ADAMTS1 alters blood vessel morphology and TSP1 levels in LNCaP and LNCaP-19 prostate tumors

Gustavsson, Heléne; Tešan, Tajana; Jennbacken, Karin; Kuno, Kouji; Damber, Jan‐Erik; Welén, Karin

doi:10.1186/1471-2407-10-288

Cited by 27 publications

(30 citation statements)

References 31 publications

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“…As previous tumor studies have shown, the alteration of ADAMTS1 levels is accompanied by changes in the overall tumor structure and consistency, and specifically it has significant effects on the vasculature [4, 5, 20–23]. Therefore we decided to explore the vascular pattern in our model.…”

Section: Resultsmentioning

confidence: 99%

Stroma-derived but not tumor ADAMTS1 is a main driver of tumor growth and metastasis

et al. 2016

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The matrix metalloprotease ADAMTS1 (A Disintegrin And Metalloprotease with ThromboSpondin repeats 1) has been involved in tumorigenesis although its contributions appeared ambiguous. To understand the multifaceted actions of this protease, it is still required a deeper knowledge of its implication in heterogeneous tumor-stroma interactions. Using a syngeneic B16F1 melanoma model in wild type and ADAMTS1 knockout mice we found distinct stroma versus tumor functions for this protease. Genetic deletion of ADAMTS1 in the host microenvironment resulted in a drastic decrease of tumor growth and metastasis. However, the downregulation of tumor ADAMTS1 did not uncover relevant effects. Reduced tumors in ADAMTS1 KO mice displayed a paradoxical increase in vascular density and vascular-related genes; a detailed characterization revealed an impaired vasculature, along with a minor infiltration of macrophages. In addition, ex-vivo assays supported a chief role for ADAMTS1 in vascular sprouting, and melanoma xenografts showed a relevant induction of its expression in stroma compartments. These findings provide the first genetic evidence that supports the pro-tumorigenic role of stromal ADAMTS1.

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Section: Resultsmentioning

confidence: 99%

Stroma-derived but not tumor ADAMTS1 is a main driver of tumor growth and metastasis

et al. 2016

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“…46 VLDLR has been shown to be associated with obesity from both animal studies [47][48][49] and human GWAS.…”

Section: Discussionmentioning

confidence: 99%

“…45 From animal studies, brahma gene expression is found to be restricted to mesodermal tissues involved in early vasculogenesis and heart morphogenesis. 46 VLDLR has been shown to be associated with obesity from both animal studies [47][48][49] and human GWAS. 50 Recently, a pathway analyses based on results from a GWAS has identified plausible biological links between VLDR with vascular endothelial growth factor, which is known to affect angiogenesis and atherosclerosis.…”

Section: Discussionmentioning

confidence: 99%

“…The composition of cardiac jelly essential for myocardial morphogenesis is dynamically controlled by ADAMTS1 and its chromatin-based transcriptional regulation 47 . Modifications to this gene expression are associated with markedly changed blood vessel morphology 48 . GRK5 Leu41 decreased the risk for adverse cardiovascular outcomes 59 .…”

Section: Supplementarymentioning

confidence: 99%

“…SMARCA is a member of the SWI/SNF family of proteins and is highly similar to the brahma protein, where it has been hypothesized that cardiac hypertrophy and the fetal gene expression program are associated with distinguishable binding of brahma and SMARCA4 on genes. 45 From animal studies, brahma gene expression is found to be restricted to mesodermal tissues involved in early vasculogenesis and heart morphogenesis.46 VLDLR has been shown to be associated with obesity from both animal studies [47][48][49] and human GWAS. …”

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confidence: 99%

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International Genome-Wide Association Study Consortium Identifies Novel Loci Associated With Blood Pressure in Children and Adolescents

