ST3

Gene Summary

Gene:ST3; suppression of tumorigenicity 3
Aliases: CCTS, TSHL
Location:11q13-q23
Summary:-
Databases:OMIM, HGNC, GeneCard, Gene
Source:NCBIAccessed: 09 March, 2017

Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 09 March 2017 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Staging
  • STAT3 Transcription Factor
  • Neoplasm Metastasis
  • Neoplasm Proteins
  • RNA
  • Breast Cancer
  • Biomarkers, Tumor
  • Stromal Cells
  • Carcinoma in Situ
  • Nuclear Proteins
  • Transfection
  • Northern Blotting
  • Squamous Cell Carcinoma
  • Neoplasm Invasiveness
  • Lymphatic Metastasis
  • Messenger RNA
  • Neoplastic Cell Transformation
  • Metalloendopeptidases
  • Gene Expression
  • Chromosome 11
  • Base Sequence
  • Cancer DNA
  • MUC1
  • Fibroblasts
  • Carcinoma
  • Cancer RNA
  • Collagenases
  • MMP11
  • Neoplasm Recurrence, Local
  • Molecular Sequence Data
  • Wound Healing
  • Cancer Gene Expression Regulation
  • Breast
  • Estrogen Receptors
  • Urokinase-Type Plasminogen Activator
  • Ductal Breast Carcinoma
  • In Situ Hybridization
  • RTPCR
  • Xenopus laevis
  • Transcription Factors
Tag cloud generated 09 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (2)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: ST3 (cancer-related)

Timofeeva OA, Tarasova NI, Zhang X, et al.
STAT3 suppresses transcription of proapoptotic genes in cancer cells with the involvement of its N-terminal domain.
Proc Natl Acad Sci U S A. 2013; 110(4):1267-72 [PubMed] Free Access to Full Article Related Publications
Activation of STAT3 in cancers leads to gene expression promoting cell proliferation and resistance to apoptosis, as well as tumor angiogenesis, invasion, and migration. In the characterization of effects of ST3-H2A2, a selective inhibitor of the STAT3 N-terminal domain (ND), we observed that the compound induced apoptotic death in cancer cells associated with robust activation of proapoptotic genes. Using ChIP and tiling human promoter arrays, we found that activation of gene expression in response to ST3-H2A2 is accompanied by altered STAT3 chromatin binding. Using inhibitors of STAT3 phosphorylation and a dominant-negative STAT3 mutant, we found that the unphosphorylated form of STAT3 binds to regulatory regions of proapoptotic genes and prevents their expression in tumor cells but not normal cells. siRNA knockdown confirmed the effects of ST3-HA2A on gene expression and chromatin binding to be STAT3 dependent. The STAT3-binding region of the C/EBP-homologous protein (CHOP) promoter was found to be localized in DNaseI hypersensitive site of chromatin in cancer cells but not in nontransformed cells, suggesting that STAT3 binding and suppressive action can be chromatin structure dependent. These data demonstrate a suppressive role for the STAT3 ND in the regulation of proapoptotic gene expression in cancer cells, providing further support for targeting STAT3 ND for cancer therapy.

Choi SY, Jang JH, Kim KR
Analysis of differentially expressed genes in human rectal carcinoma using suppression subtractive hybridization.
Clin Exp Med. 2011; 11(4):219-26 [PubMed] Related Publications
The existence and treatment of rectal cancer are important for the function of defecation and the quality of life. However, the precise mechanisms of rectal carcinogenesis remain unclear. To screen the overexpressed gene in rectal carcinoma, we performed suppressive subtractive hybridization (SSH) on rectal carcinoma cells and the corresponding normal rectal cells. A total of 64 recombinant clones were subjected to DNA sequencing analysis, and 9 known genes were found to overexpressed in the tumors compared with those of the normal tissues. The genes are ST3 beta-galactoside alpha-2,3-sialyltransferase (ST3GAL5), interferon-induced transmembrane protein 3 (IFITM3), platelet-derived growth factor A-associated protein 1 (PDAP1), AlkB alkylating repair homolog 3 (ALKBH3), nucleoside diphosphate linked moiety X (Nudix)-type motif 14 (NUDT14), calponin 2 (CNN2), mitogen-activated protein kinase 14 (MAPK14), aconitase 1 (ACO1), and selenophosphate synthetase 1 (SEPHS1). The expression profiles of the genes were further confirmed in rectal carcinoma cells and the corresponding normal rectal cells of 12 patients by quantitative real-time RT-PCR. Our results revealed that ST3GAL5, IFITM3, PDAP1, ALKBH3, NUDT14, CNN2, MAPK14, ACO1, and SEPHS1 may be involved in rectal carcinogenesis.

