficient isolation of pure cell populations and even of single cells from mixed tissues. The most promising aspect of LAM is its combination with different molecular downstream analyses of microdissected cells at the levels of the genome, the transcriptome and the proteome. This review focuses on the two basic techniques of laser-assisted microdissection and on its applications in molecular pathology.

Genomics↗

PubMed2005

Inactivation of Ets 1 transcription factor by a specific decoy strategy reduces rat C6 glioma cell proliferation and mmp-9 expression.

Malignant gliomas represent the most aggressive tumours of the central nervous system and are characterised by both extensive proliferation and invasive growth. Matrix degrading proteases called matrix metalloproteinases (MMPs), particularly MMP-9, play a crucial role in glioma infiltration. The activity of these enzymes is regulated at different levels. In this regard, the control of transcriptional activity by specific transcription factors is believed to be very important. In the present study, we examined whether rat C6 glioma cells express the Ets 1 transcription factor and whether inhibition of Ets 1 by a specific decoy strategy affects C6 glioma cell proliferation and mmp-9 expression. We found that C6 glioma cells express Ets 1 and can efficiently be transfected with an Ets 1-specific decoy oligodesoxynucleotide (ODN). This ODN significantly reduces cell proliferation and mmp-9 expression, the latter in a dose-dependent manner. We conclude that inhibition of transcription factors, which play a role for glioma development and progression such as Ets 1 by specific decoy approaches, might represent useful tools for experimental therapeutic strategies against malignant gliomas.

Animals↗

PubMed2005

Cellular retinoic acid-binding protein 2 is down-regulated in prostate cancer.

Prostate cancer is among the most frequent tumours in industrialized nations and many questions remain open concerning the molecular events underlying its development and progression. In the present study we have combined cDNA array hybridization to laser-assisted microdissection (LAM) in order to investigate differences in gene expression between epithelial and stromal cells of prostate cancer and normal peripheral prostate tissue. Results have been verified for selected candidate genes by quantitative real-time RT-PCR. Using this approach and immunohistochemistry we could demonstrate a down-regulation of cellular retinoic acid binding protein 2 (CRABP2) mRNA and protein in carcinoma cells compared to normal glandular cells. CRABP2 is a main regulator of anti-carcinogenic activities of retinoic acid and may become a novel diagnostic marker and experimental therapeutic tool for prostate cancer. In addition, results of cDNA array hybridization suggest an up-regulation of 34 further genes and a down-regulation of 6 genes in cancer tissues compared to normal peripheral prostate tissues. Several of these genes have already been reported to be associated with carcinogenesis in organs such as the prostate.

Aged↗

PubMed2004

Pathogen burden, inflammation, proliferation and apoptosis in human in-stent restenosis. Tissue characteristics compared to primary atherosclerosis.

Pathogenic events leading to in-stent restenosis (ISR) are still incompletely understood. Among others, inflammation, immune reactions, deregulated cell death and growth have been suggested. Therefore, atherectomy probes from 21 patients with symptomatic ISR were analyzed by immunohistochemistry for pathogen burden and compared to primary target lesions from 20 stable angina patients. While cytomegalovirus, herpes simplex virus, Epstein-Barr virus and Helicobacter pylori were not found in ISR, acute and/or persistent chlamydial infection were present in 6/21 of these lesions (29%). Expression of human heat shock protein 60 was found in 8/21 of probes (38%). Indicated by distinct signals of CD68, CD40 and CRP, inflammation was present in 5/21 (24%), 3/21 (14%) and 2/21 (10%) of ISR cases. Cell density of ISR was significantly higher than that of primary lesions (977 +/- 315 vs. 431 +/- 148 cells/mm(2); p < 0.001). There was no replicating cell as shown by Ki67 or PCNA. TUNEL(+) cells indicating apoptosis were seen in 6/21 of ISR specimens (29%). Quantitative analysis revealed lower expression levels for each intimal determinant in ISR compared to primary atheroma (all p < 0.05). In summary, human ISR at the time of clinical presentation is characterized by low frequency of pathogen burden and inflammation, but pronounced hypercellularity, low apoptosis and absence of proliferation.

Aged↗

PubMed2004

Distribution of extracellular matrix proteins in pterygia: an immunohistochemical study.

