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Prostate cancer mortality rate higher in men with diabetes

Men with type 2 diabetes are less likely to develop prostate cancer than patients without diabetes. However, the mortality rate is higher. Researchers of the German Centre for Diabetes Research (DZD) from Tübingen and experts of Helmholtz Zentrum München and the urology department of Tübingen University Hospital were able to show that in the affected individuals the androgen receptor and the mitogenic forms of the insulin receptor were more strongly expressed. This could explain why patients with diabetes have a poorer prognosis for prostate cancer.

Prostate cancer and type 2 diabetes are among the most common diseases in men. Although studies indicate that people with diabetes suffer more frequently from cancer, men with diabetes do not increasingly suffer from prostate cancer. On the contrary, meta-analyses of studies have shown that diabetes patients are less likely to develop this carcinoma. However, the mortality rate is higher.

This is also confirmed by current research carried out by researchers at the Institute for Diabetes Research and Metabolic Diseases (IDM) of Helmholtz Zentrum München at the University of Tübingen, a partner of the DZD, in cooperation with the department of urology at Tübingen University Hospital.

The research team recently analysed the data of patients who had their prostate removed due to cancer. As expected, among them were fewer patients with diabetes than in the general population. However, prostate cancer patients with diabetes were significantly more likely to have metastases in the lymph nodes. In addition, the proportion of patients who are at very high risk according to the guidelines of the National Comprehensive Cancer Network was significantly higher among those with diabetes.

But how do prostate carcinomas differ in men with and without diabetes? What makes prostate carcinoma in patients with metabolic disease so aggressive? The researchers investigated these questions in another study. For this purpose, they analysed 70 tumour samples from patients without diabetes and 59 samples from patients with type 2 diabetes.

Since male sex hormones (androgens) play an important role in the development of prostate cancer, the scientists investigated the androgen signalling chain. We conducted a gene expression analysis of key proteins and found that in men with diabetes, the androgen receptor (AR) was increased," said Dr Martin Heni, who led the study at the IDM. The signalling pathway mediated by AR was also more strongly activated.

The scientists identified another difference: "Insulin receptors of isoform A are increasingly expressed in the prostate carcinomas of patients with diabetes," said Dr Stefan Lutz, first author of the study. These can bind insulin-like growth factors (IGFs). This contributes to increased cell growth and cell division. Normally, adults mainly express the isoform B, which does not bind IGF.

In addition, in patients with diabetes, the steroid biosynthesis in the tumour is also altered. Less protective oestrogen receptor ligands are formed. This further strengthens the androgen signalling pathway in tumours.

Our research provides new insights into why prostate cancer is so aggressive in men with type 2 diabetes," said Heni, summarising the results. Prostate carcinoma in men with type 2 diabetes has a poorer prognosis and must therefore be diagnosed and treated earlier and more comprehensively than prostate cancer in nondiabetics," said Professor Arnulf Stenzl, head physician of the urology department of Tübingen University Hospital.

Abstract 1
Extract: Prostate cancer (PCa) and type 2 diabetes mellitus are under the most frequent diseases in men with a tremendous impact on morbidity and mortality (Giovannucci, et al. 2010). Incidence of many common types of cancer is known to be higher in diabetes (Giovannucci et al. 2010). However, studies reported that incidence of PCa is not increased in men with type 2 diabetes, some studies even found reduced prevalence (Kasper, et al. 2009). In contrast, PCa survival is markedly reduced in patients with coincident type 2 diabetes (Chen, et al. 2017). The underlying molecular mechanisms for shortened survival are still under ongoing debate and not fully understood. They might include altered insulin or IGF-1 signaling and enhanced androgen receptor activity. Of note, diabetes and PCa share numerous risk factors, most importantly the nonmodifiable risk factor age and the modifiable risk factor obesity (Giovannucci et al. 2010). Although PCa incidence is not elevated in obese men, patients with excess bodyweight are reported to display higher cancer-related mortality (Ma, et al. 2008). Carefully adjusted studies for these risk factors investigating the impact of diabetes on PCa outcomes and aggressiveness are sparse. To better understand why PCa related survival is shortened in men with concommittant diabetes, we evaluated the relation of diabetes with TNM-staging and an established PCa risk score (Mohler, et al. 2016), independent of age and body weight …

Authors
Stefan Zoltán Lutz, Tilman Todenhöfer, Robert Wagner, Jörg Hennenlotter, Jana Marlene Ferchl, Marcus Oliver Scharpf, Peter Martus, Harald Staiger, Andreas Fritsche, Arnulf Stenzl, Hans-Ulrich Häring, Martin Heni

Abstract 2
Objective: While prostate cancer does not occur more often in men with diabetes, survival is markedly reduced in this patient group. Androgen signaling is a known and major driver for prostate cancer progression. Therefore, we analyzed major components of the androgen signaling chain and cell proliferation in relation to type 2 diabetes.
Methods: Tumor content of 70 prostate tissue samples of men with type 2 diabetes and 59 samples of patients without diabetes was quantified by an experienced pathologist, and a subset of 51 samples was immunohistochemically stained for androgen receptor (AR). mRNA expression of AR, insulin receptor isoform A (IR-A) and B (IR-B), IGF-1 receptor (IGF1R), Cyp27A1 and Cyp7B1, PSA gene KLK3, PSMA gene FOLH1, Ki-67 gene MKI67, and estrogen receptor beta (ESR2) were analyzed by RT-qPCR.
Results: AR mRNA and protein expression were associated with the tumor content only in men with diabetes. AR expression also correlated with downstream targets PSA (KLK3) and PSMA (FOLH1) and increased cell proliferation. Only in diabetes, AR expression was correlated to higher IR-A/IR-B ratio and lower IR-B/IGF1R ratio, thus, in favor of the mitogenic isoforms. Reduced Cyp27A1 and increased Cyp7B1 expressions in tumor suggest lower levels of protective estrogen receptor ligands in diabetes.
Conclusions: We report elevated androgen receptor signaling and activity presumably due to altered insulin/IGF-1 receptors and decreased levels of protective estrogen receptor ligands in prostate cancer in men with diabetes. Our results reveal new insights why these patients have a worse prognosis. These findings provide the basis for future clinical trials to investigate treatment response in patients with prostate cancer and diabetes.

Authors
Stefan Zoltán Lutz, Jörg Hennenlotter, Marcus Oliver Scharpf, Corinna Sailer, Louise Fritsche, Vera Schmid, Konstantinos Kantartzis, Robert Wagner, Rainer Lehmann, Lucia Berti, Andreas Peter, Harald Staiger, Andreas Fritsche, Falko Fend, Tilman Todenhöfer, Arnulf Stenzl, Hans-Ulrich Häring, Martin Heni

[link url="https://www.dzd-ev.de/en/latest/news/news/article/42340/index.html"]DZD material[/link]
[link url="http://erc.endocrinology-journals.org/content/early/2018/01/12/ERC-17-0465"]Endocrine-related Cancer abstract[/link]
[link url="https://www.sciencedirect.com/science/article/pii/S2212877817306841?via%3Dihub"]Molecular Metabolism abstract[/link]

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