Wang L, Xiang YN, Zhang YH, et al.
Collagen triple helix repeat containing-1 in the differential diagnosis of dermatofibrosarcoma protuberans and dermatofibroma.
Br J Dermatol. 2011; 164(1):135-40 [PubMed] Related Publications
BACKGROUND: The distinction between dermatofibroma (DF) and dermatofibrosarcoma protuberans (DFSP) is a well-known challenge for dermatopathologists. Immunohistochemical stains have been used to augment routine histological examination to aid in differentiating DF from DFSP. Collagen triple helix repeat containing-1 (Cthrc1) was identified as a novel gene expressed in the adventitia and neointima on arterial injury. It is indicated to be a cell type-specific inhibitor of transforming growth factor-β, which in turn impacts collagen type I and III deposition, neointimal formation, and dedifferentiation of stem cells. Cthrc1 has also been shown to be highly active and potent in degrading extracellular matrix proteins and was found to be overexpressed in several malignant tumours, such as breast cancer and malignant melanoma. To our knowledge, however, expression of Cthrc1 in DFSP and DF has not been studied before.
OBJECTIVES: To assess the expression of Cthrc1 in DFSP and DF and to ascertain whether Cthrc1 is superior to antibodies traditionally used in differentiating DF from DFSP.
METHODS: Immunohistochemical staining was performed on 23 cases of DFSP and 35 cases of DF, using antibodies to Cthrc1, CD34, factor XIIIa, CD10 and stromelysin-3 (ST3).
RESULTS: Twenty-two of 23 (96%) DFSP samples were positive for Cthrc1, whereas 32 of 35 (91%) DF samples were negative. CD34 was expressed in most DFSPs (22 of 23, 96%), whereas it was completely negative in most cases of DF (29 of 35, 83%). Expression of factor XIIIa was found in most cases of DF (33 of 35, 94%), whereas it was completely absent in 21 of 23 (91%) DFSP cases. Expression of CD10 was found in most cases of DF (30 of 35, 86%), whereas it was completely absent in 13 of 23 (57%) DFSP cases. ST3 was expressed strongly in most cases of DF (32 of 35, 91%), whereas it was completely absent in 18 of 23 (78%) DFSP cases. The preferential Cthrc1 staining of DFSP in comparison with DF was statistically significant (P < 0·01).
CONCLUSIONS: We confirmed that Cthrc1 is a positive marker for DFSP and that Cthrc1 staining might be more reliable than markers traditionally used. Cthrc1 was not positive in absolutely [corrected] all cases of DFSP, and combination with CD34, factor XIIIa and ST3 immunostaining could make the distinction more reliable.

Fiorentino M, Fu L, Shi YB
Mutational analysis of the cleavage of the cancer-associated laminin receptor by stromelysin-3 reveals the contribution of flanking sequences to site recognition and cleavage efficiency.
Int J Mol Med. 2009; 23(3):389-97 [PubMed] Free Access to Full Article Related Publications
The matrix metalloproteinase stromelysin-3 (ST3) has long been implicated to play an important role in cell fate determination during normal and pathological processes. Using the thyroid hormone-dependent Xenopus laevis metamorphosis as a model, we have previously shown that ST3 is required for apoptosis during intestinal remodeling and that laminin receptor (LR) is an in vivo substrate of ST3 during this process. ST3 cleaves LR at two distinct sites that are conserved in mammalian LR. Human ST3 and LR are both associated with tumor development and cancer progression and human LR can also be cleaved by ST3, implicating a role of LR cleavage by ST3 in human cancers. Here, we carried out a series of mutational analyses on the two cleavage sites in LR. Our findings revealed that in addition to primary sequence at the cleavage site (positions P3-P3', with the cleavage occurring between P1-P1'), flanking sequences/conformation also influenced the cleavage of LR by ST3. Furthermore, alanine substitution studies led to a surprising finding that surrounding sequence and/or conformation dictated the site of cleavage in LR by ST3. These results thus have important implications in our understanding of substrate recognition and cleavage by ST3 and argue for the importance of studying ST3 cleavage in the context of full-length substrates. Furthermore, the LR cleavage mutants generated here will also be valuable tools for future studies on the role of LR cleavage by ST3 in vertebrate development and cancer progression.

Aronica E, Boer K, Redeker S, et al.
Differential expression patterns of chloride transporters, Na+-K+-2Cl--cotransporter and K+-Cl--cotransporter, in epilepsy-associated malformations of cortical development.
Neuroscience. 2007; 145(1):185-96 [PubMed] Related Publications
Malformations of cortical development are recognized causes of chronic medically intractable epilepsy. An increasing number of observations suggests an important role for cation-chloride co-transporters (CCTs) in controlling neuronal function. Deregulation of their expression may contribute to the mechanisms of hyperexcitability that lead to seizures. In the present study the expression and cell-specific distribution of Na+-K+-2Cl--cotransporter (NKCC1) and K+-Cl--cotransporter (KCC2) were studied immunocytochemically in different developmental lesions, including focal cortical dysplasia (FCD) type IIB (n=9), hemimegalencephaly (HMEG, n=6) and ganglioglioma (GG, n=9) from patients with medically intractable epilepsy and in age-matched controls. In normal control adult cortex, NKCC1 displayed low neuronal and glial expression levels. In contrast KCC2 showed strong and diffuse neuropil staining. Notable glial immunoreactivity (IR) was not found for KCC2. NKCC1 was highly expressed in the majority of FCD, HMEG and GG specimens. NKCC1 IR was observed in neurons of different size, including large dysplastic neurons, in balloon cells (in FCD and HMEG cases) and in glial cells with astrocytic morphology. The immunoreactivity pattern of KCC2 in FCD, HMEG and GG specimens was characterized by less neuropil staining and more intrasomatic IR compared with control. KCC2 IR was observed in neurons of different size, including large dysplastic neurons, but not in balloon cells or in glial cells with astrocytic morphology. Double-labeling experiments confirmed the differential cellular distribution of the two CCTs and their expression in GABA(A) receptor (alpha1 subunit)-positive dysplastic neurons. The cellular distribution of CCTs, with high expression of NKCC1 in dysplastic neurons and altered subcellular distribution of KCC2 resembles that of immature cortex and suggests a possible contribution of CCTs to the high epileptogenicity of malformations of cortical development.

