EAU 2020: Scientists Find a Switch Which May Make Prostate Cancer Spread

San Francisco, CA (UroToday.com) — Scientists have found a switch that is associated with prostate cancers spreading or forming metastases (secondary tumours). The researchers caution that this work is still at an early stage, and needs further investigation to see if it applies to all prostate cancers. Up to 15% of patients have a high risk of prostate cancers, potentially leading to significantly increased mortality over time. The work is presented at the virtual European Association of Urology Congress.

The researchers, from the University of Leuven in Belgium, worked with a group of 44 patients who had high-risk prostate cancer (see notes for definition). Twenty-five of the patients were cured after treatment, but 19 went on to develop metastatic prostate cancer. The scientists then compared differences in the number of copies of DNA segments in the two groups. They found that these patients who went on to develop metastatic disease had many more copies of the AZIN1 gene, indicating that it was associated with a more aggressive disease.

To test this, the team changed the activity of the AZIN1 gene, found on chromosome 8, in both cell culture and a mouse model. They found that reducing the activity (expression) of the gene resulted in reduced metastases.

Lead researcher, Dr. Lisa Moris (Molecular Endocrinology Laboratory, Leuven, Belgium) said:

“We were able to show that the regulation of the AZIN1 gene is closely associated with the risk of the tumour spreading. We need to do a lot more research on AZIN1 to see if the relation with metastases is generally applicable to prostate cancers; there are many different types and causes of prostate cancer, so this finding is still a long way from any clinical application. What we can say is that this finding applies to the patients we tested, who were followed up over a period of 10 years, as well as our mouse and in-vitro models. There are also some initial findings that this gene may have an effect on other cancers.

We are currently looking at what exactly this gene does, to see if we can find a way of regulating it in real-life cancers. This is still a long way from any clinical application, but opening a way to controlling whether tumours risk spread would be a significant step towards controlling prostate cancer."
Commenting, the EAU’s Adjunct Secretary General responsible for Science, Professor Arnulf Stenzl (Tübingen, Germany) said:

“More than 10 years ago the influence of Antizyme Inhibitor 1 as a small protein for cell transformation and promotion of tumour growth was discovered. Recently a role in the progression and metastasis of a variety of tumours including breast, colorectal, lung and gastric cancer has been suggested. Some of this interest has arisen because of the role of AZIN1 in the methylation of HPV warts and a possible connection to HPV-associated malignancies.

The study by Moris et al. looks like a promising clue for those prostate cancers which are aggressive and metastasizing. At a time when more than 80% of all newly diagnosed prostate cancers are diagnosed in a localized stage, and the value of any treatment may be arguable in some patients, studies like this are important. They may clarify which patients will benefit from immediate and directed treatment, and which will benefit from active surveillance. The results of this study may also give us a clue for targeting AZIN1 to prevent metastasis”.
Professor Stenzl was not involved in this work, this is an independent comment.

Prostate cancer is the most common male cancer, with around 400,000 new cases every year in Europe, with 76,000 deaths in the EU. In the UK, there are over 46,000 new cases of prostate cancer every year, leading to more than 11,000 deaths. Germany has 14,434 annual deaths, France 9,041, Italy 7,523 (see https://ec.europa.eu/eurostat/statistics-explained/pdfscache/39738.pdf, page 13). More than a million European men undergo prostate cancer biopsies every year.

High-risk: High-risk prostate cancer can be very variable. Even after removal of the prostate, between 4.6% and 20.3% of patients die from prostate cancer within 10 years. Prostate cancer is defined as “high-risk” if it meets one of the following 3 criteria. The level of prostate Specific Antigen (PSA) is 20ng/ml or above, OR when the Gleason score is 8-10 (the Gleason score is taken from microscopic analysis of the tumour cells), OR when the staging is level cT3a or above (meaning the tumour is pushing outside of the prostate).

Malignant cancer: A tumour becomes malignant when it spreads outside the original site (in this case, the prostate)

Metastasis: a tumour becomes metastatic when it spreads to a secondary site distant from the original tumour.

The 35th European Association of Urology Congress takes place online from 17-19 July 2020. This replaces the physical conference which was scheduled to take place in Amsterdam. The EAU Congress is the largest and most important urology congress in Europe, with up to 14,000 attendees. Conference website https://eaucongress.uroweb.org/

Conference Abstract Nr 1126 (Monday, 23 March 2020, 15:45 - 17:15 Grey Area, RAI Auditorium)
Genomic analysis of localized prostate cancer identifies AZIN1 as driver of metastatic Progression

Introduction & Objectives
Localised prostate cancer (PCa) is infamous for its heterogeneity in clinical course, which has led to the development of the widely accepted sub-stratification of low-, intermediate- and high-risk PCa. However, this still fails to accurately distinguish between patients who will develop metastatic disease and those who will not. It would be an enormous step forward if we could identify those genomic aberrations that lead to the metastatic spread of the primary tumor, since this could be used for prognostication and targeted therapeutic approaches.

Materials & Methods
An integrative analysis of DNA copy number aberrations and gene expression data of two clinically identical high risk PCa patient groups after RP with different clinical outcomes (metastases or not) was performed. This highlighted a focal amplification of 8q22.3 with a higher expression of the residing AZIN1 gene in the metastatic group. In vitro analyses were performed with standard molecular biology methodology to evaluate the effect ofAZIN1 on the metastatic potential of PCa cells. For in vivo analyses, intravenous xenografts of PC3-FLucs after transient induction of AZIN1 knockdown were created. Metastatic spread and metabolic activity was evaluated via bioluminescent scanning (IVIS Spectrum).

A focal amplification with overexpression of the residing AZIN1 gene was unique for metastatic high-risk PCa patient. In vitro analyses confirmed that modulation of AZIN1 expression determines both growth and migratory potential as well as the polyamine levels of different PCa cell lines. In our in vivo intravenous xenograft mouse model, metastatic spread was reduced upon AZIN1 knockdown. RNA sequencing after knockdown of AZIN1 in PC3cells revealed several transcriptional programs which are activated/deactivated upon AZIN1 knockdown. This showed among others a significant upregulation of genes involved in extracellular matrix composition, including genes encoding for subunits of collagen IV which is an integral part of the basement membrane.

The association of high AZIN1 levels with the metastatic HRPCa phenotype suggests a role for AZIN1 as possible predictor and/or target for metastatic HRPCa. Modulation of AZIN1 levels in different PCa cells influences both cell growth and migratory potential. Lower levels of AZIN1 reduces metastatic spread in our metastatic xenograft model. Ongoing experiments focus on identifying mechanisms by which AZIN1 regulates/induces a pro-metastatic environment.

Moris L.1, Van Den Broeck T.1, Gevaert T.2, Smeets E.1, Helsen C.1, Handle F.1, Van Poppel H.2,Everaerts W.2, Lambrechts D3, Buerki C.4, Davicioni E.5, Joniau S.2, Claessens F.1

1. KU Leuven, Molecular Endocrinology Laboratory, Leuven, Belgium, 2.University Hospitals Leuven, Dept. of Urology, Leuven, Belgium, 3. KU Leuven, Laboratory of Translational Genetics, Leuven, Belgium, 4. GenomeDx, Dept. of Biosciences, Vancouver, Canada, 5.GenomeDx, Dept. of Biosciences, Leuven, Belgium

This work was funded by KU Leuven.

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