Interleukin-6 (IL-6) is a pleiotropic cytokine that is involved in the physiology of virtually every organ system. It is secreted by T-cells and macrophages to stimulate immune response. Its deregulation also impacts many types of cancer. IL-6 gene transcription is induced in many different normal tissues in response to stimuli, such as virus infection, bacterial endotoxin, LPS, and serum. Efficient induction of IL-6 promoter requires C/EBP family members, NF-kB and NF-IL6. Its promoter is also inhibited by p53 and Rb. There are two different IL-6 receptors which can associate directly with IL-6. One is membrane bound form the other is soluble form. Soluble IL-6 receptor (sIL-6R) can bind IL-6 and induce homodimers or heterodimers of glycoprotein 130 which is also called IL-6R betta chain. The three components of this complex can induce signal transduction by activation of cytoplasmic tyrosine kinase (JAK pathway) and modification of transcription factors (phosphorylation of STAT1 and STAT3). It has been found that an elevated serum IL-6 level correlated with and adverse prognosis in patients with several different typrs of cancer, including multiple myeloma, lymphoma, ovarian cancer, prostate cancer, and metastatic renal cell carcinoma. IL-6 in the serum or plasma from patients may be present in several different forms, including high-moleculer-weight complexes that contain sIL-6R, anti-IL-6R antibodies, or small chaperone proteins. To date, a role for IL-6 has been implicated in almost every cancer examined. In breast cancer, IL-6 inhibits the growth of breast cancer cells either alone or in combination with THF-α and IL-1. IL-6 also may be involved in inducing migration and metastases, and confer muti-drug resistance in breast cancer cells. In colon cancer, IL-6 exhibited growth-stimulatory effects on a panel of colon cancer cell lines. Recent studies also suggested that inflammation and IL-6/IL-6R expression play a role in the pathogenesis of colon cancer. In lung cancer, IL-6 may have an inhibitory effect on the growth of lung cancer although some studies suggest a correlation between IL-6 level and disease status. In multiple myeloma which is one of the most studied tumor types in relation to IL-6, preclinical, translational correlations and early Phase I studies suggest that blocking IL-6 production may lead to effective therapy. There are still many different cancers related with IL-6. Indeed, IL-6 is one of the most ubiquitously deregulated cytokines in cancer, and increased levels of IL-6 have been observed in virtually every tumor studied. Therapeutic targeting of IL-6 and its receptor in cancer has strong biologic rationale, and there is preliminary evidence suggesting that targeting of the IL-6 system may be beneficial in the treatment of cancer.
More information about this paper can be found from http://www3.interscience.wiley.com/cgi-bin/fulltext/116316741/HTMLSTART
Inflammablog is a place to post short reviews about selected subjects in immunology, inflammation, and infection, and have them commented on (and possibly even improved) by friends and colleagues. It was started by John Cohen at University of Colorado School of Medicine in Denver, and Zoë Cohen at University of Arizona in Tucson. We each teach a course in immunity/inflammation in Fall 2007, and want students to post here so that other students at both schools can comment.
We particularly want this to be a place to practice clear communication to people who have a background in science, but are not experts in this area. Sort of the Café Scientifique crowd.
We particularly want this to be a place to practice clear communication to people who have a background in science, but are not experts in this area. Sort of the Café Scientifique crowd.
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6 comments:
In general, how could you explain the apparent dichotomy among IL-6 inhibiting breast cancer growth, simulating prostate cancer growth, and maybe both stimulating and inhibiting lung cancer growth? If, as you say, it is highly expressed in many different types of solid tumors, then is there differential expression of specific STATs, IL-6 receptors, or NF-kB regulatory proteins? (i.e. is it not really the IL-6, but its binding partners doing the damage?)
Yes, I think it’s not just IL-6 but other binding proteins or down-steam signaling pathway proteins (molecules) that did the damage. For example, in prostate cancer, IL-6 acts like an autocrine growth factor and blocks the apoptotic signals. In some experiment from breast cancer cell lines like MCF-7, they found IL-6 can inhibit cell growth by blocking key intracellular signaling events.
All these signals have to combine with IL-6R and may induce different down steam pathways and different transcription activators which can cause different results. To me, I think IL-6 isn’t easily induced. Once it is induced, it can circulate around the body and trigger the signaling pathways. Most of these are immunoresponse which can alarm our body like acute phase response. However, the relationship between IL-6 and cancers still depends on different situation and has controversy.
Thanks! I agree...it seems like cancer in each tissue is more different than similiar even among solid tumors, in terms of how they interact with the stroma, at least.
I agree that all of the in vitro data, where IL6 was thrown on cancer cell lines, definitley varies. And this doesn't tell a straight story for how IL6 could play a role in cancer. Reports on IL6 expression in human breast tumors are also varied. Several studies report that there is a decrease in expression of IL6 protein and mRNA in breast tumors in aggressive cancers (1-2). Another study showed that there was no difference in IL6 mRNA levels between normal and neoplastic human breast tissue (3). A few studies report that tumor IL6 protein expression increases with the severity of the lesion (1,4). While IL6 expression in primary breast tumors may be inconsistent, studies on the relationship between circulating IL6 levels and stage of breast cancer have been consistent. Numerous studies report that serum IL6 levels are an independent negative prognostic indicator in breast cancer (1, 5-7). Breast cancer patients have significantly higher serum IL6 levels than healthy individuals (8-9). Further, the level of serum IL6 increases as the clinical stage of disease progresses (8, 10). Increased serum IL6 correlates with increased metastasis, with reduced progression free survival and shorter overall survival in metastatic breast cancer patients (5, 7, 11-13). Cumulatively, these studies demonstrate that elevation of serum IL6 definitively correlates with a poor prognosis in breast cancer. One hypothesis from these data is that circulating IL6 could promote later stages of metastasis, like survival of tumor cells in circulation, extravasation of tumor cells into secondary sites or angiogenesis at the secondary site. (The reason I have so many references is that this was part of my non-thesis project comprehensive exam proposal.)
1) Knupfer et al., 2007.
2) Basolo et al., 1996.
3) Green et al., 1997.
4) Garcia-Tunon et al., 2005.
5) Zhang et al., 1999.
6) Hussein et al., 2004.
7) Bozcuk et al., 2004.
8) Kozlowski et al., 1995.
9) Jiang et al., 2000.
10) Jablonska et al., 2001.
11) Salgado et al., 2003.
12) Bachelot et al., 2003.
13) Yokoe et al., 2000.
So I think fritzj7630 brings up an interesting point... how do you explain IL-6 inhibiting break cancer and stimulating prostate cancer. I think another interesting point is whether or not this inhibitory and stimulation changes with the severity of the cancer... in other words does the stage of the cancer affect whether or not IL-6 plays a role in inhibiting or stimulating growth. I bring this up becuase of the newly described T cell subset Th17 which is implicated in chronic inflammation. This subset require TGF-beta and IL-6 to differentiate and be activated. The point of interest comes with the dichotomy mentioned for IL-6 and the dichotomy known about TGF-beta. In early stages of cancer, TGF-beta is known to have a growth inhibitory effect. In later stages, TGF-beta can cause a metastatic phenotype. So, these IL-6 results are really interesting and I hate to say this again, but I'm in love w/ these Th17 and wonder what role they're playing.
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