Behavior Of Ovarian Cancer Cells Research Articles

Effect of down-regulation of HE4 gene expression on biologic behavior of ovarian cancer cells

To investigate the effects of HE4 gene knockdown on the proliferation, adhesion and invasion of the ovarian cancer cells SKOV3. The knockdown of HE4 gene was performed by RNAi technology. The recombinant plasmids (pSUPER-HE4 shDNAs) were constructed and transfected into human ovarian cancer cells SKOV3. HE4 expression was then identified by real-time PCR and Western blot analysis. The invasion and adhesion ability of transduced cells were determined. In addition, cell proliferation and growth were analyzed by colonies formation assay. Knockdown of HE4 was achieved, and further confirmed by real-time PCR and Western blot. The proliferation of HE4-down-regulated cells was not affected, but the invasion ability of the transfected cells was reduced (P < 0.05) and the adhesion ability was also reduced to 27.3%. HE4 expression is down-regulated effectively by the constructed HE4 shDNA, and thus knockdown of HE4 inhibits the adhesion and invasion of SKOV3 cells.

Abstract B66: Novel ovarian cancer transplantable models generated from MUC1KrasPten tumors show different in vitro and in vivo biological behaviors

Abstract Introduction: Sustained improvement in the development of new therapeutic approaches in ovarian cancer depends in part on the availability of adequate preclinical models for in vivo testing of treatment efficacy. We recently developed triple transgenic (MUC1KrasPten.Tg) mice expressing human MUC1 oncoprotein as self and carrying the conditional K-rasG12D oncoallele (loxP-Stop-loxP-K-rasG12D/+) and the floxed Pten gene (PtenloxP/loxP). The MUC1KrasPten.Tg mice develop MUC1-expressing endometrioid ovarian tumors that closely mirror the human disease and respond to human MUC1-based immune therapy. Compared to the KrasPten mice, tumors from MUC1KrasPten.Tg mice had a higher potential for loco-regional spread, suggesting active MUC1 involvement in local and distant tumor spread. Approach: In order to study in vitro and in vivo MUC1 roles in tumor growth and metastasis and interactions between MUC1 signaling and Kras and Pten pathways, we generated several new murine ovarian cancer cell lines. These cell lines express human MUC1 as self, while simultaneously carrying constitutively active oncogenic Kras and defective Pten tumor suppressor. The originating cells were derived from either the MUC1KrasPten primary ovarian tumor or the liver implant via trypsinization into single cell suspension. Cells were cultured in vitro for at least 20 passages to generate the stable MKP-T (from primary tumor) and MKP-L (from liver metastasis) ovarian cancer cell lines. Clonal populations were obtained via limiting dilution assays. Results: Although derived from the same host, the MKP-T and MKP-L cells showed different K-ras status reflective of tumor heterogeneity in vivo. Unlike the MKP-L cells, the MKP-T cells display loss of K-ras heterozygosity. MKP-T and MKP-L showed variable expression pattern of MUC1, EpCAM, folate receptor, ALDH, cytokeratin and vimentin, demonstrating how the anatomical location of each originating tumor influences the cell line's in vitro phenotype. Furthermore, although both cell lines can grow IP tumors in syngeneic triple transgenic MUC1KrasPten.Tg, single transgenic MUC1.Tg as well as wild-type C57BL/6J-bgJ mice, they carry distinct in vivo phenotypes. MKP-L cells grow slower in vitro (doubling time 27.5 hours) and in vivo and trigger distant metastases to the lungs. MKP-T cells multiply at higher rate in vitro (doubling time 13.2 hours) and in vivo and generate larger loco- regional tumors. Two sub-lines (MKP-T-2F8-Asc and MKP-L-Lng) derived from MKP-T ascites and MKP-L lung metastasis, respectively, by in vivo clonal selection, showed stable and high MUC1 expression, further demonstrating its in vivo roles for both loco-regional as well as distant spread. In line with their Kras status, MEK 1/2 inhibitor AZD6244 (currently tested in several Phase II clinical trials) showed more inhibition on MKP-T cells than on MKP-L cells in vitro, providing support for its use in this preclinical models. Conclusions: We have generated several novel murine cancer cell lines and characterized the first immune competent transplantable ovarian cancer model expressing human MUC1 as a transgene. The cell lines show various levels of MUC1 and display different metastatic behaviors in vitro and in vivo. MKP-L cells metastasize to the lungs and represent the first in vivo model for distant metastasis in ovarian cancer. Our novel preclinical models are uniquely suited for in vivo combination therapies targeting MUC1, Kras and Pten/PI3K pathways and provide new tools for elucidating the biological behaviors of ovarian cancer cells both in vitro and in vivo. Citation Format: Lixin Zhang, Raluca Budiu, Joan Brozick, Anda Vlad. Novel ovarian cancer transplantable models generated from MUC1KrasPten tumors show different in vitro and in vivo biological behaviors. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr B66.