Parmar¹,

Taal²,

Timpson³

et al. 2016

Circ Cardiovasc Genet

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266S ystolic and diastolic blood pressure (SBP and DBP) are complex phenotypes, with known environmental and genetic risk factors.1 Elevated SBP and DBP are associated with premature mortality 2,3 and cardiovascular diseases. 2,4-9 Clinical Perspective on p 278Recent genome-wide association studies (GWAS) have identified genetic variants associated with adult SBP and DBP and hypertension. [10][11][12][13][14][15][16][17][18][19][20][21][22][23][24] Several of these loci are in biologically plausible candidate genes, for example, those that influence the renin-angiotensin system. 25 There are established patterns of age-related changes in BP in industrialized populations, which support a potential interaction of genetic variants with age-related changes to environmental exposures in these populations. 26,27 For genetic variants that directly modulate childhood BP, effects might change with age, might differ between developmental periods (early life, childhood, and adolescence), and might also differ to those variants that act in adulthood.Children and adolescents are rarely treated with antihypertensives, whereas from middle age onwards, an increasing proportion of adults are using such medications. 26 Consequently, it is easier to examine genetic variants that are associated with untreated SBP and DBP in children. Variation in SBP, and to Background-Our aim was to identify genetic variants associated with blood pressure (BP) in childhood and adolescence. Methods and Results-Genome-wide association study data from participating European ancestry cohorts of the EarlyGenetics and Lifecourse Epidemiology (EAGLE) Consortium was meta-analyzed across 3 epochs; prepuberty (4-7 years), puberty (8-12 years), and postpuberty (13-20 years). Two novel loci were identified as having genome-wide associations with systolic BP across specific age epochs: rs1563894 (ITGA11, located in active H3K27Ac mark and transcription factor chromatin immunoprecipitation and 5′-C-phosphate-G-3′ methylation site) during prepuberty (P=2.86×10-8) and rs872256 during puberty (P=8.67×10 -9 ). Several single-nucleotide polymorphism clusters were also associated with childhood BP at P<5×10 -3. Using a P value threshold of <5×10 -3 , we found some overlap in variants across the different age epochs within our study and between several single-nucleotide polymorphisms in any of the 3 epochs and adult BPrelated single-nucleotide polymorphisms. Conclusions-Our results suggest that genetic determinants of BP act from childhood, develop over the lifecourse, and show some evidence of age-specific effects. Parmar et al Blood Pressure GWAS in Children 267a lesser extent DBP, in adolescence and early adulthood is associated with subsequent adult risk of coronary heart disease and stroke. 28,29 Understanding the risk factors, including genetic variation, that are associated with SBP and DBP through childhood and into adolescence may therefore inform an improved understanding of the life course pathogenesis of adult hypertension and cardiovascular disease...

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The metalloproteinase ADAMTS1: A comprehensive review of its role in tumorigenic and metastatic pathways

Tan

Ricciardelli

Russell

2013

Intl Journal of Cancer

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As it was first characterized in 1997, the ADAMTS (A Disintegrin and Metalloprotease with ThromboSpondin motifs) metalloprotease family has been associated with many physiological and pathological conditions. Of the 19 proteases belonging to this family, considerable attention has been devoted to the role of its first member ADAMTS1 in cancer. Elevated ADAMTS1 promotes pro-tumorigenic changes such as increased tumor cell proliferation, inhibited apoptosis and altered vascularization. Importantly, it facilitates significant peritumoral remodeling of the extracellular matrix environment to promote tumor progression and metastasis. However, discrepancy exists, as several studies also depict ADAMTS1 as a tumor suppressor. This article reviews the current understanding of ADAMTS1 regulation and the consequence of its dysregulation in primary cancer and ADAMTS1-mediated pathways of cancer progression and metastasis.In cancer, the remodeling of the host tissue environment is fundamental for the dismantling of normal tissue structural constraints, establishment of vascular supply and invasion of metastatic cells. For this aberrant remodeling to occur, cancers cells rely on the proteolytic activity of extracellular matrix (ECM) proteases to facilitate the degradation of structural proteins that make up the ECM. 1,2 Metalloproteases belonging to the ADAMTS family have been widely implicated in tissue remodeling events manifested in cancer development, growth and progression. [3][4][5][6][7][8][9][10][11][12][13][14] There are 19 ADAMTS proteases identified in humans. They share homology in the catalytic ADAM-metalloprotease and disintegrin domains, but differ in the variable numbers of thrombospondin-like motifs and other carboxyl-terminal domains associated with ECM interaction. 15,16 Unlike the transmembrane ADAM family, ADAMTS proteases are secreted and bind to the ECM through their C-terminal regions. 17 33 Among them, the modulated expression of ADAMTS1 has been the most characterized in cancer and is the focus of this review.ADAMTS1 was initially described as a mediator of inflammation 34 but its activity has since become appreciated in organogenesis, [35][36][37][38] blood/lymph vessel formation, [39][40][41][42][43][44][45] ovarian folliculogenesis 39 and ovulation. 23,46 In these physiological events, ADAMTS1 remodels the ECM through the proteolytic degradation of key substrates such as chondroitin sulfated proteoglycans [47][48][49][50] and collagen. 51-53 ADAMTS1 also acts as an inhibitor of angiogenesis by sequestering proangioigenic stimuli, vascular epithelial growth factor (VEGF) and preventing its interaction with its receptor. 41,45 The dysregulation of ADAMTS1 often leads to pathological manifestations of altered ECM 54-56 and/or vascular density 57-60 and many studies have highlighted its functional activity during tumorigenic transformation. 14,[61][62][63][64][65][66][67] ADAMTS1 dysregulation is linked to four of the most commonly diagnosed cancers. But, conflicting reports currently surround its exp...

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ADAMTS1 alters blood vessel morphology and TSP1 levels in LNCaP and LNCaP-19 prostate tumors

Cited by 27 publications

References 31 publications

Stroma-derived but not tumor ADAMTS1 is a main driver of tumor growth and metastasis

Stroma-derived but not tumor ADAMTS1 is a main driver of tumor growth and metastasis

International Genome-Wide Association Study Consortium Identifies Novel Loci Associated With Blood Pressure in Children and Adolescents

The metalloproteinase ADAMTS1: A comprehensive review of its role in tumorigenic and metastatic pathways

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