Skoglund J, Emterling A, Arbman G, et al.
Clinicopathological significance of stromelysin-3 expression in colorectal cancer.
Oncology. 2004; 67(1):67-72 [PubMed] Related Publications
OBJECTIVE: Stromelysin-3 (ST3) is a member of the matrix metalloproteinases and suggested to play a role in tissue remodeling observed in growth and metastasis of tumors. ST3 overexpression in breast cancer is associated with a worse outcome. Our aims were to analyze ST3 expression in primary colorectal tumors and metastases, and further to identify relationships of the expression to clinicopathological factors.
MATERIALS AND METHODS: ST3 expression was immunohistochemically analyzed in 200 primary colorectal adenocarcinomas and 36 corresponding lymph node metastases.
RESULTS: Scoring was performed by counting the percentages of positive cells and the percentages of positive areas. One hundred and one (51%) cases showed < or = 5% positive cells and 99 (49%) >5% positive cells. One hundred and two (51%) cases showed < or = 30% positive area and 98 (49%) >30% positive area. ST3 expression determined by both scoring methods was individually related to females, distally located tumors, infiltrative growth pattern and microsatellite stability. No relationship was found with age, Dukes' stage, differentiation and survival.
CONCLUSIONS: These results suggest that ST3 protein was more involved in the pathway of colorectal cancer development in females, distal locations, infiltrative growth patterns and microsatellite stability.

Zou W, McDaneld L, Smith LM
Caveolin-1 haploinsufficiency leads to partial transformation of human breast epithelial cells.
Anticancer Res. 2003 Nov-Dec; 23(6C):4581-6 [PubMed] Related Publications
BACKGROUND: Caveolin-1 (Cav-1), a principal component of caveolae membranes, may function as a tumor suppressor in several types of human cancer.
MATERIALS AND METHODS: In this report, we employed a retrovirus-mediated poly-A gene trapping approach to inactivate expression of genes that may be involved in transformation of mammary cells and screened for cell growth in soft agar.
RESULTS: We found two anchorage-independent clones (ST1 and ST3) that expressed reduced levels (approximately 50%) of Cav-1 mRNA and protein, suggesting the inactivation of one allele of Cav gene. However, haploinsufficiency of Cav-1 expression did not induce significant tumor formation when tested in nude mice.
CONCLUSION: Cav-1 haploinsufficiency in human breast epithelial cells can lead to partial transformation.

Hamstra DA, Pagé M, Maybaum J, Rehemtulla A
Expression of endogenously activated secreted or cell surface carboxypeptidase A sensitizes tumor cells to methotrexate-alpha-peptide prodrugs.
Cancer Res. 2000; 60(3):657-65 [PubMed] Related Publications
Methotrexate (MTX) is one of the most commonly used agents in the treatment of solid malignancies; however, the toxicities of MTX to bone marrow and gastrointestinal tract complicate this therapy. We, therefore, propose a gene-dependent enzyme prodrug therapy to limit these toxicities by localizing the production of MTX to the site of the tumor. The combination of MTX-alpha-peptide prodrugs, which cannot be internalized by the cellular reduced folate carrier, with carboxypeptidase A (CPA), which can remove the blocking peptide, has been demonstrated previously in vitro using antibody-dependent enzyme prodrug therapy. CPA is normally synthesized as a zymogen that is inactive without proteolytic removal of its propeptide by trypsin. Therefore, to adapt this system to gene-dependent enzyme prodrug therapy, a mutant form of CPA was engineered, CPA(ST3), that does not require trypsin-dependent zymogen cleavage but is instead activated by ubiquitously expressed intracellular propeptidases. Purification, peptide sequencing, and kinetic analysis indicated that mature CPA(ST3) is structurally and functionally similar to the trypsin-activated, wild-type enzyme. In addition, CPA(ST3)-expressing tumors cells were sensitized to MTX prodrugs in a dose- and time-dependent manner. To limit diffusion of CPA, a cell surface localized form was generated by constructing a fusion protein between CPA(ST3) and the phosphatidylinositol linkage domain from decay accelerating factor. SDS-PAGE and flow cytometric analysis of infected tumor cells indicated that CPA(DAF) was cell surface localized. Finally, after retroviral transduction, this enzyme/prodrug strategy exhibited a potent bystander effect, even when <10% of the cells were transduced, because extracellular production of MTX sensitized both transduced and nontransduced cells.

Merrie AE, Yun K, Gunn J, et al.
Analysis of potential markers for detection of submicroscopic lymph node metastases in breast cancer.
Br J Cancer. 1999; 80(12):2019-24 [PubMed] Free Access to Full Article Related Publications
We have developed sensitive assays for cytokeratin (K) 8, 16, 19, stromelysin 3 (ST3), MUC1 and maspin mRNAs using reverse transcription polymerase chain reaction (RT-PCR) and used these to assess lymph node status in patients undergoing surgery for breast cancer. In addition the RT-PCR assays were tested against lymph nodes from non-cancer patients to determine their specificity. Despite high sensitivity RT-PCR assays for K8, K16, K19, ST3 and maspin were not found to be useful as markers of submicroscopic disease as transcripts of these genes were detected in the great majority of control lymph nodes tested. Expression of MUC1 was also not found to be useful as it was both insensitive and non-specific. The importance of assessing potential markers against an adequately sized control population is demonstrated, as failure to do so can lead to erroneous conclusions.