PURPOSE: This study was carried out to monitor the expression of extracellular matrix proteins (ECMs) and metalloproteinases (MMPs) in pterygial tissue. METHODS: Twenty primary nasal pterygia were studied by indirect routine immunohistochemistry using 13 different primary antibodies against 8 ECMs (five collagens, fibronectin, heparan sulfate, and laminin) fibroblast growth factor (bFGF), von Willebrand factor (vWF), and 3 MMPs (8, 9, and 13). Secondary antibodies were fluoresceinated. Intensity of reaction on individual sections was graded semi-quantitatively. RESULTS: No expression of collagens I, II, and VII was found. Antibodies against collagen III reacted strongly positively (+++) with the entire pterygial stroma. Collagen IV expression was strongly positive in the wall of pterygial blood vessels, moderately positive (++) in the epithelial basement membrane, and only weakly positive (+) all over the stroma. Antibodies against fibronectin reacted moderately positively with stroma, blood vessel walls and epithelial basement membrane. Heparan sulfate was strongly expressed in the blood vessel walls and epithelial basement membrane. Antibodies against bFGF reacted only with pterygial epithelium. Laminin was strongly expressed in blood vessel wall, moderately (++) in the epithelial basement membrane and weakly over the entire stroma. vWF was strongly positive (+++) with pterygial blood vessel walls. Antibody reactions for MMPs differed. It was strong with pterygial epithelium (MMPs 8, 9 and 13), strong to moderate with pterygial stroma (MMPs 8 and 13 versus 9), and absent to weak with pterygial vascular walls (MMPs 8 and 13 versus 9). CONCLUSIONS: This study documents the presence of several ECMs but excludes the expression of others in pterygial tissues. The results especially indicate an active involvement of MMPs 8, 9 and 13 in the pathogenesis of pterygia.

Adult↗

PubMed2004

Establishment of an orthotopic tumour model for hepatocellular carcinoma and non-invasive in vivo tumour imaging by high resolution ultrasound in mice.

BACKGROUND/AIMS: In this study we established an orthotopic tumour model for hepatocellular carcinoma and evaluated a non-invasive high resolution ultrasound technique for diagnosis and follow-up of intrahepatic HCC. METHODS: Orthotopic liver tumours were induced by intrahepatic tumour cell injection of 10(5) Hepa129 hepatoma cells. Tumour establishment and growth were assessed by explorative laparotomy, ultrasound technique and hepatectomy one and two weeks after tumour cell implantation. Tumour establishment was confirmed histologically in liver sections. RESULTS: Our results show that the Hepa129 hepatoma cell line is suitable for orthotopic tumour establishment and that tumours can be diagnosed correctly by ultrasound imaging in all cases as confirmed by explorative laparotomy, hepatectomy and cross-sections. Tumour diameters obtained by explorative laparotomy correlated significantly with diameters assessed by ultrasound (r=0.7; P<0.0001). Tumour burden was slightly overestimated (1.2-fold) by ultrasound one week after tumour induction and relative tumour extensions increased 1.7-fold and 1.8-fold within one week as determined by subsequent explorative laparotomy or ultrasound imaging, respectively. CONCLUSIONS: These data demonstrate in a systematic study that ultrasound imaging can be used as a reliable tool to detect and to follow up orthotopic liver tumours in this tumour model in mice.

Animals↗

PubMed2003

Stromal expression of invasion-promoting, matrix-degrading proteases MMP-1 and -9 and the Ets 1 transcription factor in HNPCC carcinomas and sporadic colorectal cancers.

Hereditary nonpolyposis colorectal cancers (HNPCCs) are an important subgroup of colorectal carcinomas. Compared to sporadic variants, they present several particular features, the most important of which are less invasive and metastatic properties linked to a more favorable prognosis. This contrasts to the generally poor differentiation of the epithelial tumor component. Since matrix-degrading proteases secreted by stromal fibroblasts contribute significantly to tumor invasion, we analyzed the stromal expression of 2 matrix metalloproteinases (MMP-1 and -9) and of one of their regulators, the Ets 1 transcription factor, by both immunohistochemistry and in situ hybridization in sporadic colorectal carcinomas and HNPCC tumors. We found that MMP-1 and -9 as well as Ets 1 are upregulated in the fibroblastic stroma during the development from sporadic adenomas to invasive carcinomas. HNPCC tumors exhibited a significantly lower expression of Ets 1, MMP-1 and -9. These findings on the basis of lower matrix-degrading properties of the fibroblastic tumor stroma in HNPCC tumors might help to explain why, in spite of their less differentiated phenotype, HNPCC tumors have a less invasive and metastatic potential compared to sporadic cancers.

Adenoma↗