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Dual Role of IL-6 in Maintaining the resistance of Gastrointestinal stromal tumor and tumor angiogenesis

ABSTRACT: Resistance is a major obstacle to the effective treatment of many tumor types, including Gastrointestinal stromal tumor (GIST). Although Imatinib (IM) is considered the gold standard for targeted therapy in GIST, resistance to IM ultimately occurs in many patients, leading to disease progression. The precise mechanisms underlying this resistance remain poorly understood. Our study reveals that high expression of Interleukin-6 (IL-6) is closely associated with poor survival outcomes in patients with GIST. Elevated levels of IL-6 not only sustain the viability of GIST cells but also promote tumoral angiogenesis within the tumor microenvironment (TME) via paracrine mechanisms. Notably, the combination of the IL-6 receptor inhibitor Tocilizumab (TCZ) with IM significantly inhibited tumor growth in a GIST xenograft mouse model. Mechanistic investigations indicate that IL-6, through its interaction with IL-6R, reactivates the PI3K/Akt/mTOR signaling pathway, which is suppressed by IM. Additionally, as a secreted protein, IL-6 regulates the secretion of vascular endothelial growth factors controlled by the JAK2/STAT3 signaling pathway in endothelial cells via paracrine action. Thus, IL-6 may serve as a critical biomarker for predicting the prognosis of GIST, and the combined treatment strategy of IM with TCZ shows promising potential in overcoming resistance in GIST.

ORGANISM(S): Homo sapiens

PROVIDER: GSE289088 | GEO | 2025/02/12

REPOSITORIES: GEO

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Project description:This a model from the article: A mathematical model for IL-6-mediated, stem cell driven tumor growth and targeted treatment Fereshteh Nazari, Alexander T. Pearson, Jacques Eduardo Nor, Trachette L. Jackson. PloS Computational Biology, 2018 Jan. 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. Author Summary: A small population of cancer stem cells that share many of the biological characteristics of normal adult stem cells are believed to initiate and sustain tumor growth for a wide variety of malignancies. Growth and survival of these cancer stem cells is highly influenced by tumor micro-environmental factors and molecular signaling initiated by cytokines and growth factors. This work focuses on quantifying the influence of IL-6, a pleiotropic cytokine secreted by a variety of cell types, on cancer stem cell self-renewal and survival. 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. This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2011 The BioModels.net Team. For more information see the terms of use. To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.

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Dual Role of IL-6 in Maintaining the resistance of Gastrointestinal stromal tumor and tumor angiogenesis

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