Mouse Model Demonstrates Importance of Interleukin-6 to Spread of Prostate Cancer

By LabMedica International staff writers
Posted on 15 Jun 2015

Cancer researchers used a recently developed mouse model of metastatic prostate cancer to determine what factors are involved in the processes that trigger cell proliferation and drive progression of the disease.

Investigators at Cold Spring Harbor Laboratory (NY, USA) worked with the RapidCaP GEM (genetically engineered mouse) modeling system that uses surgical injection for viral gene delivery to the prostate.

Image: Researchers using RApidCaP, a mouse model of human metastatic prostate cancer, have identified an immune system marker that may help to distinguish patients who will and will not respond to hormone therapy. That marker is IL-6, an immune system component whose presence is indicated in brown patches in the image at left, in a section of lung tissue (blue) colonized by prostate cancer cells. The middle image of the same section of lung tissue indicates activation of STAT3, a protein that is the downstream target of IL-6 signaling. The image at right of the same tissue section demonstrates the presence of PCNA in the invading prostate cells, a marker of metastasis (Photo courtesy of Trotman Laboratory, Cold Spring Harbor Laboratory).

Discussing their results in the March 31, 2015, online edition of the journal Cancer Discovery, the investigators explained that this metastasis was driven by MYC, and not AKT, activation. MYC (v-myc myelocytomatosis viral oncogene homolog protein) is a transcription factor that activates expression of a great number of genes through binding on consensus sequences and recruiting histone acetyltransferases (HATs). By acting as a transcriptional repressor in normal cells, MYC has a direct role in the control of DNA replication. Akt, also known as protein kinase B, is a serine/threonine-specific protein kinase that plays a key role in multiple cellular processes such as glucose metabolism, apoptosis, cell proliferation, transcription, and cell migration.

The investigators showed that cell–cell communication by interleukin-6 (IL-6) drove the AKT–MYC switch through activation of the AKT-suppressing phosphatase PHLPP2 (PH domain and leucine rich repeat protein phosphatase-like), when PTEN and p53 were lost together, but not separately. IL-6 then communicated a downstream program of STAT3 (signal transducer and activator of transcription 3)-mediated MYC activation, which drove cell proliferation.

Loss-of-function mutations of the PTEN (phosphatase and tensin homolog) gene are present in 60% to 70% of metastatic cancers in humans. PTEN acts as a tumor suppressor gene thanks to the role of its protein product in regulation of the cycle of cell division, preventing cells from growing and dividing too rapidly. Mutations in the P53 gene contribute to about half of the cases of human cancer. In these mutants normal p53 protein function is blocked, and the protein is unable to stop multiplication of the damaged cell.

IL-6 is secreted by T-cells and macrophages to stimulate immune response during infection and after trauma, especially burns or other tissue damage leading to inflammation. Advanced/metastatic cancer patients have higher levels of IL-6 in their blood. One example of this is pancreatic cancer, with noted elevation of IL-6 present in patients correlating with poor survival rates. Hence, there is an interest in developing anti-IL-6 agents as therapy against many of these diseases.

"Our research suggests that IL-6 could be a marker for when the disease switches to a more dangerous state that is ultimately hormone therapy-resistant," said senior author Dr. Lloyd Trotman, an associate professor at Cold Spring Harbor Laboratory. "We are really hopeful that translating the IL-6 discovery into the clinics could help us stratify patients into good responders and bad responders. For any hospital this would be a major breakthrough. The gain could be immense; because today's problem is that the variability in response of humans to hormone therapy is amazing. For one man this therapy might be great, might reduce disease burden dramatically for many, many, years, and be an extreme benefit. For others there is almost no response, and it is still not clear to clinicians who is who."

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Cold Spring Harbor Laboratory