Organotypic-liver slide culture systems to explore the role of extracellular vesicles in pancreatic cancer metastatic behavior and guide new therapeutic approaches

ABSTRACT

Introduction: Recent studies suggested that extracellular vesicles (EVs) play a role both in the metastatic niche formation and in the progression of several tumors, including pancreatic cancer. In particular, the effects of EVs on metastasis should be studied in model systems that take into account both the tumor cells and the metastatic site/tumor microenvironment. Studies with labeled EVs or EV-secreting cells in ex vivo models will reflect the physiological and pathological functions of EVs. The organotypic-tissue slide culture systems can fulfill such a role.

Areas covered: This review provides an overview of available organotypic-culture slide systems. We specifically focus on the assay system of liver culture-slides in combination with pancreatic tumors, which can be modulated to test the efficacy of new therapeutic approaches.

Expert opinion: The intercellular exchange of EVs has emerged as a biologically relevant phenomenon to drive cancer metastasis. However, further models need to be developed to better elucidate the functional roles of EVs. The use of novel organotypic slide culture systems provides the opportunity to explore the role of EVs in the metastatic behavior of pancreatic cancer, decreasing the use of costly and cumbersome organoid or animal models.

KEYWORDS:

• Extracellular vesicles
• metastasis
• tumor microenvironment
• preclinical models
• organotypic-tissue slide culture systems
• pancreatic cancer

Article highlights

• Metastasis is a major cause of morbidity and mortality in patients with different tumors, including pancreatic cancer, but most of the underlying biological mechanisms are currently unknown.

• Extracellular vesicles (EVs) are nanosized, membranous vesicles that can transfer their functional cargo to neighboring and/or distal cells contributing to both physiological and pathological processes, including metastasis.

• Studying the effects of EVs on metastases requires models to trace their effects in recipient cancer cells and microenvironment tissues.

• The tissue-slide culture systems can be used to test changes in invasiveness induced by extracellular vesicles.

• Liver tissues of both human and animal origin can be used in combination with human cancer cells.

• The employment of organotypic-liver slide culture systems in oncological studies conforms to the 3Rs concept of reduction, refinement, and replacement of animal models.

• The inclusion of tissue-slide culture systems models in the preclinical research workflow may foster the advancement of better cancer treatments and fighting metastasis.

This box summarizes key points contained in the article.

Acknowledgments

The authors would like to thank Tim Heistek (CNCR. AmsterdamUMC) for assisting with the vibratome experiments.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This work was supported by the CCA Foundation 2015 and 2018 grants (E.G.); KWF Dutch Cancer Society grants #11957/13598 (E.G.); AIRC/Start-Up and IG-24444 grant (E.G.); Indonesian Endowment Fund Scholarship (I.G.P.S.) and Rotary Global Grant GG2123321 (A.C.)