Metastasis of ovarian cancer is mediated by kallikrein related peptidases

Ovarian cancer, in particular epithelial ovarian cancer (EOC), is commonly diagnosed when the tumor has metastasized into the abdominal cavity with an accumulation of ascites fluid. Combining histopathology and genetic variations, EOC can be sub-grouped into Type-I and Type-II tumors, of which the latter are more aggressive and metastatic. Metastasis and chemoresistance are the key events associated with the tumor microenvironment that lead to a poor patient outcome. Kallikrein-related peptidases (KLKs) are aberrantly expressed in EOC, in particular, in the more metastatic Type-II tumors. KLKs are a family of 15 serine proteases that are expressed in diverse human tissues and involved in various patho-physiological processes. As extracellular enzymes, KLKs function in the hydrolysis of growth factors, proteases, cell membrane bound receptors, adhesion proteins, and cytokines initiating intracellular signaling pathways and their downstream events. High KLK levels are differentially associated with the prognosis of ovarian cancer patients, suggesting that they not only have application as biomarkers but also function in disease progression, and therefore are potential therapeutic targets. Recent studies have demonstrated the function of these proteases in promoting and/or suppressing the invasive behavior of ovarian cancer cells in metastasis in vitro and in vivo. Both conventional cell culture methods and three-dimensional platforms have been applied to mimic the ovarian cancer microenvironment of patients, such as the solid stromal matrix and ascites fluid. Here we summarize published studies to provide an overview of our understanding of the role of KLKs in EOC, and to lay the foundation for future research directions.

Upregulation of endogenous ICAM‐1 reduces ovarian cancer cell growth in the absence of immune cells

Ovarian cancer is a difficult-to-treat cancer with a 5-year survival rate of only ∼45%, due to late diagnosis and therapy resistance. In need of new therapeutic approaches, induction of intercellular adhesion molecule (ICAM)-1 expression might be of interest, since the expression of ICAM-1 is lower in ovarian cancer cells compared with healthy ovarian cells and correlated with decreased tumorigenicity. Whereas ICAM-1 expression on tumor cells is of importance for attracting immune cells, ICAM-1 might also induce tumorigenicity and chemoresistance. In ovarian cancer, such a role of ICAM-1 is unclear. Here, we investigated whether ICAM-1 has a cell-biological role by bidirectional modulation of ICAM-1 expression using ICAM-targeting artificial transcription factors. For a panel of ovarian cancer cells, tumor growth and cisplatin sensitivity were evaluated. Induction of ICAM-1 expression (ranging from 3- to 228-fold on mRNA level and 1.7- to 108-fold on protein level) resulted in indications of decreased ovarian cancer cell growth and reduced cisplatin sensitivity. Repression ranged from 48 to 94% on mRNA level and 47 to 91% on protein level. This study shows that, next to its established immunogenic role, ICAM-1 affects cell biological behavior of ovarian cancer cells and, importantly, that reexpression by artificial transcription factors represents a powerful approach for functional validation of genes epigenetically silenced in cancer, such as ICAM-1.