Pacheco MM, Mourão M, Mantovani EB, et al.
Expression of gelatinases A and B, stromelysin-3 and matrilysin genes in breast carcinomas: clinico-pathological correlations.
Clin Exp Metastasis. 1998; 16(7):577-85 [PubMed] Related Publications
The purpose of this study was to investigate the association among matrix metalloproteinases (gelatinases A and B, stromelysin-3 (ST3) and matrilysin) mRNAs expressed in primary breast carcinomas and standard prognostic parameters and clinical outcome. mRNA levels were determined by Northern analysis in samples of 81 breast cancer patients (median follow-up, 40 months) and 27 samples of uninvolved adjacent breast tissue. Proteases were expressed by the majority of the tumors and normal breast tissues examined. ST3, gelatinase A and matrilysin mRNAs were more often expressed at high levels in carcinomatous than in normal breast tissues. Differences in the distribution of gelatinase B mRNA were not found. However, paired normal tissues generally produced weaker signals when compared to matched tumor samples. Univariate analysis showed no significant association of gelatinase A and matrilysin mRNAs with the classical prognostic markers (age, menopausal status, stage, size, nodal status, vascular infiltrate, necrosis, steroid receptors, metastasis and survival). Overexpression of ST3 was more frequently found in tumors of post-menopausal women (P < 0.022). Elevated expression of gel B mRNA was associated with the presence of vascular infiltrate (P < 0.026), necrosis (P < 0.039), PR negative tumors (P < 0.014) and inversely correlated to the number of survivors (P < 0.021). Multivariate analysis including 68 patients for whom all information was available indicated that neither stromelysin correlated significantly with pathological, clinical or biochemical features. High levels of gelatinase A and B mRNAs were inversely associated with the number of survivors. Our findings suggest that measurements of gelatinase A and B mRNAs expression in breast carcinoma may help to identify patients with an aggressive form of the disease.

Porte H, Triboulet JP, Kotelevets L, et al.
Overexpression of stromelysin-3, BM-40/SPARC, and MET genes in human esophageal carcinoma: implications for prognosis.
Clin Cancer Res. 1998; 4(6):1375-82 [PubMed] Related Publications
Molecular markers can improve staging and predict aggressive clinical behavior in esophageal cancer, thus helping to define appropriate therapeutic protocols and to identify patients who will benefit from surgery. We therefore characterized, by Northern blot and/or immunohistochemistry, the relative expression of three effectors involved in the invasion, angiogenesis, and dissemination of tumor cells in esophageal cancer versus nontumoral mucosae: (a) stromelysin-3 (ST3), a member of the metalloproteinase family; (b) basement membrane 40/secreted protein acidic and rich in cysteine (BM-40/SPARC), an extracellular matrix-associated protein involved in angiogenesis; and (c) the hepatocyte growth factor receptor MET, which triggers the scattering of epithelial cells. Results were analyzed in relation to clinicopathological parameters (cpTNE) including tumor size (T), lymph node status (N), periesophageal tissue invasion (E), disease recurrence, and overall survival. The ST3, BM-40/SPARC, and MET genes were found to be overexpressed in tumor samples compared to control mucosa. BM-40/SPARC and MET mRNA levels were not linked to any one of the cpTNE, indicating that this overexpression occurs at an early stage of neoplastic progression. In contrast, ST3 expression, identified by immunohistochemistry in fibroblastic cells surrounding neoplastic islets, correlated with tumor size and periesophageal tissue invasion. Of the 36 patients studied, those with high ST3 levels had shorter disease-free survival than those with low levels, but there was no relationship between the cpTNE and disease recurrence or survival. Our study demonstrates that ST3, BM-40/SPARC, and MET are involved in different steps of esophageal carcinogenesis and that ST3 overexpression is a marker of aggressive clinical behavior. We conclude that in esophageal cancer, ST3 might help to assess survival and the risk of recurrence after surgical resection.

Masson R, Lefebvre O, Noël A, et al.
In vivo evidence that the stromelysin-3 metalloproteinase contributes in a paracrine manner to epithelial cell malignancy.
J Cell Biol. 1998; 140(6):1535-41 [PubMed] Free Access to Full Article Related Publications
Stromelysin-3 (ST3; Basset, P., J.P. Bellocq, C. Wolf, I. Stoll, P. Hutin, J.M. Limacher, O.L. Podhajcer, M.P. Chenard, M.C. Rio, P. Chambon. 1990. Nature. 348:699-704) is a matrix metalloproteinase (MMP) expressed in mesenchymal cells located close to epithelial cells, during physiological and pathological tissue remodeling processes. In human carcinomas, high ST3 levels are associated with a poor clinical outcome, suggesting that ST3 plays a role during malignant processes. In this study we report the ST3 gene inactivation by homologous recombination. Although ST3 null mice (ST3-/-) were fertile and did not exhibit obvious alterations in appearance and behavior, the lack of ST3 altered malignant processes. Thus, the suppression of ST3 results in a decreased 7, 12-dimethylbenzanthracene-induced tumorigenesis in ST3-/- mice. Moreover, ST3-/- fibroblasts have lost the capacity to promote implantation of MCF7 human malignant epithelial cells in nude mice (P < 0.008). Finally, we show that this ST3 paracrine function requires extracellular matrix (ECM)-associated growth factors. Altogether, these findings give evidence that ST3 promotes, in a paracrine manner, homing of malignant epithelial cells, a key process for both primary tumors and metastases. Therefore, ST3 represents an appropriate target for specific MMP inhibitor(s) in future therapeutical approaches directed against the stromal compartment of human carcinomas.

