Presentation
Cytokine deregulation in cancer

https://doi.org/10.1016/S0753-3322(01)00140-8Get rights and content

Abstract

Endogenous cytokines are aberrantly produced in many cancers, and serve as autocrine growth factors or indicators in immune response to the tumors. Hence, cytokine deregulation is likely to participate in the development or evolution of the malignant process. Over the last few years, endogenous cytokine levels have been correlated with phenotypic manifestations of cancer and with prognosis. For instance, serum IL-6 levels are elevated in both relapsed and newly-diagnosed Hodgkin’s and non-Hodgkin’s lymphoma, and these levels correlate with established prognostic features. Furthermore, in diffuse large cell lymphoma, serum IL-6 level is an independent prognostic variable for both complete remission and failure-free survival. Serum IL-10 levels are also elevated in lymphoid malignancies and predict outcome. In some cases, it may be that the balance between endogenous cytokine agonists and antagonists is disrupted. For instance, in chronic myelogenous leukemia, high cellular (leukocyte) levels of IL-1 beta and low levels of IL-1 receptor antagonist (IL-1RA) are seen in advanced disease and correlate with reduced survival. The molecular mechanisms underlying cytokine deregulation are now being investigated, with preliminary data suggesting heterogeneous genetic driving forces, including oncogene aberrations and viral infection.

Section snippets

IL-6 in relapsed hodgkin’s and non-Hodgkin’s lymphomas

During the 1980s, it was noted that patients who were treated with recombinant interferon (IFN)-gamma developed fever and night sweats reminiscent of B symptoms 19, 20. However, when levels of IFN-gamma were measured in the serum of lymphoma patients, no elevations were found 〚15〛. Furthermore, phytohemagglutinin-stimulated T lymphocytes from these individuals were actually deficient in IFN-γ production. These preliminary results suggested that IFN-γ was an unlikely cause of B symptoms.

IL-6 in diffuse large cell lymphoma

Diffuse large cell lymphoma (DLCL) is an aggressive lymphoma. About 50% of patients are curable. Patients who relapse after induction generally do so within 2 to 3 years and most of these patients succumb to their disease. Prognostic factors are critical to identifying the patients likely to relapse and designing better therapeutic regimens for them.

Serum IL-6 levels in DLCL patients were found to be significantly higher than those in normal volunteers (N = 33; median, undetectable; range,

Evidence for a pathogenic role for IL-6 in lymphomas

To date, prognostic variables for lymphomas (as well as for the majority of other cancers) have been clinical features that do not participate in the development of the disease process. They therefore represent surrogate markers for underlying biological variables. In contrast, there are several lines of evidence that support a pathogenic role for IL-6 in lymphoma. First, overexpression of IL-6 in transgenic mice is associated with the development of lymphomas 28, 29. Second, high IL-6 levels

Interleukin-10

Interleukin-10 (IL-10) is a pleiotropic cytokine produced by type 2 helper cells (Th2), as well as by monocytes and macrophages, and normal and neoplastic B lymphocytes. It is highly homologous to an open reading frame of Epstein-Barr virus (EBV) called BCRFI, and EBV infection of B-cells upregulates IL-10. IL-10 production has strong immunosuppressive effects via inhibition of TH1 type cytokines, including interferon gamma and interleukin-2 (table II). On B-cells, IL-10 has a potent

Homeostasis

A balance between cytokine agonists and antagonists is required for normal homeostasis. Several studies suggest that this balance is disrupted in some tumors. For instance, acute myelogenous leukemia cells show high levels of IL-1 beta and low levels of IL-1RA. (IL-1RA suppresses IL-1 activity by binding to the IL-1 receptor without agonist activity.) IL-1 beta acts as an autocrine growth factor for this leukemia as well as for chronic myelogenous leukemia. In patients with advanced chronic

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