SPARC Is a Key Regulator of Proliferation, Apoptosis and Invasion in Human Ovarian Cancer

BackgroundSecreted protein acidic and rich in cysteine (SPARC), a calcium-binding matricellular glycoprotein, is implicated in the progression of many cancers. In this study, we investigated the expression and function of SPARC in ovarian cancer.MethodscDNA microarray analysis was performed to compare gene expression profiles of the highly invasive and the low invasive subclones derived from the SKOV3 human ovarian cancer cell line. Immunohistochemistry (IHC) staining was performed to investigate SPARC expression in a total of 140 ovarian tissue specimens. In functional assays, effects of SPARC knockdown on the biological behavior of ovarian cancer cells were investigated. The mechanisms of SPARC in ovarian cancer proliferation, apoptosis and invasion were also researched.ResultsSPARC was overexpressed in the highly invasive subclone compared with the low invasive subclone. High SPARC expression was associated with high stage, low differentiation, lymph node metastasis and poor prognosis of ovarian cancer. Knockdown of SPARC expression significantly suppressed ovarian cancer cell proliferation, induced cell apoptosis and inhibited cell invasion and metastasis.ConclusionSPARC is overexpressed in highly invasive subclone and ovarian cancer tissues and plays an important role in ovarian cancer growth, apoptosis and metastasis.

Suppression of EphB4 improves the inhibitory effect of mTOR shRNA on the biological behaviors of ovarian cancer cells by down-regulating Akt phosphorylation

The aim of the present study was to examine the effects of suppression of EphB4 and/or mTOR on the biological behaviors of ovarian cancer cells, and the potential regulatory pathways. Antisense EphB4 vectors and shRNA vectors targeting mammalian target of rapamycin (mTOR) were constructed and transfected into A2780 and SKOV3 cells (two ovarian cancer cell lines). The effects of the antisense EphB4 vectors and the shRNA vectors on the proliferation, apoptosis and invasion of ovarian cancer cells were measured, and the expression of EphB4, mTOR and Akt detected. The results showed that transfection with mTOR shRNA could inhibit growth, induce apoptosis, and reduce invasive ability of ovarian cancer cells, which was accompanied by downregulation of EphB4, mTOR and Akt. The inhibitory effects on cell growth caused by mTOR shRNA alone were weaker than those by antisense pEGFP-C1-EphB4. In the antisense pEGFP-C1-EphB4-transfected cells, it was found that EphB4 knockdown could decrease the mTOR expression and slightly reduce the Akt phosphorylation. Significant suppressive effects on cell growth were observed in cells co-transfected with antisense pEGFP-C1-EphB4 and mTOR shRNA. In co-transfection group, the expression levels of EphB4, mTOR and Akt were distinctly lower than those in other groups. It was concluded that suppression of EphB4 may inhibit the growth of ovarian cancer cells by downregulation of the PI3K/Akt/mTOR pathway, and reverse Akt phosphorylation induced by mTOR shRNA. Inhibition of EphB4 and mTOR combined may cooperatively suppress the biological behaviors of ovarian cancer cells.

RETRACTED: High-mobility group protein B1 (HMGB1) is a novel biomarker for human ovarian cancer

High mobility group box l (HMGB1), a nuclear and extracellular protein, is implicated in some physiologic and pathologic conditions. In this study, we investigated the expression and function of HMGB1 in ovarian cancer. cDNA microarray analysis was performed to compare gene expression profiles of the highly invasive and the low invasive subclones derived from the SKOV3 human ovarian cancer cell line. Immunohistochemistry (IHC) staining was performed to investigate HMGB1 expression in a total of 100 ovarian tissue specimens. In functional assays, effects of HMGB1 knockdown on the biological behavior of ovarian cancer cells were investigated. HMGB1 was overexpressed in the highly invasive subclone compared with the low invasive subclone. High HMGB1 expression was associated with poor clinicopathologic features. Knockdown of HMGB1 expression significantly suppressed ovarian cancer cell proliferation accompanied by decreased cyclin D1 and PCNA expression, and inhibited cell migration and invasion accompanied by decreased MMP2 and MMP9 activities. HMGB1 is a newly identified gene overexpressed in ovarian cancer and associated with poor clinicopathologic features. HMGB1 may serve as a new biomarker and a therapeutic target for ovarian cancer in the future.

