Veli-Matti Kähäri

Regulation of matrix metalloproteinase expression in tumor invasion

Degradation of basement membranes and stromal extracellular matrix (ECM) is crucial for invasion and metastasis of malignant cells. Degradation of ECM is initiated by proteinases secreted by different cell types participating in tumor cell invasion, and increased expression or activity of every known class of proteinases (metallo‐, serine‐, aspartic‐, and cysteine) has been linked to malignancy and invasion of tumor cells. Studies performed over the last decade have revealed that matrix metalloproteinases (MMPs) play a crucial role in tumor invasion. Expression of MMP genes is transcriptionally regulated by a variety of extracellular factors including cytokines, growth factors, and cell contact to ECM. This review will summarize the current view on the role of MMPs in tumor growth, invasion, and survival, and focus on the role of mitogen‐activated protein kinases and AP‐1 and ETS transcription factors in the regulation of MMP gene expression during invasion process.—Westermarck, J., Kähäri, V.‐M. Regulation of matrix metalloproteinase expression in tumor invasion. FASEB J. 13, 781–792 (1999)

Matrix metalloproteinases in cancer: Prognostic markers and therapeutic targets

Degradation of extracellular matrix is crucial for malignant tumour growth, invasion, metastasis and angiogenesis. Matrix metalloproteinases (MMPs) are a family of zinc‐dependent neutral endopeptidases collectively capable of degrading essentially all matrix components. Elevated levels of distinct MMPs can be detected in tumour tissue or serum of patients with advanced cancer and their role as prognostic indicators in cancer is studied. In addition, therapeutic intervention of tumour growth and invasion based on inhibition of MMP activity is under intensive investigation and several MMP inhibitors are in clinical trials in cancer. In this review, we discuss the current view on the feasibility of MMPs as prognostic markers and as targets for therapeutic intervention in cancer.

Matrix metalloproteinases in skin.

Abstract Matrix metalloproteinases (MMPs) are a family of zinc‐dependent endopeptidases collectively capable of degrading essentially all extracellular matrix components. These enzymes can be produced by several different types of cells in skin such as fibroblasts, keratinocytes. macro‐phages, endothelial cells, mast cells, and eosinophils and their activity can be specifically inhibited by TIMPs (tissue inhibitors of metalloproteinases), which bind to active MMPs with 1:1 stoichiometry. In general, MMPs are not constitutively expressed in skin but are induced temporarily in response to exogenous signals such as various cytokines. growth factors, cell‐matrix interactions and altered cell‐cell contacts. At present, more evidence is accumulating thai MMPs play an important role in proteolytic remodeling of extracellular matrix in various physiologic situations, including developmental tissue morphogenesis, tissue repair, and angiogenesis. On the other hand, MMPs play an important pathogenetic role in excessive breakdown of connective tissue components, e.g. in rheumatoid arthritis, oslteoarthritis, chronic ulcers, dermal photoageing, and periodontitis, as well as in tumor cell invasion and metastasis. In this review we discuss the role of MMPs and TIMPs in human skin based on new observations on the regulation of the expression of MMPs, on their substrate specificily, and MMP expression in physiologic and pathologic conditions of skin involving matrix remodeling. Furthermore, therapeutic modalities based on regulating MMP activity will be reviewed.

CIP2A Inhibits PP2A in Human Malignancies

Inhibition of protein phosphatase 2A (PP2A) activity has been identified as a prerequisite for the transformation of human cells. However, the molecular mechanisms by which PP2A activity is inhibited in human cancers are currently unclear. In this study, we describe a cellular inhibitor of PP2A with oncogenic activity. The protein, designated Cancerous Inhibitor of PP2A (CIP2A), interacts directly with the oncogenic transcription factor c-Myc, inhibits PP2A activity toward c-Myc serine 62 (S62), and thereby prevents c-Myc proteolytic degradation. In addition to its function in c-Myc stabilization, CIP2A promotes anchorage-independent cell growth and in vivo tumor formation. The oncogenic activity of CIP2A is demonstrated by transformation of human cells by overexpression of CIP2A. Importantly, CIP2A is overexpressed in two common human malignancies, head and neck squamous cell carcinoma (HNSCC) and colon cancer. Thus, our data show that CIP2A is a human oncoprotein that inhibits PP2A and stabilizes c-Myc in human malignancies.

