The Blockade of Tumoral IL1β-Mediated Signaling in Normal Colonic Fibroblasts Sensitizes Tumor Cells to Chemotherapy and Prevents Inflammatory CAF Activation.

Natalia Guillén Díaz-Maroto,Gemma Garcia-Vicién,Giovanna Polcaro,David G Molleví,Nerea Albert,María Bañuls,Alberto Villanueva

doi:10.3390/ijms22094960

Abstract

Heterotypic interactions between newly transformed cells and normal surrounding cells define tumor’s fate in incipient carcinomas. Once homeostasis has been lost, normal resident fibroblasts become carcinoma-associated fibroblasts, conferring protumorogenic properties on these normal cells. Here we describe the IL1β-mediated interplay between cancer cells and normal colonic myofibroblasts (NCFs), which bestows differential sensitivity to cytotoxic drugs on tumor cells. We used NCFs, their conditioned media (CM), and cocultures with tumor cells to characterize the IL1β-mediated crosstalk between both cell types. We silenced IL1β in tumor cells to demonstrate that such cells do not exert an influence on NCFs inflammatory phenotype. Our results shows that IL1β is overexpressed in cocultured tumor cells. IL1β enables paracrine signaling in myofibroblasts, converting them into inflammatory-CAFs (iCAF). IL1β-stimulated-NCF-CM induces migration and differential sensitivity to oxaliplatin in colorectal tumor cells. Such chemoprotective effect has not been evidenced for TGFβ1-driven NCFs. IL1β induces the loss of a myofibroblastic phenotype in NCFs and acquisition of iCAF traits. In conclusion, IL1β-secreted by cancer cells modify surrounding normal fibroblasts to confer protumorogenic features on them, particularly tolerance to cytotoxic drugs. The use of IL1β-blocking agents might help to avoid the iCAF traits acquisition and consequently to counteract the protumorogenic actions these cells.

Highlights

During the initial steps of the tumorigenic process, newly transformed malignant cells compete with the normal microenvironment to overcome the inhibitory signals that normal tissue imposes [1]
The interplay between tumor cells and their neighboring normal cells occurs even at early stages of tumorigenesis, when few transformed epithelial cells interact with pericryptal myofibroblasts
These fibroblasts play an important role in regulating the normal colorectal stem cell niche, controlling normal tissue homeostasis and facilitating tumor progression when homeostasis is lost [21], and is probably the main source of carcinoma-associated fibroblasts (CAFs) after appropriate stimulation

Summary

Introduction

During the initial steps of the tumorigenic process, newly transformed malignant cells compete with the normal microenvironment to overcome the inhibitory signals that normal tissue imposes [1]. Of the various hypotheses that have been proposed [5], the most plausible is that pericryptal fibroblasts subjacent to the basement membrane enveloping epithelial glands become activated when tumor cells disrupt the basal membrane and start to invade. Such activation depends on juxtacrine and paracrine bidirectional crosstalk [6], which is mainly mediated by integrins, cadherins, soluble factors [7], and exosome cargo [8]. Pericryptal fibroblasts activate several mechanisms of innate inflammatory signals, MAP3K8 and IL1R1 being key mediators in the process [9]

Methods

Results

Conclusion