Regulation of colony stimulating factor-1 expression and ovarian cancer cell behavior in vitro by miR-128 and miR-152

BackgroundColony stimulating factor-1 (CSF-1) plays an important role in ovarian cancer biology and as a prognostic factor in ovarian cancer. Elevated levels of CSF-1 promote progression of ovarian cancer, by binding to CSF-1R (the tyrosine kinase receptor encoded by c-fms proto-oncogene).Post-transcriptional regulation of CSF-1 mRNA by its 3’ untranslated region (3’UTR) has been studied previously. Several cis-acting elements in 3’UTR are involved in post-transcriptional regulation of CSF-1 mRNA. These include conserved protein-binding motifs as well as miRNA targets. miRNAs are 21-23nt single strand RNA which bind the complementary sequences in mRNAs, suppressing translation and enhancing mRNA degradation.ResultsIn this report, we investigate the effect of miRNAs on post-transcriptional regulation of CSF-1 mRNA in human ovarian cancer. Bioinformatics analysis predicts at least 14 miRNAs targeting CSF-1 mRNA 3’UTR. By mutations in putative miRNA targets in CSF-1 mRNA 3’UTR, we identified a common target for both miR-128 and miR-152. We have also found that both miR-128 and miR-152 down-regulate CSF-1 mRNA and protein expression in ovarian cancer cells leading to decreased cell motility and adhesion in vitro, two major aspects of the metastatic potential of cancer cells.ConclusionThe major CSF-1 mRNA 3’UTR contains a common miRNA target which is involved in post-transcriptional regulation of CSF-1. Our results provide the evidence for a mechanism by which miR-128 and miR-152 down-regulate CSF-1, an important regulator of ovarian cancer.

Gab2 regulates the migratory behaviors and E-cadherin expression via activation of the PI3K pathway in ovarian cancer cells

Ovarian cancer, the most deadly gynecologic malignancy, is often diagnosed late and at the advanced stage when the cancer cells have already migrated and invaded into other tissues and organs. Better understanding of the mechanism of metastasis in ovarian cancer cells is essential to the design of effective therapy. In this study, we investigated the function of scaffolding adaptor protein Gab2 in ovarian cancer cells. Gab2 is found to be overexpressed in a subset of ovarian tumors and cancer cell lines. Gab2 expression mainly regulates the migratory behaviors of ovarian cancer cells. Overexpression of Gab2 promotes the migration and invasion, and down-regulates E-cadherin expression in ovarian cancer cells with low-Gab2 expression. Conversely, knockdown of Gab2 expression inhibits the migration and invasion, and promotes E-cadherin expression in ovarian cancer cells with high-Gab2 expression. By expressing Gab2 wild type and Gab2 mutants that are defective in activation the PI3K and Shp2-Erk pathways, we find that Gab2 inhibits E-cadherin expression and enhances the expression of Zeb1, a transcription factor involved in epithelial-to-mesenchymal transition (EMT), and cell migration and invasion through the activation of the PI3K pathway. Knockdown of Zeb1 expression blocks Gab2-induced suppression of E-cadherin expression and increase in cell invasion. LY294002 and GDC-0941, inhibitors of PI3K, or Rapamycin, an inhibitor of PI3K downstream target mTOR, can reverse the effects of Gab2 on migration and invasion. Overall, our studies reveal that Gab2 overexpression, via activation of the PI3K-Zeb1 pathway, promotes characteristics of EMT in ovarian cancer cells.

Versican induces a pro-metastatic ovarian cancer cell behavior which can be inhibited by small hyaluronan oligosaccharides

The assembly of pericellular matrix containing hyaluronan (HA) and versican has been shown to be a pre-requisite for proliferation and migration of mesenchymal cells. In this study, we investigated whether treatment with recombinant versican could induce the formation of a pericellular matrix by ovarian cancer cells (OVCAR-3, OVCAR-5, and SKOV-3) and promote their motility, invasion, and adhesion to peritoneal cells in vitro. We also determined whether versican-induced pericellular matrix formation and metastatic cancer cell behavior could be blocked by small HA oligosaccharides. Only combined treatment with recombinant versican and HA resulted in pericellular matrix formation by OVCAR-5 and SKOV-3 but not by OVCAR-3 cells, which lack the HA receptor, CD44. The motility of OVCAR-5 and SKOV-3 cells was significantly increased in scratch wound and chemotaxis assays following treatment with recombinant versican and HA. Versican and HA also promoted invasion of SKOV-3 and OVCAR-5 cells but had no effect on OVCAR-3 cells. We have demonstrated that exogenous HA significantly increased OVCAR-5 and SKOV-3 adhesion to peritoneal cells but adhesion was not further increased by versican treatment. Small HA oligomers (6-10 disaccharides) were able to significantly block formation of pericellular matrix by OVCAR-5 cells, as well as the increased motility and invasion induced by recombinant versican. HA oligomers also significantly blocked OVCAR-5 adhesion to peritoneal cells both in the presence and absence of exogenous HA. The dependence of CD44 for the versican and HA mediated effects were demonstrated by the inhibition of pericellular matrix formation as well as motility and invasion of OVCAR-5 cells following treatment with CD44 neutralizing antibody in the presence of versican and HA. We conclude that the acquisition of a HA/versican pericellular matrix by ovarian cancer cells increases their metastatic potential. HA oligomers can block this mechanism and are promising inhibitors of ovarian cancer dissemination.

