Mini reviewCytokines in breast cancer
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
References (116)
- et al.
CYP2C and IL-6 expression in breast cancer
Breast
(2004) Investigation of interleukin-6 (IL-6), soluble IL-6 receptor (sIL-6R) and soluble gp130 (sgp130) in sera of cancer patients
Biomed Pharmacother
(2001)- et al.
Subcutaneous administration of recombinant glycosylated interleukin 6 in patients with cancer: pharmacokinetics, pharmacodynamics and immunomodulatory effects
Cytokine
(2000) - et al.
Interleukin-12 in anti-tumour immunity and immunotherapy
Cytokine Growth Factor Rev
(2002) - et al.
Serum interleukin 6, plasma VEGF, serum VEGF, and VEGF platelet load in breast cancer patients
Clin Breast Cancer
(2002) - et al.
Tumour necrosis factor- alpha, interleukin-6, and fasting serum insulin correlate with clinical outcome in metastatic breast cancer patients treated with chemotherapy
Cytokine
(2004) Lymphokines and the immune response: the central role of interleukin-2
Curr Opin Immunol
(1991)- et al.
Interleukin-2 and interleukin-15: immunotherapy for cancer
Cytokine Growth Factor Rev
(2002) - et al.
The biology of IL-12: coordinating innate and adaptive immune responses
Cytokine Growth Factor Rev
(2003) - et al.
The interferon-beta and tamoxifen combination induces apoptosis using thioredoxin reductase
Biochim Biophys Acta
(2000)
Polymorphism in the genes of alpha and beta tumour necrosis factors (TNF-alpha and TNF-beta) and gamma interferon (IFN-gamma) among Iranian women with breast cancer
Cancer Lett
Interferon-alpha in tumour immunity and immunotherapy
Cytokine Growth Factor Rev
The effects of interleukin 10 and interferon gamma cytokine gene polymorphisms on survival after autologous bone marrow transplantation for patients with breast cancer
Biol Blood Marrow Transplant
Introduction: cytokines and cancer
Cytokine Growth Factor Rev
Some theoretical and practical limitations of interleukin-2. Ten cases of advanced breast cancer treated with continuous infusion of IL-2
Cancer Treat Rev
Enhancement of the anti-tumour activity of a peripheral blood progenitor cell graft by mobilization with interleukin 2 plus granulocyte colony-stimulating factor in patients with advanced breast cancer
Exp Hematol
Beta-interferon and interleukin-2 prolong more than three times the survival of 26 consecutive endocrine dependent breast cancer patients with distant metastases: an exploratory trial
Biomed Pharmacother
Steroid receptor enhancement by natural interferon-beta in advanced breast cancer
Eur J Cancer
Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway
Biochem J
Cellular and molecular immunology (chapter 12, 346–344; chapter 18, 475–499)
Interleukin-1 family expression in human breast cancer: interleukin-1 receptor antagonist
Cancer Invest
The interleukin-1 family of cytokines and receptors in human breast cancer: implications for tumour progression
Int J Oncol
Interleukin 1 system and sex steroid receptor expression in human breast cancer: interleukin 1 alpha protein secretion is correlated with malignant phenotype
Clin Cancer Res
Retinoic acid induces expression of the interleukin-1beta gene in cultured normal human mammary epithelial cells and in human breast carcinoma lines
J Cell Physiol
The influence of inflammatory cytokines on estrogen production and cell proliferation in human breast cancer cells
Endocr J
Regulation of interleukin-6 secretion from breast cancer cells and its clinical implications
Breast Cancer
Targeted anti-interleukin-6 monoclonal antibody therapy for cancer: a review of the rationale and clinical evidence
Clin Cancer Res
The role of cytokines in regulating estrogen synthesis: implications for the etiology of breast cancer
Breast Cancer Res
Breast cancer cells induce osteoclast formation by stimulating host IL-11 production and downregulating granulocyte/macrophage colony-stimulating factor
Int J Cancer
Interleukin-12-related cytokine gene expression in carcinomas of the breast, lung, and larynx: a study at tissue level
Cancer Detect Prev
Inhibition by interleukin 18 of osteolytic bone metastasis by human breast cancer cells
Anticancer Res
Perioperative levels of interleukin-1beta and interleukin-6 in women with breast cancer
Clin Exp Obstet Gynecol
Association between immunity and prognostic factors in early stage breast cancer patients before adjuvant treatment
Breast Cancer Res Treat
Concentration of interleukin-6 (IL-6), interleukin-8 (IL-8) and interleukin-10 (IL-10) in blood serum of breast cancer patients
Rocz Akad Med Bialymst
Serum interleukin-6 levels correlate to tumour progression and prognosis in metastatic breast carcinoma
Anticancer Res
Prognostic value of serum levels of interleukin 6 and of serum and plasma levels of vascular endothelial growth factor in hormone-refractory metastatic breast cancer patients
Br J Cancer
Circulating interleukin-6 predicts survival in patients with metastatic breast cancer
Int J Cancer
An analysis of serum interleukin-6 levels to predict benefits of medroxyprogesterone acetate in advanced or recurrent breast cancer
Oncology
Expression of interleukin-6, interleukin-6 receptor, and glycoprotein 130 correlates with good prognoses for patients with breast carcinoma
Cancer
Cytokine genotype polymorphisms in breast carcinoma: associations of TGF-beta1 with relapse
Cancer Invest
Interleukin-6-174G → C polymorphism is associated with improved outcome in high-risk breast cancer
Cancer Res
The -174 G/C gene polymorphism in interleukin-6 is associated with an aggressive breast cancer phenotype
Br J Cancer
Increased serum interleukin-8 in patients with early and metastatic breast cancer correlates with early dissemination and survival
Clin Cancer Res
Correlation of tissue and plasma RANTES levels with disease course in patients with breast or cervical cancer
Clin Cancer Res
Prognostic value of serum IL-18 and nitric oxide activity in breast cancer patients at operable stage
Am J Clin Oncol
Serum levels of interleukin-18 and sICAM-1 in patients affected by breast cancer: preliminary considerations
Int J Biol Markers
Selective in vitro growth of T lymphocytes from normal human bone marrows
Science
IFN- gamma and Fas/FasL are required for the antitumour and antiangiogenic effects of IL-12/pulse IL-2 therapy
J Clin Invest
Effects of interferon- alpha on cellular proliferation and adhesion of breast carcinoma cells
Oncol Rep
Synergistic antitumour effect of a combination of toremifene and interferon-alpha on ZR-75-1 human breast cancer cells: dependence on interferon-alpha subtype
Oncol Rep
Cited by (233)
Aged breast matrix bound vesicles promote breast cancer invasiveness
2024, BiomaterialsElucidation of interleukin-19 as a therapeutic target for breast cancer by computational analysis and experimental validation
2023, Saudi Journal of Biological SciencesTranscription factor NFE2L3 promotes the proliferation of esophageal squamous cell carcinoma cells and causes radiotherapy resistance by regulating IL-6: NFE2L3 causes radiotherapy resistance in ESCC
2022, Computer Methods and Programs in BiomedicineBreast cancer: epidemiology and viral ethology associated with human papillomavirus and mouse mammary tumor virus
2022, Oncogenic Viruses Volume 1: Fundamentals of Oncoviruses
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.