In Vivo Clearance of Apoptotic Debris From Tumor Xenografts Exposed to Chemically Modified Tetrac: Is There a Role for Thyroid Hormone Analogues in Efferocytosis?

Kavitha Godugu,Hung-Yun Lin,Shaker A Mousa,Paul J Davis,Gennadi V Glinsky

doi:10.3389/fendo.2022.745327

Abstract

Apoptosis is induced in cancer cells and tumor xenografts by the thyroid hormone analogue tetraiodothyroacetic acid (tetrac) or chemically modified forms of tetrac. The effect is initiated at a hormone receptor on the extracellular domain of plasma membrane integrin αvβ3. The tumor response to tetrac includes 80% reduction in size of glioblastoma xenograft in two weeks of treatment, with absence of residual apoptotic cancer cell debris; this is consistent with efferocytosis. The molecular basis for efferocytosis linked to tetrac is incompletely understood, but several factors are proposed to play roles. Tetrac-based anticancer agents are pro-apoptotic by multiple intrinsic and extrinsic pathways and differential effects on specific gene expression, e.g., downregulation of the X-linked inhibitor of apoptosis (XIAP) gene and upregulation of pro-apoptotic chemokine gene, CXCL10. Tetrac also enhances transcription of chemokine CXCR4, which is relevant to macrophage function. Tetrac may locally control the conformation of phagocyte plasma membrane integrin αvβ3; this is a cell surface recognition system for apoptotic debris that contains phagocytosis signals. How tetrac may facilitate the catabolism of the engulfed apoptotic cell debris requires additional investigation.

Highlights

The phagocytotic clearance of apoptotic cells in nonmalignant and malignant tissues is a process designated efferocytosis [1–6]
Human glioblastoma U87-luc and GBM 052814 cells were grown in Dulbecco’s Modified Eagle’s Medium (DMEM) that was supplemented with 10% fetal bovine serum (FBS), 1% penicillin, and 1% streptomycin
The anticancer activity of tetrac and chemically modified tetrac in preclinical studies is associated with extensive tumor cell apoptosis and with frank xenograft shrinkage and no local accumulation of cellular debris

Summary

Introduction

The phagocytotic clearance of apoptotic cells in nonmalignant and malignant tissues is a process designated efferocytosis [1–6]. We have described a cell surface receptor for thyroid hormone analogues on integrin avb that is generously expressed by cancer cells [7, 8]. Thyroid Hormone Analogues and Efferocytosis receptor, hormone analogue tetraiodothyroacetic acid (tetrac) and chemically modified tetrac induce tumor cell apoptosis by multiple mechanisms [8–10]. This pharmacologic anticancer activity has been associated in human tumor xenografts with substantial graft shrinkage and disappearance of apoptotic cell debris [11–17]. The mechanisms of anticancer activity of thyroid hormone analogue actions on tumor cells have been extensively studied; here we examine these actions for ways in which they may contribute to efferocytosis. Tetrac derivatives are anti-angiogenic and the clearance of blood vessel debris in angiogenic models has been found to be efficient and is not associated with hemorrhage [18, 19]; this is in contrast to certain other anti-angiogenic agents such as antibodies to vascular growth factors [20, 21]

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