Matrix metalloproteinases in tumor invasion

Abstract. Controlled degradation of extracellular matrix (ECM) is essential for the growth, invasion, and metastasis of malignant tumors, and for tumor-induced angiogenesis. Matrix metalloproteinases (MMPs) are a family of zinc-dependent neutral endopeptidases collectively capable of degrading essentially all ECM components and they apparently play an important role in all these aspects of tumor development. Furthermore, recent evidence suggests that MMPs also play a role in tumor cell survival. In this review, we discuss the current concept concerning the role of MMPs and their inhibitors in tumor invasion, as a basis for prognosis and targeted therapeutic intervention in cancer.

Trendsin Molecular Medicine: Matrix metalloproteinases and their inhibitors in tumour growth and invasion

Thymic peptides, a heterogenous family of polypeptidic hormones synthesized within the thymus, not only exert important regulatory effects within both the immune and neuroendocrine systems but are also themselves subject to control by hormones derived from the hypothalamic-pituitary-adrenal axis (HPA) and other endocrine glands. Regarding thymic hormonal function, thymulin production is up-regulated by several hormones, including prolactin, growth hormone and thyroid hormones. Other aspects of the physiology of thymic epithelial cells can also be modulated by hormones and neuropeptides, particularly cytokeratin expression, cell growth and production of extracellular matrix proteins, thus characterizing the pleiotrophic action of these molecules on the thymic epithelium. Conversely, thymic-derived peptides also regulate hormone release from the HPA axis and may act directly on target endocrine glands of this axis, modulating gonadal tissues. In addition, it has recently been shown that thymulin can modulate some peripheral nervous sensory functions, including those related to sensitivity to pain. According to the dose given, thymulin induces or reduces hyperalgesia related to both mechanical and thermal nociceptors and thus represents an important interface between the immune, endocrine and nervous systems.

Collagenase-3 (MMP-13) is expressed by hypertrophic chondrocytes, periosteal cells, and osteoblasts during human fetal bone development.

Collagenase‐3 (MMP‐13) is a novel matrix metalloproteinase, the expression of which has so far only been documented in human breast carcinomas and osteoarthritic cartilage. In this study we have examined the expression of MMP‐13 during human fetal development. Northern blot hybridizations revealed abundant expression of MMP‐13 mRNAs in total RNA from fetal cartilage and calvaria at gestational age of 15 weeks. By in situ hybridization MMP‐13 transcripts were detected in chondrocytes of hypertrophic cartilage in vertebrae of the spinal column and in the dorsal end of ribs undergoing ossification, as well as in osteoblasts and periosteal cells below the inner periosteal region of ossified ribs. In contrast, no expression of MMP‐13 could be detected in osteoclasts. Furthermore, expression of MMP‐13 mRNA was detected in osteoblasts and fibroblasts primarily on the inner side of calvarial bone of the skull at 16 weeks of gestation. Expression of MMP‐13 mRNA by primary human fetal chondrocytes in culture was enhanced by transforming growth factor‐β (TGF‐β) and inhibited by bone morphogenetic protein‐2 (BMP‐2). No expression of MMP‐13 mRNA could be noted in other fetal tissues, including the skin, lungs, neural tissue, muscle, and liver. These results suggest that MMP‐13 plays an important role in the extracellular matrix remodeling during fetal bone development both via endochondral and intramembranous ossification. Dev. Dyn. 208:387–395, 1997.

