A common signalling molecule mediates the spread of prostate cancer

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Research perspective written by Tumas Beinortas
Cold Spring Harbor Laboratory
Cold Spring Harbor, New York, USA

How can I explain the importance of this research to the general public?

Prostate cancer is the commonest cancer in men and is usually not aggressive. However, aggressive types of prostate cancer readily metastasise. Scientists previously identified the changes in genome that are associated with more aggressive disease, however the mechanism behind how these changes lead to proliferation of the disease was not known.

In this publication scientists demonstrated how one molecule, normally responsible for causing inflammation in healthy organism, can cause the growth of metastasis in one type of prostate cancer. The team has used cells, mice and other molecular techniques to understand the pathway, clarifying how the communication between cancer cells through this inflammatory molecule works and leads to growth of metastases.

The results of the study indicate a potential new identifier of early metastatic disease and provide the key targets for development of therapies of metastatic prostate cancer.

Why is this important for researchers in fields other than cell biology?

This study demonstrates that the proliferation of aggressive prostate cancer cells of common genotype is mediated by inflammatory interleukin and activation of a common proto-oncogene. These cancer cells secrete the interleukin, which mediates the proliferation of neighbouring stromal cells. Proinflammatory interleukin achieves a downstream activation of proto-oncogene, which competes with a well-known tumor suppressor protein through a recently discovered mechanism to induce proliferation. This study offers a potential causative biomarker of metastatic prostate cancer and potential drugs targets for metastatic prostate cancer of common genotype.

Why is this important for researchers in the same field?

This study demonstrates that IL-6 mediates the proliferation of metastatic cells through downstream activation of Myc expression and Akt suppression in Pten and p53 co-deficient mice prostate cancer models. This study provides evidence that co-deletion of Pten and p53 using Cre-lox increased the production of IL-6, activation of STAT3 and proliferation of other cells in mouse embryonic fibroblasts, which was ablated by shRNA against IL-6. In vivo Pten and p53 codeletion resulted in increased blood IL-6 levels and proliferation of neighbouring stromal cells in a paracrine fashion through activation of Myc proto-oncogene. Metastatic nodules in these mice demonstrate proliferation of Pten and p53 negative cells mediated by Myc-Phllp2 dependent suppression of Akt kinase.

Original article

MYC Drives Pten/Trp53-Deficient Proliferation and Metastasis due to IL6 Secretion and AKT Suppression via PHLPP2
Dawid G. Nowak, Hyejin Cho, Tali Herzka, Kaitlin Watrud, Daniel V. DeMarco, Victoria M.Y. Wang, Serif Senturk, Christof Fellmann, David Ding, Tumas Beinortas, David Kleinman, Muhan Chen, Raffaella Sordella, John E. Wilkinson, Mireia Castillo-Martin, Carlos Cordon-Cardo, Brian D. Robinson, and Lloyd C. Trotman
Cancer Discovery, published online 1 June 2015

Acknowledgements

This work was supported by the Pershing Square Sohn Cancer Research Alliance, the American Cancer Society, the NIH, the Department of Defense, the STARR Foundation, and the Robertson Research Fund of CSHL, Long Island Cruisin’ for the Cure, and Glen Cove Cares. The original text was published by the American Association for Cancer Research.