The involvement of IL-1 in tumorigenesis, tumor invasiveness, metastasis and tumor-host interactions

Abstract

Interleukin-1 (IL-1) includes a family of closely related genes; the two major agonistic proteins, IL-1alpha and IL-1beta, are pleiotropic and affect mainly inflammation, immunity and hemopoiesis. The IL-1Ra antagonist is a physiological inhibitor of pre-formed IL-1. Recombinant IL-1alpha and IL-1beta bind to the same receptors and induce the same biological functions. As such, the IL-1 molecules have been considered identical in normal homeostasis and in disease. However, the IL-1 molecules differ in their compartmentalization within the producing cell or the microenvironment. Thus, IL-1beta is solely active in its secreted form, whereas IL-1alpha is mainly active in cell-associated forms (intracellular precursor and membrane-bound IL-1alpha) and only rarely as a secreted cytokine, as it is secreted only in a limited manner. IL-1 is abundant at tumor sites, where it may affect the process of carcinogenesis, tumor growth and invasiveness and also the patterns of tumor-host interactions. Here, we review the effects of microenvironment- and tumor cell-derived IL-1 on malignant processes in experimental tumor models and in cancer patients. We propose that membrane-associated IL-1alpha expressed on malignant cells stimulates anti-tumor immunity, while secretable IL-1beta, derived from the microenvironment or the malignant cells, activates inflammation that promotes invasiveness and also induces tumor-mediated suppression. Inhibition of the function of IL-1 by the IL-1Ra, reduces tumor invasiveness and alleviates tumor-mediated suppression, pointing to its feasibility in cancer therapy. Differential manipulation of IL-1alpha and IL-1beta in malignant cells or in the tumor's microenvironment can open new avenues for using IL-1 in cancer therapy.

Interleukin-1β activates focal adhesion kinase and Src to induce matrix metalloproteinase-9 production and invasion of MCF-7 breast cancer cells

“…Among these cytokines, interleukin-1β (IL-1β) is abundant in tumor tissues and stimulates tumor growth, invasion, carcinogenesis and host-tumor association (7). IL-1β-knockout mice are resistant to the development of chemically induced tumors (8), and exhibit suppressed tumor invasion and angiogenesis (9,10).…”

FSP1+ Fibroblasts Promote Skin Carcinogenesis by Maintaining MCP-1-Mediated Macrophage Infiltration and Chronic Inflammation

“…8 -10 Fibroblast-derived cytokine IL-1 and chemokine (C-X-C motif) ligand 14 have been shown to play vital roles as immune modulators. 11,12 Most of these studies, however, came from tumor transplantation experiments, which focus mainly on the role of fibroblasts during the growth of transplanted tumor cells. The physiological role of fibroblasts and the corresponding molecular mechanisms during chemical carcinogenesis is largely unknown.…”

Fluorouracil and bevacizumab plus anakinra for patients with metastatic colorectal cancer refractory to standard therapies (IRAFU): a single-arm phase 2 study

“…Conversely, IL-1α is typically expressed by malignant cells. 13 The pro-oncogenic properties of IL-1α are its capacity to induce activation of NFKB and STAT3 pathways and to promote tumor aggressiveness. 14,15 Neutralization of IL-1α was proposed to have the potential to lessen tumor growth and to reverse or improve debilitating morbidities associated with the disease.…”