Munck-Wikland E, Heselmeyer K, Lindholm J, et al.
Stromelysin-3 mRNA expression in dysplasias and invasive epithelial cancer of the larynx.
Int J Oncol. 1998; 12(4):859-64 [PubMed] Related Publications
Matrix metalloproteinases are believed to play an important role in tumor progression, invasion and metastasis. In order to investigate if the expression of stromelysin-3 (ST3) mRNA could add prognostic information concerning invasive laryngeal cancer and/or be indicative of a high risk for tumor progression in laryngeal dysplasias ST3 expression was analyzed by in situ hybridisation of formalin fixed paraffin embedded laryngeal specimens. Furthermore, all specimens underwent image cytometry (ICM) DNA analysis, and, p53 immunostaining. Invasive epithelial cancer, both localized (T1, T2) cancers, cured, as well as not cured, by radiotherapy, and cases with regional lymph node metastases were studied. Furthermore, high grade and low grade dysplasias, selected for rapid, slow and non-progression, as well as non-neoplastic inflammatory lesions were investigated. Expression of the ST3 gene was found in 9 out of 14 (64%) invasive cancer lesions, and in 3 out of 10 (30%) dysplasias, thus indicating that ST3 expression correlates to tumor progression. The ST3 positive laryngeal cancer lesions displayed a higher degree of DNA aberration than the ST3 negative lesions thus suggesting that ST3 positivity could indicate highly malignant tumors. Of the three ST3 positive dysplasias, the first progressed rapidly to cancer in situ with suspected microinvasion. The second ST3 positive dysplasia progressed to invasive cancer within five months. The third ST3 positive dysplasia had been radically excised and hereby cured. All but one of the dysplastic lesions showed p53 immunoreactivity, and all dysplasias exhibited aneuploid cells. ST3 expression appears to be a late event in the multistage process of carcinogenesis and could prove useful as an indicator of dysplasias with imminent risk for progression to invasive cancer.

Holm R, Flørenes VA, Erikstein B, Nesland JM
Expression of stromelysin-3 in medullary carcinoma of the breast.
Anticancer Res. 1997 Sep-Oct; 17(5B):3725-7 [PubMed] Related Publications
Matrix metalloproteinases are belived to play a central role in the invasion and metastasis of human cancers by mediating the degration of extracellular matrix components. Expression of stromelysin-3 (ST3), a new member of matrix metalloproteinase family, was investigated by in situ hybridization in 32 tissue samples of medullary carcinoma of the breast. Eighty-four per cent of the cases showed ST3 gene expression in stromal cells adjacent to tumor cells. Therefore, expression of ST3 in stromal cells may be expected to play a significant role in the destruction of extracellular matrix and invasion of medullary carcinoma of the breast.

Ahmad A, Marshall JF, Basset P, et al.
Modulation of human stromelysin 3 promoter activity and gene expression by human breast cancer cells.
Int J Cancer. 1997; 73(2):290-6 [PubMed] Related Publications
The matrix-degrading enzyme family of matrix-metalloproteinases (MMPs) has been implicated in the process of tumour metastasis. Cellular protein and RNA localisation techniques have been used to show that, whilst several MMP genes are expressed in both cancer and stromal cells, stromelysin 3 is expressed only in stromal fibroblasts adjacent to cancer cells. Immunohistochemical and in situ hybridisation evidence suggests that neoplastic cells can stimulate stromal cell MMP production either in a paracrine fashion or by a cell-cell contact mechanism. Using 2 different lengths of the human stromelysin 3 (ST3) gene 5' flanking sequence cloned upstream of luciferase and CAT reporter genes, we now show that human breast cancer cells can directly activate the ST3 promoter. The putative response element in the ST3 promoter, which lies between 0.46 and 3.4 kb upstream of the transcription start site, is able to effect a 2- to 3-fold increase in downstream gene expression. We further show that this transcriptional up-regulation definitely occurs via a paracrine, and possibly via a cell-cell contact, mechanism. Confirmation that this ST3 promoter activation results in ST3 gene induction of a similar magnitude was shown using Northern blotting of stimulated fibroblasts. Our data provide further evidence that cancer cells can induce fibroblast MMP expression and help to explain the in vivo expression pattern of ST3 in breast cancer.

Nöel AC, Lefebvre O, Maquoi E, et al.
Stromelysin-3 expression promotes tumor take in nude mice.
J Clin Invest. 1996; 97(8):1924-30 [PubMed] Free Access to Full Article Related Publications
Stromelysin-3 (ST3) is a matrix metalloproteinase expressed in human carcinomas in ways suggesting that it may play a role in tumor progression. To test this possibility, we have performed gene transfer experiments using both anti-sense and sense ST3 expression vectors, and malignant cells either expressing (NIH 3T3 fibroblasts) or not (MCF7 epithelial cells) endogenous ST3. We have compared the ability of parental and transfected cells to cause subcutaneous tumor development in nude mice. 3T3 cells expressing anti-sense ST3 RNA showed reduced tumorigenicity, and MCF7 cells expressing mouse or human ST3 were associated with reduced tumor-free period leading to a significant increased tumor incidence(P<10(-4)). However, once established, the ST3 expressing tumors did not grow faster than those obtained with the parental MCF7 cell line. In addition, tumors obtained after sub-cutaneous injection of ST3-expressing or nonexpressing cells did not exhibit obvious histological differences, and careful examination did not reveal any local invasive tissue areas nor systemic metastases. These in vivo observations were in agreement with those obtained in vitro showing that ST3 expression did not modify proliferative nor invasive properties of transfected cells. Altogether, these results indicate that ST3 expression promotes tumor take in nude mice, presumably by favoring cancer cell survival in a tissue environment initially not permissive for tumor growth. These findings represent the first experimental evidence showing that ST3 can modulate cancer progression.

