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

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.

IL-36 signalling enhances a pro-tumorigenic phenotype in colon cancer cells with cancer cell growth restricted by administration of the IL-36R antagonist

“…Studies of IL-1 signalling showed that inhibition of IL-1R signalling by IL-1Ra could reduce liver and lung metastasis in B16 murine melanoma tumours, with similar findings more recently reported in a mouse model of breast cancer [ 32 , 33 ]. Furthermore, IL-1β treated normal colonic myofibroblasts have been demonstrated to be able to induce CRC cell line migration in vitro, further highlighting the complex nature of IL-1 signalling and cellular migration [ 34 ]. Our study shows both IL-36β and IL-36γ are able to potently stimulate cellular migration and invasion in human and murine CRC cells, both of which are hallmarks of metastasis.…”

Dickkopf 1 is expressed in normal fibroblasts during early stages of colorectal tumorigenesis

“…35,36 Kalluri and Zeisberg 35 showed that fibroblasts adjacent to the basement membrane become activated when tumor cells disrupt the basement membrane and initiate invasion, which has further been speculated to be dependent on integrin and soluble factor-mediated cross-talk. 36 Taken together, the results of this study could be attributed to such bidirectional action; however, further studies are essential to precisely understand the underlying mechanisms. Several genetic abnormalities occur in the adenoma-carcinoma sequence, and the study demonstrates the potential of adenoma organoids to mimic TME and aid in the identification of the peripheral factors for tumor malignancy.…”

Interplay between Signaling Pathways and Tumor Microenvironment Components: A Paradoxical Role in Colorectal Cancer

“…Thus, after VCAM-1 knocking-down in tumor cells or the depletion of macrophages, the pro-tumor effect of CAFs is partly abolished [ 200 ]. Recently, it has been demonstrated that IL1β, secreted by CRC cells, modifies surrounding normal fibroblasts in order to acquire protumorigenic characteristics and generate particularly chemoresistant cells [ 201 ]. Mechanistically, FGF-1/-3/FGFR4 signaling in cancer-associated fibroblasts promotes tumor progression in colon cancer through ERK and MMP-7 [ 202 ].…”