Extracellular matrix rigidity modulates neuroblastoma cell differentiation and N-myc expression

• Type of Material: Article
• Authors: Wilbur Lam, Emory University; Lizhi Cao, University of California Berkeley; Vaibhavi Umesh, University of California Berkeley; Albert J. Keung, University of California Berkeley; Shamik Sen, University of California Berkeley; Sanjay Kumar, University of California Berkeley
• Language: English
• Date: 2010-02-09
• Publisher: BMC (part of Springer Nature)
• Publication Version: Final Published Version
• Copyright Statement: © 2010 Lam et al; licensee BioMed Central Ltd.
• License: Creative Commons Attribution 2.0 Generic
• Final Published Version (URL): http://dx.doi.org/10.1186/1476-4598-9-35
• Title of Journal or Parent Work: Molecular Cancer
• ISSN: 1476-4598
• Volume: 9
• Issue: 1
• Start Page: 35
• End Page: 35
• Grant/Funding Information: This work was supported by an NIH National Research Service Award (F32HL078531 to W.A.L.), the Hammond Research Fellowship of the National Childhood Cancer Foundation/Children's Oncology Group (to W.A.L.), a Biomedical Research Fellowship from The Hartwell Foundation (to W.A.L.), NDSEG and NSF Graduate Research Fellowships (to A.J.K.), an Arnold and Mabel Beckman Foundation Young Investigator Award (to S.K.), an NIH Director's New Innovator Award (1DP2OD004213 to S.K., part of the NIH Roadmap for Medical Research), an NIH Physical Sciences in Oncology Center Grant (1U54CA143836 to S.K.) and a UC Berkeley Junior Faculty Research Grant (to S.K.).
• Keywords: TRANS-RETINOIC ACID; STIFFNESS; HIGH-RISK NEUROBLASTOMA; 13-CIS-RETINOIC ACID; NEURO-BLASTOMA; MORPHOLOGICAL-DIFFERENTIATION; Oncology; ADHESION; Biochemistry & Molecular Biology; SUBSTRATE; SH-SY5Y CELLS; Life Sciences & Biomedicine; Science & Technology; ACTIVATION
• Research Categories: Health Sciences, Oncology; Chemistry, Biochemistry; Biology, Neuroscience

Abstract

Neuroblastoma is a pediatric malignancy characterized by tremendous clinical heterogeneity, in which some tumors are extremely aggressive while others spontaneously differentiate into benign forms. Because the degree of differentiation correlates with prognosis, and because differentiating agents such as retinoic acid (RA) have proven to decrease mortality, much effort has been devoted to identifying critical regulators of neuroblastoma differentiation in the cellular microenvironment, including cues encoded in the extracellular matrix (ECM). While signaling between tumor cells and the ECM is classically regarded to be based purely on biochemical recognition of ECM ligands by specific cellular receptors, a number of recent studies have made it increasingly clear that the biophysical properties of the ECM may also play an important role in this cross-talk. Given that RA-mediated neuroblastoma differentiation is accompanied by profound changes in cell morphology and neurite extension, both of which presumably rely upon mechanotransductive signaling systems, it occurred to us that mechanical cues from the ECM might also influence RA-mediated differentiation, which in turn might regulate clinically-relevant aspects of neuroblastoma biology. In this study, we tested this hypothesis by subjecting a series of neuroblastoma culture models to ECM microenvironments of varying mechanical stiffness and examined the regulatory role of ECM stiffness in proliferation, differentiation, and expression of tumor markers. We find that increasing ECM stiffness enhances neuritogenesis and suppresses cell proliferation. Remarkably, increasing ECM stiffness also reduces expression of N-Myc, a transcription factor involved in multiple aspects of oncogenic proliferation that is used for evaluating prognosis and clinical grading of neuroblastoma. Furthermore, the addition of RA enhances all of these effects for all ECM stiffnesses tested. Together, our data strongly support the notion that the mechanical signals from the cellular microenvironment influence neuroblastoma differentiation and do so synergistically with RA. These observations support further investigation of the role of microenvironmental mechanical signals in neuroblastoma proliferation and differentiation and suggest that pharmacological agents that modulate the underlying mechanotransductive signaling pathways may have a role in neuroblastoma therapy