Sound-based assembly of a microcapillary network in a saturn-like tumor model for drug testing

Our plain-English summary of Sound-based assembly of a microcapillary network in a saturn-like tumor model for drug testing, by N. Di Marzio, P. Ananthanarayanan, A.G. Guex, et al (Materials Today. Bio, 2022).

The study

• Authors: N. Di Marzio, P. Ananthanarayanan, A.G. Guex, M. Alini, C. Riganti, T. Serra
• Journal: Materials Today. Bio
• Published: 2022;16:100357
• Cited by: 16 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

The tumor microenvironment (TME), consisting of extracellular matrix, proteins, stromal cells, and a vascular system, is reported to have a key role in cancer progression and prognosis. Thereby, the interaction between the vascular network and tumor mass is an important feature of the TME since the anticancer agents which are delivered to the TME can trigger the vascular response and influence the therapeutic outcome of the treatment. To identify and develop new therapeutic strategies, 3D in vitro models that recapitulate the complexity of the TME are urgently needed. Among them, vascularized tumor models are a promising approach, allowing to target tumor angiogenesis and reduce tumor growth. By using sound patterning, cells can be condensed locally into highly reproducible patterns through the action of mild hydrodynamic forces. Here, we use a soundwave-driven cell assembly approach to create a ring-shaped microcapillary network in fibrin hydrogel. Then, we generate a 3D vascularized tumor model by combining a tumor heterotypic spheroid, consisting of fibroblasts and Malignant Pleural Mesothelioma (MPM) cells, with the surrounding vascular ring. Based on its shape, we name it Saturn-like vascularized Tumor Model (STM). The growth of the microcapillary network is monitored over time by fluorescence imaging. The area covered by the microcapillary network, and its continuous increase in presence of the heterotypic tumor spheroid was monitored. Interestingly, this effect is enhanced when treating the STM with the anticancer agent Cisplatin. Overall, we show the use of sound patterning as a fast and cell-friendly approach to spatially organize and condense cells, to generate a 3D in vitro platform from which simple readouts of drug tests can be extracted by image analysis, with the potential to provide a model system for tailored tumor therapy.

© 2022 The Authors.

In plain English

This laboratory study used human cells, not people or animals, and did not study asbestos exposure. The authors used low-frequency sound vibration to arrange blood-vessel lining cells (HUVEC) and pericytes in fibrin gel into a ring that formed a network of tiny capillaries. They placed a ball of cells (a spheroid) made of malignant pleural mesothelioma cells and lung fibroblasts on top and called this the Saturn-like Tumor Model. They treated it for 4 days with the drug cisplatin, the drug bevacizumab, or both. The rings had a mean diameter of 1781 μm, with a standard deviation of 142 μm. With the tumor spheroid present, the network area grew until day 2. Without the spheroid, it shrank from day 1. In the tumor model, cisplatin and cisplatin plus bevacizumab raised an image-based ring measure at day 4 by 30% and 33% compared with untreated controls. Bevacizumab alone lowered it by 5%. In separate gene tests, cisplatin raised RNA levels of vessel-growth genes, including VEGFA, in capillary cells, tumor spheroids, and the two combined. The authors concluded that the model detected vessel-growth stimulation during anticancer treatment.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory (in vitro) study building and testing a 3D cell-culture tumor model: a sound-patterned ring of capillary-forming cells in fibrin gel with a mesothelioma tumor spheroid placed on top
• Who was studied: Human cells, not patients. The cells were GFP-expressing human umbilical vein endothelial cells (HUVEC), human pericytes from placenta, human normal lung fibroblasts (MRC-5), and primary human epithelioid malignant pleural mesothelioma cells. The mesothelioma cells were obtained after diagnostic thoracoscopies and supplied by the Biologic Bank of Malignant Mesothelioma, S. Antonio e Biagio Hospital, Alessandria, Italy. The article does not state how many patients the mesothelioma cells came from.
• Exposure: No asbestos exposure was studied. The model was treated for 4 days, with daily renewal, with cisplatin (50 μM), bevacizumab (10 μg per mL), or both. These treatments were compared with growth medium alone (EGM-2).
• Main results:
  • Sound patterning produced rings of cells with a mean diameter of 1781 μm (standard deviation 142 μm) and a mean thickness of 416 μm (standard deviation 124 μm). These figures came from 4 independent experiments with at least 25 patterns each. Without sound, the cells were spread evenly.
  • The image signal peak from the capillary ring was twofold higher and wider when the ring was cultured with the tumor spheroid than when it was cultured alone.
  • In the tumor model (ring plus spheroid), the area under the curve of the ring signal at day 4 rose by 30% with cisplatin and by 33% with cisplatin plus bevacizumab, compared with the EGM-2 control (P less than 0.05).
  • In the tumor model, bevacizumab alone decreased the area under the curve by 5% compared with EGM-2 (P less than 0.05).
  • Without the tumor spheroid, the area under the curve showed no significant differences among the treatment groups.
  • With the spheroid present, capillary network area was measured relative to day 1. In the untreated model it reached 145 plus or minus 10% growth at day 2 and fell to 98 plus or minus 21% at day 4. With cisplatin it was 156 plus or minus 20% at day 2 and stayed at 155 plus or minus 23% at day 4, which was significantly different from control (P less than 0.05). With cisplatin plus bevacizumab it was 160 plus or minus 20% at day 4, which was also significantly different. Bevacizumab alone did not differ significantly from the untreated model.
  • Without the spheroid, network area decreased from day 1 in all treatment conditions and continued to shrink until day 4.
  • In separate gene-expression (RNA) tests, cisplatin significantly increased, at the transcriptional level, several factors that promote vessel growth, including VEGFA, in the HUVEC and pericyte cells. The same genes, plus others, were increased in the mesothelioma spheroids.
  • The pattern of increased vessel-growth genes was also seen when the capillary cells and mesothelioma spheroid were grown together.
  • When the two drugs were combined, the gene-expression effects of cisplatin outweighed those of bevacizumab.
• The authors' conclusion: The authors concluded that sound patterning is a simple tool for creating reproducible vascular structures in a 3D lab model. They stated that the model was validated by detecting stimulation of vessel growth in the presence of anticancer treatment. They also stated that it could be a versatile tool for investigating new therapeutics.
• Limitations the authors state:
  • The capillary ring was not perfused (no fluid flowed through it). The authors described a perfusion system as future work that would more closely mimic capillaries in the body.
  • The authors suggested that the gel matrix might interfere with antibody drugs such as bevacizumab, so that only higher concentrations may reach their target in the model.

Topics

Medical terms in this study, explained in our Lexicon: Tumor Microenvironment, Prognosis, Angiogenesis, Fibroblast, Pleural Mesothelioma, Cisplatin.

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