A mathematical model for IL-6-mediated, stem cell driven tumor growth and targeted treatment.

Fereshteh Nazari,Alexander T Pearson,Jacques Eduardo Nör,Trachette L Jackson,Philip K Maini

doi:10.1371/journal.pcbi.1005920

Fereshteh Nazari, Alexander T Pearson + Show 3 more

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https://doi.org/10.1371/journal.pcbi.1005920

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Abstract

Targeting key regulators of the cancer stem cell phenotype to overcome their critical influence on tumor growth is a promising new strategy for cancer treatment. Here we present a modeling framework that operates at both the cellular and molecular levels, for investigating IL-6 mediated, cancer stem cell driven tumor growth and targeted treatment with anti-IL6 antibodies. Our immediate goal is to quantify the influence of IL-6 on cancer stem cell self-renewal and survival, and to characterize the subsequent impact on tumor growth dynamics. By including the molecular details of IL-6 binding, we are able to quantify the temporal changes in fractional occupancies of bound receptors and their influence on tumor volume. There is a strong correlation between the model output and experimental data for primary tumor xenografts. We also used the model to predict tumor response to administration of the humanized IL-6R monoclonal antibody, tocilizumab (TCZ), and we found that as little as 1mg/kg of TCZ administered weekly for 7 weeks is sufficient to result in tumor reduction and a sustained deceleration of tumor growth.

Highlights

It is widely believed, based on increasing evidence, that a small population of tumorigenic cells, which are in many ways similar to normal adult stem cells, is responsible for the initiation and maintenance of malignant tumors [1,2,3,4,5]
We present a mathematical model for IL-6 mediated, cancer stem cell driven tumor growth that operates at the following levels: (1) the molecular level—capturing cell surface dynamics of receptor-ligand binding and receptor activation that lead to intra-cellular signal transduction cascades; and (2) the cellular level—describing tumor growth, cellular composition, and response to treatments targeted against IL-6
We develop a predictive computational framework that aims to advance our current understanding of the differential impact of IL-6 on cancer stem cell (CSC) self-renewal and Head and neck squamous cell carcinoma (HNSCC) growth and investigate the mechanisms of tumor reduction associated targeted treatment with the anti-IL-6 receptors (IL-6R) antibody Tocilizumab

Summary

Introduction

It is widely believed, based on increasing evidence, that a small population of tumorigenic cells, which are in many ways similar to normal adult stem cells, is responsible for the initiation and maintenance of malignant tumors [1,2,3,4,5]. IL-6 is a pleiotropic cytokine, secreted by a variety of cell types, that is a key player in number of cellular processes including proliferation, survival, differentiation, migration and invasion [14]. It is commonly overexpressed in most cancer types including HNSCC [8, 14, 15]

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