Abstract
BackgroundVitronectin is a multifunctional glycoprotein known in several human tumors for its adhesive role in processes such as cell growth, angiogenesis and metastasis. In this study, we examined vitronectin expression in neuroblastoma to investigate whether this molecule takes part in cell-cell or cell-extracellular matrix interactions that may confer mechanical properties to promote tumor aggressiveness.MethodsWe used immunohistochemistry and image analysis tools to characterize vitronectin expression and to test its prognostic value in 91 neuroblastoma patients. To better understand the effect of vitronectin, we studied its in vitro expression using commercial neuroblastoma cell lines and in vivo using intra-adrenal gland xenograft models by immunohistochemistry.ResultsDigital image analysis allowed us to associate vitronectin staining intensity and location discriminating between territorial vitronectin and interterritorial vitronectin expression patterns. High territorial vitronectin expression (strong staining associated with pericellular and intracellular location) was present in tumors from patients with metastatic undifferentiating neuroblastoma, that were MYCN amplified, 11q deleted or with segmental chromosomal profiles, in the high-risk stratification group and with high genetic instability. In vitro studies confirmed that vitronectin is expressed in tumor cells as small cytoplasmic dot drops. In vivo experiments revealed tumor cells with high and dense cytoplasmic vitronectin expression.ConclusionsThese findings highlight the relevance of vitronectin in neuroblastoma tumor biology and suggest its potential as a future therapeutic target in neuroblastoma.
Highlights
Vitronectin is a multifunctional glycoprotein known in several human tumors for its adhesive role in processes such as cell growth, angiogenesis and metastasis
We found that: 1) Strong VN intensity was associated with a pericellular and intracellular location; it is mostly present in the pericellular region and stored intracellularly to a lesser extent
The pericellular region concerned two tiny sites: the matrix adjacent to the cell membrane like a capsular territory, and a layer surrounding the capsular matrix of each cell or nests of grouped cells; we labeled this expression pattern territorial VN. 2) Weak to moderate VN intensity was associated with intercellular location; we named this expression interterritorial VN (Fig. 1)
Summary
Vitronectin is a multifunctional glycoprotein known in several human tumors for its adhesive role in processes such as cell growth, angiogenesis and metastasis. The ECM regulates development and homeostasis, whereas in tumors it displays mechanical properties such as stiffness that confer malignant characteristics to cell behaviour including proliferation, cell-death resistance, angiogenesis, invasion and metastasis [1,2,3]. VN is present in plasma as a monomeric or dimeric structure (folded or native form) and in the ECM of several tissues as a multimeric formation (unfolded or active form) [9, 10].
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