Modeling the Leukemia Microenviroment In Vitro.

Cristina Scielzo,Paolo Ghia

doi:10.3389/fonc.2020.607608

Abstract

Over the last decade, the active role of the microenvironment in the pathogenesis, development and drug resistance of B cell malignancies has been clearly established. It is known that the tissue microenvironment promotes proliferation and drug resistance of leukemic cells suggesting that successful treatments of B cell malignancies must target the leukemic cells within these compartments. However, the cross-talk occurring between cancer cells and the tissue microenvironment still needs to be fully elucidated. In solid tumors, this lack of knowledge has led to the development of new and more complex in vitro models able to successfully mimic the in vivo settings, while only a few simplified models are available for haematological cancers, commonly relying only on the co-culture with stabilized stromal cells and/or the addition of limited cocktails of cytokines. Here, we will review the known cellular and molecular interactions occurring between monoclonal B lymphocytes and their tissue microenvironment and the current literature describing innovative in vitro models developed in particular to study chronic lymphocytic leukemia (CLL). We will also elaborate on the possibility to further improve such systems based on the current knowledge of the key molecules/signals present in the microenvironment. In particular, we think that future models should be developed as 3D culture systems with a higher level of cellular and molecular complexity, to replicate microenvironmental-induced signaling. We believe that innovative 3D-models may therefore improve the knowledge on pathogenic mechanisms leading to the dissemination and homing of leukemia cells and consequently the identification of therapeutic targets.

Highlights

To date, a cure for cancer remains a major unmet clinical need and the possibility to achieve it relies on an increasing knowledge of the fundamental biological and molecular mechanisms leading to neoplastic transformation
In vitro 3D tissue models could provide a third approach that bridges the gap between traditional 2D culture and animal models [5]. 3D cultures have obtained popularity in the study of solid tumor biology, being able to address several questions that are difficult to unravel by using conventional 2D culture models, such as in the event of metastasis and invasion, aggressiveness, dormancy and cell-cell interactions [6]
Organoids are more complex and are developed from embryonic induced-pluripotent and somatic stem cells and cancer cells or from primary tumor biopsy. The latter have the advantage of preserving the intact structure of the original tumor tissue along with its heterogeneity, morphology and gene pathways [7]. These 3D models are widely used for solid tumor but it is becoming clear that they may be relevant for hematological cancers, in particular when assessing in vitro responses to drugs where 2D models poorly predict the actual clinical outcome [8]

Summary

Modeling the Leukemia Microenviroment In Vitro

Reviewed by: Chris Pepper, Brighton and Sussex Medical School, United Kingdom Tanja Nicole Hartmann, University of Freiburg Medical Center, Germany Yair Herishanu, Tel Aviv Sourasky Medical Center, Israel. The cross-talk occurring between cancer cells and the tissue microenvironment still needs to be fully elucidated. In solid tumors, this lack of knowledge has led to the development of new and more complex in vitro models able to successfully mimic the in vivo settings, while only a few simplified models are available for haematological cancers, commonly relying only on the co-culture with stabilized stromal cells and/or the addition of limited cocktails of cytokines. We will review the known cellular and molecular interactions occurring between monoclonal B lymphocytes and their tissue microenvironment and the current literature describing innovative in vitro models developed in particular to study chronic lymphocytic leukemia (CLL).

INTRODUCTION

The Tissue Microenvironment in B Cell Malignancies

Findings

The Cellular and Molecular Components of the Tissue Microenvironment