Humanization of Tumor Stroma by Tissue Engineering as a Tool to Improve Squamous Cell Carcinoma Xenograft.

Sara Guerrero-Aspizua,Andrea González-Masa,Fernando Larcher,Claudio J Conti,Marcela Del Río,Marta García,Esteban Chacón-Solano

doi:10.3390/ijms21061951

Abstract

The role of stroma is fundamental in the development and behavior of epithelial tumors. In this regard, limited growth of squamous cell carcinomas (SCC) or cell-lines derived from them has been achieved in immunodeficient mice. Moreover, lack of faithful recapitulation of the original human neoplasia complexity is often observed in xenografted tumors. Here, we used tissue engineering techniques to recreate a humanized tumor stroma for SCCs grafted in host mice, by combining CAF (cancer associated fibroblasts)-like cells with a biocompatible scaffold. The stroma was either co-injected with epithelial cell lines derived from aggressive SCC or implanted 15 days before the injection of the tumoral cells, to allow its vascularization and maturation. None of the mice injected with the cell lines without stroma were able to develop a SCC. In contrast, tumors were able to grow when SCC cells were injected into previously established humanized stroma. Histologically, all of the regenerated tumors were moderately differentiated SCC with a well-developed stroma, resembling that found in the original human neoplasm. Persistence of human stromal cells was also confirmed by immunohistochemistry. In summary, we provide a proof of concept that humanized tumor stroma, generated by tissue engineering, can facilitate the development of epithelial tumors in immunodeficient mice.

Highlights

In the past decade, it has become clear that the behavior of a malignant tumor is related to the malignant cell itself, and to the properties of the stromal microenvironment of the tumor [1,2]
We describe our efforts to humanize tumor stroma in an animal model, by tissue engineering techniques, with the goal of achieving tumors xenografts that mimics the actual behavior of human squamous cell carcinomas (SCC)
In order to provide a pro-tumorigenic humanized stroma to facilitate the growth of the SCC, we used two different approaches (Figure 1)

Summary

Introduction

It has become clear that the behavior of a malignant tumor is related to the malignant cell itself, and to the properties of the stromal microenvironment of the tumor [1,2]. The most relevant cellular component of the tumor stroma are activated fibroblasts, characterized by an increased expression of α-smooth muscle actin (αSMA) and vimentin, a change from the fusiform to stellate shape, and enhanced ECM production [4]. They alter the repertoire of paracrine signals including those related with immunoregulation [5]. These alterations appear to be the result of epigenetic changes that make these newly acquired properties irreversible. The focus of many laboratories has shifted to investigate the possible role of the ECM in cancer development and to the concomitant role of tumor fibroblasts to the synthesis and maintenance of this specific pro-tumorigenic ECM [6,7]

Methods

Results

Conclusion