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Science Signaling Podcast: 3 August 2010

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Science Signaling  03 Aug 2010:
Vol. 3, Issue 133, pp. pc16
DOI: 10.1126/scisignal.3133pc16

Abstract

This is a conversation with Martine Smit about a Research Article published in the 3 August 2010 issue of Science Signaling.

(Length: 7 min; file size: 3.2 MB; file format: mp3; location: http://podcasts.aaas.org/science_signaling/ScienceSignaling_100803.mp3)

Technical Details

Length: 7 min

File size: 3.2 MB

File Format: mp3

RSS Feed: http://stke.sciencemag.org/rss/podcast.xml

Listen to Podcast: http://podcasts.aaas.org/science_signaling/ScienceSignaling_100803.mp3

Educational Details

Learning Resource Type: Audio

Context: High school upper division 11-12, undergraduate lower division 13-14, undergraduate upper division 15-16, graduate, professional, general public and informal education

Intended Users: Teacher, learner

Intended Educational Use: Learn, teach

Discipline: Cell biology, human biology, immunology, neuroscience, virology

Keywords: Science Signaling, cancer, cell proliferation, chemokine, G protein–coupled receptor, GPCR, HCMV, human cytomegalovirus, tumor, US28, vascularization

Transcript

Host – Annalisa VanHookWelcome to the Science Signaling Podcast for August 3rd, 2010. I’m Annalisa VanHook, and today I’m speaking with Martine Smit, a researcher at the Leiden/Amsterdam Center for Drug Research at the University of Amsterdam. A new study from her group identifies a signaling pathway through which human cytomegalovirus could induce tumor cell proliferation and angiogenesis (1).

Interviewee – Martine SmitHCMV is a widespread human herpesvirus that persists in a latent form. It’s primarily asymptomatic in immunocompetent individuals, yet it may cause pathologies, such as pneumonitis, hepatitis, and retinitis in immunocompromised hosts.

Interviewer – Annalisa VanHookWhat is the relationship between HCMV and cancer? I understand there’s been some evidence implicating HCMV in cancer progression?

Interviewee – Martine SmitYeah, so HCMV is not considered to be an oncogenic virus itself, yet it’s suggested to act as an oncomodulator. And HCMV has been proposed to promote development of various types of cancer, and it has been detected as an active infection in several forms of cancer, including prostate cancer, colon cancer, and malignant glioblastoma.

Interviewer – Annalisa VanHookSo, it hasn’t been shown to induce tumors, but it’s been shown to support their development?

Interviewee – Martine SmitYeah. So, the exact role of HCMV as a promoting factor in these tumors, is not clear yet. But, HCMV-encoded proteins are thought to drive oncogenic processes, either directly, through interference of the signaling pathways, or indirectly through induction of autocrine or paracrine signaling.

Interviewer – Annalisa VanHookYou specifically study HCMV-encoded chemokine receptors, which are cell surface receptors that normally function in the immune system. Why does the virus have chemokine receptors?

Interviewee – Martine SmitWell, actually it’s a very intriguing question, and it’s indeed believed that the viruses use these viral chemokine receptors to evade the immune system because the viral chemokine receptors may bind a wide range of chemokines—and by this means, the virus clears the chemokines from the environment and thereby can escape immune surveillance. Yet, since we know that chemokine receptors are, play a key role in inflammatory processes and are crucial in cancer, we believe that the viral chemokine receptors expressed by those viruses may, in fact, play a role in virus-associated pathologies.

Interviewer – Annalisa VanHookWhich viral-encoded chemokine receptor specifically did you look at in this study?

Interviewee – Martine SmitYeah so, at the VU University of Amsterdam we’ve been specifically looking at the viral chemokine receptor referred to as US28. And a hallmark of this viral receptor is that it displays constitutive activity and is able to activate various signal transduction pathways linked to proliferation.

Interviewer – Annalisa VanHookIt’s active, even in the absence of ligand?

Interviewee – Martine SmitYes, correct. It has this spontaneous activity, but it can, in fact, also be, bind chemokines, which can also active other signaling pathways.

Interviewer – Annalisa VanHookIn the work that you describe in the paper, you took this virally encoded chemokine receptor, US28, out of the virus and expressed just that receptor in cultured cells. What effect did that have on the cells?

Interviewee – Martine SmitSo when we expressed this US28 in cells, we observed increased concentration of interleukin-6, so IL-6, in the supernatant of these US28 expressing cells. And we observed that this IL-6 was actually associated with increased activation of the STAT3 signaling pathway. And since IL-6 itself is a target gene of STAT3, this led us to think that the US28-dependent production and secretion of IL-6 leads to autocrine and paracrine STAT3 activation through establishment of a positive feedback loop, and thereby promoting proliferation of both the infected cell, as well as the neighboring cells.

Interviewer – Annalisa VanHookIs it the production of IL-6 that promotes cellular proliferation?

Interviewee – Martine SmitYes. So, we did all kinds of experiments to sort of inhibit IL-6 production by using an shRNA or inhibitors of this pathway or antibodies targeting IL-6. And we saw a reduction of the proliferative processes. And what’s also important was that we also did this in the viral context. So, what we did, we infected cells with the HCMV virus, and we saw—again—increases of IL-6 levels, and STAT3 activity was increased. But, when we infected cells with the CMV strain in which the US28 gene was deleted, we did not see this increase of IL-6, nor the STAT3 activation—meaning that US28 is, in fact, a key determinant in this process.

Interviewer – Annalisa VanHookDid you go look at human tumors to look for evidence of US28 activity—for example, upregulation of IL-6?

Interviewee – Martine SmitYes—yes, we did. So, we were fortunate to have this specific antibody directed at US28. And in collaboration with Cecilia Söderberg-Nauclér, we analyzed tumor specimens from glioblastoma patients. And analysis of this human glioblastoma tissue revealed, in fact, US28, as well as activated STAT3 in cells specifically lining the blood vessels, suggesting that US28 may play a role in tumor vascularization. And, importantly, also this increased phospho-STAT3 expression correlated with poor patient outcome.

Interviewer – Annalisa VanHookUS28 is just one of, I think, four chemokine receptors that are encoded in the HCMV genome. Is it possible that these other three chemokine receptors are also adding to this virus’ ability to promote cancer?

Interviewee – Martine SmitYes, so for UL33—that’s one of the other ones—it’s also a constitutively active receptor—we’ve shown that earlier, and now we’ve recently looked into it into more detail. And also this receptor activates proliferative signaling. So, we believe that they might actually act in a concerted fashion. And then, there are two other ones—US27 and UL78–and those appear to be silent, but I’m sure that they are there for a reason. But, we need to do more research on that.

Interviewer – Annalisa VanHookThank you, Dr. Smit.

Interviewee – Martine SmitYou’re welcome.

Host – Annalisa VanHookThat was Martine Smit, senior author of a Research Article published in the August 3rd issue of Science Signaling. That article is by Slinger and colleagues, and it’s titled, “HCMV-Encoded Chemokine Receptor US28 Mediates Proliferative Signaling Through the IL-6-STAT3 Axis” (1).

music

That wraps up this Science Signaling Podcast. If you have any questions or suggestions, please write to us at sciencesignalingeditors{at}aaas.org. This show is a production of Science Signaling and of AAAS—Advancing Science, Serving Society. I'm Annalisa VanHook, and on behalf of Science Signaling and its publisher, the American Association for the Advancement of Science, thanks for listening.

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