MedicalResearch: What is the background for this study?
Dr. Morales-Montor: Cytokines are highly inducible, secretory proteins that mediate intercellular communication in the immune system. They are grouped in several protein families referred as tumour necrosis factors, interleukins, interferons and colony stimulating factors. In recent years, it has become clear that some of these proteins as well as their receptors are produced in the organisms under physiological and pathological conditions. The exact initiation process of breast cancer is unknown, although several hypotheses have emerged. Inflammation has been proposed as an important player in tumor initiation, promotion, angiogenesis and metastasis, all phenomena in which cytokines are prominent players. The data we have hitherto let us suggest that cytokines play an important role in the regulation of both induction and protection in breast cancer. This knowledge could be fundamental for the proposal of new therapeutic approaches to particularly breast cancer and other cancer related disorders.
MedicalResearch: What are the main findings?
We discuss and present the latest evidence to support a regulatory role for cytokines (proteins that mediate communication between cells of the immune system) in breast cancer and other cancer-related disorders. Also, we report the link between cytokines, inflammation, and obesity, which is a significant risk factor for breast cancer. Other topics discussed in the article include the association between cytokines and blood vessel formation, breast cancer metastasis, immunosuppression and the ability of breast cancer cells to evade the immune system, and the potential role of cytokines as prognostic factors.
The process by which breast cancer is initiated is unknown, for which several hypotheses have emerged. Inflammation has been proposed to mediate the initiation and promotion of tumors, angiogenesis, and metastasis. Inflammatory cells are attracted by oncogenic changes, hypoxia, cytokines, and chemokines, among other factors. Inflammation in a tumor microenvironment comprises infiltrating immune cells and activated fibroblasts which secrete cytokines, chemokines, and growth factors to which the tumor responds. Obesity can result in an inflammatory environment that can contribute to tumorigenesis. Menopause and increased age are also associated with systemic inflammation. In turn, cancer therapy can effect an inflammatory tumor microenvironment by provoking extensive tumor cell death. Several cytokines regulate the inflammatory tumor microenvironment. IL-1, IL-6, IL-11, and TGF-b stimulate cancer cell proliferation and invasion, and cytokine receptor activation and intracellular signaling by NF-kB accelerate tumor progression.
MedicalResearch: What should clinicians and patients take away from your report?
Dr. Morales-Montor: Quality of life is a significant issue in breast cancer patients and survival. Patients experience pain, sleep disturbances, and fatigue, even after treatment has ended. More than 54% of patients develop moderate to severe pain during the treatment trajectory.
Increasing evidence suggests that modulation of immune activation through greater secretion of proinflammatory cytokines accelerates the development of distressing symptoms in women with breast cancer. Increased levels of IL-1 and IL-6 are associated with pain and sleep disturbances in breast cancer survivors. The physiological and immunological systems, which control inflammatory pathways, might be involved. Moreover, sleep problems have been associated with CRF, depression, and poorer overall quality of life. Sleep regulatory functions can also be affected by cytokines, such as IL-1, IL-6, and TNF-a.
However, new data on breast cancer immunology from the past several years suggest that many long-established and widely accepted paradigms be revised. We have reviewed data that have led to novel models of the biology and function of breast cancer cells. The cytokines that we have discussed are regulated by molecules that were originally believed to be exclusive to the endocrine system, such as sex steroids. These findings engendered a new concept of bidirectional communication between the endocrine and immune systems under normal circumstances, not necessarily during disease. Also, the development of drugs that specifically target cytokines, such as the IL-6/sIL-6R pathway, will be valuable in the treatment of breast cancer, in which immune inflammation has a protagonic function.
MedicalResearch: What recommendations do you have for future research as a result of this study?
Dr. Morales-Montor: Immunotherapy targeted at the tumor microenvironment is a promising research área. Also, since metastasis is a complication as a result of breast cáncer, normalization of abnormal vessels in mammary tumors is an interestig área of research. The development of nanoparticles can be also valuable in directing specific drugs to the tumor. Based on their function in breast cancer development, cytokines are attractive targets for new treatments. Furthermore, cytokines can potentiate or impair the efficacy of current breast cancer therapies.
Esquivel-Velázquez Marcela, Ostoa-Saloma Pedro, Palacios-Arreola Margarita Isabel, Nava-Castro Karen E., Castro Julieta Ivonne, and Morales-Montor Jorge. Journal of Interferon & Cytokine Research. January 2015, 35(1): 1-16. doi:10.1089/jir.2014.0026.