Reduced metastasis of transgenic mammary cancer in urokinase-deficient mice

Almholt, Kasper; Lund, Leif R.; Rygaard, Jørgen; Nielsen, Boye Schnack; Danø, Keld; Rømer, John; Johnsen, Morten

doi:10.1002/ijc.20631

Cited by 138 publications

(129 citation statements)

References 52 publications

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“…Lymphangiogenesis in the ovary is dependent on ADAMTS1 activity, 3,43 and in breast cancers enhanced lymphangiogenesis provides a route for dissemination to lymph nodes and eventually metastasis to distal tissues such as lung. 44 Although we found the lowest proportion of lymph node metastases in Adamts1 Ϫ/Ϫ mice, the infrequency of lymph node metastases of PyMT tumors (consistent with previous reports 45 ) precludes any interpretation of a role for ADAMTS1 in dissemination to lymph nodes.…”

Section: Discussionsupporting

confidence: 88%

The ADAMTS1 Protease Gene Is Required for Mammary Tumor Growth and Metastasis

Ricciardelli

Frewin

Tan

et al. 2011

The American Journal of Pathology

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The A disintegrin and metalloprotease with thrombospondin motifs (ADAMTS) family of proteins is composed of extracellular metalloproteases, including ADAMTS1, originally identified in cachexigenic colon cancer cells. 1,2 Mice with Adamts1-null mutation exhibit urogenital defects and female infertility because of impaired remodeling of ovarian extracellular matrix (ECM), but ovarian steroid production and lactation are normal. 3-5 A range of ECM proteins have been identified as potential ADAMTS1 substrates, including collagens, 6 nidogen, 7 and syndecan-4 8 ; however, the proteoglycans versican and aggrecan have been consistently shown to be key ADAMTS1 targets. 4,9,10 ADAMTS1 processing of versican is important in cell migration during wound healing, 11 endothelial cell invasion, 12 and remodeling of cardiac jelly ECM during heart morphogenesis. 13 These observations indicate that ADAMTS1 mediates acute regulated tissue remodeling processes that occur in development and in adult reproductive tissues, but also in cancer growth and metastasis.Emerging evidence associates ADAMTS1 expression with metastatic potential. Elevated expression of ADAMTS1 is characteristic of breast cancer cell lines 14,15 and human breast cancers with high bone metastatic potential. 16 Likewise, local invasion and lymph node metastasis of pancreatic cancer is associated with elevated Adamts1. 17 Overexpression of full-length ADAMTS1 in

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Section: Discussionsupporting

confidence: 88%

The ADAMTS1 Protease Gene Is Required for Mammary Tumor Growth and Metastasis

Ricciardelli

Frewin

Tan

et al. 2011

The American Journal of Pathology

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“…For example, α3β1 integrin is required for adhesion to laminin during pulmonary metastasis 100 , whereas blocking αvβ1 integrin inhibited metastasis through suppression of expression of the protease urokinase plasminogen activator (uPA) 11 . The data for αvβ1 integrin are consistent with the inhibition of metastasis associated with uPA deficiency in the MMTV-PyMT model of breast cancer 101 . Early experiments by Liotta and colleagues showed that co-injection of tumour cells with fibronectin in experimental metastasis models increased tumour cell adhesion and metastasis 102 .…”

Section: Adhesion and Invasion In The Establishment Of Metastasissupporting

confidence: 76%

Microenvironmental regulation of metastasis

2008

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Metastasis is a multistage process that requires cancer cells to escape from the primary tumour, survive in the circulation, seed at distant sites and grow. Each of these processes involves ratelimiting steps that are influenced by non-malignant cells of the tumour microenvironment. Many of these cells are derived from the bone marrow, particularly the myeloid lineage, and are recruited by cancer cells to enhance their survival, growth, invasion and dissemination. This Review describes experimental data demonstrating the role of the microenvironment in metastasis, identifies areas for future research and suggests possible new therapeutic avenues.A variety of stromal cells in the surrounding environment are recruited to tumours, and these not only enhance growth of the primary cancer but also facilitate its metastatic dissemination to distant organs. Cancer cells in an aggressive primary mass are adept at exploiting that particular tissue microenvironment; however, once they leave these favourable surroundings, they must possess traits that will allow them to survive in new environments. In order for a metastasis to occur, the intravasated cancer cell must survive in the circulation, arrive at the target organ (seeding), extravasate into the parenchyma and show persistent growth 1 . Each of these stages is inefficient and some are rate limiting 1,2 . For example, senescence or apoptosis of cancer cells at the stage of entry into the metastatic site prevents the spread of the majority of circulating cells [2][3][4] . Seeding can occur to multiple organs, but metastatic tumours may grow in only one or a few 5 . There is also increasing evidence that in some cases cancer cells can lie dormant for many years, and that seeding may occur several years before diagnosis of the primary tumour [6][7][8][9][10] . In another phenomenon, termed angiogenic dormancy, there is a balance of proliferation and apoptosis that results in micrometastases that do not progress further 11,12 . The microenvironment clearly suppresses NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript the malignancy of these potentially metastatic cells 10 , and their re-activation to form a clinically relevant metastasis probably occurs through perturbations in the microenvironment. Nevertheless, despite this evidence for early seeding and dormancy, tumour size and grade are the main predictors of metastasis, and this has been reinforced in recent studies in mouse models 13 and by gene expression analysis that linked large tumour size with metastasis-enhancing gene signatures 14 . It has been hypothesized that this may be due to metastatic re-seeding to primary tumours 15 . If this is the case, nothing is currently known about the underlying mechanisms. Successful metastatic outgrowth thus depends on the cumulative ability of cancer cells to appropriate distinct microenvironments at each step in the metastatic cascade: the primary tumour, systemic circulation and the final metastatic site. In this Review we discuss instruct...

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“…For RA and possibly for osteoarthritis, my coinvestigators and I as well as other investigators have argued that uPA may be a therapeutic target, provided that the possible complication of persistent fibrin upon its blockade does not occur (1)(2)(3)9,24). Its inhibition may also have benefit, for example, in cancer metastasis (25), cardiac fibrosis (26), and lung inflammation (27). What is sorely needed for an understanding of the biology and pathology associated with the PA/plasmin system are potent and highly specific inhibitors of the PA activities that have the appropriate pharmacokinetics.…”

Section: Resultsmentioning

confidence: 99%

Plasminogen activator/plasmin system in arthritis and inflammation: Friend or foe?

Hamilton¹

2008

Arthritis & Rheumatism

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Reduced metastasis of transgenic mammary cancer in urokinase-deficient mice

Cited by 138 publications

References 52 publications

The ADAMTS1 Protease Gene Is Required for Mammary Tumor Growth and Metastasis

The ADAMTS1 Protease Gene Is Required for Mammary Tumor Growth and Metastasis

Microenvironmental regulation of metastasis

Plasminogen activator/plasmin system in arthritis and inflammation: Friend or foe?

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