Hyaluronan in Peritumoral Stroma and Malignant Cells Associates with Breast Cancer Spreading and Predicts Survival

Auvinen, Päivi; Tammi, Raija; Parkkinen, Jyrki; Tammi, Markku; Ågren, Ulla M.; Johansson, Risto; Hirvikoski, Pasi; Eskelinen, Matti; Kosma, Veli‐Matti

doi:10.1016/s0002-9440(10)64757-8

Cited by 465 publications

(412 citation statements)

References 36 publications

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“…It has been shown that HArich environment in brain ECM significantly correlates with cancer aggressiveness (29)(30)(31)(32)(33). Glioma cells express high levels of the HA receptors CD44 and RHAMM.…”

Section: Discussionmentioning

confidence: 99%

17-Allylamino-17-Demethoxygeldanamycin Down-Regulates Hyaluronic Acid–Induced Glioma Invasion by Blocking Matrix Metalloproteinase-9 Secretion

Kim¹,

Kwak²,

Lee³

et al. 2008

Molecular Cancer Research

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Hyaluronic acid (HA) has been implicated in cell adhesion, motility, and tumor progression in gliomas. We previously reported that HA stimulates secretion of matrix metalloproteinase-9 (MMP-9) and induces glioma invasion. However, the molecular mechanism of HA action and therapeutic strategies for blocking HA-induced MMP-9 secretion remain unknown. Here, we report that the Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) blocks MMP-9 secretion and that HA-induced nuclear factor-KB (NF-KB) activation is mediated by IKB kinase, which phosphorylates the NF-KB inhibitor IKBA and promotes its degradation. In addition, using an RNA interference approach, we show that the focal adhesion kinase plays a critical role in mediating HA-induced NF-KB activation, which resulted in increased MMP-9 expression and secretion, cell migration, and invasion. Importantly, we show that 17-AAG acts by blocking focal adhesion kinase activation, thereby inhibiting IKB kinasedependent IKBA phosphorylation/degradation, NF-KB activation, and MMP-9 expression. This leads to suppression of HA-induced cell migration and invasion. Based on our data, we propose that 17-AAG is a candidate drug for treatment of highly invasive gliomas resulting from HA-induced, NF-KB -mediated MMP-9

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Section: Discussionmentioning

confidence: 99%

17-Allylamino-17-Demethoxygeldanamycin Down-Regulates Hyaluronic Acid–Induced Glioma Invasion by Blocking Matrix Metalloproteinase-9 Secretion

Kim¹,

Kwak²,

Lee³

et al. 2008

Molecular Cancer Research

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“…HA is associated with a wide variety of malignant tumors and has been implicated in cancer progression [3][4][5][6][7][8][9]. However, the importance of HA in osteosarcoma has not yet been investigated in terms of basic or clinical relevance.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, HA binding proteins control these cellular behaviors through interactions with HA and assembly of pericellular matrices [2]. Increased HA levels are also observed in malignant tumors, which include gastric cancer, colorectal cancer, breast cancer, glioma, lung carcinoma and ovarian cancer [3][4][5][6][7][8][9]. Studies in vitro have demonstrated that HA levels correlate with the invasive and metastatic capacity of tumor cells [10].…”

Section: Introductionmentioning

confidence: 99%

Antisense inhibition of hyaluronan synthase-2 in human osteosarcoma cells inhibits hyaluronan retention and tumorigenicity

Nishida

Knudson

et al. 2005

Experimental Cell Research

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Osteosarcoma is a common malignant bone tumor associated with childhood and adolescence. The results of numerous studies have suggested that hyaluronan plays an important role in regulating the aggressive behavior of various types of cancer cells. However, no studies have addressed hyaluronan with respect to osteosarcomas. In this investigation, the mRNA expression copy number of three mammalian hyaluronan synthases (HAS) was determined using competitive RT-PCR in the osteoblastic osteosarcoma cell line, MG-63. MG-63 are highly malignant osteosarcoma cells with an abundant hyaluronan-rich matrix. The results demonstrated that HAS-2 is the predominant HAS in MG-63. Accumulation of intracellular hyaluronan increased in association with the proliferative phase of these cells. The selective inhibition of HAS-2 mRNA in MG-63 cells by antisense phosphorothioate oligonucleotides resulted in reduced hyaluronan accumulation by these cells. As expected, the reduction in hyaluronan disrupted the assembly of cell-associated matrices. However, of most interest, coincident with the reduction in hyaluronan, there was a substantial decrease in cell proliferation, a decrease in cell motility and a decrease in cell invasiveness. These data suggest that hyaluronan synthesized by HAS-2 in MG-63 plays a crucial role in osteosarcoma cell proliferation, motility and invasion.

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“…The intensity of HA in the stroma was found to be an independent prognostic factor for overall survival according to Cox's multivariate analysis (Auvinen et al, 2000). HA interacts with tumor cells through the hyaluran-binding protein RHAMM by which it regulates ras signaling.…”

Section: Oncogenic Signals Of Ecm Componentsmentioning

confidence: 99%

New insights into the role of extracellular matrix during tumor onset and progression

Pupa

Ménard

Forti

et al. 2002

Journal Cellular Physiology

303

210

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Recently, a view of the tumor as a functional tissue interconnected with the microenvironment has recently been described. For many years, the stroma has been studied in the context of the malignant lesion, and only rarely has its role been considered before carcinogenic lesions appear. Recent studies have provided evidence that stromal cells and their products can cause the transformation of adjacent cells through transient signaling that leads to the disruption of homeostatic regulation, including control of tissue architecture, adhesion, cell death, and proliferation. It is now well established that tumor progression requires a continually evolving network of interactions between neoplastic cells and extracellular matrix. A relevant step of this process is the remodeling of microenvironment which surrounds tumors leading to the release of ECM-associated growth factors which can then stimulate tumor and/or endothelial cells. Finally, tumor cells reorganizing the extracellular matrix to facilitate communications and escape the homeostatic control exerted by the microenvironment modify response to cytotoxic treatments.

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Hyaluronan in Peritumoral Stroma and Malignant Cells Associates with Breast Cancer Spreading and Predicts Survival

Cited by 465 publications

References 36 publications

17-Allylamino-17-Demethoxygeldanamycin Down-Regulates Hyaluronic Acid–Induced Glioma Invasion by Blocking Matrix Metalloproteinase-9 Secretion

17-Allylamino-17-Demethoxygeldanamycin Down-Regulates Hyaluronic Acid–Induced Glioma Invasion by Blocking Matrix Metalloproteinase-9 Secretion

Antisense inhibition of hyaluronan synthase-2 in human osteosarcoma cells inhibits hyaluronan retention and tumorigenicity

New insights into the role of extracellular matrix during tumor onset and progression

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