Matrix Metalloproteinases as Therapeutic Targets in Cancer

Degradation of extracellular matrix is crucial for malignant tumor growth, invasion, metastasis and angiogenesis. Matrix metalloproteinases (MMPs) are a family of zinc-dependent neutral endopeptidases collectively capable of degrading essentially all matrix components. Elevated levels of distinct MMPs can be detected in tumor tissue or serum of patients with advanced cancer, and their role as prognostic indicators in cancer has been widely examined. In addition, therapeutic intervention in tumor growth and invasion based on inhibition of MMP activity is under intensive investigation and several MMP inhibitors (MMPIs) are in clinical cancer trials. Even though results of the first clinical trials in advanced cancer have been mostly disappointing, there are also positive results. Recent observations show, that certain MMPs limit tumor growth. Therefore, identification of proper MMPs for therapeutic intervention with array-based molecular classifications of tumors and targeting these with more specific MMPIs in combination with conventional chemotherapy is expected to provide a feasible approach for cancer therapy. MMPIs represent a totally different therapeutic modality from proven anti-cancer drugs and thus traditional approaches to evaluate drug efficiency cannot be used without modification. In this review, we discuss the current view on the feasibility of MMPs as targets for therapeutic intervention in cancer.

p38 mitogen-activated protein kinase-dependent activation of protein phosphatases 1 and 2A inhibits MEK1 and MEK2 activity and collagenase 1 (MMP-1) gene expression

ABSTRACT Degradation of collagenous extracellular matrix by collagenase 1 (also known as matrix metalloproteinase 1 [MMP-1]) plays a role in the pathogenesis of various destructive disorders, such as rheumatoid arthritis, chronic ulcers, and tumor invasion and metastasis. Here, we have investigated the role of distinct mitogen-activated protein kinase (MAPK) pathways in the regulation of MMP-1 gene expression. The activation of the extracellular signal-regulated kinase 1 (ERK1)/ERK2 (designated ERK1,2) pathway by oncogenic Ras, constitutively active Raf-1, or phorbol ester resulted in potent stimulation of MMP-1 promoter activity and mRNA expression. In contrast, activation of stress-activated c-Jun N-terminal kinase and p38 pathways by expression of constitutively active mutants of Rac, transforming growth factor β-activated kinase 1 (TAK1), MAPK kinase 3 (MKK3), or MKK6 or by treatment with arsenite or anisomycin did not alone markedly enhance MMP-1 promoter activity. Constitutively active MKK6 augmented Raf-1-mediated activation of the MMP-1 promoter, whereas active mutants of TAK1 and MKK3b potently inhibited the stimulatory effect of Raf-1. Activation of p38 MAPK by arsenite also potently abrogated stimulation of MMP-1 gene expression by constitutively active Ras and Raf-1 and by phorbol ester. Specific activation of p38α by adenovirus-delivered constitutively active MKK3b resulted in potent inhibition of the activity of ERK1,2 and its upstream activator MEK1,2. Furthermore, arsenite prevented phorbol ester-induced phosphorylation of ERK1,2 kinase-MEK1,2, and this effect was dependent on p38-mediated activation of protein phosphatase 1 (PP1) and PP2A. These results provide evidence that activation of signaling cascade MKK3-MKK3b→p38α blocks the ERK1,2 pathway at the level of MEK1,2 via PP1-PP2A and inhibits the activation of MMP-1 gene expression.

Transforming growth factor-β signaling in cancer invasion and metastasis

Transforming growth factor‐β (TGF‐β) family members are polypeptides with dual tumor suppressive and oncogenic effects. They signal through serine/threonine kinase receptor complexes, which phosphorylate cytoplasmic mediators, the Smads. Upon phosphorylation, Smads translocate to the nucleus and associate with transcriptional coactivators or corepressors, and regulate the transcriptional activation of various TGF‐β responsive genes. In addition, TGF‐β activates cellular mitogen‐activated protein kinase signaling pathways, which crosstalk with Smad signaling and regulate growth, survival and motility of cells. During tumorigenesis, malignantly transformed cells often lose the response to the tumor suppressive effects of TGF‐β, which, in turn, starts to act as an autocrine tumor promoting factor by enhancing cancer invasion and metastasis. In this review, we summarize current view on the role of TGF‐β signaling in tumorigenesis, with emphasis on cancer invasion and metastasis. On the basis of these recent observations, we discuss new therapeutic strategies targeting TGF‐β signaling at distinct levels as a basis for inhibiting tumor growth, angiogenesis, invasion and metastasis.