Porte H, Chastre E, Prevot S, et al.
Neoplastic progression of human colorectal cancer is associated with overexpression of the stromelysin-3 and BM-40/SPARC genes.
Int J Cancer. 1995; 64(1):70-5 [PubMed] Related Publications
The interaction of neoplastic cells with the extracellular matrix is a critical event for the initiation of cancer invasion and metastasis. This study was designed to evaluate the potential implication of stromelysin-3 (ST3), a newly identified member of the matrix-degrading metalloproteinase family, and of BM-40/SPARC, a glycoprotein associated with the extracellular matrix, during the progression of human colorectal cancers. We analyzed the relative abundance of ST3 and BM-40/SPARC transcripts by Northern blot, and their distribution by in situ hybridization, in normal mucosa, benign adenomas, and primary colorectal adenocarcinomas and their liver metastases. The ST3 and BM-40/SPARC transcripts were overexpressed in primary colorectal cancers and their liver metastases compared to non-neoplastic mucosa. These transcripts were localized in stromal fibroblasts adjacent to the neoplastic foci. Overexpression of ST3 correlated with the progression of human colorectal tumors toward local invasion and liver metastasis. Induction of these genes also occurred in diverticulitis and digestive neoplasms such as gastric and esophageal carcinomas.

Engel G, Heselmeyer K, Auer G, et al.
Correlation between stromelysin-3 mRNA level and outcome of human breast cancer.
Int J Cancer. 1994; 58(6):830-5 [PubMed] Related Publications
The expression level of stromelysin-3 (ST3) mRNA was analyzed by in situ hybridization of formalin-fixed, paraffin-embedded primary breast-tumor samples from 76 patients. Digital image analysis of the dark-field in situ hybridization signal was used to measure the maximal level of ST3 expression in each tumor. All 55 invasive ductal carcinomas and 9 of 10 invasive lobular carcinomas were positive for ST3. Invasive tumors had significantly higher levels of ST3 than in situ tumors. Furthermore, ST3 levels were higher in invasive ductal carcinomas than in invasive lobular carcinomas. The ST3 expression level was significantly correlated to fatal metastatic disease (mean follow-up 104 months). ST3 levels of < 2,500 units were associated with distant metastasis in 46% of patients, whereas levels of > 2,500 units were associated with metastasis in 79% of patients selected for study. ST3 mRNA levels did not correlate with tumor size, microvessel density, DNA ploidy or estrogen-receptor levels. Studies of ST3 expression may provide information valuable for the understanding of breast cancer biology and for prognosis.

Basset P, Wolf C, Rouyer N, et al.
Stromelysin-3 in stromal tissue as a control factor in breast cancer behavior.
Cancer. 1994; 74(3 Suppl):1045-9 [PubMed] Related Publications
BACKGROUND: It has long been proposed that secreted proteinases, including the matrix metalloproteinases, play an important part in tumor progression in mediating extracellular matrix remodeling. More recently, it has been suggested that extracellular proteinases also regulate growth factors and cytokines that may contribute to tumor progression.
METHODS: RNA in situ hybridization and immunohistochemistry were used to study the expression, in breast and other types of human carcinomas, of the stromelysin-3 (ST3) gene, which encodes a putative new member of the matrix metalloproteinase family.
RESULTS: The ST3 gene is overexpressed in most types of human carcinomas, including breast carcinoma where ST3 RNA was detected in 95% (99 of 104) of invasive primary tumors. Both ST3 protein and RNA are detected in fibroblastic cells immediately surrounding the cancer cells, but not in the malignant cells or in stromal cells at a distance from them. The ST3 gene also is expressed in some in situ breast carcinomas, where ST3 expression correlates with the known risk of these tumors to become invasive.
CONCLUSIONS: ST3 is the paradigm of tumor proteinases that are not expressed in the malignant cells of human carcinomas but in fibroblastic cells of tumor stroma. ST3 represents a potential new prognostic parameter to identify subpopulations of aggressive tumors, particularly to evaluate the likelihood of in situ breast carcinoma progression to invasive cancer. Furthermore, the specific expression of the ST3 gene in fibroblastic cells immediately surrounding cancer cells suggests that ST3 may be involved in tumor progression and that it represents a potential target for cancer treatment.

Hähnel E, Dawkins H, Robbins P, Hähnel R
Expression of stromelysin-3 and nm23 in breast carcinoma and related tissues.
Int J Cancer. 1994; 58(2):157-60 [PubMed] Related Publications
Biological functions proposed for the ST3 and nm23 genes in tumour development and progression seem to be directly opposed. Stromelysin-3 (ST3) is a putative member of the matrix metalloproteinase family. ST3 has been implicated in the progression of epithelial malignancies, specifically with regard to an invasive (and therefore potentially metastasizing) phenotype. The nm23 gene, on the other hand, encodes a nucleoside diphosphate kinase which allegedly has a metastasis-suppressor-type function. It was therefore of interest to compare the expression of ST3 and nm23 in various surgically excised normal and neoplastic breast tissues. RNA was isolated from over 200 surgical specimens and studied by Northern blots. Normal breast tissues did not express ST3, and ST3 expression was detected in only 1 of 20 normal axillary lymph nodes. None of 7 fibroadenomas expressed ST3. In contrast, 60% of primary and metastatic breast carcinomas contained ST3-mRNA. The expression of ST3 was mainly confined to invasive carcinomas and was observed less frequently in pure ductal carcinoma in situ (DCIS) lesions. Our results support the suggestion that ST3 expression is related to the malignant process in breast cancer. The role of nm23 is far less clear-cut.