Abstract B222: MUC16/CA125 synthetic lethal kinase screen for novel ovarian cancer targets

Abstract Background: MUC16 is a tethered, cell surface mucin which is over expressed on ovarian cancer cells and encodes the CA125 antigen. The CA125 antigen is present in the serum of women with ovarian cancer and appears to be an independent adverse marker of prognosis. Elements of the MUC16 molecule appear to promote invasion, alter gene expression and will induce malignant transformation in NIH 3T3 cells. We have previously demonstrated that MUC16 expression alters the expression of invasion/metastasis genes and genes linked to drug resistance. We hypothesize that the forced expression of MUC16 induces changes that might be relected in altered kinase activities and provides an opportunity to specifically target the MUC16+ ovarian cancer cell. Methods: A human kinome siRNA library (2 siRNA's/well) was purchased from Qiagen. A2780 cells with and without MUC16 expression were labeled with GFP or mCherry Fluorescence proteins and plated in 96 well plates at 25000 cells/well. Each siRNA was plated into six replicate wells and analyzed for inhibition compared to negative controls and a proprietary “All Star Death” siRNA mix. If the candidate siRNA inhibited the proliferation of MUC16+ cells statistically (p&amp;lt;0.05) more than MUC16 negative cells at 72hrs, that siRNA was scored as a “hit”. Results: To date, we have screened siRNA's for a total of 160 of the planned 714 kinases. From the initial screen, we identified 28 kinase candidates for additional evaluation. Two additional siRNA's per kinase were obtained for confirmatory screening. From this initial group of kinases, inhibition of 3 kinases (CHEK1, ABL1 and CDK4) were significantly more inhibitory for MUC16+ cells than the syngeneic MUC16- comparator. Eight additional kinases (including CSK, CHUK, ILK and LTK) were more inhibited in the MUC16+ cells for 3 of 4 tested siRNA's for the target kinase. Although CDK4 protein levels were not altered in MUC16 transformed A2780 cells, CDK4 inhibitors were differentially active between the MUC16 +/- syngeneic pair and additional testing with other small molecule inhibitors is ongoing. Conclusions: 1)MUC16 expression alters the biologic behavior of ovarian cancer cells and 2)MUC16 targeted, syngeneic screening of kinase siRNA libraries can identify potential clinical target candidates for ovarian cancer selected for MUC16. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B222.

Overexpression of RhoA enhances peritoneal dissemination: RhoA suppression with Lovastatin may be useful for ovarian cancer

Small guanosine triphosphatase RhoA has been known to re-organize cytoskeletons and regulate cell migration. The present authors have previously reported that expression of RhoA is significantly increased in advanced ovarian carcinomas and also in the peritoneal disseminated lesions. The present study investigated whether overexpression of RhoA could alter the progressive behavior of ovarian cancer cells. The effect of various Rho inhibitors on the biological behavior of ovarian cancer cells in vitro and in vivo was also examined. A stable RhoA-transfectant of an ovarian cancer cell line SKOV3 was generated and examined in vitro for alterations of proliferative activity and invasiveness, and also in the nude mice model for peritoneal dissemination. In addition, the effect of a specific Rho inhibitor (C3 exoenzyme), Rho kinase inhibitor (Y27632) and hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (Lovastatin and Pravastatin) were studied in vitro and in vivo. Forced overexpression of RhoA did not alter proliferative activity but significantly increased the invasiveness in vitro, which was suppressed by addition of C3 exoenzyme, Y27834, Lovastatin and Pravastatin. In the nude mice model, the frequency of dissemination and the number of disseminated lesions were significantly increased in the RhoA transfectant than in the control. In addition, oral administration of Lovastatin significantly decreased the number of metastatic sites compared with the control. These findings suggest that upregulation and/or activation of RhoA play an important role in the peritoneal dissemination of ovarian carcinoma, and that Lovastatin might be a candidate for the possible, novel treatment for ovarian carcinoma patients with peritoneal dissemination.

