Mini review
Cytokines in breast cancer

https://doi.org/10.1016/j.cytogfr.2006.07.002Get rights and content

Abstract

In recent decades many advances have occurred in the understanding of the role of cytokines in breast cancer. New signalling pathways of interleukin (IL)-1 family, IL-6, IL-11, IL-18, interferons (IFNs) and interferon regulatory factors 1 (IRF-1) and 2 (IRF-2) have been found within tumour microenvironments and in metastatic sites. Some cytokines (IL-1, IL-6, IL-11, TGFβ) stimulate while others (IL-12, IL-18, IFNs) inhibit breast cancer proliferation and/or invasion. Similarly, high circulating levels of some cytokines seem to be favourable (soluble IL-2R) while others are unfavourable (IL-1β, IL-6, IL-8, IL-10, IL-18, gp130) prognostic indicators. So far IL-2, IFNα, IFNβ and occasionally IFNγ, IL-6, IL-12 have been the cytokines used for anti tumour treatment of advanced breast cancer either to induce or increase hormone sensitivity and/or to stimulate cellular immunity. Disappointing results occurred in most trials; however, two long-term pilot studies suggest that IL-2 and IFNβ, when used appropriately can have a positive effect on clinical benefit and overall survival of patients with minimal residual disease after chemotherapy or with disseminated disease controlled by conventional endocrine therapy.

Introduction

Cytokines are glycoproteins of low molecular weight, which are rapidly synthesized and usually secreted by different healthy and diseased cells (mainly mononuclear phagocytes and activated T lymphocytes) mainly after stimulation. They act on many different adjacent target cells (pleiotropism) often in an additive, synergistic, or antagonistic manner. In multicellular organisms, cytokines are intercellular mediators that regulate survival, growth, differentiation, and the effector functions of cells [1]. Therefore, it is not surprising that cytokines significantly affect the growth of tumours in vivo. On the other hand, they are also produced by cancer cells and represent a network with a large variety of molecularly and functionally different members that may act as tumour growth-promoting or inhibiting factors. As they affect the growth and function of immunocompetent cells, they can activate or modulate specific or non-specific antitumor responses. Furthermore, because cytokines are mediators of the effector response from innate and acquired cellular immunities [2], they are probably involved in the mechanism from tumour cell evasion of the immunosurveillance system.

This review summarizes principal recent findings on the relationship between cytokines and breast cancer and their role in effecting patient prognosis. Additionally, this review deeply explores the body of knowledge acquired in the last decade for therapeutic antitumoral purpose in advanced breast cancer.

Section snippets

Interactions with breast cancer cells

The interleukin (IL) -1 family of cytokines (IL-lα, IL-1β), the IL-1 receptor antagonist (IL-1Ra) and receptors (IL-1RI and IL-1RII) have been found to be frequently expressed in breast cancer cell lines, in human breast cancer tissue, and within the tumour microenvironment [3], [4], [5]. This local expression of IL-1/IL-1R cytokine family can control, via autocrine and/or paracrine mechanisms, the tumour cell subpopulation expression of other protumorigenic cytokines, such as the expression of

Clinical trials in advanced breast cancer patients

Many cytokines have shown a potent therapeutic antitumour effect in preclinical models. However, translation to clinical practice is limited, and at present, IFNα and IL-2 are the only cytokines approved for oncologic indications [79].

Table 2 shows the rationale and the therapeutic schedule of the cytokines that have been used for antitumour treatment of advanced breast cancer.

Discussion and conclusions

In recent decades, many experimental in vitro and in vivo studies have advanced the comprehension of the role of cytokines in oncology. Some cytokines (IL-1, IL-6, IL-11, TGFβ) stimulate while others (IL-12, IL-18, IFNs) inhibit breast cancer proliferation and/or invasion. Similarly, high circulating levels of some cytokines seem to be favourable (soluble IL-2R) while others are unfavourable (IL-1β, IL-6, IL-8, IL-10, IL-18, gp130) prognostic indicators. However, IL-2 is a potent stimulator of

Andrea Nicolini is Clinical Researcher at the Department of Internal Medicine at Pisa University. He was winner of fellowships at the European School of Oncology and of a grant by Cancer Prevention and Detection Journal. His research over the past 15 years was mainly devoted to the field of breast cancer, in particular to the use of serum tumour markers in the “early” detection and treatment of metastatic disease and to the function of cell mediated immunity. Another area of research was the

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    Andrea Nicolini is Clinical Researcher at the Department of Internal Medicine at Pisa University. He was winner of fellowships at the European School of Oncology and of a grant by Cancer Prevention and Detection Journal. His research over the past 15 years was mainly devoted to the field of breast cancer, in particular to the use of serum tumour markers in the “early” detection and treatment of metastatic disease and to the function of cell mediated immunity. Another area of research was the role of needle aspiration techniques and the use of tissue tumour markers (galectin 3) in the preoperative diagnosis of thyroid cancer. Dr. Nicolini has published about 200 original papers (including chapters of books), most of them in peer reviewed Journals and many review articles. He is teacher of Internal Medicine and Clinical Oncology for academic Institutes besides he is scientific advisor of Biomedicine and Pharmacotherapy and regularly has served as reviewer for many scientific Journals.

    Angelo Carpi is Clinical Researcher at the University Hospital of Pisa, 1972–1986. Associate Professor of Internal Medicine, Pisa University, 1984 to today. Vice-Director Postgraduate School of Endocrinology, 1997 to 2003, Medical Faculty, University of Pisa. About 200 scientific publications in peer-reviewed journals. Principal fields: thyroid and breast tumours, male infertility, vascular endothelium. Editor of Biomedicine & Pharmacotherapy. Reviewer for International Journals with impact factor mainly in the fields of internal medicine and endocrinology. Identified as international ‘recognised authority’ by the UCLA School of Los Angeles and the Faculty of Medicine of the Haifa University. Recently involved in research on biomaterials, director of a unit in a project of the CNR (National Research Council) on biomaterials.

    Dr. Giuseppe Rossi obtained his B.Sc. degree from the University of Pisa in 1978 and his PhD (Medical Statistics) in 1983 from the University of Pavia. He currently is a Senior Scientist at the National Research Council (Unit of Epidemiology and Biostatistics – Institute of Clinical Physiology) and Professor of Statistics in Medicine at the University of Pisa. His research is focused on clinical and environmental epidemiology. Dr. Rossi has published about 100 original papers (including chapters of books), most of them in peer reviewed Journals. He served as secretary and treasurer of the Italian Region of the International Biometric Society.

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