Spanakis E, Brouty-Boyé D
Evaluation of quantitative variation in gene expression.
Nucleic Acids Res. 1994; 22(5):799-806 [PubMed] Free Access to Full Article Related Publications
We investigate the behaviour of the gene-expression rate as a statistical variable using autoradiographic data for 39 transcripts from a heterogeneous set of 80 breast-tissue cultures. Despite standardization, the data distributions of all transcripts showed intervals of normality and intervals of systematic departure from normality which most frequently resulted in a significant skewness and/or kurtosis. Non-normal shapes are attributed to modulation of gene expression. This statistical particularity creates difficulties in the evaluation of differences among specimens. Using classical parametric and non-parametric procedures for normal and non-normal variation, respectively, we demonstrate that large differences in optical density are neither necessary nor sufficient for associating expression rates with biological factors. The transcripts coding for the metalloprotease stromelysin-3 (ST3) and for the receptor to insulin-like growth factors (IGFR) are used as examples and their variation is presented in detail. ST3 expression appeared to be specifically associated with mammary stroma fibroblasts derived from post-radiation fibrosis lesions. IGFR was expressed at higher rates in mammary gland and skin fibroblasts than in mammary epithelial cells and was subject to frequent and strong modulation.

Rouyer N, Wolf C, Chenard MP, et al.
Stromelysin-3 gene expression in human cancer: an overview.
Invasion Metastasis. 1994-1995; 14(1-6):269-75 [PubMed] Related Publications
Stromelysin-3 (ST3) belongs to the family of matrix metalloproteinases, a group of proteolytic enzymes which are believed to play a role in tumor invasion and metastasis. In the present study, we report that the ST3 gene, which was initially identified in invasive breast carcinoma, is expressed in most other invasive human carcinomas, but rarely in sarcomas and other nonepithelial tumors. In carcinomas, both ST3 RNA and protein were specifically detected in fibroblastic cells immediately surrounding the cancer cells. In agreement with this observation, the carcinomas which are known to progress without inducing a prominent tumor stroma are also those which usually do not express the ST3 gene. ST3 gene expression was also observed in noninvasive carcinomas of the breast, uterus cervix and bladder, where the probability of detecting ST3 RNA and protein positively correlated with the known risk of these lesions evolving towards invasion. Taken together, these observations further support the hypothesis that ST3 may contribute to tissue-remodeling processes associated with carcinoma progression, and may represent a new prognostic factor to define populations of aggressive tumors.

Kawami H, Yoshida K, Ohsaki A, et al.
Stromelysin-3 mRNA expression and malignancy: comparison with clinicopathological features and type IV collagenase mRNA expression in breast tumors.
Anticancer Res. 1993 Nov-Dec; 13(6A):2319-23 [PubMed] Related Publications
mRNA expression of stromelysin-3 (ST3) and 72K type IV collagenase (cIVase) in 4 human breast cancer cell lines and 55 resected breast tumors were examined using Northern blot analysis. In 4 cell lines ST3 was not expressed at all, while cIVase gene expression was detected in 3 of them. The ST3 expression was found more specifically in malignant tumors (39/40, 97.5%) than in benign ones (4/15, 26.7%), although cIVase was expressed in all tumor specimens. The quantitative analysis showed that ST3 expression in malignancies was significantly greater than that in benign tumors (P = 0.0007), while cIVase expression was not (P = 0.1381). ST3 gene expression was also closely related to the presence of lymph node metastasis (P = 0.047), while cIVase was not (P = 0.1091). These results suggest, therefore, that ST3 is expressed more specifically by stromal cells surrounding cancer cells than cIVase. Since ST3 mRNA expression was independent of the EGFR, ER and erbB2 protein expression, ST3 may be a new potent prognostic guide for breast carcinomas, which can detect highly malignant subpopulations.

Wolf C, Rouyer N, Lutz Y, et al.
Stromelysin 3 belongs to a subgroup of proteinases expressed in breast carcinoma fibroblastic cells and possibly implicated in tumor progression.
Proc Natl Acad Sci U S A. 1993; 90(5):1843-7 [PubMed] Free Access to Full Article Related Publications
The expression of the stromelysin 3 (ST3) gene, which encodes a putative matrix metalloproteinase, was studied during breast cancer progression. The ST3 gene is expressed in all invasive breast carcinomas, in a number of their metastases, and in some in situ carcinomas where the probability of detecting ST3 transcripts correlates with the known risk of these carcinomas to become invasive. ST3 RNA and protein were specifically detected in fibroblastic cells immediately surrounding the neoplastic cells in both primary and metastatic tumors. This expression pattern distinguishes the ST3 gene from other matrix metalloproteinase genes, most notably from the 72-kDa type IV collagenase gene, which can be expressed in fibroblastic cells distributed throughout the stroma of primary breast carcinomas. Furthermore, high levels of 72-kDa type IV collagenase, but not of ST3 transcripts, are detected in benign breast fibroadenomas. Interestingly, the urokinase and ST3 genes exhibit very similar patterns of expression in breast carcinomas, which suggests that their products may cooperate during cancer progression.

Basset P, Wolf C, Chambon P
Expression of the stromelysin-3 gene in fibroblastic cells of invasive carcinomas of the breast and other human tissues: a review.
Breast Cancer Res Treat. 1993; 24(3):185-93 [PubMed] Related Publications
Stromelysin-3 (ST3) is a putative new matrix metalloproteinase (MMP) which may play a role in the progression of human carcinomas, and exhibits unique structural and functional characteristics among the MMP family. The ST3 gene, which is generally not expressed at significant levels in benign breast tumors, has been found to be expressed in all invasive breast carcinomas tested so far. The gene is also expressed in some in situ breast carcinomas, which have a higher probability to become invasive. ST3 RNA and protein are specifically found in fibroblastic cells immediately surrounding the neoplastic cells, both in invasive and in situ breast carcinomas. The same expression pattern is observed in other types of human carcinomas, and the highest ST3 RNA levels are observed in tumors that exhibit high local invasiveness. The ST3 gene is also expressed in fibroblastic cells during the inflammatory phase of wound healing, which suggests that ST3 gene expression in stromal fibroblasts may be under the control of factors produced by inflammatory cells during wound healing, and by cancer cells during carcinoma progression. ST3 may thus represent a stroma-derived factor necessary for the progression of epithelial malignancies, and its manipulation may possibly be used to develop new anti-cancer agents.