Inhibin Resistance Is Associated with Aggressive Tumorigenicity of Ovarian Cancer Cells

Malignant ovarian epithelial tumors have been shown to have decreased inhibin production relative to activin production compared with normal ovarian surface epithelial (OSE) cells and nonmalignant ovarian tumors. Activin stimulates proliferation of many ovarian cancer cell lines. Inhibin antagonizes the action of activin, and inhibin-deficient mice develop gonadal tumors, suggesting that inhibin may be a tumor suppressor. However, its effects on OSE and ovarian cancer cells are unknown. We hypothesize that activin and inhibin are important regulators of biological activity in ovarian cancers. We found that inhibin A decreased murine OSE proliferation, whereas activin A had no effect. Activin A increased the proliferation of four of eight ovarian cancer cell lines (SKOV3, OCC1, OVCAR3, and A2780-s). Inhibin A decreased the proliferation of SKOV3, A2780-s, and OVCAR3 but had no effect on OCC1, ES-2, HEY, A2780-cp, and OVCA429 cells. When injected into nude mice, the inhibin-resistant cancer cell lines resulted in shorter survival time compared with the inhibin-responsive cells. Further investigations on SKOV3 and OCC1 cells showed that activin A increased invasion through Matrigel. Inhibin A decreased both basal and activin-induced proliferation and invasion of SKOV3 but had no effect on OCC1 cells. Reverse transcription-PCR analyses showed that the SKOV3 and OCC1 cells produced activin, but only SKOV3 produced inhibin. Analysis of the activin/inhibin signaling pathways indicated that Smad anchor for receptor activation was elevated in SKOV3 and OCC1 cells and that an up-regulation of the activin receptor expression may explain the inhibin resistance of OCC1 cells. Our results suggest that activin responsiveness may be gained during transformation of OSE cells and that inhibin resistance may contribute to the aggressive behavior of ovarian cancer cells.

TGFbeta1 stimulates the secretion of matrix metalloproteinase 2 (MMP2) and the invasive behavior in human ovarian cancer cells, which is suppressed by MMP inhibitor BB3103.

The present study investigated the modulatory role of transforming growth factor beta 1 (TGFbeta1) on the secretion of matrix metalloproteinases (MMPs) and tested whether the altered secretion of MMPs could directly affect the invasive behavior of ovarian cancer cells. To this aim, human ovarian cancer SKOV3 cells were treated once with vehicle or various concentrations of TGFbeta1 for 24 h. Gelatinase activities in conditioned media were analyzed by zymography and densitometry. TGFbeta1 dose-dependently stimulated the secretion of a 68-kDa gelatinase, which was characterized as an MMP because its activity was inhibited by a metalloproteinase inhibitor 1,10-phenanthroline, and by a synthetic MMP inhibitor BB3103. In addition, we used aminophenylmercuric acetate (APMA) to activate latent gelatinases. APMA time-dependently decreased the activity of 68-kDa gelatinase, and increased the activities of 64- and 62-kDa gelatinolytic bands. The 68-kDa gelatinase was further characterized as MMP2 (gelatinase A) by immunoblotting analysis. We then tested TGFbeta1 effect on the invasive potential of SKOV3 cells as assessed by the migration ability through reconstituted basement membrane, and further investigated whether TGFbeta1 may act through modulating the MMP activity to affect ovarian cancer cell invasion. The results show that TGFbeta1 stimulated the invasive behavior of SKOV3 cells, and that MMP inhibitor BB3103 abrogated this effect of TGFbeta1. In conclusion, this study indicates that TGFbeta1 may act partly through stimulating the secretion of MMP in promoting the invasive behavior of human ovarian cancer cells. Furthermore, this work supports the idea that specific MMP inhibitors of the hydroxamate class could be therapeutically useful in controlling cancer cell invasion/metastasis.