Magnetic Compression of Tumor Spheroids Increases Cell Proliferation In Vitro and Cancer Progression In Vivo.

Gaëtan Mary,Irène Nagle,Marc Pocard,Atef Asnacios,Cynthia Pimpie,Myriam Reffay,Claire Wilhelm,Brice Malgras,Jose Efrain Perez,Nathalie Luciani

doi:10.3390/cancers14020366

Abstract

Simple SummaryClinical studies are still debating on the long-term benefits and consequences of endoscopic procedures that expand a stent through a tumor, leading to its compression. Herein, due to the development of magnetic tumor spheroids as magnetically deformable models of a mature tumor, we evidence that anisotropic tumor compression can trigger an increase in vitro of cancer cell proliferation and can induce in vivo amplified malignancy. It confirms other evidence of the impact of a mechanical compression on the metastasis ability and invasion potential of cancer cells.A growing tumor is submitted to ever-evolving mechanical stress. Endoscopic procedures add additional constraints. However, the impact of mechanical forces on cancer progression is still debated. Herein, a set of magnetic methods is proposed to form tumor spheroids and to subject them to remote deformation, mimicking stent-imposed compression. Upon application of a permanent magnet, the magnetic tumor spheroids (formed from colon cancer cells or from glioblastoma cells) are compressed by 50% of their initial diameters. Such significant deformation triggers an increase in the spheroid proliferation for both cell lines, correlated with an increase in the number of proliferating cells toward its center and associated with an overexpression of the matrix metalloproteinase−9 (MMP−9). In vivo peritoneal injection of the spheroids made from colon cancer cells confirmed the increased aggressiveness of the compressed spheroids, with almost a doubling of the peritoneal cancer index (PCI), as compared with non-stimulated spheroids. Moreover, liver metastasis of labeled cells was observed only in animals grafted with stimulated spheroids. Altogether, these results demonstrate that a large compression of tumor spheroids enhances cancer proliferation and metastatic process and could have implications in clinical procedures where tumor compression plays a role.

Highlights

Cancer progression is associated with angiogenesis, and tumor expansion can trigger the collapse of surrounding blood and lymphatic vessels, can lead to an increase in blood flow resistance and an accumulation of interstitial fluid, and can cause additional mechanical stresses [3]
self-expanding metal stent (SEMS) implantation in mice developing obstructive colon cancer resulted in a decrease in the survival time for treated animals [8], hinting at a possible mechanical SEMS-dependent stimulation of cancer progression
Magnetic labeling of mouse colon cancer cells (CT26) with iron oxide nanoparticles upon overnight incubation at Fe = 0.5 mM provided each cell with a magnetic moment at saturation of about Mcell = 7 × 10−13 A·m2, which corresponds to 11 pg of iron internalized per cell

Summary

Introduction

The tumor mass has to deform and disrupt the organization of the surrounding healthy tissue, which in return, resists its expansion. This growth gives rise to a constantly evolving mechanical map. In breast cancers, stiffness increases from ~3 kPa in normal tissue to ~40 kPa in high-grade carcinoma [1,2]. Cancer progression is associated with angiogenesis, and tumor expansion can trigger the collapse of surrounding blood and lymphatic vessels, can lead to an increase in blood flow resistance and an accumulation of interstitial fluid, and can cause additional mechanical stresses [3]. SEMS implantation in mice developing obstructive colon cancer resulted in a decrease in the survival time for treated animals [8], hinting at a possible mechanical SEMS-dependent stimulation of cancer progression

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