Muller D, Wolf C, Abecassis J, et al.
Increased stromelysin 3 gene expression is associated with increased local invasiveness in head and neck squamous cell carcinomas.
Cancer Res. 1993; 53(1):165-9 [PubMed] Related Publications
Matrix metalloproteinases are believed to play an important role in tumor invasion and metastasis. To examine the expression of the stromelysin 3 (ST3) gene, a new member of the matrix metalloproteinase gene family, 111 head and neck squamous cell carcinomas and 21 metastatic lymph nodes were analyzed by Northern blot. ST3 gene expression was observed in 106 carcinomas and 19 metastatic nodes, but in only 2 of 60 samples of corresponding normal tissue tested in parallel. ST3 RNA, by in situ hybridization, and ST3 protein, by immunohistochemical analysis, were specifically detected in fibroblastic cells immediately surrounding invasive cancer cells. This fibroblastic expression of the ST3 gene is characteristic among the matrix metalloproteinase genes known to be overexpressed in head and neck carcinomas, since stromelysin 2 transcripts were specifically detected in neoplastic cells, and type I collagenase transcripts in both neoplastic cells and stromal fibroblasts. Furthermore, there was a highly significant positive correlation (P < 0.0001) between ST3 RNA levels and local invasiveness by the cancer cells, suggesting that enhanced expression of the ST3 gene may contribute to the neoplastic phenotype in head and neck carcinomas.

Wolf C, Chenard MP, Durand de Grossouvre P, et al.
Breast-cancer-associated stromelysin-3 gene is expressed in basal cell carcinoma and during cutaneous wound healing.
J Invest Dermatol. 1992; 99(6):870-2 [PubMed] Related Publications
Ten cases of basal cell carcinoma (BCC), including nine of the nodulo-ulcerative type and one of the morphea-form type, were investigated for stromelysin-3 (ST3) gene expression by in situ hybridization. The ST3 gene, which codes for a putative matrix metalloproteinase expressed in stromal cells of invasive breast carcinomas, was also expressed in stromal cells of BCCs when they displayed active local invasiveness. ST3 RNA was specifically detected in fibroblastic cells of tumor areas exhibiting loss of peripheral palisading in cancer cell islands. This pattern of expression was characteristic of the ST3 gene and was not observed with any of the other matrix metalloproteinase genes tested. We suggest that ST3 gene expression, which was also observed in fibroblasts during cutaneous scar formation, corresponds to a normal wound-healing response that has been subverted in carcinomas.

Schwarz KB, Moore TJ, Willoughby RE, et al.
Growth of group A rotaviruses in a human liver cell line.
Hepatology. 1990; 12(4 Pt 1):638-43 [PubMed] Related Publications
Recent observations in children with rotavirus gastroenteritis and in infant mice given rotavirus vaccine by oral administration suggest that this well-known gastrointestinal pathogen may infect the liver. To examine this possibility, the susceptibility of Hep G2 cells to infection with a variety of rotavirus strains was tested. These cells were used because they are considered to be well differentiated and exhibit many liver-specific functions. The Hep G2 cells supported the growth of the simian strain rhesus rotavirus (MMU 18006), a strain currently being used in vaccine trails, but did not support the growth of any human strain (D, DS1, Price or ST3). The rhesus rotavirus infection was cytopathic and resulted in release of lactate dehydrogenase. Rhesus rotavirus growth in Hep G2 cells displayed trypsin-enhanced infectivity and was inhibited by pretreatment of cells with Arthrobacter ureafaciens neuraminidase but not with neuraminidase from Clostridium perfringens. Hep G2 cells were also permissive for another simian strain (SA11), a bovine strain (UK) and single gene substitution reassortants containing VP7 (the major outer capsid neutralization protein) from a human rotavirus strain and the remaining 10 genes from either rhesus rotavirus or UK. In general, UK and its reassortants produced lower levels of antigen than did rhesus rotavirus and its reassortants. Hep G2 cells and other hepatic cell lines may prove to be useful tools to explore the hepatotropic potential of wild-type rotaviruses and candidate vaccine strains.

Hayman LA, Evans RA, Ferrell RE, et al.
Familial cavernous angiomas: natural history and genetic study over a 5-year period.
Am J Med Genet. 1982; 11(2):147-60 [PubMed] Related Publications
In a kindred of 122 individuals we found 5 individuals with cerebral vascular malformation, 3 representing typical cavernous angiomas. The condition was inherited as an autosomal dominant trait with variable expressivity. Forty-three relatives were examined prospectively by cranial computed tomography (CCT) and lesions were found in 15; 7 were followed prospectively with CCT scans for 5 years. Angiography in 5 of these cases failed to demonstrate the lesion. In 3 patients with previously normal CCT scans a change in blood volume or membrane permeability allowed visualization of the lesion on contrast scans. In 2 individuals, both parents of affected children, a normal CCT scan was found. This emphasizes the limitations of CCT in detecting this disorder. Biochemical and red blood cell immunological genetic linkage studies were done in 36 persons. No linkage was found with any of the markers. The natural history of this disorder, characterized by marked clinical and radiographic variation in site of lesion, and the timing and severity of intracranial hemorrhage, make it a useful model for investigating contributing factors and consequences of intracranial hemorrhage in general. For at-risk and affected patients early and sequential CCTs are necessary. Familial cavernous angioma should be included in the differential diagnosis of all young persons presenting with cerebrovascular impairment, seizures, intracranial calcifications or hemorrhage.

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